PF 2007 - Vol 33

Table of Contents*
PHARMACOPEIAL FORUM VOL. 33 NO. 1 JAN.–FEB. 2007
STANDARDS DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
HOW TO USE PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Section Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Committee Designations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
POLICIES AND ANNOUNCEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
USP Seeks Candidates for Three Expert Committees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
USP Forms Stakeholder Forum to Address the Food Chemicals Codex; First Meeting Set for February 2007 . . . . . . 18
Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
In Memoriam: Joseph Robinson, Ph.D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Vice President of Pharmacopeial Education Named . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Implementation Period for Official Revisions to USP–NF Extended . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Catalog to be Removed From Pharmacopeial Forum Print Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Stimuli Articles to be Posted on the USP’s Website . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Pharmacopeial Education Courses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Visit the USP Website at http://www.usp.org . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
International Correspondence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
How to Submit Comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Pharmacopeial Forum Public Review and Comment Period Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Priority New Monograph Items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
INTERIM REVISION ANNOUNCEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Conjugated Estrogens Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ERRATA LIST FOR USP–NF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
IN-PROCESS REVISION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Alprazolam Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bismuth Subsalicylate Oral Suspension (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bupropion Hydrochloride Extended-Release Tablets (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Calcitriol (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Citalopram Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Cladribine (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Clopidogrel Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Cytarabine for Injection (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Dimethyl Sulfoxide Gel (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Enoxaparin Sodium [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Enoxaparin Sodium Injection [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Eprinomectin (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Fluvastatin Sodium (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Fosinopril Sodium and Hydrochlorothiazide Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Hydrocortisone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Isosorbide Dinitrate Extended-Release Tablets (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Levalbuterol Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Levalbuterol Inhalation Solution [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Norethindrone Acetate and Ethinyl Estradiol Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Pamidronate Disodium for Injection (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Phenylbutazone Boluses (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Phenylbutazone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Progesterone Vaginal Suppositories (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Salicylic Acid (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
* The USP–NF (USP 31–NF 26), the Supplement (Supp), or the Interim Revision Announcement (IRA) for which the revision proposal is targeted is
shown in parentheses next to each proposed item.
Pharmacopeial Forum
2 Contents* Vol. 33(1) [Jan.–Feb. 2007]
Valganciclovir Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Valganciclovir Tablets [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
DIETARY SUPPLEMENTS—MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Ubidecarenone Capsules (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Ubidecarenone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
GENERAL CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
h11i USP Reference Standards (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
GENERAL INFORMATION CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
h1225i Validation of Compendial Procedures (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
REAGENTS, INDICATORS, AND SOLUTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Reagent Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2-Aminoheptane [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Calconcarboxylic Acid [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Calconcarboxylic Acid Triturate [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Dimethicone, viscosity 500 centistokes [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Lactose (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Propylamine Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Sodium Phosphate Dibasic Dihydrate [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Triethylamine (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Volumetric Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Ceric Sulfate, Tenth-Normal (0.1 N) (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Potassium Permanganate, Tenth-Normal (0.1 N) (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Chromatographic Reagents [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
REFERENCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Description and Solubility (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
PREVIOUS PF PROPOSALS STILL PENDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
CANCELED PROPOSALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
PHARMACOPEIAL PREVIEWS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
STIMULI TO THE REVISION PROCESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Instructions to Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
NOMENCLATURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
# 2007 The United States Pharmacopeial Convention, Inc. All Rights Reserved.
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] Contents* 3
THE JOURNAL OF STANDARDS DEVELOPMENT AND OFFICIAL COMPENDIA REVISION
Executive Vice President and Chief Executive Officer Please address comments on PF
Roger L. Williams, M.D. content to Executive Secretariat
Chief Standards Officer, Acting USP–NF, 12601 Twinbrook Pkwy.,
Roger L. Williams, M.D. Rockville, MD 20852
Vice President, Department of Standards Development
Todd L. Cecil, Ph.D. Telephone: 1-301-816-8345
Vice President, Department of Patient Safety Fax: 1-301-816-8373
Diane Cousins, R.Ph. http://www.usp.org
Vice President, International Affairs
Nancy Blum, M.P.H.
Vice President, Volunteer and Organizational Affairs Pharmacopeial Forum is covered in Current Contents/Life Sciences
Angela G. Long and in the Science Citation Index (SCI), in International Pharmaceu-
Vice President, Monograph and Reference Standard Development tical Abstracts, and in Current Awareness in Biological Sciences.
Ronald G. Manning, Ph.D.
Vice President, Publications The United States Pharmacopeial Convention comprises representa-
Margaret Becker tives from colleges and national and state organizations of medicine
Director, Information Programs and pharmacy. It publishes the U.S. Pharmacopeia and National For-
Deborah G. Perfetto, Pharm.D. mulary, the legally recognized compendia of standards for drugs and
Director, Publications products of other health care technologies. The USP and NF include
Linda M. Guard assays and tests for the determination of strength, quality, and purity
Director, Scientific Reports and requirements for packaging and labeling.
Stefan P. Schuber, Ph.D.
Supervisor, Publishing Technologies This publication was paginated using Advent 3B2 Publishing Soft-
Debbie Miller ware.
Senior Production Coordinator
Suzanne M. Anderson
Senior Production Coordinator
Evelyn Bryant Printed in USA by Port City Press, Baltimore, Maryland
Production Coordinator
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Electronic and Desktop Publishing Moving?
Derrick Boone Our subscribers’ records and publication labels are computer-
Manager, Publication Support generated. Please send your new address, and your latest label, or an
Kate Meringolo exact copy of it, to: USPC, PF Customer Service Dept., 12601
Senior Editors Twinbrook Parkway, Rockville, MD 20852.
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Editors
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Proofreader, Spanish
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Standards Development
STANDARDS DEVELOPMENT
This section presents an overview of the public review and comment process, conducted through Pharmacopeial Forum (PF), for
the development of official pharmaceutical standards.
Pharmacopeial Forum
6 STANDARDS DEVELOPMENT Vol. 33(1) [Jan.–Feb. 2007]
USP publishes Pharmacopeial Forum (PF) bimonthly as the working vehicle of the USP Council of Experts. PF provides inter-
ested parties an opportunity to review and comment as the Council of Experts develops or revises standards for the United States
Pharmacopeia and the National Formulary (USP–NF).
PF includes the following:
1. Potential revisions—entirely new standards, revision ideas, and drafts not yet targeted for official adoption (Pharmacopeial
Previews)
2. Proposed revisions—new or revised standards targeted for official adoption (In-Process Revision)
3. Adopted revisions—new or revised standards that become official and binding before the publication of the next USP–NF or
Supplement (Interim Revision Announcement)
USP welcomes comments and data on potential, proposed, or official standards. Comments, along with USP’s responses, will be
published either in PF Briefings, the Commentary section of PF, the Commentary section of Supplements to USP–NF, or the
Commentary section of USP–NF.
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] STANDARDS DEVELOPMENT 7
The chart below shows the public review and comment process and its relationship to standards development.
Questions on the process should be addressed to Director, Executive Secretariat, U.S. Pharmacopeia, 12601 Twinbrook Parkway,
Rockville, MD 20852 (e-mail: execsec@usp.org).
HOW TO USE PF
How to Use PF
This section provides descriptions of the various parts of PF. It also includes Committee Designations and the Staff Directory.
Pharmacopeial Forum
10 HOW TO USE PF Vol. 33(1) [Jan.–Feb. 2007]
The contents of the different sections of PF are briefly described below. A more detailed description of each section is provided at
the beginning of that section. A general description of the types and amount of information expected in a Request for Revision is
available in the Guideline for Submitting Requests for Revision to the USP–NF on the USP website (www.usp.org/USPNF/
submitMonograph/subGuide.html).
Proposed and Adopted Revisions to the USP–NF

Section Content How Readers Can Respond
Pharmacopeial BRIEFING: Scientific rationale for potential inclusion or change. May Review drafts and provide comments to
Previews include other information useful to the analyst such as the brand name the appropriate staff liaison cited in the
How to Use PF
Early ideas for revisions of the column used in developing the proposed procedure and the USP Briefing preceding each Preview.
scientific staff liaison who handled the issue.
Potential revisions not yet targeted for official adoption that require a
longer public review and comment process because of
issues such as:
— the controversial nature of an item;
— the application of new technologies that require further
study; and
— articles produced by multiple sources.
In-Process Revision BRIEFING: Scientific rationale for proposed changes. May include Review material and send comments
Revisions targeted for other information useful to the analyst such as the brand name of promptly to USP staff liaison (see the
adoption the column used in developing the proposed procedure and the USP Staff Directory). Guidelines on how to
scientific staff liaison who handled the issue. comment are found at the end of the
New and revised standards that have been approved for publication Policies and Announcements section.
by the appropriate USP Committee when it is considering whether to
advance standards to official status (see Standards Development).
New or revised text is marked with symbols (&& or .. or ~) to spec-
~
ify the tentative earliest date on which the revision would be officially
adopted.
Harmonization BRIEFING: Scientific rationale for the potential inclusion or change or Review material and provide comments
Items the Pharmacopeial for the proposed change. The designated stage of harmonization. The to the appropriate staff liaison cited in the
Discussion Group (PDG) stage determines whether an item appears under Pharmacopeial Pre- Briefing preceding each Preview or In-
is working to harmonize views or under In-Process Revision, both separate sections of Harmo- Process Revision.
internationally nization.
For In-Process Revision, new or revised text is marked with symbols
(&&) to specify the tentative, earliest date on which the revision would
be officially adopted.
Interim Revision Standards that have been adopted and will become officially binding Review to see if affected by any of the
Announcement on the specified date. Effective date is specified in the section’s intro- changes. Note effective date when stan-
Adopted standards ductory page or within parentheses following a particular item. New dards become official and ensure compli-
or revised text is set off by the symbols ... ance.
Pending Proposals In order for an item to be adopted into the USP–NF and become offi- Review items to track pending propos-
cially binding, it must first be proposed and published in the PF to als.
allow the public an opportunity to review and comment upon it. When
an item is adopted, it is published in either the USP–NF, its supple-
ments, or an IRA. Those items that have not yet been adopted are still
pending.
Canceled Proposals Canceled proposals are items that were published in PF and were Review items to track canceled propos-
pending, but have since been canceled. Note that canceled proposals.
als may be republished to be considered in the future for adoption into
the USP–NF.
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] HOW TO USE PF 11
Other Sections
Committee Designations
Names of the committees (composed of volunteer scientific experts) that USP staff work with on the development of standards.
Staff Directory
Names of all USP scientific staff liaisons with contact information.
Policies and Announcements

General scientific and policy issues affecting USP–NF standards and processes
Update on standards-related issues being considered by USP
How to Use PF
Where to find summaries of meetings of the Council of Experts
Guidelines on how to comment
Publication and comment schedules
Stimuli to the Revision Process

Articles on standards development issues authored by the USP Council of Experts, USP staff, or other interested parties
Discussions of issues on which USP desires public input prior to further development
Nomenclature
Latest adopted United States Adopted Names (USAN) and International Nonproprietary Names (INN) for drugs
Revisions to existing names as a supplement to the USP Dictionary of USAN and International Drug Names
Suggested, proposed, and recommended USAN and INN
Information on how nonproprietary drug names are devised
Articles relevant to compendial nomenclature issues
Index
Cumulative directory for the content of all issues of PF beginning with PF 32(1).
Chromatographic Reagents Used in USP–NF and Pharmacopeial Forum

Update of chromatographic reagents based on the proposals published in this issue of PF.
Pharmacopeial Forum
EXPERT COMMITTEE DESIGNATIONS*

2005–2010
AER Aerosols
BB BBP B&B Blood and Blood Products
BB CGT B&B Cell, Gene, and Tissue Therapies
BB PP B&B Proteins and Polysaccharides
How to Use PF
BB VV B&B Vaccines and Virology

BPC Biopharmaceutics
CRX Compounding Pharmacy
DS-BA Dietary Supplements—Bioavailability
DSB Dietary Supplements—Botanicals
DS-GC Dietary Supplements—General Chapters
DSI Dietary Supplements—Information
DSN Dietary Supplements—Non-Botanicals
EM1 Excipient Monographs 1
EGC Excipient General Chapters
GC General Chapters
GTMDB General Toxicity and Medical Device Biocompatibility
IH International Health
MSA Microbiology and Sterility Assurance
MD-ANT Monograph Development—Antibiotics
MD-AA Monograph Development—Antivirals and Antimicrobials
MD-CV Monograph Development—Cardiovascular
MD-CCA Monograph Development—Cough, Cold, and Analgesics
MD-GRE Monograph Development—Gastrointestinal, Renal, and Endocrine
MD-OOD Monograph Development—Ophthalmology, Oncology, and Dermatology
MD-PP Monograph Development—Psychiatrics and Psychoactives
MD-PS Monograph Development—Pulmonary and Steroids
NOM Nomenclature
P&S Packaging and Storage
PPI Parenteral Products—Industrial
PDF Pharmaceutical Dosage Forms
PW Pharmaceutical Waters
SMU Safe Medication Use
SCC Sterile Compounding
Pharmacopeial Forum
EXPERT COMMITTEE DESIGNATIONS* (Continued)

2005–2010
RMI Radiopharmaceuticals and Medical Imaging Agents

RI Radiopharmaceutical Information
RS Reference Standards
STAT Statistics
How to Use PF
VET Veterinary Drugs
VMI Veterinary Medicine Information
*
HDQ Indicates USP Headquarters items.
Pharmacopeial Forum
STAFF DIRECTORY
This updated directory reflects assignment changes based on 2005–2010 Expert Committees. The general USP telephone
number, (301) 881-0666, may still be used for general inquiries or when a particular Expert Committee is not identified. The fax
number is (301) 816-8373.
STAFF E-MAIL PHONE ASSIGNMENT

How to Use PF
Clydewyn M. Anthony, Ph.D., cma@usp.org (301) 816-8139 Monograph Development—

Scientist Cough, Cold, and Analgesics
(MD-CCA)
Fouad Atouf, Ph.D., fa@usp.org (301) 816-8365 B&B Cell, Gene, and Tissue
Senior Scientific Associate Therapies (BB CGT)
Shawn C. Becker, M.S., B.S.N., R.N., scb@usp.org (301) 816-8216
Director, Patient Safety
Daniel K. Bempong, Ph.D., dkb@usp.org (301) 816-8143 Pulmonary and Steroids
Senior Scientist (MD-PS)
Nancy Blum, nlb@usp.org (301) 816-8161
Vice President, International
Affairs
William E. Brown, web@usp.org (301) 816-8380 Biopharmaceutics (BPC);
Senior Scientist Pharmaceutical Dosage
Forms (PDF)
Damián A. Cairatti, dac@usp.org (301) 816-8307 USP–NF Spanish Edition
Senior Scientist
Larry N. Callahan, Ph.D., lnc@usp.org (301) 816-8385 B&B Proteins and Polysaccha-
Senior Scientist rides (BB PP)
Todd L. Cecil, Ph.D., tlc@usp.org (301) 816-8234
Vice President, Standards
Development
Diane Cousins, R.Ph., ddc@usp.org (301) 816-8215
Vice President, Patient Safety
Behnam Davani, Ph.D., bd@usp.org (301) 816-8394 Monograph Development—
Senior Scientist Antivirals and Antimicrobials
(MD-AA)
Ian F. DeVeau, Ph.D., ifd@usp.org (301) 816-8178 Veterinary Drugs (VET);
Director, Veterinary Drugs Veterinary Medicine
and Radiopharmaceuticals Information (VMI)
Shawn F. Dressman, Ph.D., sfd@usp.org (301) 816-8261 Reference Standards (RS)
Director, Reference Standards
Evaluation
Lawrence Evans, Ph.D., le@usp.org (301) 816-8389 Dietary Supplements—General
Scientist Chapters (DS-GC); Dietary
Supplements—Non-
Botanicals (DSN)
Gabriel I. Giancaspro, Ph.D., gig@usp.org (301) 816-8343
Director, Dietary
Supplements
Brian D. Gilbert, Ph.D., bg@usp.org (301) 816-8223
Scientist
Elena Gonikberg, Ph.D., eg@usp.org (301) 816-8251 Monograph Development—
Senior Scientist Gastrointestinal, Renal, and
Endocrine (MD-GRE)
Antonio Hernandez-Cardoso, ahc@usp.org (301) 816-8308 USP Spanish Edition;
Scientist, Latin American General Chapters (GC)
Specialist
Desmond G. Hunt, Ph.D., dgh@usp.org (301) 816-8341 Packaging and Storage
Senior Scientific Associate (P&S); Parenteral Products—
Industrial (PPI)
Pharmacopeial Forum

Robert Jacoby, raj@usp.org (301) 998-6823
Manager, Editorial Services
Ping Jin, Ph.D., pj@usp.org (301) 998-6827 Dietary Supplements—
Senior Scientific Associate Bioavailabilty (DS-BA)
James W. Kelly, Ph.D., jwk@usp.org (301) 816-8167 Compounding Pharmacy (CRX)
Scientist
Jymeann King, R.Ph., jk@usp.org (301) 816-8507 Drug Information
Drug Information Specialist
How to Use PF
Robert Lafaver, rhl@usp.org (301) 816-8335 Excipient Monographs 1 (EM1);
Scientist Excipient General Chapters (EGC)
Angela G. Long, agl@usp.org (301) 816-8382
Vice President, Volunteer and
Organizational Affairs and
Executive Secretariat
Victor Xiaobin Lu, Ph.D., vxl@usp.org (301) 816-8336 B&B Vaccines and Virology
Senior Scientist (BB-VV)
Anju K. Malhotra, akm@usp.org (301) 816-8346
Manager, Scientific Administration
Ronald G. Manning, Ph.D., rgm@usp.org (301) 816-8562
Vice President, Monograph
and Reference Standard
Development
Feiwen Mao, fm@usp.org (301) 816-8320 Monograph Development—
Senior Scientific Associate Ophthalmology, Oncology,
and Dermatology (MD-OOD)
Margareth R. Marques, Ph.D., mrm@usp.org (301) 816-8106 Biopharmaceutics (BPC);
Senior Scientist and Latin Pharmaceutical Dosage
American Liaison Forms (PDF); Reagents
Marcia D. Mayfield, mxm@usp.org (301) 816-8358
Manager, Monograph Development
Kate Meringolo, kxm@usp.org (301) 816-8377
Manager, Publication Support
Elizabeth Miller, Pharm.D., epc@usp.org (301) 816-8217 Safe Medication Use (SMU)
Manager
Kevin Moore, Ph.D., ktm@usp.org (301)816-8369 Harmonization;
Scientist Monograph Improvement
Tina S. Morris, Ph.D., tsm@usp.org (301) 816-8397
Director, Biologics and
Biotechnology
Amy Neal, DVM, an@usp.org (301) 998-6786 Veterinary Medicine Information
Senior Scientist (VMI)
Claudia C. Okeke, Ph.D., cco@usp.org (301) 816-8243 Sterile Compounding (SCC)
Scientific Fellow,
Patient Safety
Horacio Pappa, Ph.D., hp@usp.org (301) 816-8319 General Chapters (GC);
Senior Scientist and Latin Statistics (STAT)
American Liaison
W. Larry Paul, Ph.D., wlp@usp.org (301) 816-8331 Nomenclature (NOM)
Scientific Fellow
Denise Penn, R.Ph., dsp@usp.org (301) 816-8392 Drug Information
Deborah G. Perfetto, Pharm.D., dgp@usp.org (301) 816-8317
Director, Information Programs
Sujatha Ramakrishna, Ph.D., syk@usp.org (301) 816-8349 Monograph Development—
Scientist Cardiovascular (MD-CV)
Pharmacopeial Forum

Ravi Ravichandran, Ph.D., rr@usp.org (301) 816-8330 Monograph Development—
Senior Scientist Psychiatrics and
Psychoactives (MD-PP)
Gary E. Ritchie, M.S., ger@usp.org (301) 816-8353 General Chapters (GC);
Scientific Fellow for PAT Pharmaceutical Waters (PW);
Statistics (STAT)
Karen A. Russo, Ph.D., kar@usp.org (301) 816-8379 Monograph Acquisition and
Director, Small Molecules Infrastructure
and Monograph Acquisition
How to Use PF
Leonel Santos, lxs@usp.org (301) 816-8168 International Health (IH)

Senior Scientist
Dandapantula Sarma, Ph.D, dns@usp.org (301) 816-8354 Dietary Supplements—
Senior Scientist Information (DSI)
Stefan P. Schuber, Ph.D., sps@usp.org (301) 816-8551
Director, Scientific Reports
Maged H. M. Sharaf, Ph.D., mhs@usp.org (301) 816-8318 Dietary Supplements—
Senior Scientist Botanicals (DSB);
Dietary Supplements—
General Chapters (DS-GC)
Catherine M. Sheehan, cxs@usp.org (301) 816-8262
Director, Excipients
Anita Y. Szajek, Ph.D., aey@usp.org (301) 816-8325 B&B Blood and Blood Products
Senior Scientist (BB BBP)
Radhakrishna S. Tirumalai, Ph.D., rst@usp.org (301) 816-8339 General Toxicity and Medical
Senior Scientist Device Biocompatibility
(GTMDB); Microbiology and
Sterility Assurance (MSA)
Beryl Voigt, bev@usp.org (301) 816-8155
Director, Executive Secretariat
Hong Wang, Ph.D., hw@usp.org (301) 816-8351 Excipient Monographs 2
Senior Scientific Associate (EM2); Excipient General
Chapters (EGC)
Andrzej Wilk, Ph.D., aw@usp.org (301) 816-8305 Radiopharmaceuticals and
Scientist Medical Imaging Agents
(RMI); Radiopharmaceutical
Information (RI)
Kahkashan Zaidi, Ph.D., kxz@usp.org (301) 816-8269 Aerosols (AER);
Senior Scientist General Chapters (GC)
POLICIES AND
ANNOUNCEMENTS
This section includes information about general scientific and policy issues that may have an impact on USP–NF standards and
processes and announcements about issues being considered by USP. This section also includes publication and comment sche-
dules.

Pharmacopeial Forum
18 POLICIES AND ANNOUNCEMENTS Vol. 33(1) [Jan.–Feb. 2007]
USP SEEKS CANDIDATES FOR THREE EXPERT Depending on deliberations in the Stakeholder Forum, Project
COMMITTEES. In accordance with Chapter 10 of the Teams on special topics of interest may be formed to generate
Bylaws of the USP Convention, USP is seeking qualified specific data and information in support of the Council of Ex-
candidates for its Expert Committees. Specifically, USP is perts’ standards-setting activities for Food Chemicals Codex.
seeking candidates to fill vacancies on the following 2005– Communications to and from other USP Stakeholder Forums
2010 Expert Committees: is expected to be valuable as USP charts its course for the
FCC.
Information: Clinical Toxicology
Contact Ms. Helen Kharab (hk@usp.org or 301-816-8224) for
Information: Nephrology and Urology
further information.
In addition, as a result of USP’s acquisition of the Food Chem-
icals Codex (FCC), the Board of Trustees and the Executive P H A R M A C O P E I A L H A R M O N I Z AT I O N . T h e
Committee of the Council of Experts have approved the for- Pharmacopeial Discussion Group (PDG) held its meeting
mation of a new Expert Committee. Candidates are also being October 23–26, 2006, in Chicago, IL. A press release
sought for this Committee: outlining its work from this and previous meetings is
available on USP’s website at http://www.usp.org/USPNF/
Standards: Food Additives pharmacopeialHarmonization/.
Expert Committee members directly influence drug quality in
the United States and many other countries by establishing IN MEMORIAM: JOSEPH ROBINSON, PH.D.
quality standards and information in the United States Phar- USP is saddened to announce that Dr. Joseph Robinson
macopeia and the National Formulary, the Food Chemicals (1939–2006) passed away in September 2006. He was a mem-
Codex, and the Medicare Model Guidelines. Expert Commit- ber of USP’s Council of Experts/Committee of Revision from
tee members also help further the best practices in pharmaceu- 1980 to 2000. During that time, he served as the chair and as a
tical science nationally and globally. member of the Expert Committee on Bioavailability, Bioequi-
valence, and Dissolution. Dr. Robinson was Professor of Phar-
The Nominations Process. Anyone can apply to be a macy in the School of Pharmacy and Professor of
potential candidate for Expert Committees via the candidate Ophthalmology in the Medical School at the University of
application on the USP website (www.usp.org/nominate). Wisconsin–Madison. He earned his B.S. and M.S. degrees
Applicants will be asked to identify the Expert Committee(s) from Columbia University in New York and his Ph.D. from
position for which they wish to be considered, and indicate the University of Wisconsin. He was a major contributor to
their professional experience, education, USP experience, the field of pharmaceutical science.
and other relevant experience.
Nominations for Expert Committee member positions close VICE PRESIDENT OF PHARMACOPEIAL
on February 15, 2007. Expert Committee member elections EDUCATION NAMED. Toby Gouker joined USP as Vice
will be held in the Spring 2007. For further information, con- President, Pharmacopeial Education, in September 2006.
tact the Department of Volunteer and Organizational Affairs at Toby has over 25 years of diverse business, technical, and
nominate@usp.org. training experience and a demonstrated track record of
success as an education and training executive. Toby comes
USP FORMS STAKEHOLDER FORUM TO ADDRESS to USP from the American Graduate University (AGU). At
THE FOOD CHEMICALS CODEX; FIRST MEETING AGU, Toby was Vice President, University Affairs,
SET FOR FEBRUARY 2007. In addition to the newly functioning as chief academic and operations officer
formed Food Additives Expert Committee, for which USP is responsible for program conception and development and
seeking chairs and members (see above article) and an delivery of courses and programs throughout the US and in
associated ad hoc Advisory Panel, USP has also formed a more than 25 other countries. He was also responsible for
Food Chemicals Codex Stakeholder Forum. Invited FCC faculty recruiting and drafting the annual business, budget,
stakeholder organizations participated in an organizing and marketing plans. Prior to joining AGU, Toby was
teleconference for the Stakeholder Forum at the end of Executive Director, Walden National Technology University,
November, and the first FCC Stakeholder Forum meeting is School of Engineering with Laureate Education. Previous
set for February 23, 2007, at the Marriott Bethesda North positions included Director, Operations, for Certis USA, and
Hotel (see USP’s website for further inform ation: Research & Development Project Manager at W. R. Grace &
http://www.usp.org/eventsEducation/calendar.html). Co. Toby received a B.S. in Chemical Engineering from
Worcester Polytechnic Institute, Worcester, MA, and an
The charge of the Food Chemicals Codex Stakeholder Forum M.B.A. from the University of Houston, Clerk Lake City,
is to provide information and advice to USP’s CEO-EVP, staff, TX. Toby is currently pursuing a Ph.D. in Information
and Council of Experts standards-setting bodies for the Food Systems Management with concentration in Online Training
Chemicals Codex. from Walden University.
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] POLICIES AND ANNOUNCEMENTS 19
U S P D I S C O N T I N U E S U S E O F ‘‘ I N T E N T T O C ATA L O G T O B E R E M O V E D F R O M
COMMENT’’ FORM. Beginning with this issue of PHARMACOPEIAL FORUM PRINT PUBLICATION.
Pharmacopeial Forum, the ‘‘Intent to Comment’’ form has Beginning with this issue of Pharmacopeial Forum, the
been removed from the back of the publication. Previously, USP Catalog is no longer being included in the back of the
the comment period for each issue of PF was 60 days. In publication. This change has been made to reduce the bulk
2005, the comment period was increased to 90 days. With of the publication and thereby increase ease of handling and
this expansion in the comment period, it was no longer use.
viewed as necessary or appropriate to routinely allow further
The USP Catalog is still available in online and stand-alone
extensions of time to comment through the ‘‘Intent to
print versions. Online bimonthly and daily catalogs can be ac-
Comment’’ form. In order to ensure that comments on a
cessed at www.usp.org/referenceStandards/catalog.html. You
proposed revision will be considered by the Expert
can also sign up to receive the USP Catalog in print (via postal
Committee in determining whether and how a proposed
mail) along with monthly email alerts—which will keep you
revision should proceed, comments should be received
informed about new Reference Standards, availability, and
within the 90-day comment period.
current lots—by sending an e-mail to marketing@usp.org or
Please direct any comments or questions on this topic to Beryl calling 301-816-8237.
Voigt, Director, Executive Secretariat (301-816-8155 or
execsec@usp.org). STIMULI ARTICLES TO BE POSTED ON THE USP
WEBSITE. Starting in 2007, the Stimuli articles that are

I M P L E M E N TAT I O N P E R I O D F O R O F F I C I A L published in Pharmacopeial Forum will be simultaneously
REVISIONS TO USP–NF EXTENDED. To provide published on the USP website. Look for them at
additional time to adopt revisions made to the compendia, www.usp.org. There are no Stimuli articles in this issue of
effective beginning with the publication of USP 30–NF 25, Pharmacopeial Forum, but those that will be published in
implementation periods for revisions to official text in the the next issue of Pharmacopeial Forum will appear on the
United States Pharmacopeia–National Formulary (USP– website in March 2007. For more information, please
NF) and its Supplements are being extended. This change is contact Stefan Schuber, Ph.D., Director, Scientific Reports
in response to stakeholder requests (see the Pharmacopeial (301-816-8551 or sps@usp.org).
Forum [PF] 31[2] Stimuli article, ‘‘The USP Revision
Process: Recommendations for Enhancements’’). As a result PHARMACOPEIAL EDUCATION COURSES. The USP
of this change, users have six months from the publication Pharmacopeial Education courses offer specialized instruction
date to implement new official texts, as opposed to the for chemists, other scientists, and professionals in the
previous 60-day period. The complete revised Publication pharmaceutical and allied industries. USP scientists and USP
Schedule for USP 30–NF 25, reflecting this new six-month science experts, who play a key role in establishing official
USP standards, teach these courses and provide expert
implementation period, is outlined below.
insights into the practical applications of official test
Publication Schedule for USP 30–NF 25
procedures and best practices in using the USP–NF and
other USP resources. The courses also give participants an
USP–NF opportunity to learn how to get involved in USP’s
Publication Publication Date Official Date standards-setting processes and the benefits of participating
USP–NF (Book) November 2006 May 1, 2007 in standards development. Courses offered in 2007 are listed
Supplement One February 2007 August 1, 2007 below. For more information and to register, visit
Supplement Two June 2007 December 1, 2007 www.usp.org/goto/pe. To discuss how USP can bring
courses to a location of your choice, call 301-816-8589, or
e-mail PharmacopeialEducation@usp.org.
Users may implement the newly official texts prior to the of-
ficial date, and the use becomes mandatory on the official date. Beginning in the 2007 calendar year, USP’s Pharmacopeial
Education (PE) program will be initiating a significant expan-
Please direct any comments or questions on this topic to Beryl
sion initiative. Both the depth and breadth of course offerings
Voigt, Director, Executive Secretariat (301-816-8155 or
will grow as the Pharmacopeial Education staff works to make
execsec@usp.org).
the science behind the standards more accessible. As this pro-
cess begins, the PE program invites you to participate by sug-
gesting titles, developing course objectives, or even joining
the teaching staff.
Pharmacopeial Forum
Calendar of Forthcoming Pharmacopeial Education Courses as of November 15, 2006

Date Name of Course Location Price
The Americas
30-31 Jan-07 Effectively Using the USP–NF—Sessions I & II Rockville, MD (USP Headquarters, 2 $1,700
days)
8-Feb-07 Navigating Chapter <467> Residual Solvents (new) Rockville, MD (USP Headquarters, 1/2 $245
day)
13-Feb-07 Navigating Chapter <467> Residual Solvents (new) Raleigh, NC (1/2-day seminar) $245*
23-Feb-07 Essentials of USP Microbiological Testing (new Irvine, CA $595
course)
27-Feb-07 Navigating Chapter <467> Residual Solvents (new) Chicago, IL (during Pittcon) $245*
Winter 2007 Navigating Chapter <467> Residual Solvents (new) Dallas/Fort Worth, TX (details to $245*
come)
15-Mar-07 Essentials of USP Microbiological Testing (new Raleigh, NC $595
course)
15-Mar-07 Analytical Method Validation (in Spanish) Mexico City, Mexico (details to come) TBD
Mar-07 Navigating Chapter (467) Residual Solvents (new) Montreal, Canada (details to come) TBD
$245*
Mar-07 Navigating Chapter (467) Residual Solvents (new) East Brunswick, NJ (details to come)
May 07 Navigating Chapter (467) Residual Solvents (new) Rockville, MD (USP Headquarters, 1/2 $245
day)
* Two identical half-day seminars, morning and afternoon, will be offered. To register, send your contact information by e-mail to
PharmacopeialEducation@usp.org to receive a flier/registration form by return e-mail. If space permits, registrations accepted less than one
week before the course will be $295.
VISIT THE USP WEBSITE AT http://www.usp.org. HOW TO SUBMIT COMMENTS. The USP welcomes and
Various resources related to Pharmacopeial standards are encourages interested parties to submit comments and data
presented, including highlights from PF.
regarding potential, proposed, or adopted (official)
standards. Submissions concerning a particular item that has
INTERNATIONAL CORRESPONDENCE. Individuals
appeared in an issue of PF should be submitted to the
who wish to correspond with the European and Japanese
appropriate USP scientific staff liaison identified at the end
Pharmacopoeias concerning monographs in the Official
of the Briefing accompanying each item. To submit
Inquiry and Consensus stages of international harmonization
comments and data to a liaison, use the e-mail address and
should address their comments to the coordinating telephone numbers listed in the Staff Directory included in
pharmacopeia, with a copy to USP, for a given article. The
every PF.
addresses for the European and Japanese Pharmacopoeias
are as follows: Please note that USP–NF is being published in an annual edi-
Technical Secretariat of the European tion with one main book and two Supplements a year. In addi-
Pharmacopoeia Commission tion, the schedule provided below will repeat every year so
B.P. 907 that users will know what to expect and will become familiar
F 67029 Strasbourg Cedex 1 with the deadlines.
France
For general inquiries or in cases where a particular liaison is
NAKASHIMA Nobumasa not identified, use the general USP telephone number 301-
Evaluation and Licensing Division
881-0666 or fax number 301-816-8373.
Pharmaceutical and Medical Safety Bureau
Ministry of Health, Labour and Welfare, Japan
Tel. +81-3-3595-2431, Fax +81-3-3597-9535
E-mail: nakashima-nobumasa@mhlw.go.jp
Pharmacopeial Forum
PHARMACOPEIAL FORUM PUBLIC REVIEW AND individual Briefing. As previously stated, as a result of the
COMMENT PERIOD DEADLINES. The full year’s comment deadline extension, the ‘‘Intent to Comment’’ form
listing of comment period deadlines and targeted official will no longer be used and will be removed from PF. The
publications appears below. In accordance with the Rules listing of comment period deadlines and the targeted official
and Procedures of the 2005–2010 Council of Experts, USP publications appear below.
has implemented a 90-day comment period by providing a
deadline for each issue of PF unless otherwise stated in the
Targeted Official
Pharmacopeial Forum Comment Deadline Publication Publication Date Official Date
PF 32(6) February 15, 2007 USP 31–NF 26 November 2007 May 2008
PF 33(1) April 16, 2007
PF 33(2) June 15, 2007 USP 31–NF 26 February 2008 August 2008
PF 33(3) August 15, 2007 1st Supplement
PF 33(4) October 15, 2007 USP 31–NF 26 June 2008 December 2008
PF 33(5) December 15, 2007 2nd Supplement
PF 34(1) April 15, 2008

All official revisions are published in the annual edition or electronic version of USP–NF is updated as each Supplement
Supplements to USP–NF (twice yearly). Between these publi- becomes available and, therefore, contains all official text up
cations, official revisions are published in PF in the Interim to and including the contents of the latest Supplement. The
Revision Announcement; these revisions are also incorporated new table below outlines the publications and their release
in the upcoming Supplement. The official publication in which and official dates, and the book or supplement that supersedes
an IRA is incorporated will depend upon publication dead- them.
lines. The IRAs appearing in PF Numbers 5 and 6 of each vol-
ume will not appear until Supplement 1. See table below. The
Publication Schedules
Publication Release Date Official Date Superseded by
4th IRA [PF 32(4)] July 1, 2006 Aug. 1, 2006 USP 30–NF 25
5th IRA [PF 32(5)] Sept. 1, 2006 Oct. 1, 2006 1st Supplement
6th IRA [PF 32(6)] Nov. 1, 2006 Dec. 1, 2006 1st Supplement
USP 30–NF 25 Nov. 1, 2006* May 1, 2007* 1st Supplement
IRA [PF 33(1)] Jan. 1, 2007* Feb. 1, 2007* 2nd Supplement
1st Supplement Feb. 1, 2007* Aug. 1, 2007* 2nd Supplement
IRA [PF 33(2)] Mar. 1, 2007* Apr. 1, 2007* 2nd Supplement
IRA [PF 33(3)] May 1, 2007* June 1, 2007* USP 31–NF 26
2nd Supplement June 1, 2007* Dec. 1, 2007* USP 31–NF 26
IRA [PF 33(4)] July 1, 2007* Aug. 1, 2007* USP 31–NF 26
IRA [PF 33(5)] Sept. 1, 2007* Oct. 1, 2007* 1st Supplement to
USP 31– NF 26
IRA [PF 33(6)] Nov. 1, 2007* Dec. 1, 2007* 1st Supplement to
USP 31– NF 26
USP 31–NF 26 Nov. 1, 2007* May 1, 2008* 1st Supplement to
USP 31– NF 26
* Tentative.
Pharmacopeial Forum
PRIORITY NEW MONOGRAPH ITEMS. USP is seeking Forum. (This list has been updated as of September 1,
monographs for the following drug substances and drug pro- 2006.) For additional information, contact Karen A. Russo,
ducts that are or soon will be off patent and thus are of the Ph.D., kar@usp.org. Monograph sponsors should consult
highest priority. USP also is seeking monographs for the ex- USP’s Guideline for Submitting Requests for Revision to the
cipients listed below. Monographs are marked received upon USP–NF.
receipt of the monograph proposal. Received monographs are
removed from this list upon publication in Pharmacopeial
Noncomplex Actives (Drug Substances)
Acarbose Alatrofloxacin Mesylate Alfuzosin Hydrochloride
(Received) (Received)
Allopurinol Sodium Aminopromazine Fumarate Aminopterin Sodium
Anagrelide Hydrochloride Arsenic Trioxide Auranfoin
Azelaic Acid Balsalazide Disodium Bentoquatam
Benzphetamine Hydrochloride Bepridil Hydrochloride Bivalirudin
Cabergoline Calcipotriene Calcium Trisodium Pentetate
(Received)
Calfactant Candesartan Cilexetil Carmustine
(Received)
Cefdinir Cefditoren Pivoxil Ceftibuten
(Received)
Ceftiofur Hydrochloride Cysteamine Bitartrate Cetrorelix
Cevimeline Chloroxine Choline Salicylate
Colfosceril Cytarabine Liposome Dalfopristin
Dapirazole Hydrochloride Desirudin Desonide
(Received)
Dexrazoxane Dextromethorphan Polistirex Difenoxin Hydrochloride
Difloxacin Hydrochloride Diltiazem Malate Doxacurium Chloride
Entacapone Epoprostenol Sodium Erythromycin Phosphate
(Received)
Erythromycin Thiocyanate Esmolol Hydrochloride Esomeprazole Magnesium
(Received)
Estazolam Estradiol Benzoate Estramustine Phosphate Sodium
(Received)
Ethanolamine Oleate Etomidate Etoposide
(Received)
Exemestane Felbamate Flavoxate Hydrochloride
Fluoromethane F 18 Foscarnet Sodium Fosfomycin Tromethamine
Gadobenate Dimeglumine Gadopentetic Acid Galantamine Hydrobromide
(Received)
Gallium Nitrate Ganirelix Glyceryl Aminobenzoate
Granisetron Hydrochloride Guanidine Hydrochloride Halobetasol Propionate
Haloperidol Decanoate Hydrocodone Polistirex Ibandronate Sodium
(Received)
Imipramine Pamoate Imiquimod Irinotecan
Isosulfan Blue Itraconazole Lamotrigine
Latanoprost Levetriacepam Levobetaxolol
Levomethadyl Acetate Lomustine Lopinavir
(Received)
Metipranolol Hydrochloride Midazolam Mifepristone
Miglitol Milrinone Lactate Misoprostol
(Received)
Mivacurium Chloride Moexipril Hydrochloride Nalbuphine Hydrochloride
Nalmefene Hydrochloride Nateglinide Nedocromil Sodium
(Received)
Nicardipine Hydrochloride Nilutamide Nisoldipine
Olopatadine Olsalazine Sodium Orbifloxacin
(Received) (Received) (Received)
Orlistat Oxcarbazepine Oxiconazole Nitrate
Pharmacopeial Forum
Noncomplex Actives (Drug Substances) (Continued)
Pantoprazole Sodium Pemirolast Potassium Pemoline

(Received)
Pentamidine Isethionate Piperonyl Butoxide Pirbuterol Acetate
(Received)
Poractant Alpha Porfimer Sodium Pramiprexole Dihydrochloride
Proguanil Hydrochloride Quetiapine Fumarate Ranitidine
Rivastigmine Tartrate Rose Bengal Rosiglitazone Maleate
Salmeterol Xinafoate Sertraline Hydrochloride Sodium Phenylbutyrate
(Received)
Sodium Phosphates Spectinomycin Sulfate Streptozocin
Sulfacytine Tacrolimus Tenofovir Disoproxil Fumarate
Terbinafine Hydrochloride Terconazole Tiludronate Disodium
Tiopronin Trandolapril Tranexamic Acid
(Received)
Tranylcypromine Sulfate Trimetrexate Glucuronate Trimipramine Maleate
(Received)

Trovafloxacin Mesylate Unoprostone Isopropyl Venlafaxine Hydrochloride
Voriconazole Zinc Tridosium Pentetate Zoledronic Acid
Noncomplex Actives (Drug Products)

Abacavir Sulfate, Lamivudine, and Zidovu- Acarbose Tablets Acetaminophen, Butalbital, Caffeine, and Co-
dine Tablets deine Phosphate Capsules
Acetaminophen, Clemastine Fumarate, and Acetazolamide Extended-Release Capsules Albuterol Extended-Release Tablets
Pseudoephedrine Hydrochloride Tablets
Albuterol for Inhalation Albuterol Inhalation Aerosol Alendronate Sodium Oral Solution
Alfuzosin Tablets Allopurinol for Injection Alprazolam Extended-Release Tablets
Alprostadil Urethral Suppository Aminopromazine Fumarate and Neomycin Aminopromazine Fumarate Injection
Sulfate Tablets
Aminopromazine Fumarate Tablets Aminopterin Sodium Tablets Amlodipine and Benazepril Hydrochloride
Capsules
Amphotericin B Injection Anagrelide Hydrochloride Capsules Arsenic Trioxide Injection
Atovaquone and Proguanil Hydrochloride Atovaquone Tablets Auranofin Capsules
Tablets
Azatadine Maleate and Pseudoephedrine Azelaic Acid Cream Azithromycin for Injection
Sulfate Extended-Release Tablets (Received)
Azithromycin Tablets Baclofen Injection Balsalazide Disodium Capsules
Beclomethasone Dipropionate Inhalation Beclomethasone Dipropionate Nasal Sus- Bentoquatam Topical Suspension
Aerosol pension
Benzocaine and Cetylpyridinium Chloride Benzocaine and Menthol Lotion Benzphetamine Hydrochloride Tablets
Lozenges
Bepridil Tablets Bicalutamide Tablets Bivalirudin Injection
Brompheniramine Maleate, Dextromethor- Budesonide Inhalation Aerosol Bupivacaine and Lidocaine Hydrochlorides
phan Hydrobromide, and Pseudoephedrine Injection
Hydrochloride Oral Solution
Buprenorphine Hydrochloride Injection Butalbital and Acetaminophen Capsules Butalbital and Acetaminophen Tablets
Calcipotriene Cream Calcipotriene Ointment Calcipotriene Topical Solution
Cabergoline Tablets Calcitriol Capsules Calcitriol Oral Solution
Calcium Acetate Capsules Calcium Trisodium Pentetate Injection Calfactant Intratracheal Suspension
Carbidopa and Levodopa Extended- Carbidopa and Levodopa Tablets for Oral Carbidopa, Levidopa, and Entacapone
Release Tablets Suspension Tablets
Carmustine for Injection Carmustine Implant Carvedilol Tablets
Cefdinir Tablets Cefditoren Pivoxil Tablets Ceftibuten Capsules
Ceftibuten for Oral Suspension Ceftiofur Hydrochloride Oral Suspension Cetirizine Hydrochloride Oral Solution
Cetirizine Hydrochloride Tablets Cetrorelix Injection Cevimeline Hydrochloride Capsules
(Received)
Chloroxine Cream Chlorpromazine Hydrochloride Extended- Choline and Magnesium Salicylates Oral So-
Release Capsules lution
Pharmacopeial Forum
Noncomplex Actives (Drug Products) (Continued)

Choline and Magnesium Salicylates Tablets Choline Salicylate Oral Solution Ciclopirox Shampoo
(Received)
Ciclopirox Topical Gel Ciclopirox Topical Solution Cilostazol Tablets
(Received)
Cimetidine Oral Solution Ciprofloxacin Hydrochloride and Hydrocor- Ciprofloxacin Otic Solution
tisone Otic Suspension
Citalopram Hydrobromide Oral Solution Citric Acid, Gluconolactone, and Magne- Cladribine Injection
sium Carbonate Irrigation
Clemastine Fumarate Syrup Clobetasol Propionate Gel Clonazepam Orally Disintegrating Tablets
Clorazepate Dipotassium Capsules Clorazepate Dipotassium Extended- Clotrimazole and Betamethasone Dipropio-
Release Tablets nate Lotion
Colestipol Hydrochloride Tablets Colfosceril and Tyloxapol Suspension Compound Undecylenic Acid Cream
Compound Undecylenic Acid Topical Pow- Conjugated Estrogens and Medroxyproges- Cromolyn Sodium Nasal Solution
der terone Acetate Tablets
Cyclosporine Modified Capsules Cyclosporine Modified Oral Solution Cyclosporine Ointment
Cyclosporine Topical Solution Cysteamine Bitartrate Capsules Cytarabine Liposome Injection
Dalfopristin and Quinupristin Injection Dantrolene Sodium Oral Suspension Dapiprazole for Ophthalmic Solution
Desirudin for Injection Desonide Cream Dexrazoxane for Injection
Dextroamphetamine Sulfate Extended- Dextromethorphan Polistirex Extended- Diazepam Injectable Emulsion

Release Capsules Release Oral Suspension
Diclofenac Sodium Ophthalmic Solution Diethylpropion Hydrochloride Extended- Difenoxin and Atropine Tablets
Release Tablets
Difloxacin Hydrochloride Tablets Dihydroergotamine Mesylate Metered Diltiazem Malate Extended-Release Tablets
Spray
Dinoprostone Vaginal Suppositories Diphenhydramine Hydrochloride and Acet- Divalproex Sodium Delayed-Release Cap-
aminophen Tablets sules
Dorzolamide and Timolol Ophthalmic So- Dorzolamide Ophthalmic Solution Doxacurium Chloride Injection
lution
Doxepin Hydrochloride Cream Doxycycline Oral Gel Econazole Nitrate Cream
Edrophonium Chloride and Atropine Sul- Enalapril Maleate and Diltiazem Malate Ex- Enalapril Maleate and Felodipine Extended-
fate Injection tended-Release Tablets Release Tablets
Enalaprilat Injection Entacapone Tablets Ephedrine Sulfate and Guaifenesin Tablets
(Received)
Epoprostenol for Injection Epoprostenol Injection Esmolol Hydrochloride Injection
Esomeprazole Magnesium Capsules Estazolam Tablets Estramustine Phosphate Sodium Capsules
Ethanolamine Oleate Injection Etidronate Disodium Injection Concentrate Etomidate Injection
Exemestane Tablets Famotidine Orally Disintegrating Tablets Felbamate Oral Suspension
Felbamate Tablets Fentanyl Lozenges Fentanyl Transdermal System
(Received)
Ferrous Fumarate and Docusate Sodium Flavoxate Hydrochloride Tablets Fluconazole Injection
Extended-Release Capsules (Received)
Fluconazole Tablets Flunisolide Inhalation Aerosol Flunisolide Nasal Spray
Fluocinolone Acetonide Shampoo Fluorescein Sodium Ophthalmic Solution Fluorometholone Ointment
Fluticasone Propionate Cream Fluticasone Propionate Inhalation Powder Fluticasone Propionate Ointment
Fluticasone Propionate Pressurized Inhaler Foscarnet Sodium Injection Fosfomycin for Oral Solution
Gabapentin Oral Solution Gabapentin Tablets Gadobenate Dimeglumine Injection
(Received)
Galantamine Tablets Gallium Nitrate Injection Ganciclovir Capsules
(Received)
Ganirelix Acetate Injection Gatifloxacin Injection Gatifloxacin Tablets
Gentamicin Sulfate Oral Solution Gentamicin Sulfate Soluble Powder Glimepiride Tablets
(Received)
Glipizide Extended-Release Tablets Granisetron Injection Granisetron Tablets
Guaifenesin and Salts Of Dextromethor- Guaifenesin and Pseudoephedrine Hydro- Guanidine Hydrochloride Tablets
phan and Pseudoephedrine Oral Solution chloride Extended-Release Tablets
Halobetasol Propionate Cream Halobetasol Propionate Ointment Haloperidol Decanoate Injection
Haloperidol Lactate Injection Haloperidol Lactate Oral Concentrate Hydralazine Hydrochloride and Hydrochlor-
othiazide Capsules
Hydrochlorothiazide Capsules Hydrochlorothiazide Oral Solution Concen- Hydrocodone Bitartrate and Acetaminophen
trate Oral Solution
Hydrocodone Bitartrate and Aspirin Tablets Hydrocodone Bitartrate and Guaifenesin Hydrocodone Bitartrate and Homatropine
Oral Solution Methylbromide Syrup
Pharmacopeial Forum

Hydrocodone Bitartrate and Homatropine Hydrocortisone Acetate Dental Paste Hydrocortisone Acetate Rectal Foam Aerosol
Methylbromide Tablets
Hydrocortisone Butyrate Lotion Hydroflumethiazide and Reserpine Tablets Hydromorphone Hydrochloride Oral Solu-
tion
(Received)
Hydroquinone Lotion Ibandronate Sodium Tablets Ibuprofen Capsules
Idarubicin Hydrochloride Injection Imipramine Pamoate Capsules Imiquimod Topical Cream
Ipratropium Bromide Inhalation Aerosol Ipratropium Bromide Inhalation Solution Irinotecan Hydrochloride Injection
Isosulfan Blue Injection Isradipine Extended-Release Tablets Itraconazole Injection
Itraconazole Oral Solution Ketoconazole Cream Ketoconazole Shampoo
Ketoprofen Capsules Ketoprofen Extended-Release Capsules Ketoprofen Tablets
(Received)
Ketotifen Fumarate Ophthalmic Solution Lactic Acid Lotion Lamivudine Tablets
(Received)
Lamotrigine Tablets Latanoprost Ophthalmic Solution Leucovorin Calcium for Injection
Levetriacepam Tablets Levobetaxolol Ophthalmic Suspension Levocabastine Ophthalmic Suspension
Levofloxacin Solution Levomethadyl Acetate Hydrochloride Oral Lincomycin Hydrochloride and Spectinomy-
Concentrate cin Sulfate Soluble Powder

Liothyronine Injection Lisinopril and Hydrochlorothiazide Tablets Lomustine Capsules
(Received)
Lopinavir and Ritonavir Solution Lopinavir Capsules Lopinavir Solution
Loratadine and Pseudoephedrine Sulfate Loratadine Orally Disintegrating Tablets Losartan Potassium Tablets
Extended-Release Tablets
(Received)
Mefloquine Hydrochloride Tablets Melphalan for Injection Mesalamine Suppositories
Mesoridazine Besylate Concentrate Metaraminol Bitartrate Injection Methacholine Chloride for Inhalation Solu-
tion
Methadone Hydrochloride Oral Concen- Methocarbamol and Aspirin Tablets Methoxsalen Softgels
trate
Methyclothiazide and Deserpidine Tablets Methylphenidate Hydrochloride Chewable Metipranolol Ophthalmic Solution
Tablets
Metronidazole Capsules Metronidazole Cream Metronidazole Extended-Release Tablets
Metronidazole Hydrochloride for Injection Metronidazole Lotion Miconazole Nitrate Topical Aerosol
Midazolam Injection Mifepristone Tablets Miglitol Tablets
(Received)
Milrinone Injection Misoprostol Tablets Mivacurium In Dextrose Injection
(Received)
Mivacurium Injection Moexipril Hydrochloride and Hydrochlor- Moexipril Hydrochloride Tablets
othiazide Tablets
Molindone Hydrochloride Oral Solution Morphine Sulfate for Injection Concentrate Morphine Sulfate Oral Solution
Morphine Sulfate Oral Solution Concen- Morphine Sulfate Tablets Mycophenolate Mofetil Capsules
trate
Mycophenolate Mofetil Oral Solution Mycophenolate Mofetil Tablets Nalbuphine Hydrochloride Injection
Nalmefene Hydrochloride Injection Naphazoline Hydrochloride and Phenira- Naphazoline Hydrochloride and Pheniramine
mine Maleate Ophthalmic Solution Maleate Ophthalmic Solution
Naproxen Extended-Release Tablets Nateglinide Tablets Nedocromil Sodium Inhalation Aerosol
Neomycin Sulfate Oral Powder Nicardipine Hydrochloride Capsules Nilutamide Tablets
Nimodipine Capsules Nisoldipine Extended-Release Tablets Nitroglycerin Extended-Release Transdermal
Film
Nitroglycerin Transdermal System Nitroglycerin Solution In Acrylic Adhesive Nizatidine Tablets
Ofloxacin In Dextrose Injection Ofloxacin Injection Ofloxacin Tablets
(Received)
Olopatadine Ophthalmic Solution Olsalazine Sodium Capsules Ondansetron Tablets
(Received)
Orbifloxacin Tablets Orlistat Capsules Orphenadrine Citrate Extended-Release
(Received) (Received) Tablets
Orphenadrine Citrate, Aspirin, and Caffeine Oxcarbazepine Suspension Oxcarbazepine Tablets
Tablets
Oxiconazole Cream Pantoprazole Sodium for Injection Pantoprazole Sodium Tablets
Paroxetine Hydrochloride Extended- Paroxetine Oral Suspension Pemirolast Potassium Ophthalmic Solution
Release Tablets
Pemoline Tablets Penicillin G Potassium Tablets for Oral So- Pentamidine Isethionate for Inhalation
lution
Pharmacopeial Forum

Pentamidine Isethionate Injection Pentazocine Hydrochloride and Aceta- Phendimetrazine Tartrate Extended-Release
(Received) minophen Tablets Capsules
Phenobarbital Capsules Phentermine Resin Complex Capsules Phenylephrine Hydrochloride and
Chlorpheniramine Maleate Extended-
Release Capsules
Phenylephrine Hydrochloride, Chlorphen- Pilocarpine Hydrochloride Ophthalmic Gel Pilocarpine Hydrochloride Ophthalmic Oint-
iramine Maleate, and Acetaminophen ment
Pilocarpine Hydrochloride Tablets Piperonyl Butoxide and Pyrethrins Aerosol Pirbuterol Acetate Inhalation Aerosol
Foam
Poractant Alpha Supension Porfimer Sodium for Injection Povacrylate Solution
Povacrylate–Iodine Topical Solution Povidone–Iodine Gauze Povidone–Iodine Swabsticks
Povidone–Iodine Topical Aerosol Foam Povidone–Iodine Vaginal Suppositories Pramipexole Dihydrochloride Tablets
Prednisolone Sodium Phosphate Oral Solu- Prochlorperazine Maleate Extended- Progesterone Capsules
tion Release Capsules
Promethazine and Phenylephrine Hydro- Promethazine and Phenylephrine Hydro- Promethazine Hydrochloride and Codeine
chlorides and Codeine Phosphate Syrup chlorides Syrup Phosphate Oral Solution
Promethazine Hydrochloride and Dextro- Propafenone Hydrochloride Tablets Pseudoephedrine Hydrochloride and Brom-
methorphan Hydrobromide Syrup pheniramine Maleate Extended-Release
Tablets
Pseudoephedrine Hydrochloride and Na- Pseudoephedrine Hydrochloride, Pseudoephedrine Hydrochloride, Guaifene-
proxen Sodium Extended-Release Tablets Chlorpheniramine Maleate, and Codeine sin, and Codeine Phosphate Oral Solution
Phosphate Oral Solution
Pseudoephedrine Sulfate and Pseudoephedrine Sulfate and Pseudoephedrine Sulfate, Dexbromphenira-
Dexbrompheniramine Maleate Extended- Dexbrompheniramine Maleate Oral Solu- mine Maleate, and Acetaminophen
Release Tablets tion Extended-Release Tablets
Pyrilamine Maleate Injection
Quinidine Sulfate Injection Ramipril Capsules Ranitidine Capsules
Rauwolfia Serpentina and Endroflumethia- Reserpine and Polythiazide Tablets Rimantadine Hydrochloride Oral Solution
zide Tablets
Risperidone Oral Solution Risperidone Orally Disintegrating Tablets Rivastigmine Tartrate Capsules
Rivastigmine Tartrate Oral Solution Rocuronium Bromide Injection Ropinirole Hydrochloride Tablets
(Received)
Rose Bengal Ophthalmic Solution Rosiglitazone Maleate Tablets Salicylic Acid and Sulfur Cleansing Lotion
Salicylic Acid and Sulfur Lotion Salicylic Acid and Sulfur Shampoo Salicylic Acid Cream
Salicylic Acid Ointment Salmeterol Inhalation Aerosol Salmeterol Xinafoate Inhalation Powder
Scopolamine Transdermal System Selegiline Hydrochloride Capsules Sertraline Hydrochloride Oral Solution
Sibutramine Hydrochloride Capsules Sodium Bicarbonate and Sodium Citrate for Sodium Bicarbonate, Sodium Citrate, and So-
Oral Solution dium Tartrate for Oral Suspension
Sodium Iodide Injection Sodium Phenylbutyrate Oral Powder Sodium Phenylbutyrate Tablets
Sodium Phosphates for Oral Suspension Sodium Phosphates Tablets Sodium Salicylate and Sulfur Shampoo
Sterile Talc Aerosol Streptozocin for Injection Sucralfate Oral Suspension
Sulconazole Nitrate Cream Sulfacetamide Sodium and Fluorometho- Sulfacetamide Sodium and Prednisolone So-
lone Ophthalmic Suspension dium Phosphate Ophthalmic Solution
Sulfacytine Tablets Sulfasalazine Oral Suspension Sulisobenzone Lotion
Sumatriptan Injection Sumatriptan Tablets Tacrolimus Capsules
Tacrolimus Injection Tacrolimus Ointment Tamsulosin Hydrochloride Capsules
(Received)
Technetium Tc 99M Teboroxime Injection Tenofovir Disoproxil Fumarate Tablets Terbinafine Hydrochloride Cream
Terbinafine Tablets Terbinafine Topical Solution Terconazole Vaginal Cream
(Received)
Terconazole Vaginal Suppositories Testosterone Transdermal System Tetracycline Hydrochloride Periodontal Fiber
Theophylline Extended-Release Tablets Tioconazole Vaginal Ointment Tiopronin Tablets
Tolnaftate Topical Aerosol Solution Topiramate Capsules Topiramate Tablets
Torsemide Injection Torsemide Tablets Trandolapril and Verapamil Hydrochloride
(Received) Extended-Release Tablets
Trandolapril Tablets Tranexamic Acid Injection Tranylcypromine Sulfate Tablets
Tretinoin Capsules Tretinoin Microsphere Gel Triamcinolone Acetonide Nasal Suspension
Trifluridine Ophthalmic Solution Trimetrexate for Injection Trimipramine Maleate Capsules
Triprolidine and Pseudoephedrine Hydro- Trolamine Salicylate Cream Trolamine Salicylate Gel
chlorides and Codeine Phosphate Syrup
Trolamine Salicylate Topical Emulsion Trovafloxacin Injection Trovafloxacin Mesylate for Injection
Pharmacopeial Forum

Undecylenic Acid Topical Foam Aerosol Unoprostone Isopropyl Ophthalmic Solu- Urea Cream
tion
Vecuronium Bromide for Injection Venlafaxine Extended-Release Capsules Venlafaxine Tablets
(Received)
Verapamil Hydrochloride Capsules Verapamil Hydrochloride Extended- Voriconazole Injection
Release Capsules
Voriconazole Oral Suspension Voriconazole Tablets Yttrium Y-90 Chloride Solution
Yttrium Y-90 Glass Microspheres Yttrium Y-90 Microspheres Injection Zidovudine and Lamivudine Tablets
(Received)
Zinc Acetate Capsules Zinc Tridosium Pentetate Injection Ziprasidone Hydrochloride Capsules
Zoledronic Acid for Injection
Excipients
Acetone Sodium Bisulfite Acetylated Monoglycerides Aconitic Acid (Achilleic Acid)
Acrylic Acid–Octyl Acrylate Copolymer Albumin Colloidal Aliphatic Polyesters
Allantoin–Sodium Pyrrolidone Carboxylate Aluminum Ammonium Sulfate Aluminum Lactate
Aluminum Oxide Aluminum Potassium Sulfate Aluminum Silicate

Aluminum Sodium Sulfate Aluminum Stearate Ammonium Bicarbonate
Ammonium Calcium Alginate Ammonium Phosphate Batylalcohol Monostearate
Beeswax, Synthetic Benzododecinium Bromide Benzyl Chloride
Benzyl Nicotinate Beta Naphthol Brominated Vegetable Oil
Butadiene–Styrene Rubber Butylated Hydromethylphenol Butylene Glycol
Butylphthalyl Butylglycolate Calcium Acid Pyrophosphate Calcium Alginate
Calcium Alginate and Ammonium Alginate Calcium Bromide Calcium Chloride Solution
Calcium Glycerophosphate Calcium Phosphate Monobasic Calcium Propionate
(Received)
Calcium Pyrophosphate Calcium Sorbate Calcium Stearoyl Lactylate
Caldiamide Sodium Calteridol Calcium Canola Oil
Capric Acid Caprylic/Capric Diglyceryl Succinate Carbon
Carboxymethyl Starch Carboxymethylamylopectin Sodium Carboxymethylcellulose Potassium
Cetostearyl Isononanoate Chlorodifluoroethane Cholic Acid
Cinnamaldehyde Cocamide Diethanolamine Cocamide Oxide
Cocoyl Caprylocaprate Crystal Gum Cutina
Cystine Dammar Gum Decanoic Acid
Decyl Oleate Dehydroacetic Acid Desoxycholic Acid
Dextrin Palmitate Dextrins Modified Diacetyl Tartaric Acid Esters Of Mono- and
Diglycerides
Dicetyl Phosphate Dichlorofluoromethane Diethyl Sebacate
Difluoroethane Diglycol Stearate Diisobutyl Adipate
Diisopropyl Adipate Diisopropylbenzothiazyl-2-Sulfenamide Dilauryl Thiodipropionate
Dimethyl Dicarbonate Dimyristoyl Lecithin Dimyristoyl Phosphatidylglycerol
Dipropylene Glycol Disodium Edisylate Disodium Guanylate
Disodium Inosinate Disodium Monooleamide Sulfasuccinate D-Mannose
Docusate Sodium/Sodium Benzoate Erythorbic Acid Erythrosine
Ethoxylated Mono- and Diglycerides Ethoxyquin Ethyl Hexanediol
Ethyl Linoleate Ethyl Maltol Ethylene Dichloride
Ethylurea Ferric Ammonium Citrate Ferric Citrate
Ferric Oxide, Brown Ferric Phosphate Ferric Pyrophosphate
Ferrous Citrate Ferrous Glycinate Ferrous Lactate
Fluorochlorohydrocarbons Formic Acid Furcelleran
Gamma-Cyclodextrin Gentistic Acid Geraniol
(Received)
Glutamic Acid Hydrochloride Gluten Glycerol Ester Of Gum Rosin (Ester Gum)
Glyceryl Laurate Glyceryl Palmitate Glyceryl Ricinoleate
Glyceryl Tristearate Glycine Hydrochloride Glycofurol
Glycol Stearate Heptafluoropropane Heptylparaben
Hexadecyl Isostearate Hexane Hexanetriol(-1,2,6-)
Hydrocarbon Gel Hydrogenated Starch Hydrolysate Hydroxyethylmethylcellulose
Hydroxylated Lecithin Hydroxypropyl Beta Cyclodextrin Indigotine
Pharmacopeial Forum
Excipients (Continued)
Inositol Iron Carbonyl Iron Subcarbonate
Isobutylated-Isoprene Copolymer Isooctylacrylate Isopropyl Isostearate
Isopropyl Stearate Isostearic Acid Isostearyl Alcohol
Lactobionic Acid Lactose Ferrin, Bovine Lactylated Fatty Acid Esters Of Glycerol and
Propylene Glycol
Lactylic Esters Of Fatty Acids Lanolin (Wool Fat), Hydrogenated Lanolin Alcohols, Acetylated
Lanolin Hydrous L-Ascorbyl Stearate Lauramine Oxide
Lauric Myristic Diethanolamide Lauric Acid Lauric Diethanolamide
Lavender Oil L-Cysteine Monohydrochloride Lecithin, Hydroxylated
L-Glutamic Acid Linoleic Acid L-Leucine
Macrogol Sorbitan Tristearate Macrogolglycerol Cocoates Macrogolglycerol Triisostearate
Magnesium Aluminum Silicate Hydrate Magnesium Aspartame Dihydrate Magnesium Aspartate
Magnesium Phosphate Tribasic Magnesium Phosphate, Diabasic, Trihydrate Magnesium Tartrate
Malt Syrup Maltitol Syrup Maltol Isobutyrate
Manganese Chloride Manganese Citrate Manganese Glycerophosphate
Manganese Hypophosphite Medical Antifoam Emulsion C Medronate Disodium
Medronic Acid Methyl Chloride Methylchloroisothiazolinone
Methylisothiazolinone Microcrystalline Cellulose, Silicified Mineral Spirits

(Received)
Monoisostearyl Glyceryl Ester Monopotassium Glutamate Monohydrate Monosodium Citrate
Mullein Leaf Myristyl Gamma-Picolinium Chloride Myristyl Lactate
N,N-Bis(2-hydroxyethyl)stearamide N-Acetyl-L-Methionine Naphtha
N-Methylpyrrolidone Non-Pareil Seeds Nutmeg Oil
(Received)
Octanoic Acid Oxystearin Palm Oil
Pentasodium Triphosphate Pentetate Calcium Trisodium Pentetate Pentasodium
Phenprobamate Phenylmercuric Acetate Phenylmercuric Nitrate
Pine Oil Polacrilin Polydextrose Solution
Polyglycerol Esters of Fatty Acids Polyglycerol Polyricinoleic Acid Polyoxyethylene Castor Oil (USP has 35)
Polyoxyl Stearate (USP has 40)
Polypropylene Oleate Polypropylene Stearyl Ether Polysorbate 65
Polyvinylacetal Polyvinylacetal Diethylanoacetate Polyvinylpolypyrrolidone
Polyvinylpyrrolidone Ethylcellulose Potassium Acid Tartrate Potassium Bromate
Potassium Carbonate Solution Potassium Dichloroisocyanurate Potassium Gibberellate
Potassium Glycerophosphate Potassium Iodate Potassium Nitrite
Potassium Phosphate Potassium Phosphate Tribasic Potassium Polymetaphosphate
Potassium Pyrophosphate Potassium Stearate Potassium Sulfate
Potassium Sulfite Potassium Tripolyphosphate Propyl Propionate
Propylene Glycol Diacetate Propylene Glycol Mono- and Diesters Purified Polyoxyl 35 Castor Oil
(Received)
Rapeseed Oil, Hydrogenated Rapeseed Oil, Superglycerinated Rice Bran Wax
Rosin Silicone Sodium Acid Pyrophosphate
Sodium Aluminosilicate Sodium Aluminum Phosphate Acidic Sodium Aluminum Phosphate Basic
Sodium Aspartate Sodium Bisulfate Sodium Bisulfite
Sodium Carbonate Hydrate Sodium Carboxymethyl Betaglucan Sodium Caseinate
Sodium Chlorate Sodium Citrate, Dibasic Sodium Citrate, Monobasic
Sodium Dehydroacetate Sodium Diacetate Sodium Erythorbate
Sodium Ferric Pyrophosphate Sodium Ferrocyanide Sodium Hypophosphite
Sodium Laureth Sulfate Sodium Lauroyl Sarcosinate Sodium Lauryl Sulfoacetate
Sodium Magnesium Aluminosilicate Sodium Magnesium Silicate Sodium Malate
Sodium Metaphosphate, Insoluble Sodium Metasilicate Sodium Methylate
Sodium Polyphosphates Glassy Sodium Potassium Tripolyphosphate Sodium Pyrophosphate
Sodium Pyrrolidone Carboxylate Sodium Sesquicarbonate Sodium Sesquinoleate
Sodium Stearoyl Lactylate Sodium Thiomalate Sodium Trimetaphosphate
Sodium Trioleate Sodium Tripolyphosphate Soy Polysaccharides
Stannous Chloride Stannous Tartrate Starch, Pregelatinized Corn
Starch, Pregelatinized Tapioca Stearalkonium Chloride Stearyl Citrate
Stearyl Monoglyceridyl Citrate Succinylated Monoglycerides Sucrose Acetate Isobutyrate
Pharmacopeial Forum
Sucrose Fatty Acid Esters Sucrose Stearate Sugar Fruit Fine
Sulfobutyl Ether Beta Cyclodextran Tallow Tallow Glycerides
Tallow Oil Tetrafluoroethane Thioglycerol
Thyme Oil Tribehenin Triceteareth-4 Phosphate
Trichloroethylene Trimyristin Trisodium Citrate
Trolamine Lauryl Sulfate Vegetable Oil Wheat Flour
Wheat Germ Oil Wheat Gluten Whey
(Received)
INTERIM REVISION
ANNOUNCEMENT
In this section readers will find the following:
The list of new USP Reference Standards that have become available
The list of assays or tests that are adopted but held in abeyance pending availability of required USP Reference Standards
New adopted (official) revisions to the USP–NF that become effective before the effective date of the next Supplement or that
were not ready for adoption by the closing date for the upcoming Supplement. (The effective date for these revisions is stated on the
next page.)
Readers should review this section to determine if they are affected by any of the changes.
Symbols—Interim revisions are shown with new text (if any) enclosed in circles, .new text.. Text enclosed in squares, &new text&,
has already been adopted in a Supplement. Where the symbols appear together with no enclosed text, such as . . or & &, it means that
text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is accompanied by a number
that indicates the IRA or Supplement in which the revision first appeared. For example, .2 indicates that the revision was officially
adopted in the Second Interim Revision Announcement, and &2S (USP29) indicates that the revision was officially adopted in the Second
Supplement to USP 29.
Errata—At the end of the Interim Revision Announcement section is a list of errata and corrections to USP 29–NF 24. The page
Interim Revision Announcement

number indicates where the item is found in USP–NF. If necessary, this list will be updated with every issue of PF. This information
will also be cumulative in future Supplements, and will appear in its corrected form in the next annual edition of USP–NF. Errata are
considered to be items erroneously published that have not received the approval of the Council of Experts and that do not reflect the
official requirement.
Pharmacopeial Forum
32 INTERIM REVISION ANNOUNCEMENT Vol. 33(1) [Jan.–Feb. 2007]
FIRST INTERIM REVISION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Conjugated Estrogens Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ERRATA LIST FOR USP–NF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] INTERIM REVISION ANNOUNCEMENT 33
INTERIM REVISION
ANNOUNCEMENT
to USP 29 and to NF 24
By authority of the United States Pharmacopeial Convention, Inc.

Prepared by the Council of Experts and published by the Board of Trustees
John W. Mauger, Chair Roger L. Williams, Executive Vice President

USP Board of Trustees and Chairman, USP Council of Experts
Roger L. Williams, M.D., Chief Standards Officer, Acting
Official February 1, 2007 Released January 1, 2007

All inquiries and comments regarding USP 29 text and NF 24 text should be addressed to the Executive Secretariat, USP–NF,
12601 Twinbrook Parkway, Rockville, MD 20852.
Pharmacopeial Forum
New USP Reference Standards USP Amifostine Thiol RS

USP Antithrombin III Human RS
The following USP Reference Standards, which were not USP Aprotinin RS
USP Aprotinin System Suitability RS
available when the associated monograph was made official, USP Cetrimonium Bromide RS
have since become available. The respective official date of USP Cladribine RS
each USP 29 or NF 24 standard, test, or assay requiring the USP Copolymer Polypropylene RS
USP Decoquinate RS
use of the following USP Reference Standards is indicated USP Cryopreserved Human Fibroblast-Derived Dermal Substitute
in parentheses after the name of the Reference Standard. Reference Photomicrographs RS
USP Diethylstilbestrol Diphosphate RS
USP Citalopram Hydrobromide RS (May 1, 2007) USP Docosyl Ferulate RS
USP Cladribine Related Compound A RS (July 1, 2007) USP Powdered Echinacea pallida Extract RS
USP Escin RS (January 1, 2007) USP Eucatropine Hydrochloride RS
USP Fluvastatin Sodium RS (March 1, 2007) USP Fluvastatin Related Compound A RS
USP Gabapentin Related Compound B RS (July 1, 2007) USP Ginkgo Terpene Lactones RS
USP Hexacosanol RS (March 1, 2007) USP Powdered American Ginseng Extract RS
USP Irbesartan Related Compound A RS (July 1, 2007) USP Glyceryl Monolinoleate RS
USP Mecamylamine Related Compound A RS (March 1, 2007) USP Glyceryl Monooleate RS
USP Naratriptan Resolution Mixture RS (May 1, 2007) USP Gonadorelin Hydrochloride RS
USP Nimodipine RS (July 1, 2007) USP Hemoglobin RS
USP Nimodipine Related Compound A RS (July 1, 2007) USP Irbesartan RS
USP Cultured Rat Pheochromocytoma Reference Photomicrographs USP Isosorbide Mononitrate RS
RS (May 1, 2007) USP Isosorbide Mononitrate Related Compound A RS
USP Polyoxyl 10 Oleyl Ether RS (July 1, 2007) USP Alpha Lipoic Acid RS
USP Ramipril Related Compound B RS (May 1, 2007) USP Maritime Pine Extract RS
USP Saccharin Sodium RS (March 1, 2007) USP Menotropins RS
USP Sulisobenzone RS (January 1, 2007) USP Methyldopa-Glucose Reaction Product RS
USP Tizanidine Related Compound A RS (July 1, 2007) USP Mibolerone RS
USP Tizanidine Related Compound B RS (July 1, 2007) USP Narasin RS
USP Tizanidine Related Compound C RS (July 1, 2007) USP Near Infrared Calibrator RS
USP Potassium Perchlorate RS
USP Pyrethrum Extract RS
Unavailable First-Time Official USP USP Quinapril Hydrochloride RS
USP Powdered St. John’s Wort Extract RS
Reference Standards USP Sargramostim RS
USP Sincalide RS
The official dates of any USP 29 or NF 24 standards, tests, USP Human Fibroblast-Derived Temporary Skin Substitute
or assays requiring the use of the following new USP Refer- Reference Photomicrographs RS
ence Standards are postponed until further notice pending USP D8-Tetrahydrocannabinol RS
USP D9-Tetrahydrocannabinol RS
availability of the respective Reference Standards. This listing USP Tizanidine Hydrochloride RS
was updated as of November 1, 2006. USP Valrubicin RS
USP Valrubicin Related Compound A RS
USP Albumin Human RS USP Vasopressin RS
USP Alteplase RS
USP Amifostine RS
Pharmacopeial Forum
MONOGRAPHS (USP) TEST 3 (for products labeled as 1.25- and 2.50-mg tablets)—If the
product complies with this test, the labeling indicates that it meets
USP Dissolution Test 3.
Medium, Apparatus, Mobile phase, Standard solution, Test
Conjugated Estrogens Tablets solution, Chromatographic system, and Procedure—Proceed as
directed for Test 1.
.Times: 2, 5, 8, and 12 hours.
.1
Times and Tolerances—The percentages of estrone sodium sulfate
dissolved at the times specified conform to Acceptance Table 2.
Change to read:
Time (hours) Amount dissolved
Dissolution h711i—Proceed as directed for Extended-Release 2 between 3% and 22%
Articles. 5 between 37% and 67%
TEST 1 (for products labeled as 0.3-, 0.45-, and 0.625-mg 8 between 66% and 96%
tablets)—If the product complies with this test, the labeling indicates 12 not less than 80%
that it meets USP Dissolution Test 1.
Medium: water; 900 mL.
.TEST 4 (for products labeled as 1.25-mg tablets)—If the product
Apparatus 2: 50 rpm.
.Times: 2, 5, and 8 hours. complies with this test, the labeling indicates that it meets USP
.1
Mobile phase—Prepare a filtered and degassed mixture of 0.025 M Dissolution Test 4.
monobasic potassium phosphate and acetonitrile (3 : 1). Make Medium: acetate buffer, pH 4.5; 900 mL.
adjustments if necessary (see System Suitability under Chromatog- Apparatus 2: 50 rpm, with sinkers.
raphy h621i). Times: 2, 4, 8, and 12 hours.
Standard solution—Transfer 10 Tablets to a 1000-mL volumetric Mobile phase—Prepare a filtered and degassed mixture of 0.025 M
flask, dilute with water to volume, and stir vigorously by mechanical monobasic potassium phosphate and acetonitrile (78 : 22). Make
means for at least 3 hours. Pipet a filtered 100-mL aliquot of the adjustments if necessary (see System Suitability under Chromatog-
solution into a 900-mL volumetric flask, and dilute with water to raphy h621i).
volume. Standard solution—Accurately weigh 20 Tablets and determine
Test solution—Filter a portion of the solution under test. [NOTE—It the average tablet weight. Grind the Tablets to a uniform fine
is recommended that the filters selected be tested for binding powder. Accurately weigh a portion of the powdered Tablets
affinity.] equivalent to the average tablet weight, transfer to a 900-mL
Chromatographic system—The liquid chromatograph is equipped volumetric flask, and dilute with Medium to volume. Stir vigorously
with a 205-nm detector and a 4.6-mm 6 3.0-cm column that by mechanical means for at least 2 hours or until the dissolution of
contains 3-mm packing L1. The flow rate is about 1.5 mL per minute. the powder is complete. Pass a portion of the extract through
Chromatograph replicate injections of the Standard solution, and a suitable 10-mm filter.
record the responses as directed for Procedure: the relative retention Test solution—Pass a portion of the solution under test through
times are about 0.9 for equilin sulfate and 1.0 for estrone sulfate, the a suitable 10-mm filter. [NOTE—It is recommended that the filters

estrone sulfate peak being the last major peak in the chromatogram; selected be tested for binding affinity.]
the resolution, R, between equilin sulfate and estrone sulfate is not Chromatographic system (see Chromatography h621i)—The
less than 1.5; and the relative standard deviation for the estrone liquid chromatograph is equipped with a 210-nm detector and
sulfate peak is not more than 1.5%. [NOTE—If estrone is present it a 3.2-mm 6 5.0-cm column that contains 5-mm packing L1. The
may be retained on the column for a period longer than 50 minutes flow rate is about 0.8 mL per minute. Chromatograph replicate
and interfere in later chromatographic runs.] injections of the Standard solution, and record the responses as
Procedure—Separately inject equal volumes (between 20 and 200 directed for Procedure: the relative retention times are about 0.9 for
mL) of the Standard solution and the Test solution into the equilin sulfate and 1.0 for estrone sulfate, the estrone sulfate peak
chromatograph, record the chromatograms, and measure the being the last major peak in the chromatogram; the resolution, R,
responses for the estrone sulfate peaks. Calculate the percentage of between equilin sulfate and estrone sulfate is not less than 1.2; and
estrone sodium sulfate released by the formula: the relative standard deviation for the estrone sulfate peak is not
more than 2.0%. [NOTE—If estrone is present, it may be retained on
100(rU / rS) the column for a period longer than 50 minutes and interfere in later
in which rU and rS are the peak responses obtained from the Test chromatographic runs.]
solution and the Standard solution, respectively. Procedure—Separately inject equal volumes (between 20 and 200
Times and Tolerances—The percentages of estrone sodium sulfate mL) of the Standard solution and the Test solution into the
dissolved at the times specified conform to Acceptance Table 2. chromatograph, record the chromatograms, and measure the
responses for the estrone sulfate peaks. Calculate the percentage of
Time (hours) Amount dissolved estrone sulfate released by the formula:
2 between 19% and 49%
8 not less than 80%
TEST 2 (for products labeled as 0.9-mg tablets)—If the product

complies with this test, the labeling indicates that it meets USP in which rU and rS are the peak responses obtained from the Test
Dissolution Test 2. solution and the Standard solution, respectively.
Medium, Apparatus, .Times,.1 Mobile phase, Standard solution, Times and Tolerances—The percentages of estrone sodium sulfate
Test solution, Chromatographic system, and Procedure—Proceed as dissolved at the times specified conform to Acceptance Table 2.
directed for Test 1.
Times and Tolerances—The percentages of estrone sodium sulfate Time (hours) Amount dissolved
dissolved at the times specified conform to Acceptance Table 2. 2 between 11% and 31%
Time (hours) Amount dissolved 4 between 43% and 63%
2 between 12% and 37% 12 not less than 87%
8 not less than 80%
Pharmacopeial Forum
TEST 5 (for products labeled as 0.3-, 0.45-, and 0.625-mg tablets)— TEST 6 (for products labeled as 0.9-mg tablets)—If the product
If the product complies with this test, the labeling indicates that it complies with this test, the labeling indicates that it meets USP
meets USP Dissolution Test 5. Dissolution Test 6.
Medium, Apparatus, Mobile phase, Standard solution, Test Medium, Apparatus, Mobile phase, Standard solution, Test
solution, Chromatographic system, and Procedure—Proceed as solution, Chromatographic system, and Procedure—Proceed as
directed for Test 4. directed for Test 4.
Times: 1, 3, and 8 hours. Times: 1, 3, and 8 hours.
Times and Tolerances—The percentages of estrone sodium sulfate Times and Tolerances—The percentages of estrone sodium sulfate
dissolved at the times specified conform to Acceptance Table 2. dissolved at the times specified conform to Acceptance Table 2.
Time (hours) Amount dissolved Time (hours) Amount dissolved
1 between 6% and 26% 1 between 3% and 23%
8 not less than 87% 8 not less than 80%
.1
Pharmacopeial Forum
ERRATA
Following is a list of errata and corrections to USP–NF. The page number indicates where the item is found and in which official or pending
official publication of USP–NF. If necessary, this list will be updated with every issue of PF. This information will also be available as a cumulative
table in future Supplements and will appear in its corrected form in a future annual edition of USP–NF. Errata are considered to be items erro-
neously published that have not received the approval of the Council of Experts and that do not reflect the official requirement. USP staff is
available to respond to questions regarding the accuracy of a particular requirement by calling 1-800-822-USPC.
Page USP–NF Title Section Description

1890 USP 29 Ramipril Related compounds Line 12 under Procedure: Change ‘‘USP Rami-
3101 USP 30 pril Related Compound B RS’’ to: USP Rami-
pril RS
2371 USP 29 Pygeum Extract Content of sterols Line 10 under Procedure: Change the formula
976 USP 30 ‘‘200C/W(RU / RS)’’ to: 1000C/W(RU / RS)
935 USP 30 Ginkgo Thin-layer chromatographic Line 1 under Spray reagent 1: Change ‘‘diphe-
identification test h201i nyl boryloxyethylamine’’ to: 2-aminoethyl di-
phenylborinate
Lines 14–19 under Procedure: Change ‘‘The
presence of flavonol glycosides in the Test solu-
tion is shown by three yellowish-brown to
green fluorescent zones, and slightly above a
blue to green fluorescent zone below the zone
due to rutin, a light blue fluorescent zone ap-
pears in the same location as that due to chloro-
genic acid, as well as two greenish-brown to
yellow fluorescent zones, located above.’’ to:
The chromatogram of the Test solution shows
a yellowish brown fluorescent zone and a light
blue fluorescent zone at RF similar to those of
rutin and chlorogenic acid, respectively, in the
chromatogram of the Standard solution. Addi-
tional yellowish green zones due to flavonoids
are detected in the chromatogram of the Test
solution. These include one zone below the ru-
tin zone, two zones between the rutin and
chlorogenic acid zones, and four zones above

the chlorogenic acid zone. Other, less intense
zones may be seen in the chromatogram of the
Test solution.
2528 USP 30 Magnesium Chloride Limit of calcium Line 4 under Procedure: Correct the typesetting
error to read: mg per mL
2604 USP 30 Methdilazine Hydro- Assay Line 13 under Procedure: Correct the typeset-
chloride Oral Solution ting error to read: mg per mL
IN-PROCESS REVISION
This section contains proposals for adoption as official USP or NF standards (either proposed new standards or proposed revisions of
current USP or NF standards). These may be any of the following: (1) items that previously appeared under Pharmacopeial Pre-
views and are now formally proposed as revisions, (2) proposed revisions placed directly under In-Process Revision, or (3) mod-
ifications of revisions previously proposed under In-Process Revision. Readers should review material in this section and provide
comments to the staff liaison (use the Staff Directory to find the contact information). Information on how to comment is found in the
Policies and Announcements section. It is important to send comments promptly so that the Committee members can consider read-
ers’ input as they are deciding whether to advance standards to official status.
Briefings Each Proposal is preceded by a Briefing in the following format:

BRIEFING
Name of Item, citations of the most recent USP publications in which this item appeared. Rationale for the
revision. Other relevant information. (For example, if a chromatographic method is being proposed, column spe-
cifications and retention times for compounds of interest.) Finally, the Committee designation (see How to Use
PF), the name of the scientific staff liaison who handled the particular issue, and the USP tracking correspondence
number, as shown in the example below:
(DSN: L. Evans) RTS—C-55678-1
Symbols Proposed revisions are shown with language proposed for deletion or replacement crossed off. New text (if any) follows,
and is enclosed in symbols and set off from the current official text by a paragraph break and by larger type (print edition only), as
shown in the examples below:
.
new text.
if slated for an Interim Revision Announcement to USP 29–NF 24 (IRA);
~
new text~USP30
if slated for USP 30–NF 25; and
&
new text&
if slated for a Supplement to USP–NF. The same symbols not set off by an extra paragraph break and enclosing text with no increase
in type size indicate recent revisions that are already official. Where the symbols appear together with no enclosed text, such as . . or
In-Process Revision
~
& or ~, it means that text has been deleted and no new text was proposed to replace it. In all revisions, the closing symbol is
&
accompanied by an identifier that indicates the particular IRA or Supplement or indicates the USP or NF as the publication where the
revision will appear if approved. For example, .2 indicates that the revision is proposed for the Second Interim Revision Announce-
ment, &2S (USP 29) indicates that the proposed revision is slated for the Second Supplement to USP 29, and ~USP30 and ~NF25 indicate that
the revisions are proposed for USP 30 and NF 25, respectively.
Official Title Changes Where the specification ‘‘Monograph title change’’ is found, it indicates that the official title stated after
that specification will be substituted for the former title in the appropriate places throughout that monograph once this revision
becomes official.
Pharmacopeial Forum
40 IN-PROCESS REVISION Vol. 33(1) [Jan.–Feb. 2007]
IN-PROCESS REVISION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Alprazolam Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bismuth Subsalicylate Oral Suspension (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Bupropion Hydrochloride Extended-Release Tablets (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Calcitriol (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Citalopram Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Cladribine (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Clopidogrel Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Cytarabine for Injection (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Dimethyl Sulfoxide Gel (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Enoxaparin Sodium [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Enoxaparin Sodium Injection [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Eprinomectin (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Fluvastatin Sodium (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Fosinopril Sodium and Hydrochlorothiazide Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Hydrocortisone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Isosorbide Dinitrate Extended-Release Tablets (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Levalbuterol Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Levalbuterol Inhalation Solution [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Norethindrone Acetate and Ethinyl Estradiol Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Pamidronate Disodium for Injection (Proposal for IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Phenylbutazone Boluses (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Phenylbutazone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Progesterone Vaginal Suppositories (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Salicylic Acid (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Valganciclovir Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Valganciclovir Tablets [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Ubidecarenone Capsules (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Ubidecarenone Tablets (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
h11i USP Reference Standards (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
h1225i Validation of Compendial Procedures (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2-Aminoheptane [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Calconcarboxylic Acid [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Calconcarboxylic Acid Triturate [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Dimethicone, viscosity 500 centistokes [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Lactose (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Propylamine Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Sodium Phosphate Dibasic Dihydrate [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Triethylamine (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
In-Process Revision

Ceric Sulfate, Tenth-Normal (0.1 N) (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Potassium Permanganate, Tenth-Normal (0.1 N) (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Chromatographic Reagents [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Description and Solubility (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Pharmacopeial Forum
Vol. 33(1) [Jan.–Feb. 2007] IN-PROCESS REVISION 41
MONOGRAPHS (USP) directed for Procedure: the resolution, R, between the internal
standard and alprazolam is not less than 2.0; and the relative
standard deviation for replicate injections is not more than
2.0%.~USP31
Procedure—Separately inject equal volumes (about 20 mL) of the
Standard preparation and the Assay preparation into the chromat-
ograph, record the chromatograms, and measure the area responses
for the major peaks. Calculate the quantity, in mg, of alprazolam
BRIEFING (C17H13ClN4) in the portion of Tablets taken by the formula:
200C(RU / RS)
Alprazolam Tablets, USP 29 page 78. It is proposed to revise the in which C is the concentration, in mg per mL, of USP Alprazolam
Assay to eliminate the cross-referencing to the monograph for RS in the Standard preparation; and RU and RS are the peak response
Alprazolam which is being revised. ratios of the alprazolam peak relative to the internal standard peak
obtained from the Assay preparation and the Standard preparation,
(MD-PP: R. Ravichandran) RTS—C50904 respectively.
Change to read:
Assay—
Mobile phase, Chromatographic system, Internal standard
solution, and Standard preparation—Prepare as directed in the
Assay under Alprazolam.
~
BRIEFING
Mobile phase—Prepare a filtered and degassed mixture of
acetonitrile, chloroform, butyl alcohol, water, and glacial Bismuth Subsalicylate Oral Suspension, page 1035 of PF 31(4)
[July–Aug. 2005]. On the basis of comments received, it is proposed
acetic acid (850 : 80 : 50 : 20 : 0.5). Make adjustments if to revise the Packaging and storage conditions.
necessary (see System Suitability under Chromatography
(MDCCA: C. Anthony) RTS—C44137
h621i).
Internal standard solution—Dissolve an accurately
weighed quantity of triazolam in acetonitrile, and dilute
with acetonitrile to obtain a solution having a known
Add the following:
concentration of about 0.25 mg per mL. &Bismuth Subsalicylate Oral Suspension
Standard preparation—Dissolve an accurately weighed
quantity of USP Alprazolam RS in Internal standard solution,
and dilute with Internal standard solution to obtain a solution
having a known concentration of about 0.25 mg per mL.
» Bismuth Subsalicylate Oral Suspension is
In-Process Revision
Transfer 5.0 mL of this solution to a 50-mL volumetric flask, a suspension that contains not less than 90.0
dilute with acetonitrile to volume, and mix.~USP31 percent and not more than 110.0 percent of the
Assay preparation—Weigh and finely powder not fewer than 20
Tablets. Transfer an accurately weighed quantity of the powder, labeled amount of C7H5BiO4. It may contain one or
equivalent to about 5 mg of alprazolam, to a 200-mL volumetric
flask. Transfer 2 mL of water and 20 mL of Internal standard more suitable buffers, coloring agents, flavors,
solution, shake vigorously for 10 minutes, dilute with acetonitrile to
volume, and mix. preservatives, stabilizers, sweeteners, and suspend-
~
Chromatographic system (see Chromatography h621i)—
ing agents.
The liquid chromatograph is equipped with a 254-nm detector
Add the following:
and a 4.6-mm 6 30-cm column that contains packing L3.
~
The flow rate is about 2 mL per minute. Chromatograph the Packaging and storage—Preserve in tight containers. avoid
Standard preparation, and record the peak responses as freezing. Store between 158 and 308. Protect from freezing.
Avoid excessive heat (over 408).~USP31
Pharmacopeial Forum
Identification— blank to set the spectrophotometer. Calculate the quantity, in

A: It meets the requirements of the tests for Bismuth mg, of C7H5BiO4 in the portion of Oral Suspension taken by
h191i. the formula:
B: It meets the requirements of the tests for Salicylate

(362.09/208.98)20(C/V)(AU / AS)
h191i, after acidifying with nitric acid.
pH h791i: between 3.0 and 5.0.

in which 362.09 and 208.98 are the molecular weights of
Microbial limits h61i—The total aerobic microbial count bismuth subsalicylate and bismuth, respectively; C is the
does not exceed 100 cfu per g, the combined yeast and mold concentration, in mg per mL, of bismuth in the Standard
count does not exceed 50 cfu per g, and it meets the preparation; V is the volume, in mL, of the Assay preparation
requirements of the tests for absence of Escherichia coli. and taken; and AU and AS are the absorbances of the Assay
of Salmonella species. preparation and the Standard preparation, respec-
Assay— tively.&1S (USP30)
Standard preparation—Transfer about 500 mg of bismuth

metal, accurately weighed, to a 200-mL volumetric flask,
dissolve in 12 mL of nitric acid, and dilute with 0.01 N nitric
acid to volume. Transfer 10.0 mL of this solution into a
500-mL volumetric flask, and dilute with 1 N nitric acid to BRIEFING
volume to obtain a solution having a concentration of 50 mg
of bismuth per mL. Bupropion Hydrochloride Extended-Release Tablets, USP 29
page 322 and page 1047 of PF 32(4) [July–Aug. 2006]. It is
Assay preparation—Transfer an accurately measured proposed to add Dissolution Test 5 because FDA has approved a new
generic version of this product. In the absence of any negative
quantity of about 10 g of Oral Suspension, previously well- comments, it is proposed to implement the inclusion of this test in
PF 33(2) [Mar.–Apr. 2007] via the Interim Revision Announcement
shaken in its original container to ensure homogeneity, to pertaining to USP 29–NF 24, with an official date of April 1, 2007.
a 200-mL volumetric flask. Add about 100 mL of 1 N nitric (BPC: M. Marques) RTS—C47416
acid, mix, and dilute with 1 N nitric acid to volume. Mix well
Change to read:
without shaking, transfer 10.0 mL of this mixture to a
100-mL volumetric flask, and dilute with 1 N nitric acid to Dissolution h711i—
volume. Centrifuge about 20 mL at 4500 rpm for at least 10

In-Process Revision
&
F O R P R O D U C T S L A B E L E D F O R D O S I N G E V E RY 1 2
minutes.
HOURS—&1S (USP30)
Procedure—Transfer an accurately measured volume of the TEST 1—
Assay preparation that contains about 0.9 mg of bismuth Apparatus 2: 50 rpm.
Times: 1, 4, and 8 hours.
subsalicylate and 10 mL of the Standard preparation to Procedure—Determine the amount of C13H18ClNO HCl dissolved
by employing UV absorption at the wavelength of maximum
separate 50-mL volumetric flasks. Add 10.0 mL of 10% absorbance at about 298 nm, using a 1.0-cm cell, on filtered portions
of the solution under test, suitably diluted with Medium, if necessary,
ascorbic acid solution and 25.0 mL of 20% potassium iodide in comparison with a Standard solution having a known concentra-
tion of USP Bupropion Hydrochloride RS in the same Medium.
solution into each volumetric flask, dilute with water to Tolerances—The percentages of the labeled amount of
C13H18ClNO HCl dissolved at the times specified conform to
volume, and mix well. Concomitantly determine the absor- Acceptance Table 2.
bances of both solutions in 1.0-cm cells at a wavelength of Time (hours) Amount dissolved
463 nm with a suitable spectrophotometer, using the reagent 4 between 60% and 85%
8 not less than 80%
Pharmacopeial Forum
Tolerances—The percentages of the labeled amount of

TEST 2—If the product complies with this test, the labeling C13H18ClNO HCl dissolved at the times specified conform to
indicates that it meets USP Dissolution Test 2. Acceptance Table 2.
Medium: 0.1 N hydrochloric acid, pH 1.5
&
(prepared by transferring about 50 mL of concentrated 1 between 30% and 55%
hydrochloric acid to 6000 mL of water, adding about 18 g of 4 between 70% and 90%
6 not less than 80%
sodium hydroxide, mixing, and adjusting with either diluted
sodium hydroxide or hydrochloric acid to a pH of
.TEST 5—If the product complies with this test, the labeling
1.5 + 0.05.);&1S (USP30)
900 mL, indicates that it meets USP Dissolution Test 5.
&
deaerated.&1S (USP30) Medium and Procedure—Proceed as directed for Test 1.
Times: 1, 2, 4, and 6 hours. Apparatus—Proceed as directed for Test 1, except to use
Determine the percentages of the labeled amount of
C13H18ClNO HCl dissolved by employing the following method. a 0.5-cm cell.
Buffer solution—Dissolve 3.45 g of sodium phosphate monobasic
monohydrate in 996 mL of water, add 4.0 mL of triethylamine, and Times: 1, 3, and 6 hours.
mix. Adjust with phosphoric acid to a pH of 2.80 + 0.05.
Mobile phase—Prepare a filtered and degassed mixture of Buffer Tolerances—The percentages of the labeled amount of
solution and methanol (65 : 35). Make adjustments if necessary (see
System Suitability under Chromatography h621i). C13H18ClNO HCl dissolved at the times specified conform to
Standard solution—Dissolve an accurately weighed quantity of
USP Bupropion Hydrochloride RS in Medium, and dilute quantita- Acceptance Table 2.
tively, and stepwise if necessary, with Medium to obtain a solution
having a known concentration similar to the one expected in the Test
solution. Time (hours) Amount dissolved
Test solution—Use portions of the solution under test, and pass
through a 0.45-mm nylon filter.
Chromatographic system (see Chromatography h621i)—The 1 between 35% and 55%
liquid chromatograph is equipped with a 298-nm detector and
a 4.6-mm 6 15-cm column that contains packing L1. The flow rate 3 between 65% and 85%
is about 1.0 mL per minute. Chromatograph the Standard solution,
and record the peak responses as directed for Procedure: the column 6 not less than 80%
efficiency is not less than 2000 theoretical plates; the tailing factor is .2
not more than 2.0; and the relative standard deviation for replicate
injections is not more than 2.0%.
Procedure—Separately inject equal volumes (about 20 mL) of the &
FOR PRODUCTS LABELED FOR DOSING EVERY 24 HOURS—
Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the peak responses. TEST 4—If the product complies with this test, the labeling
Calculate the percentage of bupropion hydrochloride dissolved at
each time point. indicates that it meets USP Dissolution Test 4.
C13H18ClNO HCl dissolved at the times specified conform to Medium: 0.1 N hydrochloric acid; 900 mL, deaerated.
Acceptance Table 2.
1 between 25% and 50% Times: 2, 4, 8, and 16 hours.
4 between 65% and 90% Procedure—Determine the amount of C13H18ClNO HCl
In-Process Revision
6 not less than 80%
dissolved by employing UV absorption at the wavelength of
TEST 3—If the product complies with this test, the labeling maximum absorbance at about 252 nm, using a 1.0-cm
indicates that it meets USP Dissolution Test 3.
Medium, Apparatus, and Procedure—Proceed as directed for Test &
1.0-mm&2S (USP30) cell, on filtered portions of the solution
1, except using the wavelength at about 250 nm.
Times: 1, 2, 4, and 6 hours. under test, suitably diluted with Medium, if necessary, in
comparison with a Standard solution having a known
concentration of USP Bupropion Hydrochloride RS in the
same Medium.
Pharmacopeial Forum
Tolerances—The percentages of the labeled amount of inclusion of the monohydrate form necessitated a change in the
Definition, the addition of the Labeling requirement, and the
C13H18ClNO HCl dissolved at the times specified conform to addition of the test for Water for the monohydrate form.
Acceptance Table 2. (MD-GRE: E. Gonikberg) RTS—C44147; C46392
2 not more than 20%

Add the following:
~
8 between 65% and
Calcitriol
85% &90%&2S (USP30)
16 not less than 80%

&1S (USP30)
C27H44O3 416.64
9,10-Secocholesta-5,7,10(19)-triene-1,3,25-triol,
(1a,3b,5Z,7E)-.
BRIEFING
(5Z,7E)-9,10-Secocholesta-5,7,10(19)-triene-1a,3b,25-
Calcitriol, page 58 of PF 32(1) [Jan.–Feb. 2006].
triol [32222-06-3].
1. Comments were received that for this material different
manufacturers have different storage conditions that are ~
supported by stability data. It is proposed to use a flexible Monohydrate [77326-95-5].~USP31
monograph approach to indicate that manufacturers can store
the material as per their labeling instruction. Possible storage Change to read:
conditions are also listed.
2. It is proposed to omit the preparation of the Standards stock
solution and the Standard solution in the test for Chromato-
graphic purity because these solutions are not used for the
determination of impurities. » Calcitriol contains not less than 97.0 percent and
3. It is proposed to revise the Definition and to specify the
calculation on an "as-is basis", instead of a ‘‘solvent-free not more than 103.0 percent of C27H44O3, calcu-
basis’’. This change is based on the following statement in the
proposed revision of the Introduction in the general chapter lated on the anhydrous solvent-free basis.~Calci-
Residual Solvents h467i published on page 1494 of PF 32(5)
[Sept.–Oct. 2006]: ‘‘Where a quantitative determination of
a residual solvent is carried out and a test for loss on drying is triol is anhydrous or contains one molecule of
not carried out, the content of residual solvent is taken into
hydration. The anhydrous form contains not less
In-Process Revision
account for calculation of the assay content of the article.’’

4. It is proposed to add a monohydrate form of Calcitriol to the
monograph. This proposal is consistent with the policy relating than 97.0 percent and not more than 103.0 percent
to inclusion of different degrees of hydration that was approved
by the Council of Experts Executive Committee in January of C27H44O3, calculated on the as-is basis. The
2005 and published on page 690 of PF 31(3) [May–June 2005]
under Policies and Announcements. As per this policy, this monohydrate form contains not less than 97.0
proposal may become official ‘‘ã Îonly when the FDA has
approved, or has not given any indication that it will not
approve, a new drug application for a drug product with percent and not more than 103.0 percent of
a different polymorphic form of the active ingredient than the
form used to manufacture the reference listed drug.’’ The C27H44O3, calculated on the anhydrous basis.~USP31
Caution—Care should be taken to prevent
inhaling particles of Calcitriol and exposing the
skin to it.
Pharmacopeial Forum
Change to read: Procedure—Separately inject equal volumes (about 50 mL)

~
of the Standard solution and Inject a volume (about 50 mL)
Packaging and storage—Preserve in tight, light-resistant
of~USP31 the Test solution into the chromatograph, record the
containers. and store under nitrogen in a refrigerator between
~ chromatograms for at least two times the retention time of the
28 and 88. Store as per labeling instructions. Possible storage
calcitriol peak, identify the impurities listed in Table 1, and
conditions, in the presence of stability data supporting those
measure the peak responses. disregarding any peak having an
conditions, could include the following: Store under nitrogen
area less than 0.1 times that of the main peak in the
in a refrigerator between 28 and 88. Store under nitrogen or
chromatogram of the Standard solution. Calculate the
argon in a freezer between –158 and –218.~USP31
percentage of any individual impurity in the portion of
Add the following: Calcitriol taken by the formula:
~
Labeling—Where it is a monohydrate form, the label so
indicates.~USP31 100(ri / rs)
USP Reference standards h11i—USP Calcitriol RS.

in which ri is the peak response of any individual peak other
Identification—
than the main calcitriol peak and the pre-calcitriol peak; and rs
A: Infrared Absorption h197Ki.
is the sum of the responses of all the peaks: not more than
B: The retention time of the major peak in the
0.5% of any individual impurity is found; and in addition to
chromatogram of the Assay preparation corresponds to that
not exceeding the limits in Table 1, not more than 1.0% of
in the chromatogram of the Standard preparation, as obtained
total impurities is found. Disregard any peak less than 0.1%.
in the Assay.
Table 1
Add the following:
~ Relative
Water, Method Ic h921i (where it is labeled as a monohy-
Retention Limit
drate): between 3.5% and 5.5%.~USP31
Name Time (%)
Change to read:
Triazoline adduct of 0.43 0.1
Chromatographic purity—[NOTE—Avoid Carry out the pre-calcitriol
procedure as rapidly as possible, avoiding unnecessary trans-Calcitriol1 0.96 0.25
In-Process Revision
exposure of solutions to light and air.] 1b-Calcitriol2 1.15 0.1
Tris buffer solution, Mobile phase, System suitability Methylene calcitriol3 1.5 0.25
solution, and Chromatographic system—Proceed as directed Any other individual — 0.1
in the Assay. unidentified impurity

1
Standard stock solution—Prepare as directed for Standard 2
(5E,7E)-9,10-secocholesta-5,7,10(19)-triene-1a,3b,25-triol
3
(5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1b,3b,25-triol
preparation in the Assay. (5Z,7E)-1a,3b-dihydroxy-17-((R)-7-hydroxy-7-methyloctan-2-yl)-
9,10-secoandrosta-5,7,10(19)-triene
Standard solution—Transfer 1.0 mL of the Standard stock
solution to a 100-mL volumetric flask, dilute with Mobile
Assay—[NOTE—Avoid Carry out the procedure as rapidly as
phase to volume, and mix.
~
possible, avoiding unnecessary exposure of solutions to light
~USP31
and air.]
Test solution—Prepare as directed for Assay preparation.
Pharmacopeial Forum
Tris buffer solution—Dissolve 1.0 g of tris(hydroxy- the responses for the major calcitriol and pre-calcitriol peaks.
methyl)aminomethane in 900 mL of water, adjust with Calculate the quantity, in mg, percentage of C27H44O3 in the
phosphoric acid to a pH of 7.0 to 7.5, dilute with water to portion of Calcitriol taken by the formula:
obtain 1000 mL, and mix.
Mobile phase—Prepare a filtered and degassed mixture of 10C(rU / rS)
acetonitrile and Tris buffer solution (55 : 45). Make adjust-
ments if necessary (see System Suitability under Chromatog-
raphy h621i).
100(CS / CU)(rU / rS)
Standard preparation—Prepare a solution of USP Calcitriol
RS in Mobile phase (without heating) having a known
in which C is the concentration, in mg per mL, of calcitriol in
concentration of about 100 mg of calcitriol per mL.
the Standard preparation; CS and CU are the concentrations, in
System suitability solution—Heat 2.0 mL of the Standard
mg per mL, of calcitriol in the Standard preparation and the
preparation at 808 for 30 minutes.
Assay preparation, respectively; and rU and rS are the sums of
Assay preparation—Transfer about 1.0 mg of Calcitriol,
the calcitriol and pre-calcitriol peak responses obtained from
accurately weighed, to a 10-mL volumetric flask, dissolve in
the Assay preparation and the Standard preparation,
and dilute with Mobile phase to volume without heating, and
respectively.~USP30
mix. Prepare a solution of Calcitriol in Mobile phase (without
heating) having a concentration of about 100 mg of calcitriol
per mL.
and a 4.6-mm 6 25-cm column that contains 5-mm packing BRIEFING
L7. The flow rate is about 1 mL per minute. The column

Citalopram Tablets, page 3715 of the Second Supplement and
temperature is maintained at 408. Chromatograph the System page 770 of PF 32(3) [May–June 2006]. It is proposed to revise the
Dissolution test to correct the expression of the results. The
suitability solution, and record the peak responses as directed percentage of drug substance dissolved is calculated in terms of
citalopram, not citalopram hydrobromide.
for Procedure: the relative retention times are about 0.9 for
(BPC: M. Marques) RTS—C50970
pre-calcitriol and 1.0 for calcitriol; and the resolution, R,
In-Process Revision
between pre-calcitriol and calcitriol is not less than 3.5. and

Change to read:
the relative standard deviation for replicate injections,
Identification—
determined from the calcitriol peak, is not more than 1.0%. A: Infrared Absorption h197Ki—
Test specimen—Extract finely ground Tablet powder containing
Chromatograph the Standard preparation, and record the about 200 mg of citalopram with 30 mL of water, and filter. Add
1 mL of 1 N sodium hydroxide
peak responses as directed for Procedure: the column
&
to the filtrate,&1S (USP30)
efficiency is not less than 10,000 theoretical plates; and the and extract with 50 mL of cyclohexane by shaking for 10 minutes.
Pass the cyclohexane layer through a silicone-treated filter paper into
relative standard deviation for replicate injections is not more a beaker. Reduce the filtrate down to 3 mL using gentle heat as
necessary. Transfer the hot solution to a small centrifuge tube.
than 1.0%. Induce crystallization while cooling by scratching the side of the test
tube with a spatula. Centrifuge the mixture, and decant off the
Procedure—Separately inject equal volumes (about 50 mL) cyclohexane. Dry the residue under vacuum in a desiccator. Mix
approximately 2 mg of the residue with approximately 300 mg of
of the Standard preparation and the Assay preparation into potassium bromide, and record the IR spectrum.
B: The retention time of the major peak in the chromatogram of
the chromatograph, record the chromatograms, and measure the Assay preparation corresponds to that in the chromatogram of
the Standard preparation, as obtained in the Assay.
Pharmacopeial Forum
C: A solution of 2 mg per mL equivalent of citalopram in water Standard solution—Prepare a solution having a concentra-
meets the requirements of the test for Bromide h191i.
tion of 0.625 mg per mL of citalopram hydrobromide through
Change to read: stepwise dilution of the Standard stock solution with Mobile
Dissolution h711i— phase.
Medium: pH 1.5 buffer (prepared by transferring 118 mL of 1 N
hydrochloric acid and 82 mL of 1 N sodium hydroxide to a 1000-mL Sensitivity solution—Prepare a solution having a concentra-
volumetric flask, diluting with water to volume, and adjusting with
1 N sodium hydroxide to a pH of 1.5); 800 mL, deaerated. tion of 0.05 mg per mL of citalopram hydrobromide through
Time: 30 minutes. stepwise dilution of the Standard solution with Mobile phase.
Procedure—Determine the amount of citalopram hydrobromide
dissolved by employing UV absorption at the wavelength of Related compounds stock solutions—Separately dissolve
maximum absorbance at about 239 nm on portions of the solution
under test passed through a 0.45-mm PVDF filter, suitably diluted accurately weighed quantities of USP Citalopram Related
with Medium, if necessary, in comparison with a Standard solution
having a known concentration (about 12 mg per mL) of USP Compound A RS, USP Citalopram Related Compound B RS,
Citalopram Hydrobromide RS in the same Medium. Calculate the
amount of citalopram hydrobromide USP Citalopram Related Compound C RS, and USP
~
~USP31 Citalopram Related Compound E RS in Mobile phase to
dissolved, in percentage, by the formula:
obtain stock solutions having known concentrations of about
0.1 mg per mL of each compound.
Peak identification solution—Prepare a mixture containing
about 0.001 mg per mL each of USP Citalopram Related
in which AU and AS are the absorbances obtained from the solution
under test and the Standard solution, respectively; CS is the Compound A RS, USP Citalopram Related Compound B RS,
concentration, in mg per mL, of the Standard solution; 324.39 and
405.30 are the molecular weights of citalopram and citalopram USP Citalopram Related Compound C RS, and USP
hydrobromide, respectively; D is the dilution factor of the solution
under test; 800 is the volume, in mL, of Medium; 100 is the Citalopram Related Compound E RS, using the Standard
conversion factor to percentage; and L is the tablet label claim, in
mg, of citalopram. stock solution as the diluent.
Tolerances—Not less than 80% (Q) of the labeled amount of
citalopram hydrobromide (C20H21FN2O HBr) Resolution solution—Dilute 0.5 mL of Citalopram related
~
(C20H21FN2O)~USP31 compound C stock solution and 25.0 mL of the Standard
is dissolved in 30 minutes.
stock solution with Mobile phase to 50 mL to obtain
Add the following: a solution containing 0.01 mg per mL of citalopram related
&
Related compounds— compound C and 0.25 mg per mL of citalopram hydrobro-
Phosphate buffer—Dissolve 3.15 g of potassium dihydro- mide.
gen phosphate and 3.60 g of disodium hydrogen phosphate Test solution—Transfer 10 Tablets into a 200-mL volumet-
(Na2HPO4 12H2O) in 1 L of water. ric flask, add 25 mL of Phosphate buffer, and shake by
In-Process Revision
Mobile phase—Prepare a filtered and degassed mixture of mechanical means until disintegrated. Add about 100 mL of
Phosphate buffer, methanol, and acetonitrile (55 : 38 : 7). a mixture of methanol and water (50 : 50), mix, and sonicate
Adjust with phosphoric acid to a pH of 6.5. Make adjustments for about 5 minutes. Allow to cool, dilute with a mixture of
if necessary (see System Suitability under Chromatography methanol and water (50 : 50) to volume, and mix thoroughly.
h621i). Allow the excipients to settle. Dilute as necessary to obtain
Standard stock solution—Dissolve an accurately weighed a final concentration of 0.5 mg per mL of citalopram. Pass
quantity of USP Citalopram Hydrobromide RS in Mobile a portion of this solution through a polytetrafluoroethylene
phase to obtain a solution having a known concentration of (PTFE) membrane filter having a 0.45-mm or finer porosity,
about 0.5 mg per mL. and use the filtrate.
Pharmacopeial Forum
Chromatographic system (see Chromatography h621i)— Procedure—Inject a volume (about 20 mL) of the Standard
The liquid chromatograph is equipped with a 239-nm detector solution and the Test solution into the chromatograph, record
and a 4.6-mm 6 15-cm column that contains 5-mm packing the chromatograms, and measure the peak responses.
L1. The column temperature is maintained at 458. The flow Calculate the percentage of each impurity in each Tablet by
rate is about 0.8 mL per minute. Inject the Standard solution, the formula:
and record the peak responses as directed for Procedure: the
citalopram peak shows no shoulders or excessive tailing; the 100(ri / rS)(324.39 / 405.30)(CS / CT)(1/F)
capacity factor, k ’, is not less than 3.5; the column efficiency
in which ri is the individual peak response for each citalopram
is not less than 5000 theoretical plates; the tailing factor is not
related compound obtained from the Test solution; rS is the
more than 1.5; and the relative standard deviation of both the
response of the corresponding peak in the Standard solution;
retention time and the response for replicate injections is not
324.39 and 405.30 are the molecular weights of citalopram
more than 5%. Inject the Sensitivity solution into the
and citalopram hydrobromide, respectively; CS and CT are the
chromatograph, and verify that the signal-to-noise ratio is at
concentrations, in mg per mL, of citalopram hydrobromide in
least 3. Inject the Resolution solution, and record the peak
responses as directed for Procedure: the resolution, R, the Standard solution and the Test solution, respectively; and
F is the relative response factor of each impurity relative to
between citalopram related compound C and citalopram is
citalopram (free base). The limits for the related compounds
not less than 3. Inject the Peak identification solution, and
record the responses as directed for Procedure: the four are listed in Table 1.&1S (USP30)
related compound peaks are baseline resolved from each Change to read:
other and the citalopram peak. [NOTE—For identification
Assay—
purposes, approximate relative retention times are given in Buffer—Transfer about 0.71 g of anhydrous dibasic sodium
phosphate to a 500-mL volumetric flask, and add about 250 mL of
Table 1.] water. Shake to dissolve, then dilute with water to volume.
Diluent—Prepare a solution of methanol and Buffer (80 : 20).
Internal standard solution—Dissolve an accurately weighed
amount of USP Citalopram Related Compound F RS in Diluent,
and dilute quantitatively, and stepwise if necessary, to obtain
a solution having a known concentration of about 0.25 mg per mL.
Mobile phase—Prepare a filtered and degassed solution of Diluent
containing about 770 mg of dodecyltrimethylammonium bromide
per L. Make adjustments if necessary (see System Suitability under
Chromatography h621i).
Table 1
In-Process Revision
Relative Retention Relative Response

Related Compound Time Factor (F) Limit (%)
Citalopram related compound A 0.43 0.77 NMT* 0.1 0.2

Citalopram related compound B 0.60 0.98 NMT 0.25
Citalopram related compound C 0.83 0.69 NMT 0.25
Citalopram related compound E 1.32 0.91 NMT 0.1
Unknown Any other individual unidentified
impurity — 1.0 NMT 0.1 0.2 each
Total known and unknown — — NMT 0.7 0.8
*
NMT = not more than.
Pharmacopeial Forum
Standard stock preparation—Dissolve an accurately weighed Change to read:

quantity of USP Citalopram Hydrobromide RS in Diluent, and dilute
quantitatively, and stepwise if necessary, with Diluent to obtain Specific rotation h781Si: between –178 and –218
a solution having a known concentration of about 1.25 mg of
citalopram hydrobromide per mL. ~
Standard preparation—Pipet 5.0 mL of the Standard stock –17.08 and –21.08.~USP30
preparation and 5.0 mL of the Internal standard solution into a Test solution: 10 mg per mL, in dimethylformamide.
50-mL volumetric flask. Dilute with Diluent to volume, and mix.
Assay preparation—Transfer 10 Tablets to a 200-mL volumetric Change to read:
flask, add 25 mL of Buffer, and shake by mechanical means until
disintegrated. Add 100 mL of methanol, and sonicate for about
5 minutes. Allow to cool to room temperature, then dilute with Related compounds—
Diluent to volume. Allow to stand until the residue settles before Buffer, Diluent, Mobile phase, System suitability solution, and
taking an aliquot for dilution. Transfer an accurately measured Chromatographic system—Proceed as directed in the Assay.
volume of the upper clear solution to a 50-mL volumetric flask to Test solution—Use the Assay preparation.
obtain a final concentration equivalent to between 0.090 and 0.10 mg Chromatographic system (see Chromatography h621i)—Chro-
per mL of citalopram matograph the System suitability solution, and record the peak
responses as directed for Procedure: the resolution, R, between
&
based on the label claim.&1S (USP30) cladribine and cladribine related compound A is not less than 1.5;
Add 5.0 mL of Internal standard solution, dilute with Diluent to and the tailing factor is not more than 2.0.
volume, and mix. Pass a portion through a filter (PTFE) having Procedure—Inject a volume (about 10 mL) of the Test solution
a 0.45-mm or finer porosity. into the chromatograph, record the chromatogram, and measure the
Chromatographic system (see Chromatography h621i)—The peak responses. Calculate the percentage of each impurity in the
liquid chromatograph is equipped with a 254-nm detector and portion of Cladribine taken by the formula:
a 4.6-mm 6 25-cm column that contains 5-mm packing L1. The
flow rate is about 1 mL per minute. The column temperature is 100(ri / rs)
maintained at 458. Inject the Standard preparation, and record the in which ri is the peak response of each individual impurity, and rs is
peak responses as directed for Procedure: the relative retention times the sum of the responses of all the peaks. Refer to Table 1 for the
are about 1.36 for citalopram related compound F and 1.0 for impurity limits.
citalopram; the resolution, R, between citalopram and citalopram
related compound F is not less than 1.5; the column efficiency is not
less than 2000 theoretical plates, calculated from the citalopram
peak; and the relative standard deviation for replicate injections is Table 1
not more than 1.5% for the citalopram peak.
Procedure—Separately inject equal volumes (about 10 mL) of the Relative
Standard preparation and the Assay preparation into the chromat- Retention
ograph, record the chromatograms, and measure the responses for Name Time Limit (%)
the citalopram peaks. Calculate the quantity, in percentage of label 2,6-Diaminopurine-2’-deoxyri- about 0.2
claim, of citalopram per Tablet taken by the formula: boside 0.41 ~
0.20~USP30
100(CS / CU)(324.39/405.30)(RU / RS) 2’-Deoxyadenosine about 0.2
in which CS and CU are the concentrations, in mg per mL, of USP 0.47 ~
Citalopram Hydrobromide RS in the Standard preparation and 0.20~USP30
citalopram hydrobromide in the Assay preparation, respectively; 2-Chloroadenine about 0.2
324.39 and 405.30 are the molecular weights of citalopram and 0.60 ~
citalopram hydrobromide, respectively; and RU and RS are the peak 0.20~USP30
response ratios of citalopram to the internal standard obtained from 2-Methoxy-2’-deoxyadenosine about 0.2
the Assay preparation and the Standard preparation, respectively. (cladribine related com- 0.91 ~
pound A) 0.20~USP30
Any other individual — 0.1
~ ~
individual unspeci- 0.10~USP30
fied~USP30
In-Process Revision
impurity
Total impurities — 1.0
BRIEFING
Change to read:
Cladribine, page 3563 of the First Supplement, page 1425 of the
Fifth Interim Revision Announcement, and page 774 of PF 32(3)
[May–June 2006]. On the basis of comments received, in the test for Limit of residual solvents—
Limit of residual solvents it is proposed to revise the column Standard solution—Transfer 15 mL of methanol and 24 mL
designation, the volume of alcohol used to prepare the Standard ~
solution, and the volume of Standard solution used in the headspace 25 mL~USP31
vial. of alcohol to a 100-mL volumetric flask containing 80 mL of water,
dilute with water to volume, and mix. Transfer 3 mL
(MD-OOD: F. Mao) RTS—C48824 ~
5 mL~USP31
of the solution to a 20-mL headspace vial. The concentrations of
methanol and alcohol in the Standard solution are 119 mg per mL
and 198 mg per mL, respectively.
Pharmacopeial Forum
~
Test solution—In a 20-mL headspace vial, dissolve 200 mg of a wavelength of~USP31
Cladribine, accurately weighed, in 5 mL of water. about 240 nm on filtered portions of the solution under test in
Chromatographic system (see Chromatography h621i)—The gas comparison with the Standard solution.
chromatograph is equipped with a headspace injector and a flame- Tolerances—Not less than 80% (Q) of the labeled amount of
ionization detector and contains a 0.53-mm 6 30-m column coated C16H16ClNO2S is dissolved in 30 minutes.
with a 5-mm film of liquid phase G16
~
G27.~USP31 Change to read:
The carrier gas is nitrogen, flowing at a rate of 4 mL per minute. The
split ratio is 5 : 1. Vials containing the Standard solution and the Test Related compounds—
solution are equilibrated for 10 minutes at 808 in the headspace
sampler. The chromatograph is programmed as follows. Initially the ~
[NOTE—For all clopidogrel related compounds, the concen-
temperature of the column is maintained at 808 for 6 minutes, then
increased at a rate of 258 per minute to 2408, and maintained at 2408 trations are expressed as bisulfate salts. Use bisulfate salt
for 20 minutes. The injection port temperature and the detector
temperature are maintained at 2508. Chromatograph the Standard equivalents stated on USP Reference Standards labels to
solution, and record the peak responses as directed for Procedure:
the resolution, R, between alcohol and methanol is not less than 1.5; calculate the concentrations as appropriate.]~USP30
and the relative standard deviation for replicate injections is not more Phosphate buffer and Mobile phase—Prepare as directed in the
than 10.0% for each of the two solvents. Assay under Clopidogrel Bisulfate.
Procedure—Separately inject equal volumes (about 1 mL) of the System suitability solution—Dissolve accurately weighed quan-
gaseous headspace of the Standard solution and the Test solution tities of USP Clopidogrel Bisulfate RS, USP Clopidogrel Related
into the chromatograph, record the chromatograms, and measure the Compound A RS, USP Clopidogrel Related Compound B RS, and
responses for the major peaks. Calculate the concentration, in ppm, USP Clopidogrel Related Compound C RS in methanol. Dilute
of each residual solvent in the portion of Cladribine taken by the quantitatively, and stepwise if necessary, with Mobile phase to obtain
formula: a solution having concentrations of about 1 mg per mL, 1 mg per mL,
5000(C/W)(rU / rS) 2 mg per mL, and 3 mg per mL, respectively.
~
in which C is the concentration, in mg per mL, of the respective Dissolve accurately weighed quantities of USP Clopidogrel
individual solvent in the Standard solution; W is the quantity, in mg,
of Cladribine taken to prepare the Test solution; and rU and rS are the Bisulfate RS and USP Clopidogrel Related Compound B RS
peak responses of the relevant solvent obtained from the Test
solution and the Standard solution, respectively: not more than 5000 in methanol, and dilute with methanol to obtain a solution
ppm of alcohol is found, and not more than 450 ppm
having concentrations of about 100 mg per mL and 200 mg per
~
3000 ppm~USP30
of methanol is found. mL, respectively. Transfer 5 mL of this solution to a 200-mL
volumetric flask, dilute with Mobile phase to volume, and
mix.~USP30
Standard solution—Dissolve accurately weighed quantities of
USP Clopidogrel Related Compound A RS and USP Clopidogrel
Related Compound C RS in methanol. Dilute quantitatively, and
stepwise if necessary, with Mobile phase to obtain a solution having
known concentrations of about 1 mg per mL and 5 mg per mL,
respectively.
BRIEFING
~
Dissolve accurately weighed quantities of USP Clopidogrel
Clopidogrel Tablets, USP 29 page 562, the Third Interim Bisulfate RS, USP Clopidogrel Related Compound A RS, and
Revision Announcement on page 743 of PF 32(3) [May–June 2006],
and page 76 of PF 32(1) [Jan.–Feb. 2006]. It is proposed to revise USP Clopidogrel Related Compound C RS in methanol to
the Procedure in the Dissolution test so that it agrees with the
In-Process Revision
validation report. obtain a solution having known concentrations of about 40 mg
(BPC: M. Marques) RTS—C50812 per mL, 250 mg per mL, and 300 mg per mL, respectively.
Transfer 5 mL of this solution to a 200-mL volumetric flask,
Change to read: and dilute with Mobile phase to volume. This solution
Dissolution h711i— contains about 1 mg of of clopidogrel bisulfate per mL, 6 mg

Medium: pH 2.0 hydrochloric acid buffer (see Buffer solutions
under Reagents, Indicators, and Solutions); 1000 mL. of clopidogrel related compound A per mL, and 7.5 mg of
Time: 30 minutes. clopidogrel related compound C per mL.~USP30
Standard solution—Dissolve an accurately weighed quantity of Test solution—Weigh and finely powder not fewer than 20 Tablets.
USP Clopidogrel Bisulfate RS in 20.0 mL of methanol, and dilute Transfer an accurately weighed portion of the powder, equivalent to
quantitatively, and stepwise if necessary, with Medium to obtain about 75 mg of clopidogrel
a solution having a known concentration corresponding to that of the ~
solution under test. (free base),~USP30
Procedure—Determine the amount of C16H16ClNO2S dissolved by
employing UV absorption at the wavelength of maximum absor-
bance at
Pharmacopeial Forum
to a 200-mL volumetric flask, add 5 mL of methanol, dilute with peak response of clopidogrel peak obtained from the
Mobile phase to volume, and mix. Allow to stand for 10 minutes,
and mix. Pass a portion of this solution through a filter having Standard solution; and the other terms are as defined
a 0.45-mm or finer porosity, and use the filtrate after discarding the
first 5 mL. above:~USP30
Chromatographic system (see Chromatography h621i)—The not more than 0.2%.1.2%.3 of clopidogrel related compound A is
liquid chromatograph is equipped with a 220-nm detector and found; not more than 1.0%.1.5%.3 of clopidogrel related compound
4.6-mm 6 15-cm column that contains packing L57. The flow rate C is found; not more than 0.2% of any other single impurity
is about 1.0 mL per minute. Chromatograph the System suitability (excluding clopidogrel related compound B) is found; and not more
solution, and record the peak responses as directed for Procedure: than 1.2%.2.5%.3 of total impurities (excluding clopidogrel related
the relative retention times are about 0.5 for clopidogrel related compound B) is found.
compound A, 0.8 and 1.2 for the two enantiomers of clopidogrel
related compound B, 1.0 for clopidogrel, and 2.0 for clopidogrel
related compound C; and the resolution, R, between clopidogrel and
each of the two enantiomers
~
the first enantiomer~USP30
of clopidogrel related compound B is not less
~
greater~USP30
than 2.5. Chromatograph the Standard solution, and record the peak
responses as directed for Procedure: the relative standard deviation BRIEFING
for replicate injections is not more than 15%
~
for each peak.~USP30 Cytarabine for Injection, USP 29 page 618. On the basis of
Procedure—Inject equal volumes (about 10 mL) of the Standard comments received, in the Assay it is proposed to revise the
solution and Test solution into the chromatograph, record the concentration of the Assay preparation to be consistent with that of
chromatograms, and measure the peak responses. Calculate the the Standard preparation.
percentage of clopidogrel related compounds
~ (MDOOD: F. Mao) RTS—C48837
A and C~USP30
in the portion of Tablets taken by the formula:
20(C/W)(rU / rS) Change to read:
in which C is the concentration, in mg per mL, of the appropriate
USP Reference Standard Assay—
Phosphate buffer, Mobile phase, Standard preparation, Resolution
solution, and Chromatographic system—Proceed as directed in the
Assay under Cytarabine.
~
Assay preparation—Separately constitute 5 vials of Cytarabine for
20(321.82/419.90)(C/W)(rU / rS) Injection in a volume of water, accurately measured, corresponding
to the volume specified in the labeling. Pool and mix the constituted
solutions in a suitable container. Transfer an accurately measured
volume of the constituted solution, equivalent to about 100 mg of
in which 321.82 is the molecular weight of clopidogrel; cytarabine, to a 100-mL volumetric flask, dilute with water to
volume, and mix.
419.90 is the molecular weight of clopidogrel bisulfate; C is
~
Transfer 5.0 mL of this solution to a 50-mL volumetric flask,
the concentration, in mg per mL, of the relevant clopidogrel
dilute with water to volume, and mix.~USP31
related compound~USP30 Procedure—Separately inject equal volumes (about 10 mL) of the
in the Standard solution; W is the weight, in mg, of clopidogrel in Standard preparation and the Assay preparation into the chromat-
the portion of Tablets used to prepare the Test solution based on the ograph, record the chromatograms, and measure the responses for
labeled quantity of clopidogrel per Tablet, Tablet weight, and the the major peaks. Calculate the quantity, in mg, of C9H13N3O5 in the
weight of the portion of Tablets used; and rU and rS are the peak portion of constituted solution taken by the formula:
In-Process Revision
responses of the corresponding related compounds obtained from the
Test solution and the Standard solution, respectively. 1000C(rU / rS)
in which C is the concentration, in mg per mL, of USP Cytarabine
~
Calculate the percentage of any other impurity (excluding RS in the Standard preparation; and rU and rS are the peak responses
clopidogrel related compound B) in the portion of Tablets respectively.
taken by the formula:
20(321.82/419.90)(CC / W)(rU / rS)
in which CC is the concentration of clopidogrel bisulfate, in

mg per mL, in the Standard solution; rU is the peak response
of any other impurity obtained from the Test solution; rS is the
Pharmacopeial Forum
Add the following:

BRIEFING
~
Enoxaparin Sodium
Dimethyl Sulfoxide Gel, USP 29 page 724. It is proposed to
replace the test for Deliverable volume h698i with the test for
Minimum fill h755i, which applies to gels.
(MD-OOD: F. Mao) RTS—C45906
Delete the following:

~
Deliverable volume h698i: meets the requirements.~USP31
Add the following:

~
Minimum fill h755i: meets the requirements.~USP31
BRIEFING
Enoxaparin Sodium, page 1876 of PF 29(6) [Nov.–Dec. 2003].

On the basis of comments received regarding the chemical structure
of Enoxaparin Sodium, it is proposed to include the 1,6-anhydro
derivative on the reducing end of the chain. It is also proposed to
change the name of the Reference Standard for USP Low Molecular
Weight Heparin Molecular Weight RS to USP Enoxaparin Sodium
Molecular Weight RS. The Appearance of solution section is being
revised to delete references to Clarity and Degree of Opalescence of
Liquids h625i and Degree of Color of Liquids h627i. Further [9041-08-1].
revisions include modification of the specification for the flow rate in
Identification test D and the specification for the absorbance reading
of the blank B2 sample under Assay (anti-factor Xa activity).
(BB BBP: A. Szajek) RTS—C47712

» Enoxaparin Sodium is the sodium salt of
a depolymerized heparin. It is obtained by alkaline
depolymerization of heparin benzyl ester. The
starting material, heparin, is obtained exclusively
In-Process Revision
from porcine intestinal mucosa. Enoxaparin

Sodium consists of a complex set of oligosaccha-
rides that have not yet been completely character-
ized. The majority of the components have a 4-
enopyranose uronate structure at the non-reducing
end of their chain. About 20 percent of the
materials contain a 1,6-anhydro derivative on the
reducing end of the chain, the range being between
15 and 25 percent. The weight-average molecular
weight of Enoxaparin Sodium is 4,500 Da, the
Pharmacopeial Forum
range being between 3,800 and 5,000 Da; about 16

Procedure—Transfer the Standard solution and the Test
percent have a molecular weight of less than 2,000 solution to NMR tubes of 5-mm diameter. Using a pulsed
Da, the range being between 12.0 and 20.0 percent; (Fourier transform) NMR spectrometer operating at not less
about 74 percent have a molecular weight between than 75 MHz for 13
C, record the 13
C NMR spectra of the
2,000 and 8,000 Da, the range being between 68.0 Standard solution and the Test solution at 408. The spectra are
and 82.0 percent. Not more than 18.0 percent have similar.
C: The ratio of the numerical value of the anti-factor Xa
a molecular weight higher than 8,000 Da. The
activity, in Anti-Factor Xa IU per mg, to the numerical value
degree of sulfation is not less than 1.8 per
of the anti-factor IIa activity, in Anti-Factor IIa IU per mg, as
disaccharide unit. It has a potency of not less
determined by the Assay (anti-factor Xa activity) and the Anti-
than 90.0 90 and not more than 125.0 125 Anti-
factor IIa activity, respectively, is not less than 3.3 and not
Factor Xa International Units (IU) per mg, and not more than 5.3.
less than 20.0 and not more than 35.0 Anti-Factor D: Molecular weight distribution and weight-average
IIa IU per mg, calculated on the dried basis. The molecular weight—
ratio of anti-factor Xa activity to anti-factor IIa Mobile phase—Prepare a 0.5 M lithium nitrate solution.
activity is between 3.3 to 5.3. Pass through a membrane filter having a porosity of 0.45 mm
or less, and degas with helium.
Packaging and storage—Preserve in tight containers, and
Calibration solutions—Prepare two calibration solutions, A
store below 408, preferably at room temperature.
and B, by dissolving about 2 mg each of USP Low-
USP Reference standards h11i—USP Benzyl Alcohol RS. Molecular-Weight Heparin Molecular Weight RS USP
USP Endotoxin RS. USP Enoxaparin Sodium RS. USP Enoxaparin Sodium Molecular Weight RS in 1 mL of
Enoxaparin Sodium Solution for Bioassays RS. USP Low- Mobile phase. Distribute the Reference Standard calibrants in
Molecular-Weight Heparin Molecular Weight RS USP alternating order of magnitude between solutions A and B.
Enoxaparin Sodium Molecular Weight RS. Standard solution—Dissolve an accurately weighed quan-
Identification— tity of about 10 mg of USP Enoxaparin Sodium RS,
A: Ultraviolet Absorption h197Ui— accurately weighed, in 1 mL of Mobile phase.
Solution: 500 mg per mL. Test solution—Dissolve an accurately weighed quantity of
In-Process Revision
Medium: 0.01 N hydrochloric acid. The spectra exhibit about 10 mg of Enoxaparin Sodium, accurately weighed, in
maxima at 231 + 2 nm. 1 mL of Mobile phase.
B: 13
C NMR spectrum (see Nuclear Magnetic Resonance Chromatographic system (see Chromatography h621i)—
h761i)— The high performance size exclusion chromatograph is
Standard solution—Dissolve 200 mg of USP Enoxaparin equipped with a differential refractive index detector, a 6-
Sodium RS in a mixture of 0.2 mL of deuterium oxide and 6 40-mm guard column and two 7.8- 6 300-mm analytical
0.8 mL of water. Add 1 drop 0.05 mL of deuterated methanol columns in series, both analytical and guard columns
to serve as an internal reference. prepacked with packing L20 L## (see Chromatographic
Test solution—Dissolve 200 mg of Enoxaparin Sodium in Reagents under Reagents, Indicators, and Solutions), and
a mixture of 0.2 mL of deuterium oxide and 0.8 mL of water. used at room temperature. The flow rate is about 0.6 mL per
Add 1 drop 0.05 mL of deuterated methanol. minute maintained constant to +0.1% +1.0%.
Pharmacopeial Forum
Procedure—Separately inject 20 mL of Calibration solu- Procedure—The solution is clear and not more intensely
tions A and B, record the chromatograms, and measure the colored than degree 6 of the range of Reference Solutions of
retention times. Inject in duplicate 20 mL of each of the the most appropriate color and not more opalescent than
Standard solution and the Test solution, and record the Reference Suspension I analyzed for clarity and degree of
chromatograms for a length of time to ensure complete color using a validated method.
elution, including salt and solvent peaks. Calculate the total Specific absorbance (see Spectrophotometry and Light-
area under each of the Standard solution and Test solution Scattering h851i)—
chromatograms, excluding salt and solvent peaks at the end. Test solution—Dissolve 50.0 mg of Enoxaparin Sodium in
Calibration curve—Plot the retention times on the y-axis 100 mL of 0.01 N hydrochloric acid.
against the peak molecular weights on the x-axis for the peaks Procedure—Obtain the UV spectra of the Standard solution
in the chromatograms of Calibration solutions A and B, and and the Test solution between 200 nm and 300 nm against
fit the data to a third-order polynomial using a suitable gel 0.01 N hydrochloric acid blank. Calculate the specific
permeation chromatography (GPC) software. absorbance at the wavelength of maximum absorbance at
Calculations—Compute the data, using the same GPC 231 + 2 nm, with reference to the dried substance, using the
software to and determine the weight-average molecular following formula:
weight, MW, for each of the duplicate chromatograms of the
Standard solution and the Test solution, and take the average A 6 100 6 1000 / [ M 6 l 6 (100 – E)]
for each solution. Correct the mean value of MW to the nearest
50. The Chromatographic system is suitable if MW of USP in which A is the absorbance at the wavelength of maximum
Enoxaparin Sodium RS is within 150 Da of the labeled MW absorbance; M is the weight, in mg, of Enoxaparin Sodium in
value. The MW for the Test solution is between 3,800 and the Test solution; l is the pathlength (typically l = 1 cm); and
5,000 Da. Using the same software, determine for each of the E is the loss on drying, in percent. The specific absorbance is
duplicate Test solution chromatograms the percentage of between 14.0 and 20.0, calculated on the dried basis.
Enoxaparin Sodium chains with molecular weights lower Bacterial endotoxins h85i—It contains not more than 0.01
than 2000 Da, M2000, the percentage of Enoxaparin Sodium USP Endotoxin Unit per USP Unit of anti-factor Xa activity.
chains with molecular weights in the range 2000 to 8000 Da,
pH h791i: between 6.2 and 7.7 in of a 10.0% solution in
M2000–8000, and the percentage of Enoxaparin Sodium chains
In-Process Revision
water.
with molecular weights greater than 8000 Da, M8000. Average
Loss on drying h731i—Dry 1 g in a vacuum at 708 for
the duplicate values and express to the nearest 0.5%. M2000 is
6 hours: it loses not more than 10.0% of its weight.
between 12.0% and 20.0%, M2000–8000 is between 68.0% and
82.0%, and M8000 is not more than 18.0%. Nitrogen content, Method II h461i: between 1.8% and
E: It responds to the test for Sodium h191i. 2.5%, calculated on the dried basis.
Appearance of solution (see Clarity and Degree of Heavy metals, Method I h231i—Prepare a 5% solution in
Opalescence of Liquids h625i and Degree of Color of water: the limit is not more than 0.0030%.
Liquids, Method I h627i) (Clarity and degree of color of Sodium content (see Spectrophotometry and Light-
liquids)— Scattering h851i)—
Test solution—Dissolve 1.0 g of Enoxaparin Sodium in 10
mL of water.
Pharmacopeial Forum
Cesium chloride solution—Prepare a solution of cesium Procedure—[ NOTE —Regenerate the anion-exchange
chloride in 0.1 N hydrochloric acid containing 1.27 mg per column and the cation-exchange column with 1 N sodium
mL. hydroxide and 1 N hydrochloric acid, respectively, between
Standard solutions—Dissolve an accurately weighed quan- two injections.] Inject the Test solution into the anion-
tity of sodium chloride in Cesium chloride solution to obtain exchange column, and collect the eluate from the cation-
a solution having a known concentration of about 0.2% exchange column in a beaker at the outlet until the ion
sodium. Dilute accurately measured volumes of this solution detector reading returns to the baseline value. Quantitatively
with Cesium chloride solution having known concentrations transfer the eluate to a titration vessel containing a magnetic
of 0.0025%, 0.0050%, and 0.0075% of sodium. stirring bar, and dilute with carbon dioxide-free water to
Test solution—Transfer an accurately weighed quantity of about 60 mL. Position the titration vessel on a magnetic stirrer
about 50.0 mg of Enoxaparin Sodium to a 100-mL volumetric and immerse the electrodes. Note the initial conductivity
flask, and dissolve in and dilute with Cesium chloride reading and titrate with approximately 0.1 N sodium hydrox-
solution to volume. ide added in 100-mL portions. [NOTE—Prepare the sodium
Procedure—Concomitantly determine the absorbances of hydroxide solution in carbon dioxide-free water.] Record the
the Cesium chloride solution (blank), Test solution, and burette reading and the conductivity meter reading after each
Standard solutions at 330.3 nm using a sodium hollow- addition of the sodium hydroxide solution.
cathode lamp and an air–acetylene flame. Using the Calculations—Plot the conductivity measurements on the
absorbances of Standard solutions, determine the sodium y-axis against the volumes of sodium hydroxide added on the
content in the Test solution after appropriate blank correction. x-axis. The graph will have three linear sections—an initial
The sodium content, calculated on the dried basis, is between downwards slope, a middle slight rise, and a final rise. For
11.3% and 13.5%. each of these sections draw the best-fit straight lines using
Molar ratio of sulfate to carboxylate (see Chromatography linear regression analysis. At the points where the first and
h621i)— second straight lines intersect and where the second and third
Mobile phase: carbon dioxide-free water. lines intersect, draw perpendiculars to the x-axis to determine
Test solution—Dissolve an accurately weighed quantity of the volumes of sodium hydroxide taken up by the sample at
about 50 mg of Enoxaparin Sodium in 10 mL of carbon those points. The point where the first and second lines
dioxide-free water. intersect corresponds to the volume of sodium hydroxide
Chromatographic system— (see Chromatography h621i)— taken up by the sulfate groups (VS). The point where the
In-Process Revision
The liquid chromatograph chromatographic system consists second and third lines intersect corresponds to the volume of
of two peristaltic pumps, a six-port injection valve, an ion sodium hydroxide consumed by the sulfate and the
detector, and two columns—one 1.5- 6 2.5-cm column carboxylate groups together (VT). Calculate the molar ratio
packed with an anion-exchange resin L## packing and one of sulfate to carboxylate by the formula:
1.5- 6 7.5-cm column packed with a cation-exchange resin
L## packing (see Chromatography h621i) (see Chromato- VS / (VT – VS)
graphic Reagents under Reagents, Indicators, and Solutions),

The molar ratio of sulfate to carboxylate is not less than 1.8.
The outlet of the anion-exchange column is connected to the
inlet of the cation-exchange column. The flow rate is about
1 mL per minute.
Pharmacopeial Forum
Benzyl alcohol content— Thrombin human solution—Reconstitute thrombin human
Mobile phase—Prepare a filtered and degassed mixture of (see Reagent Specifications in the section Reagents, Indica-
water, acetonitrile, and methanol (80 : 15 : 5 v/v). tors and Solutions) in water, and dilute in pH 7.4
Standard solution—Dissolve 100 mg of USP Benzyl Polyethylene glycol 6000 buffer to obtain a solution having
Alcohol RS in 200 mL of water. Transfer 10 mL 5 mL of a concentration of 5 Thrombin Units per mL.
this solution to a 100-mL 25-mL volumetric flask, and dilute Chromogenic substrate solution—Prepare a solution of
with water to volume. Transfer 5 mL of this solution to a 20- a suitable chromogenic substrate for an amidolytic test (see
mL volumetric flask, and dilute with water to volume. Reagent Specifications in the section Reagents, Indicators,
Test solution—Weigh 0.5 g of Enoxaparin Sodium into and Solutions) for thrombin in water to obtain a concentration
a 10-mL volumetric flask, and dissolve in 5.0 mL of 1 N of about 3 mM. Immediately before use, dilute with pH 8.4
sodium hydroxide. Allow to stand at room temperature for Buffer to 0.5 mM.
about 1 hour. Add 1.0 mL of glacial acetic acid, dilute with Standard solutions—Dilute USP Enoxaparin Sodium
water to volume, and mix. Solution for Bioassays RS with pH 7.4 Buffer to obtain
Chromatographic system (see Chromatography h621i)— four dilutions having concentrations in the range between
The liquid chromatograph is equipped with a 256-nm detector 0.015 and 0.075 USP Anti-Factor IIa Activity Unit Unit of
and a 4.6-mm 6 15-cm stainless steel column that contains anti-factor IIa activity per mL.
L7 packing. The flow rate is about 1.0 mL per minute Test solutions—Proceed as directed under Standard solu-
maintained constant to +10%. tions to obtain concentrations of Enoxaparin Sodium similar
Procedure—Separately inject equal volumes (about 20 mL) to those obtained for the Standard solutions.
of the Standard solution and the Test solution, record the Procedure—Proceed as directed under Assay (anti-factor Xa
chromatograms, and measure the peak responses. activity), except to use Thrombin human solution instead of
Calculation—Calculate the percentage of benzyl alcohol in Factor Xa solution and to use the Human antithrombin III
Enoxaparin Sodium taken by the formula, solution as described above.
Calculations—For each series, calculate the regression of
(AT 6 CS)/(AS 6 CT) the absorbance against log concentrations of the Test solutions
and of the Standard solutions, and calculate the potency of
in which AT is the benzyl alcohol peak area in the Test the enoxaparin sodium in IU of anti-factor IIa activity per mg
solution; CS is the concentration, in mg per mL, of benzyl
In-Process Revision
using statistical methods for parallel-line assays. The four

alcohol; AS is the area of the benzyl alcohol peak in the independent relative potency dilution estimates are then
Standard solution; and CT is the concentration, in mg per mL, combined to obtain the final weighted mean. balanced by the
of Enoxaparin Sodium. The percentage of benzyl alcohol is adequate factor. Then calculate the confidence limits. Express
not more than 0.1%. the anti-factor IIa activity of Enoxaparin Sodium per mg,
Anti-factor IIa activity— calculated on the dried basis. It has a potency of not less than
Acetic acid solution, pH 7.4 Polyethylene glycol 6000 20.0 and not more than 35.0 anti-Factor IIa IU per mg.
buffer, pH 7.4 Buffer, pH 8.4 Buffer, and Human antithrombin Assay (anti-factor Xa activity)—
III solution—Proceed as directed under Assay (anti-factor Xa Acetic acid solution—Transfer 42 mL of glacial acetic acid
activity), except that the concentration of the Human to a 100-mL volumetric flask, dilute with water to volume,
antithrombin III solution is 0.5 Antithrombin III Unit per mL. and mix.
Pharmacopeial Forum
pH 7.4 Polyethylene glycol 6000 buffer—Dissolve 6.08 g of Assay preparations—Proceed as directed for Standard
tris(hydroxymethyl)aminomethane and 8.77 g of sodium preparations to obtain concentrations of Enoxaparin
chloride in 500 mL of water. Add 1.0 g of polyethylene Sodium similar to those obtained for the Standard prepara-
glycol 6000, adjust with hydrochloric acid to a pH of 7.4, and tions.
dilute with water to 1000 mL. Procedure—Label 18 suitable tubes: B1 and B2 for blanks;
pH 7.4 Buffer—Dissolve 6.08 g of tris(hydroxymethyl)a- T1, T2, T3, and T4 each in duplicate for the dilutions of the
minomethane and 8.77 g of sodium chloride in 500 mL of Assay preparations; and S1, S2, S3, and S4 each in duplicate
water. Adjust with hydrochloric acid to a pH of 7.4, and dilute for the dilutions of the Standard preparations. [NOTE—Treat
with water to 1000 mL. the tubes in the order B1, S1, S2, S3, S4, T1, T2, T3, T4, T1,
pH 8.4 Buffer—Dissolve 3.03 g of tris(hydroxymethyl)a- T2, T3, T4, S1, S2, S3, S4, B2.] To each tube add the same
minomethane, 5.12 g of sodium chloride and 1.40 g of edetate volume, V, (20 to 50 mL) of Human antithrombin III solution
sodium in 250 mL of water. Adjust with hydrochloric acid to and an equal volume, V, of either the blank, pH 7.4 Buffer, or
a pH of 8.4, and dilute with water to 500 mL. an appropriate dilution of the Assay preparations or the
Human antithrombin III solution—Reconstitute a vial of Standard preparations. Mix, but do not allow bubbles to
antithrombin III (see Reagent Specifications in the section form. Incubate at 378 for 1.0 minute. Add to each tube
Reagents, Indicators, and Solutions) in water to obtain volume 2V (40 to100 mL) of Factor Xa solution, and incubate
a solution containing 5 Antithrombin III Units per mL. Dilute for 1.0 minute. Add 5V (100 to 250 mL) volume of
this solution with pH 7.4 Polyethylene glycol 6000 buffer to Chromogenic substrate solution. Stop the reaction after 4.0
obtain a solution having a concentration of 1.0 Antithrombin minutes with 5V (100 to 250 mL) volume of Acetic acid
III Unit per mL. solution. Measure the absorbance of each solution at 405 nm
Factor Xa solution—Reconstitute an accurately weighed using a suitable spectrophotometer (see Spectrophotometry
quantity of bovine factor Xa (see Reagent Specifications in the and Light-Scattering h851i) against blank B1. The reading of
section Reagents, Indicators, and Solutions) in pH 7.4 blank B2 is not more than +0.01 +0.05 absorbance units.
Polyethylene glycol 6000 buffer to obtain a solution that Calculations—For each series, calculate the regression of
gives an increase in absorbance value at 405 nm of not more the absorbance against log concentrations of the Assay
than 0.20 absorbance units per minute when assayed as preparations and of the Standard preparations, and calculate
described below but using as an appropriate volume (V, in mL) the potency of the enoxaparin sodium in IU of anti-factor IIa
of pH 7.4 Buffer instead of V mL of the enoxaparin solution. activity per mL using statistical methods for parallel-line
In-Process Revision
Chromogenic substrate solution—Prepare a solution of assays. The four independent relative potency dilution
a suitable chromogenic substrate for amidolytic test (see estimates are then combined to obtain the final weighted
Reagent Specifications in the section Reagents, Indicators, mean. balanced by the adequate factor. Its confidence limits
and Solutions) for factor Xa in water to obtain a concentration are calculated. Express the anti-factor Xa activity of
of about 3 mM. Dilute with pH 8.4 Buffer to obtain a solution Enoxaparin Sodium per mg, calculated on the dried basis.
having a concentration of 0.5 mM. The potency is not less than 90 and not more than 125 Anti-
Standard preparations—Dilute USP Enoxaparin Sodium Factor Xa IU per mg.~USP31
Solution for Bioassays RS with pH 7.4 Buffer to obtain four
dilutions in the concentration range between 0.025 and 0.2
USP Anti-Factor Xa Units per mL.
Pharmacopeial Forum
A: Add 2 mL of water to the total content of a single-dose

BRIEFING
container, or to 0.4 mL from a multiple-dose container, and
Enoxaparin Sodium Injection, page 761 of PF 31(3) [May–June 1 mL of 2% w/v protamine sulfate solution in a glass test
2005]. On the basis of comments received, it is proposed to revise
the formula in the test for Benzyl alcohol content and to clarify the tube, and mix. A creamy white precipitate is formed.
calculation of the percentage in the test for Free sulfate content to be
(w/w) instead of (w/v). Also, to eliminate references to Clarity and B: Ultraviolet Absorption h197Ui—
Degree of Opalescence of Liquids h625i and Degree of Color of
Liquids h627i, the previously proposed sections for Clarity and Standard solution: 500 mg per mL.
Color are being replaced with a section for Appearance of solution.
Medium: 0.01 N hydrochloric acid. The spectra exhibit
(BB BBP: A. Szajek) RTS—C47712 maxima at 231 + 2 nm.
Test solution—Transfer the total content of a single-dose
container, or 0.4 mL from a multiple-dose container, to a
100-mL volumetric flask. Dilute with Medium to volume.
Add the following: C: It meets the requirements of the test for Sodium h191i.
~
Enoxaparin Sodium Injection Clarity (see Clarity and Degree of Opalescence of Liquids
h625i)—The clarity of the solution does not exceed that of
suspension I.
» Enoxaparin Sodium Injection is a sterile solution Color (see Degree of Color of Liquids, Method I h627i)—The
of Enoxaparin Sodium in Water for Injection. Its color of the solution is not more than degree 4 of the range of
potency value is not less than 90.0 90 percent and reference solution of the most appropriate color for a solution
not more than 110.0 110 percent of the potency containing 100 mg of enoxaparin sodium per mL.
stated on the label in terms of USP Anti-factor Xa Appearance of solution (Clarity and degree of color of
Units. It may contain, in multiple-dose containers, liquids)—
a suitable antimicrobial preservative, such as Test solution—Dissolve a quantity equivalent to 50,000 IU

in water and dilute with the same solvent to 10 mL.
benzyl alcohol.
Procedure—The solution is analyzed for clarity and degree
Packaging and storage—Preserve in single-dose or of color using a validated method.
multiple-dose containers in Type I glass. Store between 208
and 258, excursions permitted between 158 and 308.
In-Process Revision
Benzyl alcohol content (if present)—

Labeling—Label it to indicate the amount (mg) of Enox- Mobile phase—Prepare a filtered and degassed mixture of
aparin Sodium in the total volume of contents. The label acetonitrile and water (1 : 1) water, acetonitrile, and methanol
states also that the Enoxaparin Sodium starting material is (80 : 15 : 5 v/v).
porcine derived. Standard solution—Transfer about 200 mg 75 mg,
USP Reference standards h11i—USP Benzyl Alcohol RS. accurately weighed, of USP Benzyl Alcohol RS to a 200-
USP Endotoxin RS. USP Enoxaparin Sodium RS. USP mL 50-mL volumetric flask, and dilute with Mobile phase to
Enoxaparin Sodium Solution for Bioassays RS. volume.
Identification— Test solutions—Transfer 5.0 mL of the Injection to a 50-mL
volumetric flask. Dilute with Mobile phase to volume, and
mix.
Pharmacopeial Forum
Chromatographic system (see Chromatography h621i)— Standard solutions—Prepare standard solutions at concen-
The liquid chromatograph is equipped with a 258-nm detector trations of 0.1 mg per g, 0.5 mg per g, 1 mg per g, 2 mg per g,
and a 4.0-mm 6 25-cm stainless steel column that contains 4 mg per g, and 5 mg per g by appropriate dilution of the
packing L1 256-nm detector and a 4.6-mm 6 15-cm stainless Standard sulfate stock solution in Mobile phase.
steel column that contains packing L7. The flow rate is about
1 System suitability solution—Prepare a solution containing
1.0 mL per minute maintained constant to +10%. 3 mg per mL of sulfate anion and 5 mg per mL of oxalate
Procedure—Separately inject equal volumes (about 20 mL) anion.
of the Standard solution and the Test solution, record the Test solutions—Transfer about 200 mg of a 100 mg per mL
chromatograms, and measure the peak responses. Calculate Injection, accurately weighed, to a suitable previously tared
the percentage of benzyl alcohol in the portion of enoxaparin sulfate-free vial. Add Mobile phase to obtain a total mass, MS,
sodium solution taken by the formula: of about 20 g.
(AT 6 M)/(AS 6 20), The ion chromatograph is equipped with a conductivity
detector and a 4-mm 6 5-cm anion-exchange guard column,
a 4-mm 6 25-cm anion-exchange analytical column,
prepacked with L## and L## packings (see Chromatography
(AT 6 M)/(AS 6 200)
h621i) both containing L61 packing (see Chromatographic
Reagents under Reagents, Indicators, and Solutions), and
in which AT and AS are areas of the benzyl alcohol peaks in the
a micromembrane anion autosuppressor2 or a suitable chem-
chromatograms of the Test solution and the Standard solution,
ical suppression system. The flow rate is about 2.0 mL per
respectively; and M is the mass of the benzyl alcohol
minute.
dissolved to prepare the Standard solution. The percentage
Procedure—Chromatograph about 25 mL of the System
(w/v) of benzyl alcohol in the Injection is not less than 1.35%
suitability solution. The resolution between the sulfate and
and not more than 1.65%.
oxalate peaks is greater than 1. Separately inject 25 mL of the
Bacterial endotoxins h85i—It contains less than 0.01 USP
Standard solutions and the Test solution into the chromato-
Endotoxin Unit per unit of anti-factor Xa activity in USP Anti-
graph, and plot the standard curve of sulfate peak height as
factor Xa Units Unit.
a function of sulfate concentration (in mg per g) in the
Free sulfate content— Standard solutions. From the sulfate peak height in the
In-Process Revision
Mobile phase—Prepare a 3.0 mM sodium carbonate chromatogram determine the concentration of sulfate, T, in mg
solution. Make adjustments if necessary. per g, in the Test solution using the standard curve. Calculate
Standard sulfate stock solution—Prepare a solution of the percentage of free sulfate content (w/v) (w/w) in the
sodium sulfate in Mobile phase in a suitable sulfate-free Injection taken by the formula:
container such that the concentration of sulfate is accurately
known at about 1 g per L. Transfer about 5 g, accurately T 6 MS / 10m
weighed, of the solution to a similar container, and add
Mobile phase to obtain about 25 g of solution.
1 2
Available as Lichrospher 100 RP 18, Pore size 100 Å, Particle size Available as Anion Self-Regenerating Suppressor (ASRS) from
5 mm, or equivalent. Dionex Inc, or equivalent.
Pharmacopeial Forum
in which m is the mass, in mg, of Injection aliquoted to Add the following:

~
prepare the Test solution. The percentage of free sulfate is not Eprinomectin
more than 0.12%.
Anti-factor IIa activity—Proceed as directed for Anti-factor

IIa activity under Enoxaparin Sodium.
Assay (anti-factor Xa activity)—Proceed as directed for

Assay (anti-factor Xa activity) under Enoxaparin Sodium.
Anti-factor Xa to anti-factor IIa ratio—The ratio of the
numerical value of the anti-factor Xa activity in USP Anti-
Factor Xa Units per mg to the numerical value of the anti- C50H75NO14 (Component B1a) 914.13.
factor IIa activity in USP Anti-Factor IIa Units per mg, as C49H73NO14 (Component B1b) 900.10.
determined by the Assay (anti-factor Xa activity) and the Anti-

Component B1a
factor IIa activity, respectively, is not less than 3.3 and not
more than 5.3. Avermectin A 1a , 4’’-(acetylamino)-5-O-demethyl-4’’-de-
Other requirements—It meets the requirements under oxy-, (4’’R)-;
Injections h1i, Particulate Matter in Injections h788i, and ( 2 a E , 4 E , 5 ’ S , 6 S , 6 ’ R , 7 S , 8 E , 11 R , 1 3 S , 1 5 S , 1 7 a R , 2 0 -

Sterility Tests h71i.~USP31 R,20aR,20bS)-6’-(S)-sec-Butyl-
5’,6,6’,7,10,11,14,15,17a,20,20a,20b-dodecahydro-
20,20b-dihydroxy-5’,6,8,19-tetramethyl-17-oxo-
s p i r o [ 11 , 1 5 - m e t h a n o - 2 H , 1 3 H , 1 7 H - f u r o [ 4 , 3 , 2 -
pq][2,6]benzodioxacyclooctadecin-13,2’-[2H]pyran]-7-
BRIEFING yl-4-O-(4-acetamido-2,4,6-trideoxy-3-O-methyl-a- L -
lyxo-hexopyranosyl)-2,6-dideoxy-3-O-methyl-a-L-ara-
Eprinomectin. Because there is no existing USP monograph for
this drug substance, a new monograph is being proposed. The test bino-hexopyranoside (or (4’’R)-4’’-(acetylamino)-5-O-de-
for Limit of residual solvents is a GC method in which the gas
chromatograph is equipped with a flame-ionization detector and methyl-4’’-deoxyavermectin A1a) [133305-88-1].
a 0.53-mm 6 25-m capillary column coated with a 20-mm S3
stationary phase. USP has received information indicating that
a Varian Chrompack PoraPLOT Q brand of S3 column is suitable for
In-Process Revision
use. The tests for Limit of 8a-oxo-B1a and Related compounds and the
Assay are HPLC methods validated using an Inertsil C8 brand of
a 4.6-mm 6 25-cm column that contains 5-mm L7 packing. It is
noted that the system suitability requirement of the Limit of 8a-oxo-
B1a test is run under different chromatographic conditions than the
Procedure. USP has received information that the Limit of 8a-oxo-
B1a method, as proposed, is included in the approved regulatory
filings for this drug substance. Interested parties are invited to submit
comments.
(VET: I. DeVeau) RTS—C45125
Pharmacopeial Forum
Component B1b Specific rotation h781Si: between +1328 and +1408,

determined at 405 nm on the anhydrous, solvent-free, and
Avermectin A1a, 4’’-(acetylamino)-5-O-demethyl-25-de(1-
antioxidant-free basis.
methylpropyl)-4’’-deoxy-25-(1-methylethyl)-, (4’’R)-;
Test solution: 5 mg per mL, in chloroform.
( 2 a E , 4 E , 5 ’ S , 6 S , 6 ’ R , 7 S , 8 E , 11 R , 1 3 S , 1 5 S , 1 7 a R , 2 0 - Water, Method Ia h921i: not more than 2.0%, determined

R,20aR,20bS)-5’,6,6’,7,10,11,14,15,17a,20,20a,20b- on 0.250 g.
Dodecahydro-20,20b-dihydroxy-6’-isopropyl-5’,6,8,19- Residue on ignition h281i: not more than 0.1%.
tetramethyl-17-oxospiro[11,15-methano-2H,13H,17H-
Heavy metals, Method II h231i: not more than 10 ppm.
furo[4,3,2-pq][2,6]benzodioxacyclooctadecin-13,2’-
Limit of residual solvents—
[2H]pyran]-7-yl-4-O-(4-acetamido-2,4,6-trideoxy-3-O-
Standard solution I—Transfer 3.0 mL of acetonitrile, 3.0
methyl-a- L -lyxo-hexopyranosyl)-2,6-dideoxy-3-O-
mL of methanol, 3.0 mL of isopropyl acetate, and 3.0 mL of
methyl-a-L-arabino-hexopyranoside (or (4’’R)-4’’-(acety-
heptane to a 50-mL volumetric flask. Dilute with dimethyl-
lamino)-5-O-demethyl-25-de(1-methyl-propyl)-4’’-
acetamide to volume, and mix well.
deoxy-25-(1-methylethyl)avermectin A1a)
Standard solution II—Transfer 1.0 mL of Standard solution
[133305-89-2].
I to a 100-mL volumetric flask, dilute with dimethylacetamide
to volume, and mix well. Further dilute 10.0 mL of this
» Eprinomectin is a mixture of Component B1a and solution with dimethylacetamide to 50.0 mL, and mix well
Component B1b. It contains not less than 90 percent Test solution—Transfer 1 g of Eprinomectin in dimethyl-
of Component B1a and not less than 95.0 percent of acetamide to a 10-mL volumetric flask. Dilute with
dimethylacetamide to volume, and mix well.
Components B1a and B1b, calculated on the
Sensitivity solution I—Transfer 3.0 mL each of methanol,
anhydrous, solvent-free, and antioxidant-free
isopropyl acetate, and heptane to a 50-mL volumetric flask.
basis. It may contain small amounts of a suitable
Dilute with dimethylacetamide to volume, and mix well.
antioxidant.
Further dilute 50 mL of this solution with dimethylacetamide
Packaging and storage—Preserve in tight containers, and to 25 mL, and mix well.
store between 28 and 88 at ambient humidity. Sensitivity solution II—Transfer 3.0 mL of acetonitrile to
a 50-mL volumetric flask, dilute with dimethylacetamide to
Labeling—Label it to state the name(s) and amount(s) of any
In-Process Revision
volume, and mix well. Further dilute 50 mL of this solution
added substance(s). Label to indicate that it is for veterinary
with dimethylacetamide to 25 mL.
use only.
Sensitivity solution III—Transfer 5.0 mL of Sensitivity
USP Reference standards h11i—USP Eprinomectin RS.
solution I and 1.0 mL of Sensitivity solution II to a 50-mL
Identification— volumetric flask, dilute with dimethylacetamide to volume,
A: Infrared Absorption h197Mi. and mix well. [NOTE—This solution contains 100 ppm (m/m)
B: The retention times of the Component B1a peak and of methanol, isopropyl acetate, and heptane and 20 ppm (m/
the Component B1b peak in the chromatogram of the Assay m) of acetonitrile.]
preparation correspond to those in the chromatogram of the Chromatographic system (see Chromatography h621i)—
Standard preparation, as obtained in the Assay. The gas chromatograph is equipped with a flame-ionization
detector and a 0.53-mm 6 25-m fused-silica analytical
Pharmacopeial Forum
column coated with a 20-mm S3 stationary phase. The carrier System suitability mobile phase—Use the Mobile phase as
gas is helium with a flow rate of 20 mL per minute. The directed in the Assay.
chromatograph is programmed as follows: the column Mobile phase—Use a mixture of acetonitrile and Solution A
temperature is increased from 1108 at a rate of 58 per (13 : 7). Make adjustments if necessary (see System Suitability
minute to 1608 and maintained at 1608 for 5 minutes. The under Chromatography h621i).
column temperature is then increased at a rate of 308 per Standard solution—Use the Standard preparation, pre-
minute to 2208 and maintained at 2208 for 25 minutes. The pared as directed in the Assay.
injection port temperature is maintained at 2008, and the Test solution—Use the Assay preparation, prepared as
detector temperature is maintained at 2208. Chromatograph directed in the Assay.
Sensitivity solution III and Standard solution II as directed for Butylated hydroxytoluene solution—Transfer 50 mg of
Procedure: in the chromatogram obtained from Sensitivity butylated hydroxytoluene to a 100-mL volumetric flask, and
solution III, the peaks for methanol, acetonitrile, isopropyl dilute with methanol to volume. Sonicate, if necessary, and
acetate, and heptane are detectable and elute at relative mix well. Dilute 2 mL of the resulting solution with Diluent
retention times of 1, 2.1, 7.6, and 8.6, respectively. In the to 100 mL.
chromatogram obtained from Standard solution II, the System suitability determination—Use the conditions as
relative standard deviations for the areas of the solvent directed for Chromatographic system in the Assay.
peaks are not more than 5.0% for six injections. Chromatographic system (see Chromatography h621i)—
Procedure—Separately inject equal volumes (about 1 mL) The liquid chromatograph is equipped with a 280-nm detector
of Standard solution II and the Test solution. Reinject and a 4.6-mm 6 25-cm column that contains 5-mm packing
Standard solution II in duplicate after every six sample L7. The flow rate is 1.5 mL per minute, and the column
injections. The individual values for the area response of the temperature is 408. Chromatograph the Butylated hydroxytol-
two injections agree within +5% of their corresponding uene solution and the Test solution, and record the peak
average response. Calculate the percentage of each solvent responses as directed for Procedure: the retention time for the
present using the following formula: peak corresponding to butylated hydroxytoluene is approx-
imately 12 to 17 minutes, and the relative standard deviation
0.12D(rU / rS) of the peak area is not more than 3.0% for six injections. In
the chromatogram obtained from the Test solution, the
in which D is the density, in mg per mL, of acetonitrile
In-Process Revision
retention time for the peak corresponding to 8a-oxo-B1a is

(0.787), isopropyl acetate (0.870), methanol (0.796), and approximately 4 to 9 minutes.
heptane (0.684); r U is the solvent peak area in the Procedure—Separately inject equal volumes (about 15 mL)
chromatogram obtained from the Test solution; and rS is the of the Butylated hydroxytoluene solution and the Test solution
solvent peak area in the chromatogram obtained from into the chromatograph, record the chromatograms, and
Standard solution II. Not more than 0.005% of acetonitrile measure the areas for the major peaks. Calculate the content
is found, and the sum of all solvents is not more than 0.5%. of 8a-oxo-B1a, in mg, on the anhydrous, solvent-free, and
Limit of 8a-oxo-B1a— antioxidant-free basis taken by the formula:
Diluent, Solution A, Solution B, and System suitability
solution—Proceed as directed in the Assay. DCPF(rU / rS)
Pharmacopeial Forum
in which D is the dilution factor, in mL, used to prepare the Assay—

Test solution; C is the concentration, in mg per mL, of Solution A: 0.1% (v/v) solution of perchloric acid in
butylated hydroxytoluene in the Butylated hydroxytoluene water.
solution; P is the purity of butylated hydroxytoluene used to Solution B: acetonitrile.
prepare the Butylated hydroxytoluene solution; F is equal to Mobile phase—Use variable mixtures of Solution A and
0.4 and is the relative response factor for butylated Solution B as directed for Chromatographic system. Make
hydroxytoluene with respect to 8a-oxo-B1a; and rU and rS adjustments if necessary (see System Suitability under
are the peak areas for 8a-oxo-B1a and butylated hydroxytol- Chromatography h621i).
uene in the chromatograms obtained from the Test solution Diluent—Prepare a solution of four volumes of methanol
and the Butylated hydroxytoluene solution, respectively. Not and one volume of water.
more than 0.5% of 8a-oxo-B1a is found. Standard preparation—Dissolve an accurately weighed
Related compounds— quantity of USP Eprinomectin RS in Diluent to prepare
Diluent, Solution A, Solution B, Mobile phase, System a solution containing a known concentration of about 0.500
suitability solution, and Chromatographic system—Proceed mg per mL.
as directed in the Assay. System suitability solution—Transfer 4 mL of Standard
Standard solution—Use the Standard preparation, pre- preparation to an HPLC vial. Add 2 drops of 1 M sodium
pared as directed in the Assay. hydroxide and let stand for 20 minutes prior to injecting into
Test solution—Use the Assay preparation, prepared as the chromatograph.
directed in the Assay. Assay preparation—Dissolve an accurately weighed quan-
Procedure—Inject a volume (about 15 mL) of the Test tity of Eprinomectin in Diluent to prepare a solution
solution into the chromatograph, record the chromatogram, containing a known concentration of about 0.500 mg per mL.
and measure the peak areas. Calculate the percentage of Chromatographic system (see Chromatography h621i)—
eprinomectin related compounds in the portion of Eprino- The liquid chromatograph is equipped with a 245-nm detector
mectin taken by the formula: and a 4.6-mm 6 25-cm column that contains 5-mm packing
L7. The flow rate is 1.5 mL per minute, and the column
100(ri / rs) temperature is 408. The chromatograph is programmed as
follows:
in which ri is the peak area of each individual related
In-Process Revision
Time Solution A Solution B
substance obtained from the Test solution, and rs is the sum of
(minute) (%) (%) Elution
the responses of all the peaks: for related compounds with
0–15 45 55 isocratic
relative retentions of 0.23, 0.93, and 1.16 with respect to the
15–25 45?5 55?95 linear gradient
B1a peak, not more than 1.0%; for impurity A, not more than
1.0%; for impurity E, not more than 1.0%; for all other known
impurities, not more than 0.5%; for total unknown impurities,
not more than 1.0%; and for total impurities, not more than Chromatograph the System suitability solution and the
5.0% is found. Standard preparation as directed for Procedure: the relative
retention times are about 0.55, 0.77, 1.00, 1.05, and 1.28 for
impurity A, component B1b, component B1a, impurities C + D,
Pharmacopeial Forum
and impurity E, respectively. The resolution, R, between

BRIEFING
components B1b and B1a is not less than 3; the resolution, R,
between component B1a and impurities C + D is at least 1; the Fluvastatin Sodium, USP 29 page 961 and page 1682 of PF
32(6) [Nov.–Dec. 2006]. It is proposed to correct the name of an
symmetry factor for the B1a peak is not more than 1.5; and the impurity that elutes at a relative retention time of about 1.6. New
data indicate that this impurity is a lactone and not a ring-open 3-
theoretical plate count for the B1a peak is greater than 4,500. keto-5-hydroxy form. In addition, the detailed study of this impurity
resulted in an updated relative response factor of 1.0. The limit of
In the chromatogram of the Standard preparation, the relative this impurity remains unchanged at ‘‘not more than 0.1%’’.
standard deviation for the peak corresponding to B1a is not
(MD-GRE: E. Gonikberg) RTS—C48998
more than 1.0% for five injections.
Procedure—Separately inject equal volumes (about 15 mL) Change to read:
of the Standard preparation and the Assay preparation into Packaging and storage—Preserve in tight, light-resistant contain-
ers, protected from moisture. Store between 158 and 308.
the chromatograph, record the chromatograms, and measure
~
the areas for the major peaks. Calculate the percentage of Store at a temperature not exceeding 408.~USP30
component B1a by the formula: Add the following:

~
Labeling—Where it is a hydrated form, the label so
100(rU/rT)
indicates.~USP31
in which rU is the peak area of component B1a in the Change to read:
chromatogram obtained from the Assay preparation; and rT is USP Reference standards h11i—USP Fluvastatin Sodium RS. USP
Fluvastatin Related Compound A RS.
the sum of the peak areas of components B1a and B1b. ~
~USP30
Calculate the quantity, in mg, of C50H75NO14 (component USP Fluvastatin Related Compound B RS. USP Fluvastatin for
System Suitability RS.
B1a) and C49H73NO14 (component B1b) in the portion of ~
[NOTE—USP Fluvastatin for System Suitability RS contains
Eprinomectin taken by the formula:
1% to 2% of the fluvastatin sodium anti-isomer.]~USP30
DC(rU / rS)
Change to read:
Identification—
in which D is the dilution factor, in mL, used to prepare the A: Infrared Absorption h197Ki.
Assay preparation; C is the concentration, in mg per mL, of ~
[NOTE—If a difference appears in the IR spectra of the
component B1a or component B1b in the Standard prepara- analyte and the standard, dissolve equal portions of the test
In-Process Revision
tion; and rU and rS are the peak areas of component B1a or specimen and the USP Reference Standard in equal volumes
component B1b in the chromatograms obtained from the Assay of methanol. Evaporate the solutions to dryness on a steam
preparation and the Standard preparation, respectively.~USP31 bath, protecting the solutions from light, and dry at 1058 for
30 minutes. Repeat the test on the residues.]~USP31
B: Ultraviolet Absorption h197Ui.
~
~USP30
C:
~
B:~USP30
A solution (0.2 in 1) meets the requirements of the flame test for
Sodium h191i.
Pharmacopeial Forum
Change to read: Calculate the percentage of each impurity, except for 3-hydroxy-5-
keto fluvastatin, in the portion of Fluvastatin Sodium taken by the
Water, Method I h921i: not more than 4.0%; formula:
~ 100F(CS / CT)(ri (305) / rS (305))
if labeled as a hydrated form: not more than 12.0%. [NOTE—
For this monograph, the term ‘‘hydrated form’’ refers to
~
several known forms of Fluvastatin Sodium that are not 100(1/F)(CS / CT)(ri (305) / rS (305))~USP30
stoichiometric hydrates.]~USP31 in which F is the relative response factor as listed in Table 1 [NOTE—
Use F equal to 1.0 for unknown impurities]; CS is the concentration,
Change to read: in mg per mL, of USP Fluvastatin Sodium RS in the Standard
solution; CT is the concentration, in mg per mL, of Fluvastatin
Sodium in the Test solution; ri (305) is the peak response at 305 nm for
Chromatographic purity—[NOTE—Protect all solutions from light, each impurity obtained from the Test solution; and rS (305) is the peak
and use amber autosampler vials and low-actinic glassware.] response at 305 nm for the fluvastatin peak obtained from the
Solution A, Solution B, and Mobile phase—Proceed as directed in Standard solution.
the Assay. Calculate the percentage of 3-hydroxy-5-keto fluvastatin in the
System suitability stock solution—Prepare a solution in a mixture portion of Fluvastatin Sodium taken by the formula:
of methanol and acetonitrile (3 : 2) containing about 0.1 mg of USP
Fluvastatin Related Compound A RS and about 0.1 mg of USP 100F(CS / CT)(ri(365) / rS (365))
Fluvastatin Related Compound B RS per mL.
~
~USP30
~
System suitability solution—Transfer about 50 mg of USP 100(1/F)(CS / CT)(ri (365) / rS (365))~USP30
Fluvastatin for System Suitability RS, accurately weighed, to
a 100-mL volumetric flask, and dissolve in 35 mL of Solution B.
Add 5.0 mL of System suitability stock solution into the flask, dilute in which F, CS, and CT are as defined above; ri (365) is the peak
with Solution A to volume, and mix. response at 365 nm for 3-hydroxy-5-keto fluvastatin obtained from
the Test solution; and rS (365) is the peak response at 365 nm for the
~
Prepare a solution in a mixture of methanol and acetonitrile fluvastatin peak obtained from the Standard solution. In addition to
not exceeding the limits for each impurity in Table 1, not more than
(3 : 2) containing about 0.1 mg of USP Fluvastatin Related 0.1% of any other individual impurity is found; and not more than
1.0% of total impurities is found.
Compound B RS per mL. Transfer about 0.5 mL of this
solution to a 10-mL volumetric flask, and dilute to volume
with the System suitability preparation, prepared as directed
Table 1
in the Assay.~USP30
[NOTE—The System suitability stock solution and the Relative Relative
Retention Response
~
~USP30 Name Time Factor (F) Limit (%)
System suitability solution is stable for up to 6 months if stored in Fluvastatin N-ethyl 0.7 0.9 0.1
a refrigerator.] analog ~
Standard solution—Use the Standard preparation, prepared as 1.2~USP30
~
directed in the Assay. 2
~USP30
Test solution—Use the Assay preparation, prepared as directed in Fluvastatin anti- 1.2 1.0 0.8
the Assay. isomer
Chromatographic system—Proceed as directed in the Assay,
except use the liquid chromatograph equipped with either a pro- ~
3
~USP30
grammable variable wavelength detector or two separate detectors
3-Hydroxy-5-keto 1.5 0.0371 0.1
In-Process Revision
capable of monitoring at 305 nm and at 365 nm. Chromatograph the
System suitability solution, and record the peak responses at 305 nm fluvastatin ~
as directed for Procedure. Identify the peaks corresponding to ~
27.01~USP30
4
fluvastatin, fluvastatin anti-isomer, fluvastatin hydroxydiene, ~USP30
~
3-Keto-5-hydroxy 1.6 ~
1.6 0.1
~USP30 fluvastatin 0.63~USP30
and fluvastatin t-butyl ester. The resolution, R, between fluvastatin ~ ~
anti-isomer and fluvastatin is not less than 1.6; the column efficiency Fluvastatin lac- 1.0~USP31
is not less than 700 theoretical plates for the fluvastatin peak; and the
tailing factor is not more than 3.0. Chromatograph the Standard tone~USP31
solution, and record the peak responses at 305 nm as directed for
Procedure: the relative standard deviation for replicate injections is ~
not more than 1.0%. 5
~USP30
Procedure—Separately inject equal volumes (about 20 mL) of the Fluvastatin hydroxy- 2.0 1.1 0.1
Standard solution and the Test solution into the chromatograph, diene2
record the chromatograms at 305 nm and 365 nm, identify the ~
0.92~USP30
impurities listed in Table 1, and measure the peak responses. [NOTE— ~
6
~USP30
3-Hydroxy-5-keto fluvastatin is monitored using a wavelength of
365 nm, and all other compounds are monitored at 305 nm.]
Pharmacopeial Forum
Add the following:

Table 1 (Continued)
&FosinoprilSodium and
Relative Relative
Retention Response Hydrochlorothiazide Tablets
Name Time Factor (F) Limit (%)
Fluvastatin short 3.0 0.7 0.1
chain aldehyde ~
~7
1.4~USP30
~USP30
Fluvastatin t-butyl 3.4 1.1 0.2 » Fosinopril Sodium and Hydrochlorothiazide

ester ~
~
0.94~USP30 Tablets contain not less than 90.0 percent and not
(fluvastatin related
compound B)~USP30
more than 110.0 percent of the labeled amount of
3
fosinopril sodium (C30H45NNaO7P) and of hydro-
~
8
~USP30
chlorothiazide (C7H8ClN3O4S2).
1
At 365 nm
2
Fluvastatin related compound A.
~ Packaging and storage—Preserve in tight containers, and
[R*,S*-E]-(+)-7-[3-(4-Fluorophenyl)-1-ethyl-1H-indol-2-yl]-3,5-
dihydroxy-6-heptenoic
3
acid monosodium salt.~USP30 store at controlled room temperature.
Fluvastatin related compound B.
~
[R*,R*-E]-(+)-7-[3-(4-Fluorophenyl)-1-(methylethyl)-1H-
indol-2-yl]-3,5-dihydroxy-6-heptenoic acid monosodium Change to read:
salt.~USP30
~4
E-(+)-7-[3-(4-Fluorophenyl)-1-(methylethyl)-1H-indol-2- USP Reference standards h11i—USP Benzothiadiazine
yl]-3-hydroxy-5-oxo-6-heptenoic acid monosodium
~
salt.~USP30 Related Compound A RS. USP Chlorothiazide RS.~USP31
~5
E-(+)-7-[3-(4-Fluorophenyl)-1-(methylethyl)-1H-indol-2-
yl]-3-oxo-5-hydroxy-6-heptenoic acid monosodium USP Fosinopril Sodium RS. USP Fosinopril Related
~
salt. (S,E)-6-(2-(3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-2- Compound A RS. USP Fosinopril Related Compound H RS.
yl)vinyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-one monosodium
salt.~USP31~USP30
~ 6 USP Hydrochlorothiazide RS.
[E,E]-(+)-7-[3-(4-Fluorophenyl)-1-(methylethyl)-1H-
indol-2-yl]-3-hydroxy-4,6-heptadienoic acid monosodium
salt.~USP30 Change to read:
~7
3-(4-Fluorophenyl)-1-(methylethyl)-1H-indole]-2-carbox-
aldehyde.~USP30
~8
[R*,S*-E]-(+)-7-[3-(4-Fluorophenyl)-1-methylethyl-1H- Identification—
indol-2-yl]-3,5-dihydroxy-6-heptenoic acid 1,1-dimethylethyl
ester.~USP30 A: Infrared Absorption h197Fi—
FOSINOPRIL SODIUM—Transfer a portion of the finely
powdered Tablets, equivalent to about 25 mg of fosinopril
sodium, to a 100-mL beaker containing 40 mL of water, heat
In-Process Revision
BRIEFING at 308 for 5 minutes with stirring, and filter through a funnel
having a medium-porosity fritted disk. Centrifuge the filtrate
Fosinopril Sodium and Hydrochlorothiazide Tablets, page at 2500 rpm for 30 minutes. Adjust the filtrate with
2006 PF 30(6) [Nov.–Dec. 2004]. On the basis of comments
received, it is proposed to revise the test for Related compounds and hydrochloric acid to a pH of 1 to precipitate the fosinopril,
replace the tests for Assay for fosinopril and Assay for hydrochlo-
rothiazide with a single Assay because the tests as originally and filter through a fritted-disk funnel. Dissolve the
proposed cannot be used to monitor both the active ingredients in
this combination drug product. The proposed test method uses precipitate by passing methyl iosobutyl ketone through the
a liquid chromatographic system and a YMC-pack Pro RS 80A
column containing packing L1. The typical retention times for filter, and evaporate the filtrate to dryness under a stream of
fosinopril sodium and hydrochlorothiazide are between 5 to 8
minutes and 17 to 22 minutes, respectively. nitrogen. Proceed as directed, using the oily residue so
(MD-CV: S. Ramakrishna) RTS—C46947 obtained and a similarly prepared residue from 25 mg of USP
Fosinopril Sodium RS.
Pharmacopeial Forum
HYDROCHLOROTHIAZIDE—Transfer a portion of the finely Resolution solution—Transfer 5 mg of USP Fosinopril

powdered Tablets, equivalent to about 37.5 mg of hydro- Related Compound H RS into a 100-mL volumetric flask, and
chlorothiazide, to a 250-mL beaker containing 120 mL of dissolve in 5 mL of methanol. Add 2.0 mL of Standard stock
water, heat at 308 for 5 minutes with stirring, and filter solution B, dilute with methanol to volume, and mix.
through a funnel having a medium-porosity fritted disk. Wash Test solution—Use portions of the solution under test
the precipitate with 60 mL of methylene chloride and glacial passed through a 1.2-mm acrylic filter. [NOTE—Do not use
acetic acid (90 : 10) mixture, and discard the filtrate. Dissolve glass filters.]
the precipitate by passing 10 mL of methyl isobutyl ketone Chromatographic system (see Chromatography h621i)—
through the filter, and evaporate the filtrate to dryness under The liquid chromatograph is equipped with a variable
a stream of nitrogen. Proceed as directed, using the waxy wavelength detector set at 210 nm and 272 nm and a
residue so obtained and a similarly prepared residue from 37 4.6-mm 6 25-cm column, maintained at 408 that contains
mg of USP Hydrochlorothiazide RS. 5-mm packing L10. The flow rate is about 1.3 mL per minute.
B: The retention times of the fosinopril sodium and With the detector set at 215 nm, chromatograph the
hydrochlorothiazide peaks in the chromatogram of the Assay Resolution solution and the Standard solution, and record
preparation correspond to those of the Standard preparation, the peak responses as directed for Procedure: the resolution,
as obtained in the Assay. for fosinopril sodium and Assay for R, between the fosinopril related compound H peak and
~
hydrochlorothiazide, respectively. ~USP31 hydrochlorothiazide peak is not less than 1.5; and the relative
Dissolution h711i— standard deviation for replicate injections of the Standard
Medium: water; 900 mL. solution is not more than 1.5%.
Apparatus 2: 50 rpm. Procedure—Separately inject equal volumes (about 50 mL)
Time: 30 minutes. of a filtered portion of the Test solution and the Standard
Mobile phase—Prepare a filtered and degassed mixture of solution, and record the chromatograms with the detector set
0.01 M monobasic potassium phosphate (pH 3.0), methanol, at 272 nm from 0 to 5 minutes and at 210 from 5 to 9 minutes,
and acetonitrile (45 : 35 : 20). Make adjustments if necessary for hydrochlorothiazide and fosinopril sodium, respectively.
(see System Suitability under Chromatography h621i). Measure the responses for the major peaks, and calculate the
Standard stock solutions—Separately dissolve about 20 mg amount of C30H45NNaO7P and of C7H8ClN3O4S2 dissolved.
of USP Fosinopril Sodium RS and USP Hydrochlorothiazide Tolerances—Not less than 80% (Q) of the labeled amount
RS accurately weighed in 6 mL of methanol, and dilute with of C30H45NNaO7P and not less than 75% (Q) of the labeled
In-Process Revision
water to obtain solutions (Standard stock solution A and B) amount of C7H8ClN3O4S2 are dissolved in 30 minutes.
having known concentrations of about 0.1 mg per mL of USP Uniformity of dosage units: meet the requirements.
Fosinopril Sodium RS and USP Hydrochlorothiazide RS,
Change to read:
respectively.
Standard solution—Mix 25 mL of Standard stock solution Related compounds—
B and x25 mL of Standard stock solution A, and dilute with TEST 1—
water to 200 mL, x being the ratio of the respective labeled Mobile phase, Diluent, and Chromatographic system—
amounts, in mg, of fosinopril sodium to that of hydrochlo- Proceed as directed in the Assay for fosinopril sodium.
rothiazide per Tablet.
Pharmacopeial Forum
Standard solution—Dissolve an accurately weighed quan- of about 0.2 mg per mL. Dilute an aliquot (2 in 100) in
tity of USP Fosinopril Related Compound A RS in methanol Mobile phase to obtain a solution containing 0.004 mg per
to obtain a solution having a known concentration of about mL.
0.1 mg per mL. Dilute an aliquot (5 in 200) in Diluent to Test solution—Use the Assay preparation, prepared as
obtain a solution containing 0.0025 mg per mL. directed in the Assay for hydrochlorothiazide.
Test solution—Use the Assay preparation, prepared as Procedure—Separately inject equal volumes (about 25 mL)
directed in the Assay for fosinopril sodium. of the Standard solution and the Test solution into the
Procedure—Separately inject equal volumes (about 25 mL) chromatograph, record the chromatograms, and measure the
of the Standard solution and the Test solution into the responses for the major peaks. Disregard the peak for
chromatograph, record the chromatograms, and measure the fosinopril. Calculate the percentage of benzothiadiazine
peak responses for the major peaks. Disregard the peak for related compound A in the portion of Tablets taken by the
hydrochlorothiazide. Calculate the percentage of fosinopril formula:
related compound A in the portion of Tablets taken by the
formula: 20C(D/L)(rU / rS),
20 C(D/L)(rU / rS), in which C is the concentration, in mg per mL, of

benzothiadiazine related compound A in the Standard
in which C is the concentration, in mg per mL, of fosinopril solution; D is the volume, in mL, of the Test solution; L is
related compound A in the Standard solution; D is the the labeled amount, in mg per Tablet, of hydrochlorothiazide;
volume, in mL, of the Test solution; L is the labeled amount, and rU and rS are the peak responses of benzothiadiazine
in mg per Tablet, of fosinopril sodium; and rU and rS are the related compound A obtained from the Test solution and the
peak responses of fosinopril related compound A obtained Standard solution, respectively. Not more than 0.5% of
from the Test solution and the Standard solution, respectively. benzothiadiazine related compound A is found.
~
Not more than 4% of fosinopril sodium related compound A Solution A, Solution B, Diluent 2, and Mobile phase—
is found. Calculate the percentage of any other impurity in the Proceed as directed in the Assay.
portion of Tablets taken by the formula: Standard solution—Dissolve accurately weighed quantities
of USP Fosinoprol Sodium RS and USP Hydrochlorothiazide
100(ri / rs), RS in a suitable volumetric flask in Diluent 2 to obtain
In-Process Revision
a solution having a known concentration of about 0.004 mg

in which ri is the peak response for each impurity; and rs is the
per mL of each USP Reference Standard.
sum of the responses of all of the peaks: not more than 0.1%
System suitability solution—Dissolve accurately weighed
of any other individual impurity is found, and not more than
quantities of USP Chlorothiazide RS, USP Hydrochlorothi-
5.0% of total impurities is found.
azide RS, USP Fosinopril Sodium RS, USP Fosinopril
TEST 2—
Related Compound A RS, and USP Benzothiadiazine Related
Mobile phase and Chromatographic system—Proceed as
Compound A RS in a suitable volumetric flask in Diluent 2.
directed in the Assay for hydrochlorothiazide.
Dilute stepwise, if necessary, to obtain a solution having
Standard solution—Dissolve an accurately weighed quan-
a known concentration of about 0.005 mg per mL of USP
tity of USP Benzothiadiazine Related Compound A RS in
Chlorothiazide RS, USP Fosinopril Related Compound A RS,
methanol to obtain a solution having a known concentration
Pharmacopeial Forum
and USP Benzothiadiazine Related Compound A RS and Resolution solution—Prepare a solution in Mobile phase
about 0.5 mg per mL of USP Hydrochlorothiazide RS and of having a known concentration of about 0.1 mg per mL of
USP Fosinopril Sodium RS. each of USP Fosinopril Related Compound A RS and USP
Test solution—Use the Assay preparation. Fosinopril Sodium RS.
Chromatographic system—Proceed as directed in the Standard preparation—Dissolve an accurately weighed
Assay. Chromatograph the Standard solution and the System quantity of USP Fosinopril Sodium RS in Diluent to obtain
suitability solution, and record the peak responses as directed a solution having a known concentration of about 0.1 mg per
for Procedure: the resolution, R, between chlorothiazide and mL.
hydrochlorothiazide is not less than 1.8; and the relative Assay preparation—Place 5 Tablets in each of two 500-mL
standard deviation for replicate injections is not more than volumetric flasks, add 400 mL of Diluent to each flask, shake
10.0%. for 45 minutes, dilute with Diluent to volume, and mix.
Procedure—Separately inject equal volumes (about 20 mL) Centrifuge a portion of the solution at 2000 rpm for 20
of the Standard solution and the Test solution into the minutes. Mix equal volumes of the supernatant, accurately
chromatograph, record the chromatograms, and measure the measured, and dilute, if necessary, to give an expected
peak responses eluting between 2.7 minutes and 27 minutes. fosinopril sodium concentration of about 0.1 mg per mL.
Calculate the percentage of any impurity or degradation Chromatographic system (see Chromatography h621i)—
product in the portion of Tablets taken by the formula: The liquid chromatograph is equipped with a variable
wavelength detector set at 215 nm and a 3.9-mm 6 30-cm
100(r U / rS)(CS / CS)(1/F) column that contains packing L1. The flow rate is about 2 mL
per minute. Chromatograph the Resolution solution and the
in which rU is the individual peak response for each impurity Standard preparation, and record the peak responses as
obtained from the Test solution; rS is the response of the directed for Procedure: the relative retention times are 0.4 for
fosinopril sodium or hydrochlorothiazide in the Standard related compound A and 1.0 for fosinopril sodium; the
solution; F is the relative response factor of each impurity resolution, R, between the fosinopril sodium and fosinopril
relative to fosinopril sodium or hydrochlorothiazide as related compound A peaks is not less than 4.0; and the
mentioned in Table 1; and C S and CU are the concentrations, relative standard deviation for replicate injections of the
in mg per mL, of fosinopril sodium or hydrochlorothiazide in Standard preparation is not more than 1.5%.
the Standard solution and the Test solution, respectively. The Procedure—Separately inject equal volumes (about 25 mL)
In-Process Revision
limits of impurities are specified in Table 1. ~USP31
of the Standard preparation and the Assay preparation into
Delete the following: the chromatograph, record the chromatograms, and measure
~ the responses for the major peaks. Continue the chromatog-
Assay for fosinopril sodium—
raphy up to 1.5 times the retention time of the fosinopril
Mobile phase—Prepare a degassed mixture of methanol
sodium peak. Calculate the quantity, in mg, of fosinopril
and 0.2% phosphoric acid (75 : 25). Make adjustments if
sodium (C30H45NNaO7P) in the portion of each Tablet taken
by the formula:
h621i).
Diluent: a mixture of 0.2 M urea and acetonitrile (80 : 20).
100(CD)(rU / rS),
Pharmacopeial Forum
Table 1
Component Time (RRT) Factor (RRF) Limit (%)

1
Benzothiadiazine related compound A 0.81 (relative to hydrochlorothia- 1.0 NMT 0.3
zide)
Fosinopril related compound A 2 0.72 (relative to fosinopril) 1.2 NMT 0.8
Chlorothiazide3 0.90 (relative to hydrochlorothia- 1.7 NMT 0.3
zide)
Any other individual impurity — — NMT 0.20 (relative to
hydrochlorothiazide)
Total of all impurities — — NMT 0.8
1
2
4-Amino-6-chloro-1,3-benzenedisulfonamide.
3
(4S)-4-Cyclohexyl-1-[hydroxy-(4-phenylbutyl)phosphinyl]acetyl-L-proline.
6-Chloro-2(H)-1,2,4-benzothiazine-7-sulfonamide.
in which C is the concentration, in mg per mL, of USP supernatant and dilute with Mobile phase to 100 mL, and
Fosinopril Sodium RS in the Standard preparation; D is the mix, to give an expected hydrochlorothiazide concentration of
dilution factor of the Assay preparation; and rU and rS are the about 12.5 mg per mL. Centrifuge a portion of the solution at
peak responses obtained from the Assay preparation and the 2000 rpm for 20 minutes.
Standard preparation, respectively.~USP31 Chromatographic system (see Chromatography h621i)—
The liquid chromatograph is equipped with a variable
wavelength detector set at 271 nm and a 3.9-mm 6 30-cm
~
Assay for hydrochlorothiazide—
column that contains packing L1. The flow rate is about 2 mL
Mobile phase—Prepare a degassed mixture of 0.2%
per minute. Chromatograph the Resolution solution and the
phosphoric acid and methanol (85 : 15). Make adjustments
Standard preparation, and record the peak responses as
if necessary (see System Suitability under Chromatography
directed for Procedure: the relative retention times are 0.7 for
h621i).
benzothiadiazine related compound A and 1.0 for hydrochlo-
Resolution solution—Prepare a solution in Mobile phase
rothiazide; the resolution, R, between the hydrochlorothiazide
having a known concentration of about 12.5 mg per mL of
In-Process Revision
and benzathiadiazine related compound A peaks is not less

USP Hydrochlorothiazide RS and 10 mg per mL of USP
than 2.0; and the relative standard deviation for replicate
Benzothiadiazine Related Compound A RS.
injections of the Standard preparation is not more than 1.5%.
Procedure—Separately inject equal volumes (about 25 mL)
quantity of USP Hydrochlorothiazide RS in Mobile phase to
obtain a solution having a known concentration of about 12.5
mg per mL.
the responses for the major peaks. Continue the chromatog-
Assay preparation—Place 5 Tablets in each of two 500-mL
raphy up to 1.5 times the retention time of the hydrochlo-
volumetric flasks, add 50 mL of water to each flask, and
rothiazide peak. Calculate the quantity, in mg, of
shake for 15 minutes to disintegrate the Tablets. Add about
hydrochlorothiazide (C7H8ClN3O4S2) in the portion of each
350 mL of methanol, shake for 45 minutes, dilute with
Tablet taken by the formula:
methanol to volume, and mix. Mix 5.0 mL of each
Pharmacopeial Forum
a known concentration of about 0.08 mg per mL of USP

Hydrochlorothiazide RS and of USP Fosinopril Sodium RS
100(CD)(rU / rS),
and 0.025 mg per mL of the USP Chlorothiazide RS.
in which C is the concentration, in mg per mL, of USP Assay preparation—Weigh and finely powder not fewer
Hydrochlorothiazide RS in the Standard preparation; D is the than 20 Tablets. Transfer an accurately weighed portion of the
dilution factor of the Assay preparation; and rU and rS are the powder, equivalent to about 10 mg of fosinopril and 12.5 mg
peak responses obtained from the Assay preparation and the of hydrochlorothiazide, to a 100-mL volumetric flask, add
Standard preparation, respectively.~USP31 about 75 mL of Diluent 2, and sonicate for about 10 minutes.
Shake by mechanical means for 15 minutes. Dilute with
Add the following:
Diluent 2 to volume, and mix. Pass a portion of this solution
~
Assay— through a filter (PTFE or PVDF) having a 0.45-mm or finer
Solution A—Prepare a filtered and degassed solution of porosity, and collect the rest of the filtrate. Dilute further,
0.01 M monobasic potassium phosphate. Adjust with stepwise if necessary, to obtain a solution having a known
phosphoric acid to a pH of 2.0. concentration of about 0.075 mg of fosinopril sodium.
Solution B—Use acetonitrile. Chromatographic system (see Chromatography h621i)—
Mobile phase—Use variable mixtures of Solution A and The liquid chromatograph is equipped with a 206-nm detector
Solution B as directed for Chromatographc system. Make and a 4.6-mm 6 15-cm column that contains packing L1.
adjustments if necessary (see System Suitability under The flow rate is about 1.0 mL per minute. The chromatograph
Chromatography h621i). is programmed as follows.
Diluent 1—Use a mixture of water and acetonitrile (2 : 1).
Diluent 2—Use a mixture of 0.001 N hydrochloric acid and
(minutes) (%) (%) Elution
acetonitrile (2 : 1).
Standard preparation—Transfer into two separate suitable 0–2 88 12 isocratic
volumetric flasks accurately weighed quantities of USP 2–20 88?10 12?90 linear gradient
Fosinopril Sodium RS and USP Hydrochlorothiazide RS. 20–28 10 90 isocratic
Dissolve USP Fosinopril Sodium RS in Diluent 1 and USP 28–37 10?88 90?12 linear gradient
Hydrochlorothiazide RS in Diluent 2 respectively, to obtain Chromatograph the Standard preparation and the System
stock solutions having known concentrations of about 2.0 mg suitability solution (about 20 mL), and record the peak
In-Process Revision
per mL. Dilute quantitatively, and stepwise if necessary, responses as directed for Procedure: the resolution, R,
portions of these two solutions with Diluent 2 to obtain between the chlorothiazide and hydrochlorothiazide peaks is
a solution having a known concentration of 0.08 mg per mL not less than 1.8; the tailing factor is less than 2.0; and the
of USP Fosinopril Sodium RS and of USP Hydrochlorothi- relative standard deviation for replicate injections is not more
azide RS. than 2.0%.
System suitability solution—Dissolve accurately weighed Procedure—Separately inject equal volumes (about 20 mL)
quantities of USP Chlorothiazide RS, USP Hydrochlorothi- of the Standard preparation and the Assay preparation into
azide RS, and USP Fosinopril Sodium RS in a suitable the chromatograph, record the chromatograms, and measure
volumetric flask in Diluent 2 to obtain a solution having
Pharmacopeial Forum
the peak responses. Calculate the percentage of fosinopril Apparatus 2: 50 rpm.

Time: 30 minutes.
sodium (C30H45NNaO7P) in the portion of the Tablets taken Procedure—Determine the amount of C21H30O5 dissolved from
UV absorbances at the wavelength of maximum absorbance at about
by the formula: 248 nm on filtered portions of the solution under test, suitably
diluted with Medium, if necessary, in comparison with a Standard
solution having a known concentration of USP Hydrocortisone RS
in the same Medium.
100(rU / rS)(CS / CU) Tolerances—Not less than 70% (Q) of the labeled amount of
C21H30O5 is dissolved in 30 minutes.
in which r U and rS are the peak responses of fosinopril sodium Change to read:
in the Assay preparation and the Standard preparation,
Uniformity of dosage units h905i: meet the requirements.
PROCEDURE FOR CONTENT UNIFORMITY—
respectively; and C S and CU are the concentrations, in mg per
Mobile solvent, Internal standard solution, and Standard
mL, of fosinopril sodium in the Standard preparation and the preparation—Prepare as directed in the Assay under Hydrocortisone.
Assay preparation, respectively. Calculate the percentage of

&
Mobile phase, Internal standard solution, and Standard
hydrochlorothiazide (C7H8ClN3O4S2) in the portion of the preparation—Prepare as directed in the Assay.&2S (USP30)
Tablets taken by the formula: Test preparation—Transfer 1 Tablet to a suitable container, and
add about 0.3 mL of water directly on the Tablet. Allow the Tablet to
stand for about 5 minutes. Shake the container to break up the Tablet,
and sonicate briefly to ensure complete disintegration. Add a few
100(r U / rS)(CS / CU) small glass beads and 50.0 mL of the Internal standard solution to
the container. Shake the container for about 30 minutes. Dilute an
accurately measured volume of the clear supernatant with a known,
accurately measured volume of the Internal standard solution to
in which rU and rS are the peak responses of hydrochlorothi- obtain a final concentration of 0.1 mg per mL. Shake the contents of
the container to mix, and analyze the clear solution as directed for
azide in the Assay preparation and the Standard preparation, Procedure.
Procedure—
respectively; and C S and CU are the concentrations, in mg per
&
Chromatographic system and Procedure—&2S (USP30)
mL, of hydrochlorothiazide in the Standard preparation and Proceed as directed for Procedure in the Assay under Hydrocortisone
the Assay preparation, respectively.~USP31&1S (USP30) &
Proceed as directed in the Assay.&2S (USP30)
Calculate the quantity, in mg, of C21H30O5 in the Tablet taken by the
formula:
50(F2 / F1)C(RU / RS)
in which F1 is the volume, in mL, of the supernatant aliquot of the
solution from the Tablet taken for dilution; F2 is the final volume, in
mL, of the Test preparation; and the other terms are as defined for
Procedure in the Assay under Hydrocortisone.
BRIEFING &
Procedure in the Assay.&2S (USP30)
Hydrocortisone Tablets, USP 29 page 1069 and page 1083 of PF Change to read:
In-Process Revision
32(4) [July–Aug. 2006]. It is proposed to add the units of volume to

the dissolution Medium in the test for Dissolution.
Assay—
Mobile solvent, Internal standard solution, and Standard
(BPC: M. Marques) RTS—C50815 preparation—Prepare as directed in the Assay under Hydrocortisone.
&
Mobile phase—Prepare a solution containing a mixture of
Change to read: butyl chloride, water-saturated butyl chloride, tetrahydrofu-
USP Reference standards h11i—USP Hydrocortisone RS. ran, methanol, and glacial acetic acid (95 : 95 : 14 : 7 : 6).
&
USP Prednisone RS.&2S (USP30) Internal standard solution—Prepare a solution of USP
Prednisone RS in water-saturated chloroform containing 0.06
Change to read: mg per mL.
Dissolution h711i—
Medium: water; 900
~
mL.~USP31
Pharmacopeial Forum

BRIEFING
quantity of USP Hydrocortisone RS in Internal standard
solution to obtain a solution having a known concentration of Isosorbide Dinitrate Extended-Release Tablets, USP 29 page
1203, and page 3726 of the Second Supplement. It is proposed to add
about 0.1 mg per mL.&2S (USP30) Dissolution Test 2 to this monograph. In the absence of any adverse
Assay preparation—Weigh and finely powder not fewer than 10 comments, it is proposed to implement this revision via the Third
Tablets. Weigh a portion of the powder, equivalent to about 5 mg of Interim Revision Announcement pertaining to USP 30–NF 25, with
hydrocortisone, and transfer to a suitable container. Add 50.0 mL of an official date of June 1, 2007.
Internal standard solution. Shake vigorously for 30 minutes, and
centrifuge a portion of this mixture. Use the clear supernatant.
&
The liquid chromatograph is equipped with a 254-nm detector Add the following:
and a 3.9-mm 6 30-cm column that contains packing L3. .Labeling—When more than one Dissolution test is given,
The flow rate is 0.9 mL per minute. Chromatograph the the labeling states the Dissolution test used only if Test 1 is
not used..3
directed for Procedure: the resolution, R, between hydrocor-
Change to read:
tisone and prednisone is not less than 3.0; and the relative
standard deviation for four replicate injections is not more Dissolution h711i—
than 2.0%.&2S (USP30)

Procedure—Proceed as directed for Procedure in the Assay under .TEST 1—
.3
Hydrocortisone. Medium: water; 500 mL.
&
Separately inject equal volumes (about 10 mL) of the Times: 1, 2, 4, and 6 hours.
Determine the amount of C6H8N2O8 dissolved, using the following
Standard preparation and the Assay preparation into the method.
pH 3.0 Buffer solution—Add 6.6 g of ammonium sulfate,
chromatograph, record the chromatograms, and measure the accurately weighed, to 500 mL of water. Adjust with 1 N sulfuric
acid to a pH of 3.0.
responses for the major peaks.&2S (USP30) Mobile phase—Prepare a filtered and degassed mixture of
Calculate the quantity, in mg, of hydrocortisone (C21H30O5) in the methanol and pH 3.0 Buffer solution (50 : 50). Make adjustments
portion of Tablets taken by the formula: if necessary (see System Suitability under Chromatography h621i).
Chromatographic system (see Chromatography h621i)—The
50C(RU / RS) liquid chromatograph is equipped with a UV wavelength detector
in which the terms are as defined therein. and a 5-mm 6 25-cm column that contains packing L1. The flow
rate is about 1 mL per minute. Chromatograph a Standard solution of
&
C is the concentration, in mg per mL, of USP Hydrocor- USP Diluted Isosorbide Dinitrate RS in the same Medium, and
record the chromatograms as directed for Procedure: the tailing
tisone RS in the Standard preparation; and RU and RS are the factor is not more than 2.5; and the relative standard deviation is not
more than 2.0%.
peak response ratios of the hydrocortisone peak to the internal Procedure—Separately inject equal volumes (about 20 mL) of
a filtered portion of the solution under test, and record the
standard peak obtained from the Assay preparation and the chromatograms. Determine the amount of C6H8N2O8 dissolved in
comparison with a Standard solution of USP Diluted Isosorbide
Standard preparation, respectively.&2S (USP30) Dinitrate RS in the same Medium, similarly chromatographed.
In-Process Revision
Tolerances—The percentages of the labeled amount of C6H8N2O8
6 not less than 75%
indicates that the product meets USP Dissolution Test 2.
Medium: pH 1.2 simulated gastric fluid (without pepsin)
for the first hour, 900 mL; pH 7.5 simulated intestinal fluid
(without enzymes) for the subsequent hours, 900 mL.
Pharmacopeial Forum
Apparatus 2: 50 rpm, with helix sinkers. the chromatogram as directed for Procedure: the tailing factor
Times: 1, 3, 6, and 12 hours. is not more than 2.0; and the relative standard deviation for
Determine the amount of isosorbide dinitrate (C6H9NO6) replicate injections is not more than 2.0%.
dissolved by employing the following method. Procedure—Separately inject equal volumes (about 20 mL)
Buffer solution and Mobile phase—Prepare as directed in of the Standard solution and the Test solution into the
the Assay under Diluted Isosorbide Dinitrate. chromatograph, record the chromatograms, and measure the
Standard solution—Prepare two solutions, one in each peak responses. Calculate the cumulative percentage of
Medium. Dissolve an accurately weighed quantity of USP isosorbide dinitrate dissolved at each collection point,
Diluted Isosorbide Dinitrate RS in Medium, and dilute corrected for the quantities removed at previous collection
quantitatively, and stepwise if necessary, with Medium to points (not applicable for the first hour), as follows:
obtain a solution having a known concentration of about 40
mg per mL.
Test solution—Pass 5 mL of the solution under test through
a suitable 10-mm filter. Replace the Medium withdrawn at the
3 and 6 hour timepoints.
Percentage released at first hour (see Formula 1).
Proceed as directed in the Assay under Diluted Isosorbide
Percentage released at third hour (see Formula 2).
Dinitrate. Chromatograph the Standard solution, and record
Percentage released at sixth hour (see Formula 3).
Percentage released at twelfth hour (see Formula 4).
Formula 1
Formula 2
In-Process Revision
Formula 3
Formula 4
Pharmacopeial Forum
in which rU and rS are the peak responses for the Test solution Add the following:
and the Standard solution, respectively; CU is the sample ~
Levalbuterol Hydrochloride
concentration, in mg per mL, at the indicated collection time
point; CS is the concentration, in mg per mL, of the Standard
solution; 900 is the volume, in mL, of Medium; 1000 is the
conversion factor from mg to mg; 100 is the conversion factor
to percentage; LC is the tablet label claim, in mg; and 5 is the C13H21NO3 HCl 275.77
volume, in mL, of sample withdrawn and of the Medium (R)-a1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-a,a’-
replaced. diol hydrochloride [50293-90-8].
C6H8N2O8 dissolved at the times specified conform to
Acceptance Table 2.
» Levalbuterol Hydrochloride contains not less
than 98.0 percent and not more than 102.0 percent
of C13H21NO3 HCl, calculated on the anhydrous
basis.
6 between 50% and 80% Packaging and storage—Preserve in tight, light-resistant
12 not less than 75% containers, and store at controlled room temperature.
.3 USP Reference standards h11i—USP Dehydrated Alcohol
RS. USP Ethyl Acetate RS. USP Heptane RS. USP
Levalbuterol Hydrochloride RS. USP Levalbuterol Related
Compound A RS. USP Levalbuterol Related Compound B RS.
USP Levalbuterol Related Compound C RS. USP Levalbu-
terol Related Compound D RS. USP Levalbuterol Related
Compound E RS. USP Levalbuterol Related Compound F RS.
BRIEFING
USP Methyl Alcohol RS. USP 2-Propanol RS.
Identification, Infrared Absorption h197Ki.

Levalbuterol Hydrochloride; Levalbuterol Inhalation
Solution. Because there are no existing USP monographs for this
drug substance and dosage form, the following new monographs are Color of a 1% solution h631i: not more than 20 APHA
In-Process Revision
being proposed. The liquid chromatographic procedure in the test for
Related compounds is based on analyses performed with the platinum cobalt units.
Phenomenex Aqua brand or Metachem Metasil AQ brand of L1.
The typical retention time for levalbuterol hydrochloride is about 11 pH h791i: between 4.5 and 5.5, in a solution (1 in 100).
minutes. The liquid chromatographic procedure in the test for
Enantiomeric purity and chiral identity is based on the analyses
performed with the Chirobiotic T brand of L## column. Water, Method Ic h921i: not more than 0.3%.
(AER: K. Zaidi) RTS— C43029 Residue on ignition h281i: not more than 0.10%.
Heavy metals, Method I h231i: not more than 10 ppm.
Related compounds—
Solution A, Solution B, Mobile phase, and Diluent—
Proceed as directed in the Assay.
Test solution—Use the Assay preparation.
Pharmacopeial Forum
Standard solution—Dissolve accurately weighed quantities Procedure—Separately inject equal volumes (about 50 mL)
of USP Levalbuterol Hydrochloride RS, USP Levalbuterol of the Standard solution and the Test solution into the
Related Compound A RS, USP Levalbuterol Related chromatograph, record the chromatograms, and measure the
Compound B RS, USP Levalbuterol Related Compound C peak responses. Determine the area of the levalbuterol peak,
RS, USP Levalbuterol Related Compound D RS, USP and integrate all peaks with an area greater than 0.05% of the
Levalbuterol Related Compound E RS, and USP Levalbuterol area corresponding to levalbuterol peak. Calculate the
Related Compound F RS in Diluent to obtain a solution percentage of each impurity in the portion of Levalbuterol
having known concentrations of about 0.05 mg per mL of Hydrochloride taken by the formula:
each related compound and 100 mg per mL of USP
Levalbuterol Hydrochloride RS. 100(ri / rsF)
in which F is the relative response factor for each impurity; ri
is the peak response for each impurity obtained from the Test
and a 4.6-mm 6 15-cm column that contains 5-mm packing
solution; and rs is the sum of the responses of all the peaks
L1. The flow rate is about 1.0 mL per minute. The
chromatograph is programmed as follows. (see Table 1 for limits of individual impurities). Not more
than 0.5% of total impurities is found.
Solution A Solution B
Enantiomeric purity and chiral identity—
Time (%) (%) Elution
Mobile phase—Prepare a degassed mixture of acetonitrile,
0 100 0 equilibration
methanol, acetic acid, and triethylamine (500: 500: 3: 1).
Diluent—Use the Mobile phase.
50–50.01 28?0 72?100 step gradient
tity of USP Albuterol RS in Diluent to obtain a solution
50.01–55 0 100 isocratic
55–55.01 0?100 100?0 step gradient
Test solution—Transfer an accurately weighed quantity of
55.01–70 100 0 re-equilibration
Levalbuterol Hydrochloride to a suitable volumetric flask,
The column temperature is maintained at 458. Chromatograph and quantitiatively dilute with Diluent to obtain a solution
the Standard solution, and record the peak areas as directed having a concentration of about 0.8 mg per mL of
for Procedure: the tailing factor for the levalbuterol peak is
In-Process Revision
Levalbuterol Hydrochloride.
not greater than 4.0; the column efficiency determined from Chromatographic system (see Chromatography h621i)—
the levalbuterol peak is not less than 4000; the resolution, R, The liquid chromatograph is equipped with a 225-nm detector
between levalbuterol and levalbuterol related compound A is and a 4.6-mm 6 25-cm column that contains 5-mm packing
not less than 4.9, between levalbuterol related compound B L##. The flow rate is about 1.0 mL per minute. Chromato-
and levalbuterol related compound C is not less than 1.5, and graph the Standard solution, and record the peak responses as
between levalbuterol related compound D and levalbuterol directed for Procedure: the resolution, R, between levalbu-
related compound E is not less than 1.8; and the relative terol and (S)-albuterol is not less than 2.0; the tailing factor
standard deviation for replicate injection is less than 20% for levalbuterol and (S)-albuterol is not more than 2.2; the
determined from any of the six related compound peaks.
Pharmacopeial Forum
Table 1
Relative Relative
Retention Response Limit
Related Compound Time Factor (F) (%)
A 1.2 1.0 0.1
B 1.5 1.0 0.10
C 1.6 1.0 0.10
D 1.7 3.0 0.05
E 2.1 1.0 0.10
F 3.5 1.2 0.10
Any unknown impurity — — 0.10
Total unknown impurities — — 0.1
Total impurities — — 0.5
column efficiency calculated from either peak is not less than Middle standard solution—Transfer 1 mL of water and
4000; and the relative standard deviation for replicate 5 mL of butyl alcohol into an appropriate headspace vial, and
injections is not more than 20% for (S)-albuterol. seal. Using a 25-mL syringe, transfer 20 mL of the Standard
Procedure—Separately inject equal volumes (about 10 mL) stock solution into the headspace vial through the septum, and
of the Standard solution and the Test solution. The percentage mix.
of (S)-albuterol is calculated using the following equation: High standard solution—Transfer 1 mL of water and 5 mL
of butyl alcohol into an appropriate headspace vial, and seal.
100(ri / rs) Using a 50-mL syringe, transfer 30 mL of the Standard stock
solution into the headspace vial through the septum, and mix.
in which ri is the peak response for (S)-albuterol, and rs is the Test preparation—Transfer 500 mg of the article under test
sum of the responses of both levalbuterol and (S)-albuterol into an appropriate headspace vial, add 1 mL of water, and
peaks: not more than 0.2% of (S)-albuterol is found. 5 mL of butyl alcohol, seal, and mix.
Residual solvents— Chromatographic system (see Chromatography h621i)—
Standard stock solution—Transfer 1.0 mL each of USP The gas chromatograph is equipped with a flame-ionization
In-Process Revision
Ethyl Acetate RS and USP Methyl Alcohol RS, 0.5 mL of detector, a headspace sampler, and a 0.32-mm 6 50-m fused
USP 2-Propanol RS, 3.0 mL of USP Dehydrated Alcohol RS, silica column coated with a 1.0-mm layer of phase G16. The
and 0.1 mL each of toluene and USP Heptane RS into a loop temperature is 1508. All samples are equilibrated for 30
25-mL volumetric flask, and dilute with butyl alcohol to minutes at 908 in the headspace sampler. The carrier gas is
volume. helium with a flow rate of 1.6 mL per minute and a split ratio
Low standard solution—Transfer 1 mL of water and 5 mL of 1.6 : 30. The column temperature is maintained at 508 for
of butyl alcohol into an appropriate headspace vial, and seal. 5 minutes, then raised at a rate of 108 per minute to 2008. The
Using a 10-mL syringe, transfer 8.0 mL of the Standard stock injection port and detector temperatures are maintained at
solution into the headspace vial through the septum, and mix. 2008 and 2508, respectively. Chromatograph the Low
standard solution, the Middle standard solution, and the
Pharmacopeial Forum
High standard solution; and record the peak responses as Standard preparation—Dissolve an accurately weighed
directed for Procedure. Calculate the correlation coefficient quantity of USP Levalbuterol Hydrochloride RS in Diluent to
for the line (r 2). Correlation coeffcient for each impurity must obtain a solution having a known concentration of about 100
be equal or greater than 0.99. mg per mL.
Procedure—Separately inject (about 1 mL), equal volumes Assay preparation—Transfer about 10 mg of Levalbuterol
of the Low standard solution, Middle standard solution, High Hydrochloride, accurately weighed, to a 100-mL volumetric
standard solution, and the Test preparation into the flask. Dissolve in and dilute with Diluent to volume, and mix.
chromatograph, record the chromatogram, and measure the Chromatographic system (see Chromatography h621i)—
responses for the major peaks. From the graph, calculate the The liquid chromatograph is equipped with a 220-nm detector
quantity, in percentage, of each impurity found in the portion and a 4.6-mm 6 15-cm column that contains 5-mm packing
of Levalbuterol Hydrochloride taken by the formula: L1. The flow rate is about 1.0 mL per minute. The
chromatograph is programmed as follows.
100 [[(rU – y-intercept)/m (slope)] 6 6 / WU]
in which rU is the response of the Test solution; y-intercept is
from the equation of the line described by the Standard 0 91.5 8.5 equilibration
solutions; and WU is the weight, in mg, of Levalbuterol 0–15 91.5 8.5 isocratic
Hydrochloride taken. The amount of each impurity in the Test 15–15.01 91.5?0 8.5?100 step gradient
solution does not exceed the limit in the accompanying table: 15.01–20 0 100 isocratic
20–20.01 0?91.5 100?8.5 step gradient
Impurity Limit (%)
20.01–30 9l.5 8.5 re-equilibration
Ethanol 0.2
The column temperature is maintained at 358. Chromatograph
Methanol 0.10
the Standard preparation, and record the peak areas as
Ethyl acetate 0.10
directed for Procedure: the column efficiency is greater than
Isopropanol 0.050
5500 theoretical plates; the tailing factor is less than 2.3; and
n-Heptane 0.010
relative standard deviation for replicate injections is not more
Toluene 0.010
than 2.0%.
In-Process Revision
Assay— of the Standard preparation and the Assay preparation into

Solution A—Prepare a 1 in 1000 solution of phosphoric the chromatograph, record the chromatograms, and measure
acid in water, and degas. the responses for the major peaks. Calculate the quantity in
Solution B—Prepare a degassed mixture of acetonitrile, mg of C13H21NO3 HCl in the portion of Levalbuterol
methanol, water, and phosphoric acid (700: 700: 600: 2). Hydrochloride taken by the formula:
Mobile phase—Use variable mixtures of Solution A and
Solution B as directed for Chromatographic system. Make 0.1CS(rU / rS)
adjustments if necessary (see System Suitability under
Diluent—Use Solution A.
Pharmacopeial Forum
in which CS is the concentration, in mg per mL, of USP USP Reference standards h11i—USP Levalbuterol Hydro-
Levalbuterol Hydrochloride RS in the Standard preparation; chloride RS. USP Levalbuterol Related Compound A RS.
and rU and rS are the peak responses of levalbuterol USP Levalbuterol Related Compound B RS. USP Levalbu-
hydrochloride obtained from the Assay preparation and the terol Related Compound C RS. USP Levalbuterol Related
Standard preparation, respectively.~USP31 Compound D RS. USP Levalbuterol Related Compound E RS.
USP Levalbuterol Related Compound F RS. USP Levalbu-
terol Related Compound G RS.
Identification—
A: The retention time of the major peak in the

BRIEFING chromatogram of the Assay preparation corresponds to that
observed in the chromatogram of the Standard preparation,
Levalbuterol Inhalation Solution—See briefing under Levalbu-
terol Hydrochloride. as obtained in the Assay.
(AER: K. Zaidi) RTS—C43029 Color h631i: not more than 20 APHA platinum cobalt
units.
Sterility h71i: meets the requirements.

Add the following:
Uniformity of dosage units h905i: meets the require-
~
Levalbuterol Inhalation Solution ments.
Particulate matter h788i: not more than 250 particles

» Levalbuterol Inhalation Solution is a sterile,
greater than or equal to 10 microns and not more 25 particles
aqueous solution of Levalbuterol Hydrochloride, greater than or equal to 25 micron.
prepared with Sodium Chloride. It contains not less
than 90.0 percent and not more than 110.0 percent Mobile phase and Chromatographic system—Proceed as
of the labeled amount of levalbuterol hydrochloride directed for Related compounds under Levalbuterol Hydro-
(C13H21NO3 HCl). chloride.
Diluent—Dissolve about 9.0 + 0.05 g of sodium chloride
Packaging and storage—Preserve in low-density polyethyl-
In-Process Revision
in 950 mL of water. Adjust with dilute sulfuric acid to a pH of
ene single-use ampuls, with a multilayer foil overwrap. Store
4.0, and dilute with water to 1000 mL. Mix, and pass through
at controlled room temperature.
0.45-mm filter.
Labeling—The outer label indicates the dose and that the
Standard solution—Dissolve accurately weighed quantities
ampuls should be discarded if the solution is not colorless.
of USP Levalbuterol Hydrochloride RS, USP Levalbuterol
Related Compound A RS, USP Levalbuterol Related
Compound B RS, USP Levalbuterol Related Compound C
RS, USP Levalbuterol Related Compound D RS, USP
Levalbuterol Related Compound E RS, USP Levalbuterol
Related Compound F RS, and USP Levalbuterol Related
Compound G RS in Diluent to obtain a solution having
Pharmacopeial Forum
known concentrations of about 0.05 mg per mL of each not less than 3.0; and the tailing factor for levalbuterol and
related compound and 100 mg per mL of USP Levalbuterol (S)-albuterol are not more than 1.6 and 2.0, respectively. The
Hydrochloride RS. Standard solution is injected three times and the relative
Test solution—Use the Assay preparation, prepared as standard deviation for the peak area of (S)-albuterol is not be
directed in the Assay. greater than 20%.
Procedure—Separately inject equal volumes (about 50 mL) Procedure—Inject equal volumes of the appropriate
of the Standard solution and the Test solution into the Standard solution and the Test solution such that approxi-
chromatograph, record the chromatograms, and measure the mately 4.2 mg of levalbuterol are injected. The percentage of
peak responses. Determine the area of the levalbuterol peak, (S)-albuterol is calculated using the following equation:
and integrate all the peaks with an area greater than 0.05% of
100(ri / rs)
the area corresponding to levalbuterol hydrochloride. Calcu-
late the percentage of each impurity in the portion of in which ri is the peak response for (S)-albuterol, and rs is the
Inhalation Solution taken by the formula: sum of the responses of both levalbuterol and (S)-albuterol
peaks. The Test solution contains not more than 2.50%
100(ri / rs)(1/F)
(S)-albuterol.
in which F is the relative response factor for each impurity Assay—
and is equal to 1.0 for related compounds A, B, C, E, and G Solution A, Solution B, Mobile phase, and
and all unknown peaks, 3.2 for related compound D, and 1.2 Chromatographic system—Proceed as directed in the Assay
for related compound F; ri is the peak response for each under Levalbuterol Hydrochloride.
impurity obtained from the Test solution; and rs is the sum of Diluent—Dissolve about 9.0 + 0.05 g of sodium chloride
the responses of all the peaks: not more than 0.10% of related in 950 mL of water. Adjust with dilute sulfuric acid to a pH of
compound G is found; not more than 0.10% of related 4.0, and dilute with water to 1000 mL. Mix, and pass through
compound D in each ampul is found (total content of related 0.45-mm filter.
compound D should not be more than 1 mg per ampul); not Standard preparation—Dissolve an accurately weighed
more than 0.25% of total unknown impurities are found; not portion of USP Levalbuterol Hydrochloride RS in Diluent to
more than 0.10% of any unknown impurity is found; and not obtain a solution having a known concentration of 100 mg per
more than than 0.70% of total impurities is found. mL.
In-Process Revision
Enantiomeric purity and chiral identity— Assay preparation—Transfer an accurately measured

Mobile phase and Standard solution—Proceed as directed volume of Inhalation Solution to a suitable volumetric flask,
for Enantiomeric purity and chiral identity under Levalbu- and quantitatively dilute with Diluent to obtain a solution
terol Hydrochloride. having a concentration of about 100 mg of levalbuterol
Test solution—All sample concentrations are injected neat. hydrochloride per mL.
Chromatographic system (see Chromatography h621i)— Procedure—Separately inject equal volumes (about 10 mL)
The liquid chromatograph is equipped with a 225-nm detector of the Standard preparation and the Assay preparation into
and a 4.6-mm 6 250-mm column that contains 5-mm packing the chromatograph, record the chromatograms, and measure
L##. The flow rate is about 1.0 mL per minute. The minimum the responses for the major peaks. Calculate the concentra-
run time is 30 minutes. Inject 10 mL of the Standard solution. tion, in mg per mL, of C13H21NO3 HCl per ampul by the
The resolution, R, between levalbuterol and (S)-albuterol is formula:
Pharmacopeial Forum
~
Chromatograph the Standard solution, and record the peak
DC(rU / rS) responses as directed for Procedure: the column efficiency is

not less than 500 theoretical plates for ethinyl estradiol and
in which D is the dilution factor; C is the concentration of not less than 1400 theoretical plates for norethindrone; the
USP Levalbuterol Hydrochloride RS in the Standard tailing factor is not more than 2.0; and the relative standard
preparation; and rU and rS are the peak responses obtained deviation for each analyte is not more than 2.5%.~USP31
from the Assay preparation and the Standard preparation, Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the peak responses.
respectively.~USP31 Tolerances—Not less than 80% (Q) of the labeled amounts of
C22H28O3 and C20H24O2 is dissolved in 60 minutes.
BRIEFING
BRIEFING
Norethindrone Acetate and Ethinyl Estradiol Tablets, USP 29

page 1557. It is proposed to revise the Chromatographic system in Pamidronate Disodium for Injection, page 3739 of the Second
the Dissolution test to specify the emission wavelength and to add Supplement and page 1465 of PF 32(5) [Sept.–Oct. 2006]. It is
system suitability requirements. proposed to change the acceptance criteria in the Definition from
‘‘not less than 98.0 percent and not more than 108.0 percent’’ to ‘‘not
(BPC: M. Marques) RTS—C50816 less than 93.0 percent and not more than 108.0 percent’’. These
limits are representative of products currently on the market. In the
absence of any adverse comments, it is proposed to implement this
revision via the Interim Revision Announcement pertaining to USP
Change to read: 30–NF 25, with an official date of June 1, 2007.
Dissolution h711i— (MD-GRE: E. Gonikberg) RTS—C50552

0.025 M Acetate buffer solution—Accurately weigh about 5.22 g
of anhydrous sodium acetate and 2.2 g of glacial acetic acid into a
4-L volumetric flask, add 3.5 L of water, and mix. Adjust with 1 N
sodium hydroxide to a pH of 5.0 + 0.2, and dilute with water to Change to read:
volume.
Medium: 0.025 M pH 5.0 acetate buffer with 0.15% sodium » Pamidronate Disodium for Injection is a sterile,
lauryl sulfate, prepared by accurately weighing about 6 g of sodium
lauryl sulfate into a 4-L volumetric flask, adding 1.5 L of 0.025 M freeze-dried mixture of Pamidronate Disodium and
Acetate buffer solution, mixing, and diluting with 0.025 M Acetate suitable excipients. It contains not less than 98.0 percent
buffer solution to volume; 600 mL.
Apparatus 2: 75 rpm. .93.0 percent.3
Time: 60 minutes. and not more than 108.0 percent of the labeled amount
Determine the amounts of norethindrone acetate (C22H28O3) and of pamidronate disodium (C3H9NNa2O7P2).
ethinyl estradiol (C20H24O2) dissolved by employing the following
method.
In-Process Revision
Mobile phase—Prepare a filtered and degassed mixture of 0.2% Change to read:
phosphoric acid, acetonitrile, and tetrahydrofuran (540 : 380 : 80).
Make adjustments if necessary (see System Suitability under Packaging and storage—Preserve in Containers for Sterile Solids,
Chromatography h621i). as described under Injections h1i. preferably of Type III glass.
Standard solution—Dissolve accurately weighed quantities of
USP Norethindrone Acetate RS and USP Ethinyl Estradiol RS in &
&2S (USP30)
a minimum amount of acetonitrile, and dilute quantitatively, and Store at controlled room temperature.
stepwise if necessary, with Medium to obtain a solution having
known concentrations equivalent to the expected concentrations of
the solution under test. Change to read:
Test solution—Withdraw a 2-mL aliquot using a glass pipet or
syringe, and centrifuge at about 2000 rpm for about 5 minutes. Use
the supernatant. Bacterial endotoxins h85i—It contains not more than 2
Chromatographic system—The liquid chromatograph is equipped
with a 242-nm detector and a fluorescent detector with an excitation
&
3.88&2S (USP30)
wavelength set at 210 nm USP Endotoxin Units per mg of anhydrous pamidronate disodium.
~
and an emission wavelength set at 310 nm,~USP31
a 6-mm 6 40-mm column that contains 3-mm packing L1, and a
4-mm 6 12.5-mm guard column that contains 5-mm packing L1.
The flow rate is about 1 mL per minute.
Pharmacopeial Forum
BRIEFING BRIEFING
Phenylbutazone Boluses, USP 29 page 1710; Phenylbutazone Progesterone Vaginal Suppositories, USP 29 page 1820. It is
Tablets, USP 29 page 1710. In order to clarify the differences proposed to remove silica gel from the formula for Progesterone
between Phenylbutazone Boluses and Phenylbutazone Tablets, it is Vaginal Suppositories. In the original formula, silica gel was used to
proposed to add a statement to the Definition of each monograph ensure homogeneous drug distribution in the suppository mass. It
stating the nominal strengths of the drug products. also functioned as a viscosity agent for the fatty acid base used in the
formula. However, a more recent study showed that using silica gel
(VET: I. DeVeau) RTS—C48457 in progesterone suppositories did not make as much of a difference
as originally thought. The committee has decided to make such use
optional. Interested parties are encouraged to submit comments to
USP regarding any relevant issues.
Change to read:
(CRX: J. Kelly) RTS—C45575
» Phenylbutazone Boluses contain not less than 90.0
percent and not more than 110.0 percent of the labeled
amount of phenylbutazone (C19H20N2O2) Change to read:
~
and nominally not less than 1 g of phenylbutazone » Progesterone Vaginal Suppositories contain not less
per bolus.~USP31 than 90.0 percent and not more than 110.0 percent of the
labeled amount of progesterone (C21H30O2).
SUPPOSITORIES COMPOUNDED IN FATTY ACID BASE
Prepare Progesterone Vaginal Suppositories in fatty
acid base as follows (see Pharmaceutical Compound-
ing—Nonsterile Preparations h795i):
Progesterone
(micronized) . . . . . . . . . . . 25 mg to 600 mg
Silica Gel . . . . . . . . . . . . . . 25 mg
~
~USP31
BRIEFING
Fatty acid base, a sufficient
quantity to make one
Phenylbutazone Tablets, USP 29 page 1710—See briefing under suppository
Phenylbutazone Boluses. In addition, to reflect current FDA-
approved uses, it is proposed to add a Labeling section stating that Calibrate the actual molds with the fatty acid base that is
it is for veterinary use only. used for preparing the suppositories, and adjust the
formula accordingly. Mix thoroughly the Progesterone
(VET: I. DeVeau) RTS—C48456 and Silica Gel to obtain a uniform powder.
~
~USP31
Change to read: Heat the fatty acid base slowly and evenly until melted.
Slowly add the
» Phenylbutazone Tablets contain not less than 93.0 ~
Progesterone~USP31
percent and not more than 107.0 percent of the labeled
amount of phenylbutazone (C19H20N2O2) powder to the melted base, with stirring. Mix thorough-
In-Process Revision
ly, and pour into molds. Cool in a refrigerator until

~
and nominally not more than 200 mg of solidified, trim, and wrap.
phenylbutazone per tablet.~USP31 Change to read:
SUPPOSITORIES COMPOUNDED IN POLYETHYLENE

GLYCOL BASE
Add the following: Prepare Progesterone Vaginal Suppositories in poly-
~ ethylene glycol base as follows (see Pharmaceutical
Labeling—Label Tablets to indicate that they are for Compounding—Nonsterile Preparations h795i):
veterinary use only.~USP31 Progesterone (micronized) . . . 25 mg to 600 mg
Silica Gel . . . . . . . . . . . . . . 25 mg
~
~USP31
Polyethylene glycol base,

a sufficient quantity to make
one suppository
Pharmacopeial Forum
Calibrate the actual molds with polyethylene glycol base Change to read:
that is used for preparing the Suppositories, and adjust
the formula accordingly. Mix thoroughly the Progeste- Sulfate—
rone and Silica Gel to obtain a uniform powder. ~
Sulfate h221i—~USP31
~
~USP31
Dissolve 12.0 g in 37 mL of acetone, and add 3 mL of water. Titrate
potentiometrically with 0.02 M lead perchlorate, prepared by
Heat the polyethylene glycol base slowly and evenly dissolving 9.20 g of lead perchlorate in water to make 1000 mL of
until melted. Slowly add the solution, using a pH meter capable of a minimum reproducibility of
~ +0.1 mV (see pH h791i) equipped with an electrode system
Progesterone~USP31 consisting of a lead-specific electrode and a silver-silver chloride
powder to the melted base, with stirring. Mix thorough- reference glass-sleeved electrode containing a solution of tetraeth-
ly, and pour into molds. Cool, trim, and wrap. ylammonium perchlorate in glacial acetic acid (1 in 44): not more
than 1.25 mL of 0.02 M lead perchlorate is consumed (0.02%).
~
A 1.0-g portion dissolved in a mixture of alcohol and water
(1 : 1) shows no more sulfate than corresponds to 0.2 mL of
0.020 N sulfuric acid (0.02%).~USP31
Change to read:
BRIEFING
Mobile phase—Prepare a mixture of water, methanol, and glacial
Salicylic Acid, USP 29 page 1940. On the basis of comments acetic acid (60 : 40 : 1). Make adjustments if necessary (see System
received, it is proposed to make the following changes: Suitability under Chromatography h621i).
Diluent—Prepare a mixture of methanol, water, and glacial acetic
1. The test for Sulfate is being revised to use the procedure stated acid (70 : 30 : 4).
in the general chapter Chloride and Sulfate h221i because the Reference solutions—Prepare a solution in Diluent containing
solvent (acetone) used in the current official monograph is about 0.05 mg of 4-hydroxybenzoic acid and 0.025 mg of 4-
incompatible with the commercially available electrodes. hydroxyisophthalic acid per mL, and a second solution in Diluent
2. The reagents 4-hydroxybenzoic acid, 4-hydroxyisophthalic containing about 0.05 mg of 4-hydroxybenzoic acid and 0.01 mg of
acid, and phenol are being converted to USP Reference phenol per mL.
Standards because of their quantitative applications in the ~
monograph. A USP Reference standards section is being added ~USP31
and the test for Related compounds is being revised to be Standard solution—Dissolve accurately weighed quantities of 4-
consistent with this change. hydroxybenzoic acid, 4-hydroxyisophthalic acid, phenol, and the
3. The retention times of the related compounds are determined by Salicylic Acid under test
injecting the Standard solution, therefore the subsection ~
Reference solutions under Related compounds is being deleted. USP Salicylic Acid Related Compound A RS, USP Salicylic
4. The Standard solution under Related compounds uses USP
Salicylic Acid RS to simplify the calculation; the formula for Acid Related Compound B RS, USP Phenol RS, and USP
the percentage of the related compound calculation is being
revised accordingly. Salicylic Acid RS~USP31
in Diluent to obtain a solution having known concentrations of about
(MD-OOD: F. Mao) RTS—C46718 0.05 mg per mL, 0.025 mg per mL, 0.01 mg per mL, and 50 mg per
mL,
~
0.5 mg per mL,~USP31
respectively.
Add the following: Test solution—Prepare a solution of Salicylic Acid in Diluent
~ containing 50 mg per mL. Sonicate until completely dissolved.
USP Reference standards h11i—USP Phenol RS. USP Chromatographic system (see Chromatography h621i)—The
In-Process Revision
Salicylic Acid RS. USP Salicylic Acid Related Compound A a 4.6-mm 6 10-cm column containing 5-mm packing L1. The flow
rate is about 0.5 mL per minute. Chromatograph the Reference
RS. USP Salicylic Acid Related Compound B RS.~USP31 solutions,
~
Standard solution,~USP31
Pharmacopeial Forum
record the chromatograms, and note the retention times of the peaks. in the Standard solution as Ci; the response of the peak of 4-
Chromatograph the Standard solution, and record the peak responses hydroxyisophthalic acid
as directed for Procedure: the relative retention times are about 0.35, ~
0.45, 0.5, and 1.0 for 4-hydroxybenzoic acid, 4-hydroxyisophthalic salicylic acid related compound B~USP31
acid, phenol, and salicylic acid, respectively, and the peaks are all in the chromatogram obtained from the Standard solution as rSi; and
baseline-resolved from each other. Changes in the composition of the the response of any other impurity as ri. not more than 0.05% of any
Mobile phase made to optimize resolution may change the elution other impurity is found; and the sum of all of the related compounds
order of impurities. Use the chromatograms obtained from the and other impurities found is not more than 0.2%.
Reference solutions to determine the elution order of the specified ~
impurities. The limits are given in Table 1.~USP31
~
identify the peaks using the relative retention times given in
Table 1. [NOTE—For the purpose of peak identification the
approximate relative retention times are given in Table 1. The
relative retention times are measured with respect to Salicylic
Acid.]
BRIEFING
Valganciclovir Hydrochloride, page 379 of PF 32(2) [Mar.–Apr.

Table 1 2006]. It is proposed to change the column packing used in Test 2 for
Related compounds to L11 based on the original analysis and the
Name RRT Limit NDA submission. Minor editorial changes have also been made.
(MD-AA: B. Davani) RTS—C47637

Salicylic acid related 0.35 NMT 0.1%
compound A
Salicylic acid related 0.45 NMT 0.05%
compound B
Add the following:
Phenol 0.50 NMT 0.02%
~
Other impurity — NMT 0.05%
Valganciclovir Hydrochloride
Total impurities — NMT 0.2%
~USP31
record the chromatograms, and measure the areas for the major
peaks. Calculate the percentage of each relevant related compound
C14H22N6O5 HCl 390.82
2Ci [ri / (rSi – ri)]
L-Valine, ester with 9-[[2-hydroxy-1-(hydroxymethyl)eth-
~
oxy]methyl]guanine, monohydrochloride.
In-Process Revision
100(Ci / CU)(ri / rSi)~USP31

L -Valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-
in which Ci is the concentration, in mg per mL, of the relevant yl)methoxy]-3-hydroxypropyl ester, monohydrochlo-
related compound in the Standard solution;
~ ride [175865-59-5].
CU is the concentration, in mg per mL, of the Test
solution;~USP31
and ri and rSi are the peak responses for the relevant related
compounds obtained from the Test solution and the Standard » Valganciclovir Hydrochloride contains not less
solution, respectively. not more than 0.1% of 4-hydroxybenzoic acid,
0.05% of 4-hydroxyisophthalic acid, and 0.02% of phenol is found. than 97.0 percent and not more than 102.0 percent
~
~USP31
Calculate the percentage of any other impurity, other than the solvent of C14H22N6O5 HCl, calculated on the anhydrous
peak, observed in the chromatogram of the Test solution by the same
formula, except to use and solvent-free basis.
~
using~USP31
the concentration of 4-hydroxyisophthalic acid Packaging and storage—Preserve in tight containers. Store
~
salicylic acid related compound B~USP31 at 258, excursions permitted between 158 and 308.
Pharmacopeial Forum
USP Reference standards h11i—USP Valganciclovir Hy- per minute to 2408. [NOTE—Condition the column at 2408
drochloride RS. after each injection for approximately 15 minutes.] The
Identification— injection port temperature is maintained at about 2508, and
A: Infrared Absorption h197Ki. the detector temperature is maintained at about 3008.
B: Ultraviolet Absorption h197Ui. Chromatograph the System suitability solution as directed
Solution: 10 mg per mL. for Procedure: the resolution, R, between 1,4-dioxane and
Medium: methanol. toluene is not less than 8; the column efficiency, using the
C: A solution in water (1 in 20) meets the requirements of 1,4-dioxane peak, is not less than 6000 theoretical plates; and
the tests for Chloride h191i. the relative standard deviation of the response area ratios of
the isopropyl alcohol peak to the 1,4-dioxane peak for
Water, Method I h921i: not more than 8.0%, a 100-mg
replicate injections is not more than 15%.
specimen being used.
Procedure—Separately inject equal volumes (about 0.5 mL)
Residue on ignition h281i: not more than 0.10%, a 1-g
of the Standard solution and the Test solution into the
specimen being used.
chromatograph, record the chromatograms, and measure the
Heavy metals, Method I h231i: 0.002%.
peak areas. Calculate the percentages of isopropyl alcohol in
Limit of isopropyl alcohol—
the portion of Valganciclovir Hydrochloride taken by the
Internal standard solution—Transfer 100 mL of 1,4-
formula:
dioxane to a 100-mL volumetric flask, dilute with dimethyl-
formamide to volume, and mix. 100(VC /W)(RU / RS)
Standard stock solution—Transfer 1.0 mL of isopropyl
alcohol and 0.1 mL of toluene to a 100-mL volumetric flask, in which V is the volume, in mL, of the Test solution; C is the
dilute with dimethylformamide to volume, and mix. [NOTE— concentration, in mg per mL, of isopropyl alcohol in the
Toluene is used to verify the system suitability.] Standard solution; W is the weight, in mg, of Valganciclovir
Standard solution—Transfer 2.0 mL of the Internal Hydrochloride taken; and RU and RS are the peak area ratios of
standard solution to a vial. Add 100 mL of the Standard isopropyl alcohol to the internal standard obtained from the
stock solution to the Internal standard solution, and mix. Test solution and the Standard solution, respectively: not
System suitability solution—Use the Standard solution. more than 1.0% of isopropyl alcohol is found.
Test solution—Transfer between 90 mg to 100 mg of Related compounds—
In-Process Revision
Valganciclovir Hydrochloride, accurately weighed, to a vial. TEST 1—
Add 2.0 mL, accurately measured, of the Internal standard Solution A—Use 0.1 M Monobasic ammonium phosphate
solution, and mix. solution, prepared as directed in the Assay.
Chromatographic system (see Chromatography h621i)— Solution B—Use methanol.
The gas chromatograph is equipped with a flame-ionization Mobile phase—Use variable mixtures of Solution A and
detector and a 0.53-mm 6 30-m capillary column coated Solution B as directed for Chromatographic system (see Table
with a 3.0-mm phase G43. The carrier gas is helium, flowing 1). Make adjustments if necessary (see System Suitability
at a rate of about 10.5 mL per minute, and the split ratio is under Chromatography h621i).
(1 : 15). The chromatograph is programmed as follows. System suitability solution—Prepare as directed in the
Initially the column temperature is maintained at 408 for 10 Assay.
minutes, and then the temperature is increased at a rate of 258
Pharmacopeial Forum
Test solution—Use the Assay preparation. TEST 2—
Chromatographic system (see Chromatography h621i)— Solution A—Dilute 2.5 mL of triethylamine with water to
The liquid chromatograph is equipped with a 254-nm detector 1000 mL, and adjust with trifluoroacetic acid to a pH of
and a 4.6-mm 6 15-cm column that contains packing L1. 3.0 + 0.05. Pass this solution through a filter having a
The chromatograph is programmed as shown in Table 1. 0.45-mm porosity, and degas. Make adjustments if necessary
(see System Suitability under Chromatography h621i).
Table 1
Solution B—Use methanol.
Time Solution A Solution B Mobile phase—Use variable mixtures of Solution A and
(minutes) (%) (%) Elution Solution B as directed for Chromatographic system (see Table
0–5 92 8 isocratic 2). Make adjustments if necessary (see System Suitability
5–15 92?80 8?20 linear gradient under Chromatography h621i).
15–30 80?30 20?70 linear gradient System suitability solution—Prepare as directed in the
[NOTE—Equilibrate the column with starting Mobile phase for Assay.
at least 15 minutes between injections.] The column Test solution—Use the Assay preparation.
temperature is maintained at 258, and the flow rate is about Chromatographic system (see Chromatography h621i)—
1.0 mL per minute. Chromatograph the System suitability The liquid chromatograph is equipped with a 254-nm detector
solution, and record the peak responses as directed for and a 4.6-mm 6 15-cm column that contains packing L1L11.
Procedure: the resolution, R, between the first peak of The chromatograph is programmed as follows in
valganciclovir and the methoxymethylguanine peak is not Table 2.
less than 1.0, and the resolution, R, between the two peaks for
valganciclovir (R and S esters of L-valine) is not less than 3.0; Table 2
the column efficiency determined using the second peak of Time Solution A Solution B
valganciclovir is not less than 8000 theoretical plates; and the (minutes) (%) (%) Elution
tailing factor for the second peak of valganciclovir is not
more than 1.4. [NOTE—The typical retention time for the
second peak of valganciclovir is between 5 and 8.5 minutes.]
[NOTE—Equilibrate the column with starting Mobile phase for
Procedure—Inject about 20 mL of the Test solution into the
at least 15 minutes between injections.] The column
In-Process Revision
chromatograph, record the chromatogram, and measure the

temperature is maintained at 308, and the flow rate is about
peak responses. The approximate relative retention times for
1.0 mL per minute. Chromatograph the System suitability
each individual impurity are listed in Table 3. Calculate the
solution, and record the peak responses as directed for
percentage of each impurity in the portion of Valganciclovir
Procedure: the resolution, R, between the two peaks for
Hydrochloride taken by the formula:
valganciclovir (R and S esters of L-valine) is not less than 1.3;
the column efficiency determined using the second peak of
100(ri / Fi) /(ri / Fi)
valganciclovir is not less than 8000 theoretical plates; and the
tailing factor for the second peak of valganciclovir is not
in which the ri is the area response for each impurity; and Fi is
more than 1.2. [NOTE—The typical retention time for the
the relative response factor for each individual component
second peak of valganciclovir is between 6 and 9 minutes.]
listed in Table 3. The impurities meet the requirements as
specified in Table 3.
Pharmacopeial Forum
Procedure—Inject about 20 mL of the Test solution into the Test solution—Transfer about 10 mg of Valganciclovir
chromatograph, record the chromatogram, and measure the Hydrochloride, accurately weighed, to a 50-mL volumetric
peak responses. Calculate the percentage of ganciclovir flask, dissolve in and dilute with 0.001 N hydrochloric acid to
mono-N-methyl valinate impurity in the portion of Valganci- volume, and mix.
clovir Hydrochloride taken by the formula: Chromatographic system (see Chromatography h621i)—
100(ri / Fi)/(ri / Fi) and a 4.0-mm615-cm column that contains packing L## (see
Chromatography h621i). The column temperature is main-
in which Ri is the sum of the area responses of ganciclovir
tained at ambient temperature, and the flow rate is about 0.8
mono-N-methyl valinate impurity (diastereomers); and Fi is
mL per minute. Chromatograph the System suitability
the relative response factor for this impurity and valganci-
clovir as given in Table 3. The impurity limits meet the
Procedure: the resolution, R, between the second peak of the
requirements specified in Table 3.
D-valine ester pair and the first peak of the valganciclovir pair
Diastereomer ratio—Using the chromatogram for Test 1 in is not less than 3.5; and the column efficiency determined
the test for Related compounds, calculate the percentage of using the second peak of valganciclovir is not less than 1800
valganciclovir (R and S esters of L-valine) using the following theoretical plates.
formulas: Procedure—Inject about 20 mL of the Test solution into the
100[rA (rA + rB)] peak responses. Calculate the enantiomeric purity, in percent,
using the following formula:
100[rB (rA + rB)] 100[rS / (rS + rIM)]
in which rA and rB are the peak responses for valganciclovir (R in which rS is the sum of the peak responses of valganciclovir
and S esters of L-valine), respectively. The diastereomer ratio (R and S esters of L-valine) and rIM is the sum of the peak
is (45 : 55) to (55 : 45). responses of the enantiomeric impurities (R and S esters of D-
valine), respectively. The enantiomeric purity is not less than
Enantiomeric purity of valganciclovir—
97.0%.
Mobile phase—Dissolve 16.2 g of perchloric acid in 1000
In-Process Revision
mL of water, and mix. Pass this solution through a filter Assay—
having a 0.5-mm or finer porosity, and degas. Make 0.1 M Monobasic ammonium phosphate solution—Dis-
adjustments if necessary (see System Suitability under solve 11.5 g of monobasic ammonium phosphate in about
Chromatography h621i). 900 mL of water, adjust with phosphoric acid (85%) to a pH
System suitability solution—Transfer about 5 mg of USP of 2.8 + 0.2, dilute with water to obtain 1000 mL of solution,
Valganciclovir Hydrochloride RS and 0.5 mg of D-valine and mix.
esters to a 25-mL volumetric flask, dissolve in and dilute with Mobile phase—Prepare a filtered and degassed mixture of
0.001 N hydrochloric acid to volume, and mix. 0.1 M Monobasic ammonium phosphate solution and meth-
anol (92 : 8). Make adjustments if necessary (see System
Suitability under Chromatography h621i).
Pharmacopeial Forum
Table 3
Relative Relative Maximum

Test Retention Response Limit
Component Common Name Number Time Factor (%)
Valganciclovir Valganciclov 1, 2 1.00 1.00 —
a
A Ganciclovir 1 0.42 1.4 1.5
Ba Guanine 1 0.28 1.9 0.25
C a Methoxymethylguanine 1 0.81 1.0 0.3
Da, b Isovalganciclovir 1 1.26 1.0 0.5
Ea Monoacetoxyganciclovir 1 1.36 1.3 0.15
F (other identified Bis-valine ester of ganciclovir 1 1.61 0.71 0.1
impurity)
Ga, b Homologue of valganciclovir 1 1.66 1.0 0.25
H — 1 1.47 1.3 0.1
I — 1 1.52 1.4 0.1
J (other identified Ganciclovir monopropionate 1 2.09 1.1 0.15
impurity)
Ka Valganciclovir dimer 1 2.49 1.0 0.1
(stereoisomer A)
La Valganciclovir dimer 1 2.52 1.0 0.1
(stereoisomer B)
Ma Valganciclovir dimer 1 2.54 1.0 0.1
(stereoisomer C)
Na, b Ganciclovir mono-N- 2 1.2 1.0 0.3
methyl valinate
Other identified — 1 — 1.0 0.1 individual;
impurity 0.25 total
In-Process Revision
Unidentified — 1 and 2 — 1.0 0.1 individual;

impurity 0.25 total
Total of all — 1 and 2 — — 3.0
impurities
a
b
Specified impurity
Reported as the sum of diastereomers
Pharmacopeial Forum
System suitability solution—Transfer about 10 mg of USP in which rU is the peak response (sum of the two peaks for the
Valganciclovir Hydrochloride RS and 0.5 mg of meth- valganciclovir diastereomers) obtained from the Assay
oxymethylguanine to a 50-mL volumetric flask, dissolve in preparation; WU is the weight, in mg, of Valganciclovir
and dilute with 0.001 N hydrochloric acid to volume, and Hydrochloride in the Assay preparation; CF is the correction
mix. factor; and SU is the total percent of solvent and water in the
Standard preparation—Dissolve an accurately weighed test sample.
quantity of USP Valganciclovir Hydrochloride RS in 0.001 N The CF is calculated using the following formula:
hydrochloric acid, and dilute quantitatively, and stepwise if
necessary, to obtain a solution having a known concentration (WS / RS)(100 – SS /100)
of about 0.2 mg per mL.
Assay preparation—Dissolve an accurately weighed quan- in which WS is the weight, in mg, of USP Valganciclovir
tity of Valganciclovir Hydrochloride in 0.001 N hydrochloric Hydrochloride RS in the Standard preparation; RS is the area
acid, and dilute quantitatively, and stepwise if necessary, to response (sum of the two peaks for the valganciclovir
obtain a solution having a concentration of about 0.2 mg per diastereomers) obtained from the Standard preparation; and
mL. SS is the total percent of solvent and water in USP
Chromatographic system (see Chromatography h621i)— Valganciclovir Hydrochloride RS.~USP31

and a 4.6-mm 615-cm column that contains packing L1. The
column temperature is maintained at 258, and the flow rate is
about 1.0 mL per minute. Chromatograph the System
suitability solution, and record the peak responses as directed BRIEFING
for Procedure: meets the system suitability requirements as
Valganciclovir Tablets, page 384 of PF 32(2) [Mar.–Apr. 2006].
specified for Test 1 in the test for Related compounds. In the Definition, it is proposed to revise the upper acceptance
criteria limit to 105.0 percent to be consistent with the NDA
Chromatograph the Standard preparation, and record the submission. Minor editorial changes have also been made.
peak responses as directed for Procedure: the relative
standard deviation of the correction factor (CF ) for replicate
injections is not more than 1.0%. [NOTE—CF is calculated as
directed below in the Procedure.]
In-Process Revision
Add the following:
of the Standard preparation and the Assay preparation into ~
Valganciclovir Tablets
the peak responses. Calculate the percentage, on the
anhydrous and solvent-free basis, of C14H22N6O5 HCl in the
portion of Valganciclovir Hydrochloride taken by the » Valganciclovir Tablets contain not less than 93.0
formula: percent and not more than 110.0 105.0 percent of
the labeled amount of valganciclovir (C14H22N6O5).
100[(rU / WU)(CF )(100) /(100 – SU)]
Packaging and storage—Preserve in tight containers. Store
at 258, excursions permitted between 158 and 308.
Pharmacopeial Forum
USP Reference standards h11i—USP Valganciclovir Hy-

drochloride RS.
Identification—
A: Ultraviolet Absorption h197Ui—
Spectral range: 200–350 nm.
Solution: 10 mg per mL. in which WS is the weight, in mg, of USP Valganciclovir
Medium: 0.001 M hydrochloric acid. Hydrochloride RS taken to prepare the Standard solution; WC
B: The retention time of the diastereomeric peaks in the is the water content of USP Valganciclovir Hydrochloride RS;
chromatogram of the Assay preparation correspond to those 0.91 is the conversion factor from valganciclovir hydrochlo-
in the chromatogram of the Standard preparation, as obtained ride to valganciclovir free base; and P is the purity, in
in the Assay. decimals, of USP Valganciclovir Hydrochloride RS. Calcu-

late the amount, in percentage, of valganciclovir released
using the formula:
Medium: 0.1 N hydrochloric acid; 900 mL, deaerated.
Time: 30 minutes.
Standard solution—Expose the USP Valganciclovir Hy-
drochloride RS to ambient conditions overnight, and
determine the water content prior to use. Accurately weigh
in which AU and AS are the absorbances obtained from the Test
an amount, equivalent to about 100 mg of valganciclovir free
solution and the Working standard solution, respectively; CS
base, transfer to a 20-mL volumetric flask, dilute with
is the concentration, in mg per mL, of valganciclovir free base
Medium to volume, and mix.
in the Working standard solution; 900 is the volume, in mL,
Working standard solution—Transfer 5.0 mL of the
of Medium; 100 is the conversion factor to percentage; and
Standard solution to a 50-mL volumetric flask, dilute with
LC is the Tablet label claim, in mg.
Medium to volume, and mix well. Pass a portion of this
Tolerances—Not less than 80% (Q) of the labeled amount
solution through a 10-mm polyethylene filter, discarding the
of valganciclovir is dissolved in 30 minutes.
first 2 mL of the filtrate.
Test solution—Pass 10 mL of the solution under test
In-Process Revision

through a 10-mm polyethylene filter, discarding the first 2 mL
Mobile phase, Diluent, Resolution solution, and
of the filtrate.
Chromatographic system—Proceed as directed in the Assay.
Procedure—Determine the amount of C14H22N6O5 dis-
Standard solution—Prepare as directed for the Standard
solved by UV absorption at the wavelength of maximum
preparation in the Assay.
absorbance at about 254 nm on portions of the Test solution,
Test solution—Transfer 1 Tablet to a 100-mL volumetric
suitably diluted with Medium, if necessary, in comparison
flask, add about 80 mL of Diluent, and sonicate until the
with the Working standard solution, using a 0.02-cm quartz
Tablet is fully disintegrated. Dilute with Diluent to volume,
cell. Calculate the weight of valganciclovir free base using the
mix, and allow the solution to settle. Pipet 3.0 mL of the top
formula:
portion of the resulting solution into a 200-mL volumetric
Pharmacopeial Forum
flask, dilute with Diluent to volume, and mix. Pass a portion Procedure—Inject a volume (about 50 mL) of the Standard
of the solution through a filter having a 0.45-mm or finer solution and the Test solution into the chromatograph, record
porosity, and use the filtrate, discarding the initial 2 mL. the chromatogram, and measure all of the peak responses.
Procedure—Separately inject equal volumes (about 50 mL) Calculate the percentage of ganciclovir and guanine in the
of the Standard solution and the Test solution into the portion of Tablets taken by the formula:
responses for the major peaks. Calculate the quantity, in mg, WS (rU / rS)(0.91)(1/FL)(100 – SS /100)(DU /DS)(WA /WU)(100)
of valganciclovir (C14H22N6O5) in the portion of Tablets taken

in which WS is the weight, in mg, of USP Valganciclovir
by the formula:
Hydrochloride RS taken to prepare the Standard solution; rU
WS (rU / rS)(0.91)(100 – SS /100)(DU / DS) is the guanine or ganciclovir peak response obtained from the
Test solution; rS is the sum of the peak responses of the
in which WS is the weight, in mg, of USP Valganciclovir valganciclovir diastereomers obtained from the Standard
Hydrochloride RS taken to prepare the Standard solution; rU solution; 0.91 is the conversion factor for valganciclovir
and rS are the sum of the peak responses of valganciclovir hydrochloride to valganciclovir free base; F is the relative
obtained from the Test solution and the Standard solution, response factor, 1.9 and 1.4, for guanine and ganciclovir,
respectively; 0.91 is the conversion factor for valganciclovir respectively; L is the labeled amount, in mg, of valganciclovir
hydrochloride to valganciclovir free base; SS is the percent of in each Tablet; S S is the percent of water in USP
water in USP Valganciclovir Hydrochloride RS; and DU and Valganciclovir Hydrochloride RS; DU and DS are the dilution
DS are the dilution factors of the Test solution and the factors of the Test solution and the Standard solution,
Standard solution, respectively. respectively; WA is the average weight, in mg, of a Tablet;
and WU is the weight, in mg, of the powdered Tablet taken to
prepare the Test solution. Not more than 2.0% of ganciclovir
Mobile phase, Diluent, Resolution solution, and
and not more than 1.0% of guanine are found.
Calculate the individual unidentified and identified impu-
Standard solution—Use the Standard preparation in the
rities listed in Table 1 using the formula:
Assay.
Test solution—Weigh and finely powder not fewer than 20
100(ri / rs)
In-Process Revision
Tablets. Transfer an accurately weighed portion of the
powder, equivalent to about 450 mg of valganciclovir, to in which ri is the peak response for each impurity/degradant,
a 1000-mL volumetric flask, add about 800 mL of Diluent, and rs is the sum of the responses of all the peaks: not more
and sonicate until the Tablet is fully disintegrated. Dilute with than 0.2% of each unidentified individual impurity is found;
Diluent to volume, and mix. Pass a portion of this solution not more than 0.5% of total unidentified impurity/degradant is
through a filter having a 0.45-mm or finer porosity, and use the found; and not more than 3.5% of total impurities including
filtrate, discarding the initial 2 mL. all the degradation products is found.
Pharmacopeial Forum
Table 1 Standard stock preparation—Dissolve an accurately
Approximate weighed quantity of USP Valganciclovir Hydrochloride RS,
Relative and dilute quantitatively, and stepwise if necessary, with

Diluent to obtain a solution having a known concentration of
Name Component Retention time
about 0.3 mg per mL.
Guanine Degradant 0.51
Standard preparation—Pipet 6.0 mL of the Standard stock
Ganciclovir Degradant 0.66
preparation into a 20-mL volumetric flask. Dilute with
Valganciclovir 1 Active 1.00
Diluent to volume, and mix well. Pass a portion of the
Valganciclovir 2 Active 1.07
solution through a filter having a 0.45-mm or finer porosity,
Ganciclovir-mono-N- Impurity 1.21
and use the filtrate, discarding the initial 2 mL.
methyl valinate 1
Assay preparation—Transfer 5 Tablets into a 500-mL
Ganciclovir-mono-N- Impurity 1.30
volumetric flask, add about 300 mL of Diluent, and shake
methyl valinate 2
well until the Tablets are fully disintegrated. Dilute with
Methoxymethylguanine Impurity 1.45
Diluent to volume, mix, and allow the solution to settle.
Isovalganciclovir 1 Impurity 1.55
Transfer 3.0 mL of the supernatant into a 200-mL volumetric
Isovalganciclovir 2 Impurity 1.61
flask, and dilute with Diluent to volume. Pass a portion of this
Ganciclovir Divalinate Impurity 2.13
solution through a filter having a 0.45-mm or finer porosity,
Monoacetoxyganciclovir Impurity 2.31
and use the filtrate, discarding the initial 2 mL.
Isomonochloroganciclovir Impurity 2.52
Homologue 1 Impurity 2.69
Homologue 2 Impurity 2.77
and a 4.6-mm615-cm column that contains packing L11.
The flow rate is about 1.0 mL per minute. The column
Assay—
temperature is maintained at 308. Chromatograph the
Solution A—Dilute 2.5 mL of triethylamine with water to
Resolution solution as directed for Procedure: the resolution,
1000 mL, and adjust with trifluoroacetic acid to a pH of
R, between the second diastereomeric valganciclovir peak and
3.0 + 0.05.
the first ganciclovir mono-N-methylvaline peak is not less
than 2. Chromatograph the Standard preparation, and record
In-Process Revision
the peak responses as directed for Procedure: the column

Solution A and Solution B (93 : 7). Make adjustments if
efficiency for the second diastereomeric valganciclovir peak
is not less than 3000 theoretical plates; the tailing factor for
h621i).
the second diastereomeric valganciclovir peak is not more
Diluent—Dilute 1.0 mL of 1 M hydrochloric acid with
than 3; and the relative standard deviation for the total areas
water to 1.0 L, and mix.
for the two valganciclovir peaks for replicate injections is not
Resolution solution—Dissolve suitable quantities of ganci-
more than 2.0%.
clovir mono-N-methylvaline and USP Valganciclovir Hydro-
chloride RS in Diluent to obtain a solution containing about
0.1 mg per mL and 78 mg per mL, respectively.
Pharmacopeial Forum
the responses for the major peaks. Calculate the quantity, in Add the following:
~
mg, of valganciclovir (C14H22N6O5) in the portion of Tablets Labeling—Where the product contains water-soluble ubi-
taken by the formula: decarenone, this is so stated in the label.~USP31
Change to read:
WS (rU / rS)(0.91)(100 – SS /100)(DU / DS)
Disintegration and dissolution h2040i: meet the requirements of
the test for Disintegration only,
in which WS is the weight, in mg, of USP Valganciclovir
~
except where the product is labeled to contain water-soluble
Hydrochloride RS taken to prepare the Standard preparation;
ubidecarenone. Ubidecarenone Capsules labeled to contain
rU and rS are the sum of the peak responses for the
water-soluble ubidecarenone meet the requirements for the
valganciclovir diastereomers obtained from the Assay prep-
test for Dissolution, as follows.
aration and the Standard preparation, respectively; 0.91 is
the conversion factor for valganciclovir hydrochloride to
valganciclovir free base; SS is the percent of water in USP
Time: 60 minutes.
Valganciclovir Hydrochloride RS; and DU and DS are the
Determine the amount of C59H90O4 dissolved by employing
dilution factors of the Assay preparation and the Standard
the following method.
preparation, respectively.~USP31
directed in the Assay
DIETARY SUPPLEMENTS—
tity of about 25 mg of USP Ubidecarenone RS in 1 mL of
MONOGRAPHS
ethyl ether, and dilute quantitatively and stepwise with
alcohol to obtain a solution having a known concentration of
about 2.5 mg per mL. Use a freshly prepared solution only.
Test solution—Dilute quantitatively and stepwise with
alcohol an accurately measured volume of the solution
BRIEFING
under test, previously passed through a suitable 0.45-mm
filter, to obtain a solution having a concentration of about 2.5
Ubidecarenone Capsules, USP 29 page 2383 and page 3588 of
the First Supplement; Ubidecarenone Tablets, USP 29 page 2384. mg of ubidecarenone per mL.
In the current dietary supplement market, it is possible to find
Ubidecarenone Capsules containing a water-soluble form of the
In-Process Revision
dietary ingredient. These dosage forms usually claim improved
bioavailability over the traditional dosage forms containing fat-
soluble ubidecarenone. It is proposed to add to the monograph a test
that differentiates between these two distinct products. A Dissolution
test for the water-soluble form is therefore added and linked to
a Labeling requirement to indicate that the product contains a water-
soluble form of ubidecarenone.
(DSBA: P. Jin) RTS—C50931
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 100

BRIEFING
mL) of the Standard solution and the Test solution into the
chromatograph, record the chromatograms, and measure the Ubidecarenone Tablets, USP 29 page 2384—See briefing under
Ubidecarenone Capsules.
responses for the major peaks. Calculate the percentage of
C59H90O4 dissolved by the formula: (DSBA: P. Jin) RTS—C50933
Add the following:

500CD(rU / rS)100/LC
~
Labeling—Where the product contains water-soluble ubi-
in which 500 is the volume, in mL, of Medium; C is the decarenone, this is so stated in the label.~USP31
concentration, in mg per mL, of USP Ubidecarenone RS in
Change to read:
the Standard solution; D is the dilution factor used to prepare
the Test solution; r U and r S are the peak areas of the test for Disintegration only,
ubidecarenone obtained from the Test solution and the ~
except where the product is labeled to contain water-soluble
Standard solution, respectively; 100 is the conversion factor
ubidecarenone. Ubidecarenone Tablets labeled to contain
to percentage; and LC is the label claim, in mg per Capsule.
water-soluble ubidecarenone meet the requirements for
Tolerances—Not less than 75% of the labeled amount of
Dissolution as directed in the test for Disintegration and
C59H90O4 is dissolved in 60 minutes.~USP31
dissolution under Ubidecarenone Capsules.~USP31
In-Process Revision
Pharmacopeial Forum
Add the following:

GENERAL CHAPTERS ~
USP Levalbuterol Hydrochloride RS [(R)-a1-[(tert-butyla-
mino)methyl]-4-hydroxy-m-xylene-a, a-diol hydrochlori-
General Tests and Assays
de].~USP31
General Requirements for Add the following:
Tests and Assays

~
USP Levalbuterol Related Compound A RS [4-(2-tert-bu-
tylamino-ethyl)-2-hydroxymethyl-phenol].~USP31
Add the following:

~
USP Levalbuterol Related Compound B RS [a [{(1,1-di-
methylethyl)amino}methyl]-4-hydroxy-3-methyl-benzene-
methanol].~USP31
BRIEFING
Add the following:
h11i USP Reference Standards, USP 29 page 2458, page 3754 of ~
the Second Supplement, page 1832 of PF 27(1) [Jan.–Feb. 2001], USP Levalbuterol Related Compound C RS [a [{(1,1-di-
page 840 of PF 28(3) [May–June 2002], page 1468 of PF 28(5)
[Sept.–Oct. 2002], page 710 of PF 29(3) [May–June 2003], page methylethyl)amino}methyl]-4-hydroxy-3-(methoxymethyl)-
2022 of PF 29(6) [Nov.–Dec. 2003], page 613 of PF 30(2) [Mar.–
Apr. 2004], page 1338 of PF 30(4) [July–Aug. 2004], page 1674 benzenemethanol].~USP31
of PF 30(5) [Sept.–Oct. 2004], page 2092 of PF 30(6) [Nov.–Dec.
2004], page 99 of PF 31(1) [Jan.–Feb. 2005], page 507 of PF Add the following:
31(2) [Mar.–Apr. 2005], page 822 of PF 31(3) [May–June 2005],
page 1154 of PF 31(4) [July–Aug. 2005], page 1433 of PF 31(5) ~
USP Levalbuterol Related Compound D RS [5-[2-{(1,1-
[Sept.–Oct. 2005], page 1680 of PF 31(6) [Nov.–Dec. 2005], page
181 of PF 32(1) [Jan.–Feb. 2006], page 407 of PF 32(2) [Mar.– dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxy-benzalde-
Apr. 2006], page 829 of PF 32(3) [May–June 2006], page 1161 of
PF 32(4) [July–Aug. 2006], page 1491 of PF 32(5) [Sept.–Oct. hyde].~USP31
2006], and page 1779 of PF 32(6) [Nov.–Dec. 2006].
(HDQ) RTS—C42103; C43029; C45125; C46718; C47712; Add the following:

C49130 ~
USP Levalbuterol Related Compound E RS [a [{(1,1-di-
methylethyl)amino}methyl]-3-(ethoxymethyl)-4-hydroxy-
benzenemethanol].~USP31
Add the following:
~
USP Ethyl Acetate RS.~USP31 Add the following:
~
USP Levalbuterol Related Compound F RS [a [{(1,1-di-
In-Process Revision
Add the following:
~
methylethyl)amino}methyl]-4-(phenylmethoxy)-1,3-benzene-
USP Low-Molecular-Weight Heparin Molecular Weight
dimethanol].~USP31
RS USP Enoxaparin Sodium Molecular Weight RS—
[To come.]~USP31 Add the following:
~
USP Levalbuterol Related Compound G RS [a [{(1,1-di-
Add the following:
~
methylethyl)amino}methyl]-4,5-dihydroxy-1,3-benzenedi-
USP Eprinomectin RS.~USP31
methanol].~USP31
Add the following:
Add the following:
~
USP Heptane RS.~USP31
~
USP Methyl Alcohol RS.~USP31
Pharmacopeial Forum
Add the following:

~
GENERAL CHAPTERS
USP Modafinil Related Compound A RS [2-[(diphenyl-
methyl)sulfinyl]acetic acid] (C15H14O3S 274.34 CAS-
General Information
63547-24-0).~USP31
Add the following:

~
USP Modafinil Related Compound B RS [2-[(diphenyl-
methyl)sulfonyl]acetamide] (C15H15NO3S 289.36 CAS-
BRIEFING
118779-53-6).~USP31
Add the following: h1225i Validation of Compendial Procedures, USP 29 page

3050 and page 3614 of the First Supplement. In order to align the
~
USP Modafinil Related Compound C RS [2-[(diphenyl- language of this General Information Chapter with the proposed
h1226i Verification of Analytical Procedures, the General Chapters
methyl)sulfenyl]acetamide] (C15H15NOS 257.36).~USP31 Expert Committee proposes to include the concept and a reference
to h1226i under Data Elements Required for Validation.
Add the following:
(GC: H. Pappa) RTS—C50909
~
USP Modafinil Related Compound D RS [bis(diphenyl-
methyl)ether] (C26H22O 350.46).~USP31
Change to read:
Add the following:
~
USP Modafinil Related Compound E RS [bis(diphenyl-
VALIDATION
methyl)disulfide] (C26H22S2 398.55).~USP31
Validation of an analytical &procedure&1S (USP29) is the process by
Add the following: which it is established, by laboratory studies, that the performance
characteristics of the &procedure&1S (USP29) meet the requirements
~ for the intended analytical applications. Typical analytical perfor-
USP Oleic Acid RS.~USP31 mance characteristics that should be considered in the validation of
the types of &procedures&1S (USP29) described in this document are
Add the following: listed in Table 1. Because opinions may differ with respect to termi-
nology and use, each of the performance characteristics is defined in
~ the next section of this chapter, along with a delineation of a typical
USP 2-Propanol RS.~USP31 method or methods by which it may be measured.
Add the following: Table 1. Typical Analytical Characteristics Used in Method Va-
lidation
~
USP Salicylic Acid Related Compound A RS [4-hydroxy-
Accuracy
benzoic acid] (C7H6O3 138.12 CAS-99-96-7).~USP31 Precision
Specificity
In-Process Revision
Detection Limit
Add the following: Quantitation Limit
Linearity
~
USP Salicylic Acid Related Compound B RS [4-hydroxy- Range
&
Robustness&1S (USP29)
isophthalic acid ] (C8H6O4 182.13).~USP31
In the case of compendial &procedures,&1S (USP29) revalidation may
be necessary in the following cases: a submission to the USP of a
revised analytical &procedure;&1S (USP29) or the use of an established
general &procedure&1S (USP29) with a new product or raw material (see
below in Data Elements Required for Validation).
The ICH documents give guidance on the necessity for revalida-
tion in the following circumstances: changes in the synthesis of the
drug substance; changes in the composition of the drug product; and
changes in the analytical procedure.
Pharmacopeial Forum
Analytical Performance Characteristics Determination—The precision of an analytical & proce-

dure&1S (USP29) is determined by assaying a sufficient number of ali-
ACCURACY quots of a homogeneous sample to be able to calculate statistically
valid estimates of standard deviation or relative standard deviation
Definition—The accuracy of an analytical &procedure&1S (USP29) is (coefficient of variation). Assays in this context are independent anal-
the closeness of test results obtained by that &procedure&1S (USP29) to yses of samples that have been carried through the complete analyt-
the true value. The accuracy of an analytical &procedure&1S (USP29) ical procedure from sample preparation to final test result.
should be established across its range. The ICH documents recommend that repeatability should be
assessed using a minimum of nine determinations covering the spec-
Determination—In the case of the assay of a drug substance, ac- ified range for the procedure (i.e., three concentrations and three
curacy may be determined by application of the analytical &proce- replicates of each concentration or using a minimum of six determi-
dure& 1S (USP29) to an analyte of known purity (e.g., a Reference nations at 100% of the test concentration).
Standard) or by comparison of the results of the & proce-
dure&1S (USP29) with those of a second, well-characterized &proce-
dure,&1S (USP29) the accuracy of which has been stated or defined.
In the case of the assay of a drug in a formulated product, accuracy SPECIFICITY
may be determined by application of the analytical & proce-
dure&1S (USP29) to synthetic mixtures of the drug product components Definition—The ICH documents define specificity as the ability to
to which known amounts of analyte have been added within the range assess unequivocally the analyte in the presence of components that
of the &procedure.&1S (USP29) If it is not possible to obtain samples of may be expected to be present, such as impurities, degradation prod-
all drug product components, it may be acceptable either to add ucts, and matrix components. Lack of specificity of an individual an-
known quantities of the analyte to the drug product (i.e., ‘‘to spike’’) alytical procedure may be compensated by other supporting
or to compare results with those of a second, well-characterized analytical procedures. [NOTE—Other reputable international authori-
&
procedure,&1S (USP29) the accuracy of which has been stated or de- ties (IUPAC, &AOAC-I)&1S (USP29) have preferred the term ‘‘selectiv-
fined. ity,’’ reserving ‘‘specificity’’ for those procedures that are completely
In the case of quantitative analysis of impurities, accuracy should selective.] For the &tests discussed&1S (USP29) below, the above defini-
be assessed on samples (of drug substance or drug product) spiked tion has the following implications:
with known amounts of impurities. Where it is not possible to obtain Identification Tests: ensure the identity of the analyte.
samples of certain impurities or degradation products, results should Purity Tests: ensure that all the analytical procedures performed
be compared with those obtained by an independent & proce- allow an accurate statement of the content of impurities of an analyte
dure.&1S (USP29) In the absence of other information, it may be neces- (e.g., related substances test, heavy metals limit, residual solvents).
sary to calculate the amount of an impurity based on comparison of its Assays: provide an exact result, which allows an accurate state-
response to that of the drug substance; the ratio of the responses of ment on the content or potency of the analyte in a sample.
equal amounts of the impurity and the drug substance
&
(relative&1S (USP29) response factor) should be used if known. Determination—In the case of qualitative analyses (identification
Accuracy is calculated as the percentage of recovery by the assay tests), the ability to select between compounds of closely related
of the known added amount of analyte in the sample, or as the differ- structure that are likely to be present should be demonstrated. This
ence between the mean and the accepted true value, together with should be confirmed by obtaining positive results (perhaps by com-
confidence intervals. parison to a known reference material) from samples containing the
The ICH documents recommend that accuracy should be assessed analyte, coupled with negative results from samples that do not con-
using a minimum of nine determinations over a minimum of three tain the analyte and by confirming that a positive response is not ob-
concentration levels, covering the specified range (i.e., three concen- tained from materials structurally similar to or closely related to the
trations and three replicates of each concentration). analyte.
&
Assessment of accuracy can be accomplished in a variety of In the case of analytical &procedures&1S (USP29) for impurities, spec-
ways, including evaluating the recovery of the analyte (percent recov- ificity may be established by spiking the drug substance or product
ery) across the range of the assay, or evaluating the linearity of the with appropriate levels of impurities and demonstrating that these im-
relationship between estimated and actual concentrations. The statis- purities are determined with appropriate accuracy and precision.
tically preferred criterion is that the confidence interval for the slope In the case of the assay, demonstration of specificity requires that it
be contained in an interval around 1.0, or alternatively, that the slope can be shown that the procedure is unaffected by the presence of im-
be close to 1.0. In either case, the interval or the definition of close- purities or excipients. In practice, this can be done by spiking the drug
ness should be specified in the validation protocol. The acceptance substance or product with appropriate levels of impurities or excipi-
criterion will depend on the assay and its variability and on the pro- ents and demonstrating that the assay result is unaffected by the pres-
duct. Setting an acceptance criterion based on the lack of statistical ence of these extraneous materials.
significance of the test of the null hypothesis that the slope is 1.0 is If impurity or degradation product standards are unavailable, spec-
not an acceptable approach.&1S (USP29) ificity may be demonstrated by comparing the test results of samples
containing impurities or degradation products to a second well-char-
In-Process Revision
acterized procedure (e.g., a Pharmacopeial or other validated proce-
dure). These comparisons should include samples stored under
PRECISION relevant stress conditions (e.g., light, heat, humidity, acid/base hy-
drolysis, oxidation). In the case of the assay, the results should be
Definition—The precision of an analytical &procedure&1S (USP29) is compared; in the case of chromatographic impurity tests, the impurity
the degree of agreement among individual test results when the profiles should be compared.
&
procedure&1S (USP29) is applied repeatedly to multiple samplings of The ICH documents state that when chromatographic procedures
a homogeneous sample. The precision of an analytical are used, representative chromatograms should be presented to dem-
&
procedure&1S (USP29) is usually expressed as the standard deviation onstrate the degree of selectivity, and peaks should be appropriately
or relative standard deviation (coefficient of variation) of a series of labeled. Peak purity tests (e.g., using diode array or mass spectrom-
measurements. Precision may be a measure of either the degree of etry) may be useful to show that the analyte chromatographic peak is
reproducibility or of repeatability of the analytical & proce- not attributable to more than one component.
dure&1S (USP29) under normal operating conditions. In this context, re-
producibility refers to the use of the analytical procedure in different
laboratories, as in a collaborative study. Intermediate precision
DETECTION LIMIT
&
(also known as ruggedness)&1S (USP29) expresses within-laboratory
variation, as on different days, or with different analysts or equipment
within the same laboratory. Repeatability refers to the use of the Definition—The detection limit is a characteristic of limit tests. It
analytical procedure within a laboratory over a short period of time is the lowest amount of analyte in a sample that can be detected, but
using the same analyst with the same equipment. &&1S (USP29) not necessarily quantitated, under the stated experimental conditions.
Thus, limit tests merely substantiate that the amount of analyte is
Pharmacopeial Forum
above or below a certain level. The detection limit is usually ex- concentration and assay measurement. In some cases, to attain linear-
pressed as the concentration of analyte (e.g., percentage, parts per bility, the concentration and/or the measurement may be transformed.
lion) in the sample. (Note that the weighting factors used in the regression analysis
Determination—For noninstrumental &procedures,&1S (USP29) the may change when a transformation is applied.) Possible transforma-
detection limit is generally determined by the analysis of samples tions may include log, square root, or reciprocal, although other trans-
with known concentrations of analyte and by establishing the mini- formations are acceptable. If linearity is not attainable, a nonlinear
mum level at which the analyte can be reliably detected. model may be used. The goal is to have a model, whether linear or
For instrumental procedures, the same &approach&1S (USP29) may be nonlinear, that describes closely the concentration-response relation-
used as for noninstrumental &procedures.&1S (USP29) In the case of ship.&1S (USP29)
&
procedures&1S (USP29) submitted for consideration as official com- Definition of Range—The range of an analytical & proce-
pendial &procedures,&1S (USP29) it is almost never necessary to deter- dure&1S (USP29) is the interval between the upper and lower levels of
mine the actual detection limit. Rather, the detection limit is shown to analyte (including these levels) that have been demonstrated to be de-
be sufficiently low by the analysis of samples with known concentra- termined with a suitable level of precision, accuracy, and linearity
tions of analyte above and below the required detection level. For ex- using the &procedure&1S (USP29) as written. The range is normally ex-
ample, if it is required to detect an impurity at the level of 0.1%, it pressed in the same units as test results (e.g., percent, parts per mil-
should be demonstrated that the procedure will reliably detect the im- lion) obtained by the analytical &procedure.&1S (USP29)
purity at that level. Determination of Linearity and Range—Linearity should be es-
In the case of instrumental analytical procedures that exhibit back- tablished across the range of the analytical procedure. It should be
ground noise, the ICH documents describe a common approach, established initially by visual examination of a plot of signals as a
which is to compare measured signals from samples with known function of analyte concentration of content. If there appears to be
low concentrations of analyte with those of blank samples. The min- a linear relationship, test results should be established by appropriate
imum concentration at which the analyte can reliably be detected is statistical methods (e.g., by calculation of a regression line by the
established. Typically acceptable signal-to-noise ratios are 2 : 1 or method of least squares). &&1S (USP29) Data from the regression line
3 : 1. Other approaches depend on the determination of the slope of itself may be helpful to provide mathematical estimates of the degree
the calibration curve and the standard deviation of responses. What- of linearity. The correlation coefficient, y-intercept, slope of the re-
ever method is used, the detection limit should be subsequently vali- gression line, and residual sum of squares should be submitted.
dated by the analysis of a suitable number of samples known to be The range of the &procedure&1S (USP29) is validated by verifying
near, or prepared at, the detection limit. that the analytical &procedure&1S (USP29) provides acceptable preci-
sion, accuracy, and linearity when applied to samples containing ana-
lyte at the extremes of the range as well as within the range.
QUANTITATION LIMIT ICH recommends that, for the establishment of linearity, a mini-
mum of five concentrations normally be used. It is also recommended
Definition—The quantitation limit is a characteristic of quantita- that the following minimum specified ranges should be considered:
tive assays for low levels of compounds in sample matrices, such Assay of a Drug Substance (or a finished product): from 80% to
as impurities in bulk drug substances and degradation products in fin- 120% of the test concentration.
ished pharmaceuticals. It is the lowest amount of analyte in a sample Determination of an Impurity: from 50% to 120% of the &ac-
that can be determined with acceptable precision and accuracy under ceptance criterion.&1S (USP29)
the stated experimental conditions. The quantitation limit is ex-
pressed as the concentration of analyte (e.g., percentage, parts per bil- For Content Uniformity: a minimum of 70% to 130% of the test
lion) in the sample. concentration, unless a wider or more appropriate range based on the
nature of the dosage form (e.g., metered-dose inhalers) is justified.
Determination—For noninstrumental &procedures,&1S (USP29) the
quantitation limit is generally determined by the analysis of samples For Dissolution Testing: +20% over the specified range (e.g., if
with known concentrations of analyte and by establishing the mini- the &acceptance criteria&1S (USP29) for a controlled-release product
mum level at which the analyte can be determined with acceptable cover a region from 20%, after 1 hour, and up to 90%, after 24 hours,
accuracy and precision. the validated range would be 0% to 110% of the label claim).
&
&1S (USP29)
For instrumental procedures, the same &approach&1S (USP29) may be
used as for noninstrumental &procedures.&1S (USP29) In the case of
&
procedures&1S (USP29) submitted for consideration as official com-
pendial &procedures,&1S (USP29) it is almost never necessary to deter- ROBUSTNESS
mine the actual quantitation limit. Rather, the quantitation limit is
shown to be sufficiently low by the analysis of samples with known Definition—The robustness of an analytical &procedure&1S (USP29)
concentrations of analyte above and below the quantitation level. For is a measure of its capacity to remain unaffected by small but deliber-
example, if it is required that an analyte be assayed at the level of 0.1 ate variations in &procedural parameters listed in the procedure doc-
mg per tablet, it should be demonstrated that the & proce- umentation and provides an indication of its suitability&1S (USP29)
In-Process Revision
dure&1S (USP29) will reliably quantitate the analyte at that level. during normal usage. &Robustness may be determined during devel-
In the case of instrumental analytical &procedures&1S (USP29) that opment of the analytical procedure.&1S (USP29)
exhibit background noise, the ICH documents describe a common ap-
proach, which is to compare measured signals from samples with
known low concentrations of analyte with those of blank samples. SYSTEM SUITABILITY
The minimum concentration at which the analyte can reliably be
quantified is established. A typically acceptable signal-to-noise ratio If measurements are susceptible to variations in analytical condi-
is 10 : 1. Other approaches depend on the determination of the slope tions, these should be suitably controlled, or a precautionary state-
of the calibration curve and the standard deviation of responses. ment should be included in the & procedure. & 1 S ( USP 29) One
Whatever &approach&1S (USP29) is used, the quantitation limit should consequence of the evaluation of robustness and ruggedness should
be subsequently validated by the analysis of a suitable number of be that a series of system suitability parameters is established to en-
samples known to be near, or prepared at, the quantitation limit. sure that the validity of the analytical &procedure&1S (USP29) is main-
tained whenever used. Typical variations are the stability of analytical
solutions, different equipment, and different analysts. In the case of
LINEARITY AND RANGE liquid chromatography, typical variations are the pH of the mobile
phase, the mobile phase composition, different lots or suppliers of
Definition of Linearity—The linearity of an analytical &proce- columns, the temperature, and the flow rate. In the case of gas chro-
dure&1S (USP29) is its ability to elicit test results that are directly, or matography, typical variations are different lots or suppliers of col-
by a well-defined mathematical transformation, proportional to the umns, the temperature, and the flow rate.
concentration of analyte in samples within a given range. &Thus, in
this section, ‘‘linearity’’ refers to the linearity of the relationship of
Pharmacopeial Forum
System suitability tests are based on the concept that the equip- Category III—Analytical &procedures&1S (USP29) for determina-
ment, electronics, analytical operations, and samples to be analyzed tion of performance characteristics (e.g., dissolution, drug release).
constitute an integral system that can be evaluated as such. System Category IV—Identification tests.
suitability test parameters to be established for a particular &proce- For each &&1S (USP29) category, different analytical information is
dure&1S (USP29) depend on the type of &procedure&1S (USP29) being needed. Listed in Table 2 are data elements that are normally required
evaluated. They are especially important in the case of chromato- for each of &these categories.&1S (USP29)
graphic &procedures. Submissions&1S (USP29) to the USP should make Already established general &procedures (e.g., titrimetric determi-
note of the requirements under the System Suitability section in the nation of water, bacterial endotoxins)&1S (USP29) should be revalidated
general test chapter Chromatography h621i. to verify
~
verified to establish their suitability for use such as~USP31
Data Elements Required for &
&1S (USP29) Validation their accuracy (and absence of possible interference) when used for a
new product or raw material.
Compendial &test requirements&1S (USP29) vary from highly exact- The validity of an analytical &procedure&1S (USP29) can be verified
ing analytical determinations to subjective evaluation of attributes. only by laboratory studies. Therefore, documentation of the success-
Considering this &broad variety,&1S (USP29) it is only logical that dif- ful completion of such studies is a basic requirement for determining
ferent test & procedures & 1S (USP29) require different validation whether a &procedure&1S (USP29) is suitable for its intended applica-
schemes. This chapter covers only the most common categories of tion(s). &Current compendial procedures are also subject to regu-
&
tests&1S (USP29) for which validation data should be required. These lations that require demonstration of suitability under actual
categories are as follows: conditions of use&1S (USP29)
Category I—Analytical &procedures&1S (USP29) for quantitation of ~
major components of bulk drug substances or active ingredients (in- (see Verification of Analytical Procedures h1226i for princi-
cluding preservatives) in finished pharmaceutical products.
Category II—Analytical &procedures&1S (USP29) for determination ples relative to the verification of compendial proce-
of impurities in bulk drug substances or degradation compounds in
finished pharmaceutical products. These &procedures&1S (USP29) in- dures).~USP31
clude quantitative assays and limit tests. Appropriate documentation should accompany any proposal for new
or revised compendial analytical procedures.
&
Table 2. Data Elements Required for &1S (USP29)Validation
Analytical
&
&1S Category II
(USP29)
Performance &
&1S (USP29) Limit &
&1S (USP29)
&
&1S (USP29)
Characteristics Category I Quantitative Tests Category III Category IV
Accuracy Yes Yes * * No
Precision Yes Yes No Yes No
Specificity Yes Yes Yes * Yes
Detection Limit No No Yes * No
Quantitation Limit No Yes No * No
Linearity Yes Yes No * No
In-Process Revision
Range Yes Yes * * No
&
&1S (USP29)
*
May be required, depending on the nature of the specific test.
Pharmacopeial Forum
Add the following:

REAGENTS, INDICATORS, ~
Calconcarboxylic Acid Triturate—Mix 1 part of
AND SOLUTIONS calconcarboxylic acid with 99 parts of sodium chloride.
Test for sensitivity—Dissolve 50 mg of calconcarboxylic
acid triturate in a mixture of 2 mL 10 N sodium hydroxide
Reagent Specifications and 100 mL of water. The solution is blue but becomes violet
on addition of 1 mL of a 10 g per L solution of magnesium
sulfate and 0.1 mL of a 1.5 g per L solution of calcium
BRIEFING
chloride and turns pure blue on addition of 0.15 mL of 0.01 M
2-Aminoheptane. It is proposed to add this new reagent that is sodium edetate.~USP31
used to prepare the Mobile phasein some of the monographs related
to Verapamil Hydrochloride.
(HDQ: M. Marques) RTS—C50673

BRIEFING
Add the following:

Dimethicone, viscosity 500 centistokes. It is proposed to add this
~
2-Aminoheptane (2-Heptylamine; 1-Methylhexylamine), new reagent and its synonym, used in the test for Content of silicon
dioxide in the monograph for Simethicone.
C7H17N—115.22 [123-82-0]—Use a suitable grade with
a content of not less than 99%.~USP31
Add the following:

~
Dimethicone, viscosity 500 centistokes
BRIEFING
(Poly(dimethylsiloxane), viscosity 500 centistokes),
Calconcarboxylic Acid. It is proposed to add this new reagent [–Si(CH3)2O–]n—[63148-62-9]—Use a suitable grade.~USP31
used in the Assay in the monograph for Calcium Glycerophosphate.
BRIEFING
Add the following:
~
Calconcarboxylic Acid (2-Naphthalenecarboxylic acid, Lactose, USP 29 page 3136 and page 921 of PF 32(3) [May–June
2006]. It is proposed to correct the molecular weight of this reagent.
3-hydroxy-4-[(2-hydroxy-4-sulfo-1-naphthalenyl)azo];
In-Process Revision
Calcon-3-carboxylic Acid; Cal-Red), C21H14N2O7S—438.42

[3737-95-9]—Use a suitable grade.~USP31
Change to read:
Lactose, C12H22O11 H2O—342.30
~
—360.31~USP31
BRIEFING
&
[64-42-3]&1S (USP30)
—Use ACS reagent grade.
Calconcarboxylic Acid Triturate. It is proposed to add this new
indicator used in the Assay in the monograph for Calcium
Glycerophosphate.
Pharmacopeial Forum
Absorbance—To 1 mL in a 50-mL volumetric flask add 10 mL of

BRIEFING methanol and 1 mL of hydrochloric acid, and add chloroform to
volume. The absorbance of this solution, determined at the
wavelength of maximum absorbance at about 285 nm, with a suitable
Propylamine Hydrochloride. It is proposed to add this new spectrophotometer, does not exceed 0.01. [NOTE—If the absorbance
reagent, used to prepare the Buffer solution in the Assay test under exceeds 0.01, purify the triethylamine as follows. Reflux 100 mL
Triamterene and Hydrochlorothiazide Tablets. with 20 mL of water and 2 g of sodium hydrosulfite for not less than
8 hours, wash with water, dry by refluxing, using a Dean-Stark trap,
and distill, collecting only the first 75 mL of the filtrate. Store over
(HDQ: M. Marques) RTS—C51027 anhydrous sodium carbonate or anhydrous potassium carbonate.]
~
Use a suitable HPLC grade with a content of not less than
Add the following:
99.5%.~USP31
~
P ro p y l a m i n e H y d ro c h l o r i d e ( 1 - P ro p a n a m i n e
hydrochloride; n-Propylamine hydrochloride), C3H9N HCl—
95.57 [556-53-6]—Use a suitable grade with a content of
not less than 99%.~USP31
Volumetric Solutions
BRIEFING
Sodium Phosphate Dibasic Dihydrate. It is proposed to include BRIEFING

this new reagent used in the monograph for Galantamine
Hydrobromide.
Volumetric Solutions, USP 29 page 3175, page 3812 of the
(HDQ: M. Marques) RTS—C50643 Second Supplement, and page 1805 of PF 32(6) [Nov.–Dec. 2006].
For Ceric Sulfate, Tenth-Normal (0.1 N) and for Potassium
Permanganate, Tenth-Normal (0.1 N), it is proposed to update the
drying conditions of the primary standard.
Add the following:
~ (HDQ: M. Marques) RTS—C51131; C51132
Sodium Phosphate Dibasic Dihydrate (Sodium Mono-
hydrogen Phosphate; Disodium Hydrogen Phosphate), Na2H
PO4 2H2O—177.99 [10028-24-7]—Use a suitable grade
with a content of not less than 99.5%. Add the following:
[NOTE—A suitable grade is available from

&
www.emdchemicals.com, catalog number SX0713.]~USP31 Bismuth Nitrate, 0.01 mol/L
Bi(NO3)3 5H2O, 485.07
1000 mL of this solution contains 4.851 g of bismuth nitrate
In-Process Revision
BRIEFING pentahydrate
Dissolve 4.86 g of bismuth nitrate pentahydrate in 60 mL of
Triethylamine, USP 29 page 3161 and page 1283 of PF 32(4)
[July–Aug. 2006]. It is proposed to update the specifications for this dilute nitric acid, add water to make 1000 mL, and
reagent to reflect the products currently available on the market.
standardize the solution as follows.
Accurately measure 25 mL of the prepared bismuth nitrate
solution, add 50 mL of water and 1 drop of xylenol orange
Change to read:
TS, and titrate the solution with 0.01 mol/L disodium
Triethylamine, (C2H5)3N—101.19
dihydrogen ethylenediamine tetraacetate VS until the red
&
[121-44-8]&2S (USP30)
~
—Colorless liquid. ~USP29 Slightly soluble in water. Miscible with color changes to yellow. Calculate the molarity factor.&2S (USP30)
alcohol, with ether, and with cold water. Store in well-closed
containers.
Boiling range (Reagent test): between 898 and 908.
Pharmacopeial Forum
disodium VS until the red-purple color of the solution

Change to read:
changes to blue-purple.
Ceric Sulfate, Tenth-Normal (0.1 N)
Ce(SO4)2, 332.24
33.22 g in 1000 mL
Use commercially available volumetric standard solution. Stan-
dardize the solution as follows.
Accurately weigh about 0.2 g of sodium oxalate, primary standard,

previously dried for 2 hours at 105 8,
~
dried according to the instructions on its label,~USP31 Change to read:
and dissolve in 75 mL of water. Add, with stirring, 2 mL of sulfuric
acid that has previously been mixed with 5 mL of water, mix well,
add 10 mL of hydrochloric acid, and heat to between 708 and 758. Mercuric Nitrate, Tenth-Molar (0.1 M)
Titrate with 0.1 N ceric sulfate to a permanent slight yellow color. Hg(NO3)2, 324.60
Each 6.700 mg of sodium oxalate is equivalent to 1 mL of 0.1 N 32.46 g in 1000 mL
ceric sulfate. Dissolve about 35 g of mercuric nitrate in a mixture of 5 mL of
nitric acid and 500 mL of water, and dilute with water to 1000 mL.
Standardize the solution as follows.
Transfer an accurately measured volume of about 20 mL of the
solution to a conical flask, and add 2 mL of nitric acid and 2 mL of
ferric ammonium sulfate TS. Cool to below 208, and titrate with
0.1 N ammonium thiocyanate VS to the first appearance of
a permanent brownish color.
Add the following:
& Magnesium Chloride, 0.01 M

MgCl2 6H2O, 203.30
2.0330 g in 1000 mL
Dissolve about 2.04 g of magnesium chloride in 1000 mL
of freshly boiled and cooled water, and standardize the
solution as follows.
Accurately measure 25 mL of the prepared magnesium Change to read:
chloride solution. Add 50 mL of water, 3 mL of ammonia– Potassium Hydroxide, Normal (1 N)

ammonium chloride buffer TS and 0.04 g of eriochrome black KOH, 56.11
56.11 g in 1000 mL
In-Process Revision
T–sodium chloride reagent. Titrate with 0.05 M edetate Dissolve 68 g of potassium hydroxide in about 950 mL of water.
Add a freshly prepared saturated solution of barium hydroxide until
no more precipitate forms. Shake the mixture thoroughly, and allow
it to stand overnight in a stoppered bottle. Decant the clear liquid, or
Pharmacopeial Forum
filter the solution in a tight, polyolefin bottle, and standardize by the Accurately weigh about 5 g of potassium biphthalate, previously
procedure set forth for Sodium Hydroxide, Normal (1 N). crushed lightly and dried at 1208 for 2 hours, and dissolve in 75 mL
of carbon dioxide-free water. Add 2 drops of phenolphthalein TS,
and titrate with the sodium hydroxide solution to the production of
a permanent pink color. Each 204.2 mg
&
204.23 mg&1S (USP30)
of potassium biphthalate is equivalent to 1 mL of 1 N sodium
hydroxide.
NOTES—(1) Solutions of alkali hydroxides absorb carbon dioxide

when exposed to air. They should be preserved in bottles having
well-fitted, suitable stoppers, provided with a tube filled with
a mixture of sodium hydroxide and lime (soda-lime tubes) so that air
entering the container must pass through this tube, which will absorb
the carbon dioxide. (2) Prepare solutions of lower concentration
Change to read: (e.g., 0.1 N, 0.01 N) by quantitatively diluting accurately measured
volumes of the 1 N solution with sufficient carbon dioxide-free water
to yield the desired concentration.
Potassium Permanganate, Tenth-Normal (0.1 N)
KMnO4, 158.03 Restandardize the solution frequently.
3.161 g in 1000 mL
Dissolve about 3.3 g of potassium permanganate in 1000 mL of
water in a flask, and boil the solution for about 15 minutes. Insert the Change to read:
stopper in the flask, allow it to stand for at least 2 days, and filter
through a fine-porosity, sintered-glass crucible. If necessary, the
bottom of the sintered-glass crucible may be lined with a pledget of Sodium Tetraphenylboron, Fiftieth-Molar (0.02 M)
glass wool. Standardize the solution as follows. NaB(C6H5)4, 342.22
Accurately weigh about 200 mg of sodium oxalate, previously 6.845 g in 1000 mL
dried at 1108 to constant weight, Dissolve an amount of sodium tetraphenylboron, equivalent to
6.845 g of NaB(C6H5)4, in water to make 1000 mL, and standardize
~
dried according to the instructions on its label,~USP31 the solution as follows.
and dissolve it in 250 mL of water. Add 7 mL of sulfuric acid, heat to
about 708, and then slowly add the permanganate solution from Pipet two 75-mL portions of the solution into separate beakers,
a buret, with constant stirring, until a pale pink color, which persists and to each add 1 mL of acetic acid and 25 mL of water. To each
for 15 seconds, is produced. The temperature at the conclusion of the beaker add, slowly and with constant stirring, 25 mL of potassium
titration should be not less than 608. Calculate the normality. Each biphthalate solution (1 in 20), and allow to stand for 2 hours. Filter
6.700 mg of sodium oxalate is equivalent to 1 mL of 0.1 N potassium one of the mixtures through a filtering crucible, and wash the
permanganate. precipitate with cold water. Transfer the precipitate to a container,
add 50 mL of water, shake intermittently for 30 minutes, filter, and
Since potassium permanganate is reduced on contact with organic use the filtrate as the saturated potassium tetraphenylborate solution
substances such as rubber, the solution must be handled in apparatus in the following standardization procedure. Filter the second mixture
entirely of glass or other suitably inert material. It should be through a tared filtering crucible, and wash the precipitate with three
frequently restandardized. Store in glass-stoppered, amber-colored 5-mL portions of saturated potassium tetraphenylborate solution.
bottles. Dry the precipitate at 1058 for 1 hour. Each g of potassium
tetraphenylborate (KTPB) is equivalent to 955.1 mg of sodium
tetraphenylboron.
In-Process Revision
NOTES—Prepare this solution just before use.
Change to read:
Sodium Hydroxide, Normal (1 N)

NaOH, 40.00
40.00 g in 1000 mL
Dissolve 162 g of sodium hydroxide in 150 mL of carbon dioxide-
free water, cool the solution to room temperature, and filter through
hardened filter paper. Transfer 54.5 mL of the clear filtrate to a tight,
polyolefin container, and dilute with carbon dioxide-free water to
1000 mL.
Pharmacopeial Forum
Change to read: particle size. Within any category of packings or phases listed
below, there may be a wide range of columns available.
Sodium Thiosulfate, Tenth-Normal (0.1 N)
Na2S2O3 5H2O, 248.19 Where it is necessary to define more specifically the
24.82 g in 1000 mL
Dissolve about 26 g of sodium thiosulfate and 200 mg of sodium chromatographic conditions, the individual monograph so
carbonate in 1000 mL of recently boiled and cooled water.
Standardize the solution as follows. indicates.]
Accurately weigh about 210 mg of primary standard potassium
dichromate, previously pulverized and dried at 1208 for 4 hours, Change to read:
&
according to the instructions on its label, if neces-
sary,&1S (USP30)
and dissolve in 100 mL of water in a glass-stoppered, 500-mL flask.
Swirl to dissolve the solid, remove the stopper, and quickly add 3 g Packings
of potassium iodide, 2 g of sodium bicarbonate, and 5 mL of
hydrochloric acid. Insert the stopper gently in the flask, swirl to mix,
and allow to stand in the dark for exactly 10 minutes. Rinse the L1—Octadecyl silane chemically bonded to porous silica
stopper and the inner walls of the flask with water, and titrate the
liberated iodine with the sodium thiosulfate solution until the or ceramic micro-particles, 3 &
1.5&1S (USP30) to 10 mm in
solution is yellowish green in color. Add 3 mL of starch TS, and
continue the titration until the blue color is discharged. Perform diameter, &or a monolithic silica rod.&1S (USP29)
a blank determination.
L2—Octadecyl silane chemically bonded to silica gel of
Restandardize the solution as frequently as supported by
laboratory stability data. In the absence of such data, restandardize a controlled surface porosity that has been bonded to a solid
the solution weekly.
spherical core, 30 to 50 mm in diameter.
~
L3—Porous silica particles, 5 3~USP31 to 10 mm in diameter,
~
or a monolithic silica rod.~USP31
L4—Silica gel of controlled surface porosity bonded to
a solid spherical core, 30 to 50 mm in diameter.
L5—Alumina of controlled surface porosity bonded to
a solid spherical core, 30 to 50 mm in diameter.
BRIEFING L6—Strong cation-exchange packing–sulfonated fluorocar-
bon polymer coated on a solid spherical core, 30 to 50 mm in
Chromatographic Reagents, page 1293 of PF 32(4) [July–Aug.
2006]. It is proposed to (1) expand the particle size range in the L3 diameter.
designation, (2) include monolithic silica rods in the L3 and L7
designations, and (3) expand the particle size range in the L## L7—Octylsilane chemically bonded to totally porous silica
(Trehalose, Sugar KS-801) designation. ~
particles, 3 &1.5&1S (USP30) to 10 mm in diameter, or a mono-
lithic silica rod.~USP31
In-Process Revision
L8—An essentially monomolecular layer of aminopropyl-

Add the following:
silane chemically bonded to totally porous silica gel support,
3 to 10 mm in diameter.
&CHROMATOGRAPHIC L9—&&1S Irregular or spherical, totally porous silica

REAGENTS (USP29)
gel having a chemically bonded, strongly acidic cation-

exchange coating, &3 to 10 mm in diameter.&1S (USP29)
The following list of packings (L), phases (G), and supports L10—Nitrile groups chemically bonded to porous silica
(S) is intended to be a convenient reference for the particles, 5 to 10 mm in diameter.
chromatographer. [NOTE—Particle sizes given in this listing L11—Phenyl groups chemically bonded to porous silica
are those generally provided. Where other, usually finer, sizes particles, 5 &1.5&1S (USP30) to 10 mm in diameter.
are required, the individual monograph specifies the desired
Pharmacopeial Forum
L12—A strong anion-exchange packing made by chemi- anionic, and cationic water-soluble polymers. A polymetha-
cally bonding a quaternary amine to a solid silica spherical crylate resin base, cross-linked with polyhydroxylated ether
core, 30 to 50 mm in diameter. (surface containing some residual carboxyl functional groups)
L13—Trimethylsilane chemically bonded to porous silica was found suitable.
particles, 3 to 10 mm in diameter. L26—Butyl silane chemically bonded to totally porous
L14—Silica gel having a chemically bonded, strongly basic silica particles, &3&1S (USP29) to 10 mm in diameter.
quaternary ammonium anion-exchange coating, 5 to 10 mm in L27—Porous silica particles, 30 to 50 mm in diameter.
diameter. L28—A multifunctional support, which consists of a high
L15—Hexylsilane chemically bonded to totally porous purity, 100 Å, spherical silica substrate that has been bonded
silica particles, 3 to 10 mm in diameter. with anionic exchanger, amine functionality in addition to
L16—Dimethylsilane chemically bonded to porous silica a conventional reversed phase C8 functionality.
particles, 5 to 10 mm in diameter. L29—Gamma alumina, reverse-phase, low carbon percent-
L17—Strong cation-exchange resin consisting of sulfonat- age by weight, alumina-based polybutadiene spherical
ed cross-linked styrene-divinylbenzene copolymer in the particles, 5 mm in diameter with a pore volume of 80 Å.
hydrogen form, 7 to 11 mm in diameter. L30—Ethyl silane chemically bonded to totally porous
L18—Amino and cyano groups chemically bonded to silica particles, 3 to 10 mm in diameter.
porous silica particles, 3 to 10 mm in diameter. L31—A &
hydroxide-selective,&1S (USP29) strong anion-
L19—Strong cation-exchange resin consisting of sulfonat- exchange resin-quaternary amine bonded on latex particles
ed cross-linked styrene-divinylbenzene copolymer in the attached to a core of 8.5-mm macroporous particles having
calcium form, about 9 mm in diameter. a pore size of 2000 Å and consisting of ethylvinylbenzene
L20—Dihydroxypropane groups chemically bonded to cross-linked with 55% divinylbenzene.
porous silica particles, 5 to 10 mm in diameter. L32—A chiral ligand-exchange packing–L-proline copper
L21—A rigid, spherical styrene-divinylbenzene copolymer, complex covalently bonded to irregularly shaped silica
5 to 10 mm in diameter. particles, 5 to 10 mm in diameter.
L22—A cation-exchange resin made of porous polystyrene L33—Packing having the capacity to separate dextrans by
gel with sulfonic acid groups, about 10 mm in size. molecular size over a range of 4,000 to 500,000 Da. It is
L23—An anion-exchange resin made of porous poly- spherical, silica-based, and processed to provide pH stability.
methacrylate or polyacrylate gel with quaternary ammonium &
[NOTE—Available as TSKgel G4000 SWXL from Tosoh
In-Process Revision
groups, about 10 mm in size. Biosep (www.tosohbiosep.com).]&1S (USP29)
L24—A semi-rigid hydrophilic gel consisting of vinyl L34—Strong cation-exchange resin consisting of sulfonat-
polymers with numerous hydroxyl groups on the matrix ed cross-linked styrene-divinylbenzene copolymer in the lead
surface, 32 to 63 mm in diameter. form, about 9 mm in diameter.
&
[NOTE—Available as YMC-Pack PVA-SIL manufactured L35—A zirconium-stabilized spherical silica packing with
by YMC Co., Ltd. and distributed by Waters Corp. a hydrophilic (diol-type) molecular monolayer bonded phase
(www.waters.com).]&1S (USP29) having a pore size of 150 Å.
L25—Packing having the capacity to separate compounds L36—A 3,5-dinitrobenzoyl derivative of L-phenylglycine
with a molecular weight range from 100 to 5000 (as covalently bonded to 5-mm aminopropyl silica.
determined by polyethylene oxide), applied to neutral,
Pharmacopeial Forum
L37—Packing having the capacity to separate proteins by L50—Multifunction resin with reversed-phase retention
molecular size over a range of 2,000 to 40,000 Da. It is and strong anion-exchange functionalities. The resin consists
a polymethacrylate gel. of ethylvinylbenzene, 55% cross-linked with divinylbenzene
L38—A methacrylate-based size-exclusion packing for copolymer, 3 to 15 mm in diameter, and a surface area not less
water-soluble samples. than 350 m2 per g. Substrate is coated with quaternary
L39—A hydrophilic polyhydroxymethacrylate gel of ammonium functionalized latex particles consisting of styrene
totally porous spherical resin. cross-linked with divinylbenzene.
L40—Cellulose tris-3,5-dimethylphenylcarbamate coated &
[NOTE—Available as OmniPac PAX-500 and distributed
porous silica particles, 5 to 20 mm in diameter. by Dionex Corp. (www.dionex.com).]&1S (USP29)

L41—Immobilized a1-acid glycoprotein on spherical silica L51—Amylose tris-3,5-dimethylphenylcarbamate-coated,
particles, 5 mm in diameter. porous, spherical, silica particles, 5 to 10 mm in diameter.
L42—Octylsilane and octadecylsilane groups chemically &
[NOTE—Available as Chiralpak AD from Chiral Technol-
bonded to porous silica particles, 5 mm in diameter. ogies, Inc., (www.chiraltech.com).]&1S (USP29)
L43—Pentafluorophenyl groups chemically bonded to L52—A strong cation-exchange resin made of porous silica
silica particles by a propyl spacer, 5 to 10 mm in diameter. with sulfopropyl groups, 5 to 10 mm in diameter.
L44—A multifunctional support, which consists of a high &
[NOTE—Available as TSK IC SW Cation from Tosoh
purity, 60 Å, spherical silica substrate that has been bonded Biosep (www.tosohbiosep.com).]&1S (USP29)
with a cationic exchanger, sulfonic acid functionality in L53—Weak cation-exchange resin consisting of ethylvi-
addition to a conventional reversed phase C8 functionality. nylbenzene, 55% cross-linked with divinylbenzene copoly-
L45—Beta cyclodextrin bonded to porous silica particles, mer, 3 to 15 mm diameter. Substrate is surface grafted with
5 to 10 mm in diameter. carboxylic acid and/or phosphoric acid functionalized
L46—Polystyrene/divinylbenzene substrate agglomerated monomers. Capacity not less than 500 mEq/column.
with quaternary amine functionalized latex beads, about &
[NOTE—Available as IonPac CS14 distributed by Dionex
10 mm in diameter. Corp. (www.dionex.com).]&1S (USP29)
L47—High-capacity anion-exchange microporous sub- L54—A size exclusion medium made of covalent bonding
strate, fully functionalized with trimethlyamine groups, of dextran to highly cross-linked porous agarose beads, about
8 mm in diameter. 13 mm in diameter.
In-Process Revision
&
[NOTE—Available as CarboPac MA1 and distributed by &
[NOTE—Available as Superdex Peptide HR 10/30 from
Dionex Corp. (www.dionex.com).]&1S (USP29) Amersham Pharmacia Biotech (www.amershambiosciences.
L48—Sulfonated, cross-linked polystyrene with an outer com).]&1S (USP29)
layer of submicron, porous, anion-exchange microbeads, 15 L55—A strong cation-exchange resin made of porous silica
mm in diameter. coated with polybutadiene–maleic acid copolymer, about
L49—A reversed-phase packing made by coating a thin 5 mm in diameter.
layer of polybutadiene onto spherical porous zirconia &
[NOTE—Available as IC-Pak C M/D from Waters Corp.
particles, 3 to 10 mm in diameter. (www.waters.com).]&1S (USP29)

&
[NOTE—Available as Zirchrom PBD, manufactured by L56—Propyl silane chemically bonded to totally porous
ZirChrom Separations, Inc., distributed by Alltech, silica particles, 3 to 10 mm in diameter.
www.Alltechweb.com.]&1S (USP29)
Pharmacopeial Forum
&
[NOTE—Available as Zorbax SB-C3 from Agilent Tech- L## (Enoxaparin Sodium, Dowex 1X8)—[To come.]
nologies (www.agilent.com/chem).]&1S (USP29) L## (Enoxaparin Sodium, Dowex 50WX2)—[To
L57—A chiral-recognition protein, ovomucoid, chemically come.]
bonded to silica particles, about 5 mm in diameter, with a pore L## (Dalteparin Sodium, anion-exchange Dowex 1X8)—
size of 120 Å. [To come.]
&
[NOTE—Available as Ultron ES-OVM from Agilent L## (Dalteparin Sodium, cation-exchange Dowex
Technologies (www.agilent.com/chem).]&1S (USP29) 50WX2)—[To come.]
L58—Strong cation-exchange resin consisting of sulfonat- L## (Glucosamine, Shodex NH2P-50)—Polyamine chem-
ed cross-linked styrene-divinylbenzene copolymer in the ically bonded to cross-linked polyvinyl alcohol polymer,
sodium form, about 7 to 11 mm in diameter. 5 mm in diameter.
&
[NOTE—Available as Aminex HPX-87N from Bio-Rad [NOTE—Available as Shodex NH2P-50 from Shodex
Laboratories, (2000/01 catalog, #125-0143) (www.shodex.com).]
www.bio-rad.com.]&1S (USP29) L## [Valganciclovir Hydrochloride, Crownpak CR(+)]—A
L59—Packing having the capacity to separate proteins by crown ether coated on a 5-mm particle size silica gel substrate.
molecular weight over the range of 10 to 500 kDa. It is The active site is (S)-18-crown-6-ether.
spherical (10 mm), silica-based, and processed to provide [ NOTE— Available as Crownpak CR(+) from Daicel
hydrophilic characteristics and pH stability. (www.daicel.com).]
&
[NOTE—Available as TSKgel G3000SW Column (analyt- L## (Trehalose, Sugar KS-801)—Strong cation-exchange
ical column) and TSKgel Guard (guard column) from Tosoh resin consisting of sulfonated cross-linked styrene-divinyl-
~
Biosep (part numbers 05789 and 05371, respectively) benzene copolymer in the sodium form, 6 to 17 30~USP31 mm
(www.tosohbiosep.com).]&1S (USP29) in diameter.
L60—Spherical, porous silica gel, 3 or 5 mm&10 mm or [ NOTE— Available as Sugar KS-801 from Shodex
less&1S (USP30) in diameter, the surface of which has been (www.shodex.com).]
covalently modified with palmitamidopropyl &
alkyl L## (Levalbuterol, Chirobiotic T)—Glycopeptide teicopla-
amide&1S (USP30) groups and endcapped. nin linked through multiple covalent bonds to a 100-Å units
&
[NOTE—Available as Supelcosil ABZ from Supelco spherical silica.
(www.sigma-aldrich.com/supelco).]&1S (USP29) [ NOTE— Available as Chirobiotic T from Astec
L61—A hydroxide selective strong anion-exchange resin (www.astecusa.com).]
In-Process Revision
consisting of a highly cross-linked core of 13-mm micro-
porous particles having a pore size less than 10 Å units and
Phases
consisting of ethylvinylbenzene cross-linked with 55%
divinylbenzene with a latex coating composed of 85-nm G1—Dimethylpolysiloxane oil.
diameter microbeads bonded with alkanol quaternary ammo- G2—Dimethylpolysiloxane gum.
nium ions (6%). G3—50% Phenyl-50% methylpolysiloxane.
&
[NOTE—Available as Ion Pac AS-11 and AG-11 from G4—Diethylene glycol succinate polyester.
Dionex (www.dionex.com).]&1S (USP29) G5—3-Cyanopropylpolysiloxane.
L62—C30 silane bonded phase on a fully porous spherical G6—Trifluoropropylmethylpolysiloxane.
silica, 3 to 15 mm in diameter. G7—50% 3-Cyanopropyl-50% phenylmethylsilicone.
Pharmacopeial Forum
G8—80% Bis(3-cyanopropyl)-20% 3-cyanopropylphenyl-

G33—20% Carborane-80% methylsilicone.
polysiloxane (percentages refer to molar substitution).
G34—Diethylene glycol succinate polyester stabilized with
G9—Methylvinylpolysiloxane.
phosphoric acid.
G10—Polyamide formed by reacting a C36 dicarboxylic
G35—A high molecular weight compound of a polyethyl-
acid with 1,3-di-4-piperidylpropane and piperidine in the
ene glycol and a diepoxide that is esterified with nitroter-
respective mole ratios of 1.00 : 0.90 : 0.20.
ephthalic acid.
G11—Bis(2-ethylhexyl) sebacate polyester.
G36—1% Vinyl-5% phenylmethylpolysiloxane.
G12—Phenyldiethanolamine succinate polyester.
G37—Polyimide.
G13—Sorbitol.
G38—Phase G1 containing a small percentage of a tailing
G14—Polyethylene glycol (av. mol. wt. of 950 to 1050).
inhibitor.
&
[NOTE—A suitable grade is available commercially as
G16—Polyethylene glycol compound (av. mol. wt. about
‘‘SP2100/0.1% Carbowax 1500’’ from Supelco, Inc.
15,000). A high molecular weight compound of polyethylene
(www.sigma-aldrich.com/supelco).]&1S (USP29)
glycol with a diepoxide linker. Available commercially as
G39—Polyethylene glycol (av. mol. wt. about 1500).
Polyethylene Glycol Compound 20M, or as Carbowax 20M,
G40—Ethylene glycol adipate.
from suppliers of chromatographic reagents.
G41—Phenylmethyldimethylsilicone (10% phenyl-
G17—75% Phenyl-25% methylpolysiloxane.
substituted).
G18—Polyalkylene glycol.
G42—35% phenyl-65% dimethylpolysiloxane (percent-
G19—25% Phenyl-25% cyanopropyl-50% methylsilicone.
ages refer to molar substitution).
G43—6% cyanopropylphenyl-94% dimethylpolysiloxane
G21—Neopentyl glycol succinate.
(percentages refer to molar substitution).
G22—Bis(2-ethylhexyl) phthalate.
G44—2% low molecular weight petrolatum hydrocarbon
G23—Polyethylene glycol adipate.
grease and 1% solution of potassium hydroxide.
G24—Diisodecyl phthalate.
G45—Divinylbenzene-ethylene glycol-dimethylacrylate.
G25—Polyethylene glycol compound TPA. A high molec-
G46—14% Cyanopropylphenyl-86% methylpolysiloxane.
ular weight compound of a polyethylene glycol and
G47—Polyethylene glycol (av. mol. wt. of about 8000).
a diepoxide that is esterified with terephthalic acid.
G48—Highly polar, partially cross-linked cyanopolysilox-
In-Process Revision
&
[NOTE—Available commercially as Carbowax 20M-TPA
ane.&&1S (USP29)
from suppliers of chromatographic reagents.]&1S (USP29)
G## (Docosahexaenoic acid, Famewax)—Polyethylene
G26—25% 2-Cyanoethyl-75% methylpolysiloxane.
glycol, cross-linked (average molecular weight of not more
than 20,000).
G## (Tetrafluoroethane, Bentone 34/SP-1200)—Alumino-
G29—3,3’-Thiodipropionitrile.
silicate montmorrillonite that has been treated with dimeth-
G30—Tetraethylene glycol dimethyl ether.
yloctadecylammonium salts plus a low polarity ester phase.
G31—Nonylphenoxypoly(ethyleneoxy)ethanol (av. ethyl-
G## (Tetrafluoroethane, Krytox)—A perfluorinated poly-
eneoxy chain length is 30); Nonoxynol 30.
ether fluid.
G32—20% Phenylmethyl-80% dimethylpolysiloxane.
Pharmacopeial Forum
Supports S4—Styrene-divinylbenzene copolymer with aromatic –O

and –N groups, having a nominal surface area of 400 to 600
NOTE—Unless otherwise specified, mesh sizes of 80 to 100
m2 per g and an average pore diameter of 0.0076 mm.
or, alternatively, 100 to 120 are intended.
S5—40- to 60-mesh, high-molecular weight tetrafluoreth-
S1A—Siliceous earth for gas chromatography has been
ylene polymer.
flux-calcined by mixing diatomite with Na2CO3 flux and
S6—Styrene-divinylbenzene copolymer having a nominal
calcining above 9008. The siliceous earth is acid-washed, then
surface area of 250 to 350 m2 per g and an average pore
water-washed until neutral, but not base-washed. The
diameter of 0.0091 mm.
siliceous earth may be silanized by treating with an agent
S7—Graphitized carbon having a nominal surface area of
such as dimethyldichlorosilane &
[NOTE—Unless otherwise
12 m2 per g.
specified in the individual monograph, silanized support is
S8—Copolymer of 4-vinyl-pyridine and styrene-divinyl-
intended.]&1S (USP29) to mask surface silanol groups.
benzene.
S1AB—The siliceous earth as described above is both
S9—A porous polymer based on 2,6-diphenyl-p-phenylene
acid- and base-washed. &[NOTE—Unless otherwise specified
oxide.
in the individual monograph, silanized support is intend-
S10—A highly polar cross-linked copolymer of acryloni-
ed.]&1S (USP29)
trite and divinylbenzene.
S1C—A support prepared from crushed firebrick and
calcined or burned with a clay binder above 9008 with
100 m2 per g modified with small amounts of petrolatum and
subsequent acid-wash. It may be silanized.
polyethylene glycol compound.
S1NS—The siliceous earth is untreated.
&
[NOTE—Commercially available as SP1500 on Carbopack
B from Supelco (www.sigma-aldrich.com/supelco).]&1S (USP29)
surface area of less than 50 m2 per g and an average pore
diameter of 0.3 to 0.4 mm.
100 m2 per g.
S3—Copolymer of ethylvinylbenzene and divinylbenzene
S## (Tetrafluoroethene, Porapak T)—Polymer based on
having a nominal surface area of 500 to 600 m2 per g and an
highly polar ethylene glycol dimethacrylate monomer, with
average pore diameter of 0.0075 mm.
a surface area of 225–350 m2 per g.&2S (USP30)
In-Process Revision
Pharmacopeial Forum
110 Vol. 33(1) [Jan.–Feb. 2007]
REFERENCE TABLES Add the following:
~
Glipizide: White to off-white powder. Freely soluble in
dimethylformamide; soluble in 0.1 N sodium hydroxide;
slightly soluble in methylene chloride.~USP31
BRIEFING
Add the following:
Description and Relative Solubility of USP and NF Articles,
USP 29 page 3191, page 3813 of the Second Supplement, page ~
Modafinil: White odorless, to off-white, crystalline
8589 of PF 25(4) [July–Aug. 1999], page 1908 of PF 27(1) [Jan.–
Feb. 2001], page 554 of PF 28(2) [Mar.–Apr. 2002], page 1953 of powder. Slightly soluble in absolute alcohol; sparingly soluble
PF 28(6) [Nov.–Dec. 2002], page 266 of PF 29(1) [Jan.–Feb.
2003], page 1405 of PF 30(4) [July–Aug. 2004], page 1822 of PF in methanol; practically insoluble very slightly soluble in
30(5) [Sept.–Oct. 2004], page 2183 of PF 30(6) [Nov.–Dec. 2004],
page 122 of PF 31(1) [Jan.–Feb. 2005], page 591 of PF 31(2) [Mar.– water.~USP31
Apr. 2005], page 861 of PF 31(3) [May–June 2005], page 1193 of PF
31(4) [July–Aug. 2005], page 1491 of PF 31(5) [Sept.–Oct. 2005],
page 1703 of PF 31(6) [Nov.–Dec. 2005], page 188 of PF 32(1) Change to read:
[Jan.–Feb. 2006], page 662 of PF 32(2) [Mar.–Apr. 2006], page
942 of PF 32(3) [May–June 2006], page 1301 of PF 32(4) [July– Nevirapine: White to off-white, odorless to nearly odorless,
Aug. 2006], page 1541 of PF 32(5) [Sept.–Oct. 2006], and page crystalline powder. Practically insoluble in water; slightly soluble
1811 of PF 32(6) [Nov.–Dec. 2006]. in alcohol and in methanol. Hydrous form also slightly insoluble
~
(HDQ) RTS—C42103; C44665; C45125; C49299 soluble~USP31
in propylene glycol.
Add the following:
~
Eprinomectin: White to off-white powder. Insoluble in
cold water.~USP31
In-Process Revision
Pharmacopeial Forum
Pending Proposals
(Items from earlier numbers of PF that have not yet been adopted and become official)
In order for an item to be adopted into the USP–NF and become officially binding, it must first be proposed and published in the
Pharmacopeial Forum (PF) to allow the public an opportunity to review and comment upon it. When an item is adopted, it is
published in the USP–NF, its Supplements, or an IRA. Those items that have not yet been adopted are marked as Pending Proposals.
The Pending Proposals list contains these items separated into the following categories: General Notices and Requirements; USP
monographs; Dietary Supplements Monographs; General Chapters; Reference Tables; Excipients; and NF Monographs. Each entry
in the Pending Proposals list contains the monograph title and the citation of the most recent publication of the monograph. When
the appropriate USP Expert Committee is considering advancing to official status a pending proposal that is more than 2 years old, it
is republished in PF for additional opportunity for public review and comment. Reprints of PF proposals may be purchased from
USP by sending a written request for information to custsvc@usp.org.
To check the status of a Pending Proposal, please contact USP as directed below.
The briefing accompanying the monograph or general chapter lists the names of the Scientific Liaisons responsible for the proposed revisions.
The contact information (phone number and email) for the Scientific Liaison is available in the Staff Directory section of How to Use PF. For
USP–NF Online subscribers, the name and contact information for the assigned Scientific Liaison is available in the Auxiliary Information
portion of each monograph.
Call USP at 301-816-8344 and ask to speak with the Scientific Liaison assigned to the monograph or general chapter of interest.
Submit questions by email to stdsmonographs@usp.org. Please indicate the name of the monograph or general chapter in the subject line of
the email.
Following these lists the reader will find the Canceled Proposals list. These are items that were published in PF and were pending,
but have since been canceled. This list contains cumulative entries for the six issues per volume of PF [i.e., 32(1) through 32(6)].
Note that canceled proposals may be republished in PF to be considered for future adoption into the USP–NF.
PF Volume, Issue, and Page Numbers of Pending Proposals
Title and Proposal Vol. No. Page(s)
USP Monographs
Acetaminophen Extended-Release Tablets—Packaging and 32 6 1666
storage (add), Labeling, Dissolution
Acetaminophen, Chlorpheniramine Maleate, and 32 5 1434
Dextromethorphan Hydrobromide Tablets (new)
Acetazolamide Oral Solution (new) 32 1 43
Acetazolamide Oral Suspension (new) 32 1 44
Acetylcysteine—USP Reference standards, Assay 31 3 726
Medical Air—Definition, Packaging and storage 31 4 1024
Albumin Human—Definition, Packaging and storage, 31 5 1338
Expiration date, Labeling, USP Reference standards (add),
Identification A, B (add), Bacterial endotoxins (add),
Safety (add), Sterility (add), pH (add), Molecular size
distribution (add), Heat stability (add), Incubation (add)
Prekallikrein activator (add), Protein content (add), Heme
content (add), Potassium content (add), Sodium content
(add)
Albuterol Sulfate—Identification, Assay 32 5 1436
In-Process Revision
Albuterol Tablets—Assay 31 3 726
Allopurinol—Definition, Packaging and storage, 32 2 302
USP Reference standards, Chromatographic purity
(delete), Related compounds (add), Assay
Alprazolam Oral Suspension (new) 32 1 46
Alumina, Magnesia, and Calcium Carbonate Tablets— 29 6 1835
Title (name change)
Alumina, Magnesia, and Calcium Carbonate Chewable 29 6 1836
Tablets (new)
Alumina, Magnesia, Calcium Carbonate, and Simethicone 29 6 1837
Tablets—Title (name change)
Chewable Tablets (new)
Alumina, Magnesia, and Simethicone Tablets— 29 6 1841
Title (name change)
Alumina, Magnesia, and Simethicone Chewable Tablets 29 6 1842
(new)
Aluminum Sulfate and Calcium Acetate Powder 32 3 755
for Topical Solution (new)
Aminosalicylate Sodium Tablets—Limit of m-aminophenol 32 5 1437
Aminosalicylic Acid—Assay 32 5 1438
Pharmacopeial Forum
Pending Proposals (continued)
Amitriptyline Hydrochloride—USP Reference standards, 31 6 1606
Identification, Chromatographic purity (delete),
Related compounds (add), Assay
Amlodipine Besylate (new) 32 3 757
Anecortave Acetate (new) 30 2 445
Anecortave Acetate Injectable Suspension (new) 30 2 447
Apomorphine Hydrochloride—Packaging 32 5 1438
and storage
Aprotinin (new) 31 3 732
Aprotinin Injection (new) 31 3 736
Atracurium Besylate—Chromatographic purity, Assay 32 2 305
Azathioprine Oral Suspension (new) 32 1 48
Azithromycin—Labeling, USP Reference standards, 32 2 306
Limit of related substances
Aztreonam for Injection—Assay 31 3 737
Baclofen Oral Solution (new) 32 1 49
Baclofen Oral Suspension (new) 32 1 51
Bemotrizinol (new) 32 4 1044
Benazepril Hydrochloride—Absorptivity, Related 32 5 1438
compounds, Assay
Benazepril Hydrochloride Tablets (new) 32 1 52
Benzonatate Capsules—Dissolution (add) 32 1 55
Bethanechol Chloride Oral Solution (new) 32 1 55
Bethanechol Chloride Oral Suspension (new) 32 1 57
Bicalutamide (new) 31 3 738
Biological Indicators for Moist Heat, Dry Heat, and Gaseous 30 1 63
Modes of Sterilization, Metal or Plastic Carriers (new)
Modes of Sterilization, Liquid Spore Suspensions (new)
Biphasic Isophane Insulin Human Suspension (new) 31 4 1033
Bismuth Subsalicylate Oral Suspension (new) 31 4 1035
Bismuth Subsalicylate Tablets (new) 32 5 1440
Bisoctrizole (new) 32 2 309
Bisoprolol Fumarate Tablets—Labeling (add), Dissolution 32 6 1666
Bromocriptine Mesylate Capsules—Dissolution 32 1 58
Budesonide (new) 30 6 1978
Bupropion Hydrochloride Extended-Release Tablets— 32 4 1047
Drug release, Dissolution
Buspirone Hydrochloride—Content of chloride 31 3 742
Butorphanol Tartrate Nasal Solution (new) 32 4 1049
Calcitonin Salmon (new) 32 3 760
Calcitonin Salmon Nasal Solution (new) 32 3 767
Calcitonin Salmon Injection (new) 30 4 1177
Calcitriol (new) 32 1 58
Calcitriol Injection (new) 32 1 61
Calcium Carbonate and Magnesia Tablets (title change) 29 6 1852
Calcium Carbonate and Magnesia Chewable Tablets (new) 29 6 1852
Calcium Carbonate, Magnesia, and Simethicone Tablets— 29 6 1853
Title (name change)
Calcium Carbonate, Magnesia, and Simethicone Chewable 29 6 1854
In-Process Revision
Tablets (new)
Calcium Lactate—USP Reference standards (add), Identification 31 6 1608
Calcium Lactate Tablets—Identification 31 6 1609
Calcium Pantothenate—USP Reference standards, Ordinary impurities 32 1 62
Dibasic Calcium Phosphate Dihydrate—Harmonization 32 4 1329
Anhydrous Dibasic Calcium Phosphate—Harmonization 32 4 1332
Camphor—Water 31 3 742
Capecitabine (new) 32 4 1052
Capecitabine Tablets (new) 32 4 1054
Captopril Oral Solution (new) 32 1 63
Captopril Oral Suspension (new) 32 1 64
Carbamazepine—USP Reference standards, Chromatographic purity 32 1 65
(Related compounds), Assay
Carbon Dioxide—Definition, Packaging and storage 31 4 1045
Carboxymethylcellulose Sodium—Heavy metals 31 5 1349
Carboxymethylcellulose Sodium Paste—Heavy metals 31 5 1349
Carprofen (new) 32 6 1667
Carprofen Tablets (new) 32 6 1669
Carvedilol (new) 32 4 1057
Cefaclor Tablets (new) 32 2 314
Cefadroxil for Oral Suspension—Dissolution (add) 32 2 315
Pharmacopeial Forum
Cefepime Hydrochloride—Limit of N-methylpyrrolidine, Related 32 2 316
compounds
Cefonicid for Injection—Assay 32 1 67
Ceftazidime—USP Reference standards, Assay 32 1 67
Ceftazidime Injection—USP Reference standards 32 1 68
Ceftazidime for Injection—USP Reference standards 32 1 68
Cetirizine Hydrochloride (new) 32 2 317
Chlorhexidine Gluconate Oral Rinse—Assay 32 3 768
Chlorhexidine Gluconate Solution—Assay 32 3 768
Chlorophyllin Copper Complex Sodium— 32 3 769
Content of total copper
Chlorthalidone—USP Reference standards, Limit of 32 1 68
4’-chloro-3’-sulfamoyl-2-benzophenone carboxylic
acid (CCA) (Limit of chlorthalidone
related compound A), Assay
Cholestyramine Resin—Dialyzable quaternary amines 32 2 320
Cilostazol (new) 32 5 1441
Cimetidine—Identification, Chromatographic purity 32 3 769
Cimetidine Tablets—Dissolution 32 1 72
Ciprofloxacin—Chromatographic purity, Assay 32 2 320
Ciprofloxacin and Dexamethasone Otic Suspension (new) 32 2 321
Ciprofloxacin Hydrochloride—Chromatographic purity, Assay 32 2 325
Ciprofloxacin Injection—Bacterial endotoxins, Limit of 32 4 1059
ciprofloxacin ethylenediamine analog, Assay
Citalopram Hydrobromide—Labeling (add), 32 4 1060
USP Reference standards, Related compounds
Citalopram Tablets—Identification (add), 32 3 770
Related compounds, Assay
Anhydrous Citric Acid (Harmonization), Sulfate 31 3 749
Citric Acid Monohydrate (Harmonization), Sulfate 31 3 750
Citric Acid, Magnesium Oxide, and Sodium Carbonate 31 2 394
Irrigation—USP Reference standards, Assay for citric
acid (delayed implementation to January 1, 2009)
Cladribine—Specific rotation, Related compounds, 32 3 774
Limit of residual solvents
Clonazepam Oral Suspension (new) 32 1 73
Clopidogrel Bisulfate—Related compounds, Assay 32 1 74
Clopidogrel Tablets—Related compounds, Assay 32 1 76
Clotrimazole Lozenges—Dissolution 32 1 78
Cod Liver Oil—Identification 32 5 1443
Cyclopropane—Definition, Packaging and storage 31 4 1052
Cyclosporine Capsules—USP Reference standards, Labeling (add), 27 4 2721
Identification, Dissolution, Droplet size (add), Content
of alcohol (add), Assay
Dalteparin Sodium (new) 30 5 1598
Dantrolene Sodium (new) 32 2 327
Dantrolene Sodium Capsules (new) 32 4 1063
Dantrolene Sodium for Injection (new) 32 3 779
Dapsone—Assay 31 3 750
Desmopressin Acetate (new) 31 4 1052
In-Process Revision
Desmopressin Injection (new) 31 4 1057
Desmopressin Nasal Spray Solution (new) 31 4 1059
Desogestrel (new) (entire submission) 28 6 1785
Desogestrel and Ethinyl Estradiol Tablets (new) 30 5 1604
Diazepam Extended-Release Capsules—USP Reference standards, 32 2 330
Assay
Diclofenac Potassium (new) 31 5 1350
Diclofenac Potassium Tablets (new) 31 5 1352
Diclofenac Sodium Delayed-Release Tablets—Identification 31 3 751
Diclofenac Sodium Extended-Release Tablets (new) 30 2 476
Didanosine (new) 32 3 781
Didanosine for Oral Solution (new) 31 5 1357
Didanosine Tablets (new) 32 5 1444
Dihydroxyaluminum Sodium Carbonate Tablets— 29 6 1873
Title (name change)
Dihydroxyaluminum Sodium Carbonate Chewable 29 6 1873
Tablets (new)
Diltiazem Hydrochloride Extended-Release Capsules—Dissolution 32 6 1673
Diltiazem Hydrochloride Oral Solution (new) 32 1 79
Diltiazem Hydrochloride Oral Suspension (new) 32 1 80
Pharmacopeial Forum
Diphenoxylate Hydrochloride and Atropine Sulfate Oral 31 6 1612
Solution—Identification, Assay for diphenoxylate
hydrochloride (delete), Assay for atropine sulfate (delete),
Assay (add)
Diphenoxylate Hydrochloride and Atropine Sulfate Tablets— 31 6 1614
Identification, Assay for diphenoxylate hydrochloride (delete),
Assay for atropine sulfate (delete), Assay (add)
Diphtheria Toxin for Schick Test (delete) 31 6 1616
Dipyridamole Oral Suspension (new) 32 1 81
Divalproex Sodium (new) 32 6 1675
Dolasetron Mesylate Oral Solution (new) 32 1 83
Dolasetron Mesylate Oral Suspension (new) 32 1 84
Doxazosin Mesylate (new) 32 4 1066
Doxazosin Tablets (new) 29 1 64
Doxepin Hydrochloride—USP Reference standards, 32 2 330
Identification, Melting range (delete), Chloride content (delete),
Related compounds (add)
Dronabinol—USP Reference standards, Identification, 32 1 86
Limit of D8-tetrahydrocannabinol (delete),
Drospirenone (new) 32 3 787
Edetate Calcium Disodium—Harmonization 32 4 1335
Edetate Disodium—Assay 32 4 1070
Edetate Disodium Injection—Assay 32 4 1071
Egg Phospholipids (new) 31 3 757
Enoxaparin Sodium (new) 29 6 1876
Enoxaparin Sodium Injection (new) 31 3 761
Ensulizole—Assay 32 6 1677
Estradiol and Norethindrone Acetate Tablets (new) 31 5 1364
Estradiol Transdermal System (new) 31 4 1063
Estradiol Vaginal Inserts (new) 32 4 1071
Conjugated Estrogens—Definition 30 3 840
Conjugated Estrogens Tablets—Dissolution 32 4 1074
Synthetic Conjugated Estrogens (new) 31 6 1620
Esterified Estrogens—Identification, Free steroids, Assay 32 6 1678
Esterified Estrogens Tablets—USP Reference standards, Assay 32 6 1680
Ethotoin Tablets—USP Reference standards, Assay 32 2 332
Etidronate Disodium—Limit of phosphite 31 6 1625
Famotidine Injection (new) 32 2 333
Famotidine Tablets—Dissolution 32 6 1680
Fenofibrate (new) 31 3 763
Fentanyl (new) 31 6 1626
Fexofenadine Hydrochloride (postponed indefinitely)— 32 5 1447
Labeling (add), Identification, Water,
Specific surface area (delete), Limit of fexofenadine
related compound B, Related compounds
Fexofenadine Hydrochloride Capsules (postponed indefinitely)— 32 5 1449
Water, Related compounds
Fexofenadine Hydrochloride Tablets (new) 30 6 1997
Fexofenadine Hydrochloride and Pseudoephedrine 31 2 403
In-Process Revision
Hydrochloride Extended-Release Tablets (new)

Finasteride Tablets—Dissolution 32 6 1681
Fluconazole—Related compounds 32 2 335
Flucytozine Oral Suspension (new) 32 1 92
Flumazenil—USP Reference standards, Related compounds, 32 1 94
Assay
Fluorometholone Acetate (new) 31 5 1371
Flurazepam Hydrochloride—Identification 31 3 766
Fluticasone Propionate—Definition, Bromofluoromethane 32 2 337
content (delete)
Fluticasone Propionate Nasal Spray (new) 32 2 339
Fluvastatin Sodium—Packaging and storage, Labeling (add), 32 6 1682
USP Reference standards, Identification, Water,
Chromatographic purity
Fluvastatin Capsules—USP Reference standards, 32 1 105
Identification, Chromatographic purity
Fluvoxamine Maleate—Definition, Maleic acid (delete), Assay 32 5 1449
Fluvoxamine Maleate Tablets—Dissolution, Related compounds (add) 32 6 1684
Formoterol Fumarate (new) 32 5 1450
Fosinopril Sodium (new) 32 6 1686
Fosinopril Sodium Tablets (new) 30 6 2004
Pharmacopeial Forum
Fosinopril Sodium and Hydrochlorothiazide Tablets (new) 30 6 2006
Gabapentin—Labeling (delete), Limit of chloride (delete), 32 6 1689
Gabapentin Capsules (new) 32 6 1693
Gabapentin Tablets (new) 32 6 1695
Ganciclovir Oral Suspension (new) 32 1 113
Gemcitabine for Injection—USP Reference standards, 31 6 1630
Gemcitabine Hydrochloride—USP Reference standards 32 1 114
Glipizide—USP Reference standards, Related 32 5 1453
compounds, Assay
Glipizide and Metformin Hydrochloride Tablets (new) 32 4 1076
Glutaral Concentrate—Specific gravity 31 3 766
Glyburide Tablets—Labeling (add), 32 4 1080
Dissolution (add)
Glyburide and Metformin Hydrochloride Tablets (new) 31 3 766
Gonadorelin Acetate (new) 30 4 1250
Goserelin Acetate (new) 32 3 792
Helium—Definition, Packaging and storage 31 4 1077
Hepatitis B Virus Vaccine Inactivated (delete) 31 6 1641
Hydrocodone Bitartrate—USP Reference standards, 30 5 1628
Ordinary impurities (delete), Related compounds (add)
Hydrocodone Bitartrate and Homatropine Methylbromide 30 3 853
Tablets (new)
Hydrocortisone Tablets—USP Reference standards, 32 4 1083
Uniformity of dosage units, Assay
Hydroxyzine Hydrochloride—Definition, USP Reference standards, 32 5 1456
Chromatographic purity, Assay
Hypromellose—Harmonization 32 5 1573
Hypromellose Ophthalmic Solution—Assay 32 4 1084
Ibuprofen—USP Reference standards, Limit of 32 3 796
ibuprofen related compound C, Assay
Ibuprofen Oral Suspension—USP Reference standards, Limit of 32 3 796
Ibuprofen Tablets—USP Reference standards, Limit of 32 3 798
Imipenem and Cilastatin for Injection—Uniformity of dosage units (add) 32 6 1698
Imipenem and Cilastatin for Injectable Suspension—Uniformity of 32 6 1698
dosage units (add)
Indinavir Sulfate—Heavy metals, Method I, (delete), 32 2 345
Heavy metals (add), Chromatographic purity, Assay
Indium In 111 Chloride Solution—Radiochemical purity 32 6 1698
Sodium Iodide I 123 Capsules—Definition 31 6 1642
Sodium Iodide I 123 Solution—Definition, Radionuclidic purity, 31 6 1642
Bacterial endotoxins, pH
Sodium Iodide I 131 Solution—pH 31 6 1643
Iodoform—Molecular weight 32 1 115
Irbesartan—Limit of azide, Related compounds, 32 4 1084
Assay
Irbesartan Tablets (new) 32 3 799
In-Process Revision
Irbesartan and Hydrochlorothiazide Tablets (new) 29 4 1036
Diluted Isosorbide Mononitrate—USP Reference standards, Assay 32 6 1699
Isosorbide Mononitrate Tablets (new) 32 6 1700
Isosorbide Mononitrate Extended-Release Tablets (new) 32 6 1703
Ivermectin—Specific rotation, Limit of alcohol 31 6 1645
and formamide
Ketoprofen—Assay 31 3 772
Ketoprofen Extended-Release Capsules (new) 31 5 1378
Labetalol Hydrochloride Oral Solution (new) 32 1 116
Labetalol Hydrochloride Oral Suspension (new) 32 1 117
Lactulose Concentrate—Related compounds, Assay 32 6 1709
Lamivudine—Assay 32 2 346
Lansoprazole—Definition, Water, Residue on ignition, 32 6 1710
Leflunomide (new) 31 5 1380
Leflunomide Tablets (new) 32 6 1712
Leuprolide Acetate (new) 30 3 882
Levocabastine Hydrochloride (new) 31 6 1647
Levodopa—Related compounds 32 4 1085
Levofloxacin (new) 32 2 347
Lidocaine and Prilocaine Cream (new) 31 4 1087
Pharmacopeial Forum
Lindane—Definition, Assay 31 6 1648
Lipid Injectable Emulsion (new) 32 2 350
Lisinopril Tablets—Assay 32 4 1086
Loperamide Hydrochloride Oral Solution—Assay 32 2 353
Loratadine and Pseudoephedrine Sulfate Extended-Release Tablets (new) 32 6 1715
Lovastatin—Assay 32 1 118
Lovastatin Tablets—Identification, Dissolution, Assay 32 5 1458
Magaldrate and Simethicone Tablets—Title (name change) 29 6 1918
Magaldrate and Simethicone Chewable Tablets (new) 29 6 1919
Milk of Magnesia—Limit of calcium (delete) 32 2 353
Magnesium Carbonate—Limit of calcium, Assay 32 6 1719
Magnesium Carbonate and Citric Acid for Oral Solution— 31 2 419
USP Reference standards (add), Content of anhydrous
citric acid, Other requirements (delayed implementation
to January 1, 2009)
Magnesium Chloride—Limit of calcium 32 6 1720
Magnesium Citrate Oral Solution—USP Reference 31 2 420
standards (add), Assay for anhydrous citric acid
(delayed implementation to January 1, 2009)
Magnesium Citrate for Oral Solution—USP Reference 31 2 421
standards (add), Content of anhydrous citric acid,
Other requirements (delayed implementation
to January 1, 2009)
Magnesium Hydroxide—Lead (delete), 32 4 1087
Limit of lead (add)
Magnesium Hydroxide Paste—Definition, 32 4 1088
Soluble alkalies, Limit of lead (add)
Magnesium Oxide—Limit of calcium, Assay 32 6 1720
Mangafodipir Trisodium—Limit of residual solvents 31 6 1650
Mannitol Injection—Labeling 32 2 263
Meloxicam (new) 31 1 57
Meloxicam Oral Suspension (new) 32 6 1721
Meloxicam Tablets (new) 32 5 1460
Meropenem for Injection—Assay 32 6 1724
Metformin Hydrochloride Tablets—Dissolution 32 6 1725
Metformin Hydrochloride Extended-Release Tablets (new) 32 6 1726
Methylcellulose Ophthalmic Solution—Identification 31 3 780
Methylcellulose Oral Solution—Identification 31 3 780
Methylcellulose Tablets—Identification 31 3 780
Methyldopa Oral Suspension—USP Reference standards, 32 2 354
Limit of methyldopa-glucose reaction product (delete)
Methylprednisolone—Chromatographic purity 32 2 354
Metolazone Oral Suspension (new) 32 1 119
Metoprolol Tartrate—Chromatographic purity 32 4 1089
Metoprolol Tartrate Oral Solution (new) 32 1 121
Metoprolol Tartrate Oral Suspension (new) 32 1 122
Metronidazole Benzoate—USP Reference standards, 31 3 781
Related compounds
Miconazole Nitrate Cream—Identification 32 1 123
Mirtazapine—Heavy metals 31 6 1650
In-Process Revision
Mitoxantrone Injection—Packaging and storage 32 2 355

Modafinil (new) 30 5 1634
Modafinil Tablets (new) 30 5 1636
Morantel Tartrate—Definition, pH, Related compounds 32 6 1735
Morphine Sulfate Extended-Release Capsules— 32 1 124
Packaging and storage (add)
Mupirocin Calcium (new) 31 2 430
Mupirocin Cream (new) 31 2 432
Naphazoline Hydrochloride—Definition, Assay 31 4 1093
Naproxen Delayed-Release Tablets—Packaging and 32 1 124
storage
Narasin Granular—Molecular weight, Assay 32 1 124
Narasin Premix—Assay 32 1 126
Naratriptan Hydrochloride—Assay 32 5 1462
Nefazodone Hydrochloride—Related compounds 32 5 1462
Nefazodone Hydrochloride Tablets (new) 32 3 804
Netilmicin Sulfate—Definition, Assay 32 4 1089
Nevirapine Oral Suspension (new) 32 4 1090
Nevirapine Tablets (new) 32 3 807
Nimodipine—Identification, Related compounds 32 2 360
Nitrous Oxide—Definition, Packaging and storage, Assay 31 4 1099
Pharmacopeial Forum
Norethindrone Tablets—Labeling (add), Disintegration (delete), 32 6 1736
Dissolution (add)
Norgestimate—USP Reference standards, 32 4 1094
Norgestimate and Ethinyl Estradiol Tablets (new) 29 1 87
Ofloxacin—Chromatographic purity (delete), Related 30 4 1274
compounds (add)
Ofloxacin Tablets (new) 32 6 1737
Ondansetron Hydrochloride—Limit of ondansetron 32 1 126
related compound D, Assay
Ondansetron Hydrochloride Oral Suspension (new) 32 1 127
Ondansetron Injection—Chromatographic purity 32 4 1096
Ondansetron Oral Solution—Packaging and storage (add), 32 1 128
Limit of ondansetron related compound D, Related compounds
Ondansetron Orally Disintegrating Tablets—Dissolution 32 5 1463
Orlistat Capsules (new) 32 6 1739
Orphenadrine Citrate Injection—Assay 31 6 1651
Oxandrolone—Related compounds (add), Ordinary 31 1 64
impurities (delete)
Oxandrolone Tablets—Dissolution 32 5 1464
Oxaprozin—Packaging and storage (add) 32 1 130
Oxaprozin Tablets—Packaging and storage (add) 32 1 130
Oxybutynin Chloride—Related compounds 32 3 810
Oxybutynin Chloride Extended-Release Tablets (new) 32 6 1742
Oxycodone Hydrochloride Extended-Release Tablets (new) 32 6 1745
Oxygen—Definition, Packaging and storage 31 4 1107
Oxygen 97 Percent—Definition, Packaging and storage 31 4 1107
Oxytocin Injection—Definition, Packaging and storage 32 6 1750
Paclitaxel—USP Reference standards, Related compounds 32 2 361
Pamidronate Disodium for Injection—Packaging 32 5 1465
and storage, Bacterial endotoxins
Pancuronium Bromide Injection (new) 32 4 1097
Paricalcitol—Identification, Chromatographic purity, Assay 32 1 132
Paroxetine Hydrochloride—Assay 32 3 811
Pectin—Identification 31 3 783
Penicillamine Capsules—Dissolution 31 2 436
Pentazocine and Acetaminophen Tablets (new) 28 6 1838
Pentobarbital Sodium—Labeling (add), USP Reference 31 1 73
standards, Other requirements (add)
Pentobarbital Sodium Injection—Identification, Assay 32 2 364
Permethrin (new) 32 4 1100
Permethrin Cream (new) 32 4 1102
Petrolatum (new)—Harmonization 28 2 569
White Petrolatum (new)—Harmonization 28 2 570
Phenoxybenzamine Hydrochloride Capsules—Uniformity of 32 6 1750
dosage units, Related compounds (add), Assay
Phenytoin Tablets—Title (name change) 29 6 1965
Phenytoin Chewable Tablets (new) 29 6 1965
Piperacillin and Tazobactam Injection (new) 31 2 437
Piperacillin and Tazobactam for Injection (new) 31 2 439
In-Process Revision
Piroxicam Cream (new) 32 1 134
PEG 3350 and Electrolytes for Oral Solution—Title, 32 4 1104
Definition, Assay for potassium and sodium
Potassium and Sodium Bicarbonates and Citric Acid 31 2 440
Effervescent Tablets for Oral Solution—USP Reference
Potassium Bitartrate—Limit of ammonia 31 3 786
Potassium Citrate Extended-Release Tablets—USP 31 2 443
Reference standards (add), Assay (delayed implementation
to January 1, 2009)
Potassium Citrate and Citric Acid Oral Solution—USP 31 2 444
Reference standards (add), Assay for citrate
Potassium Iodide Oral Solution—Definition 31 3 786
Potassium Perchlorate—USP Reference standards (delete), 32 2 364
Assay
Potassium Sodium Tartrate—Limit of ammonia 31 3 787
Pravastatin Sodium (new) 32 3 813
Pravastatin Sodium Tablets (new) 32 3 817
Prednicarbate Cream (new) 32 3 819
Pharmacopeial Forum
Prednicarbate Ointment (new) 32 3 822
Prednisolone Sodium Phosphate—USP Reference standards, 32 2 365
Identification
Promethazine Hydrochloride—USP Reference standards, 32 4 1105
Related compounds
Promethazine Hydrochloride Tablets—USP Reference standards, 32 4 1107
Pseudoephedrine Sulfate—Ordinary impurities 32 1 135
Pyrantel Pamoate—Limit of iron 32 5 1465
Pyridoxine Hydrochloride Injection—Assay 32 2 369
Quazepam Tablets—USP Reference standards, Assay 32 2 370
Quinapril Tablets—Packaging and storage 29 4 1071
Quinidine Sulfate Oral Suspension (new) 32 1 136
Racepinephrine Hydrochloride—Identification 32 6 1752
Ramipril—Definition, Assay 31 3 787
Ranitidine Hydrochloride—Chromatographic purity, Assay 32 6 1752
Oral Rehydration Salts—USP Reference standards (add), 31 5 1399
Assay for citrate (delayed implementation to January 1, 2009)
Rifampin and Isoniazid Capsules—Dissolution 30 2 533
Rifampin, Isoniazid, and Pyrazinamide Tablets—Dissolution 30 2 534
Risperidone (new) 31 6 1659
Risperidone Tablets (new) 32 4 1109
Ritonavir—Identification, X-ray diffraction (add), 32 4 1113
Related compounds
Ropivacaine Hydrochloride Injection (new) 32 2 374
Rubella and Mumps Virus Vaccine Live (delete) 31 6 1662
Saccharin Calcium—Identification 32 4 1114
Saccharin Sodium—Identification 32 4 1114
Saquinavir Capsules—Dissolution 32 3 824
Schick Test Control (delete) 31 6 1662
Senna—Title, Definition, Packaging and storage, Labeling (add), 32 1 137
USP Reference standards (add), Botanic characteristics,
Identification, Microbial enumeration (add)
Loss on drying (add), Total ash (add), Assay (add)
Senna Pods (new) 32 1 140
Sennosides—Definition, Packaging and storage, Residue on ignition 32 1 141
Sevoflurane (new) 30 1 178
Simvastatin—Identification, Chromatographic purity, 32 1 141
Limit of lovastatin (delete), Assay
Sodium Bicarbonate—Normal carbonate, Limit 32 5 1465
of ammonia
Sodium Chloride—Limit of phosphates 31 5 1401
Sodium Chloride—Identification, Loss on drying, 32 2 264
Limit of potassium (postponed indefinitely)
Sodium Fluoride—Assay 32 5 1466
Sodium Fluoride Oral Solution—Assay 32 5 1466
Sodium Fluoride and Phosphoric Acid Topical Solution (delete) 32 3 824
Spironolactone and Hydrochlorothiazide Tablets—Dissolution 32 2 376
Streptomycin Sulfate—Assay 32 5 1467
Succinylcholine Chloride—Chromatographic purity 32 6 1754
In-Process Revision
Sulfamethazine Granulated—Assay 31 3 797

Sumatriptan Succinate Oral Suspension (new) 32 1 144
Talc—Packaging and storage (add), Limit of iron, 31 6 1662
Limit of calcium, Limit of aluminum
Tazobactam (new) 32 6 1755
Temazepam—Identification 32 1 145
Terbutaline Sulfate Inhalation Aerosol—USP Reference 31 2 450
standards, Assay
Thalidomide—Microbial limits, Chromatographic purity 32 5 1467
Thalidomide Capsules—Microbial limits (add) 32 5 1468
Thiabendazole Tablets—Title (name change) 29 6 1991
Thiabendazole Chewable Tablets (new) 29 6 1991
Thimerosal—Identification 32 1 147
Thioridazine Hydrochloride—Identification 31 3 798
Tiagabine Hydrochloride—Identification, 32 5 1468
Tiamulin Fumarate—Chemical name, Definition, 32 4 1115
Melting temperature, Chromatographic purity
Tilmicosin—Definition, Related compounds, Assay 31 3 798
Pharmacopeial Forum
Tizanidine Hydrochloride—Identification, Related compounds, 32 6 1757
Organic volatile impurities (delete), Content of chloride
(delete), Residual solvents (delete), Assay
Tizanidine Tablets (new) 32 1 147
Topiramate (new) 30 4 1307
Tramadol Hydrochloride (new) 31 2 458
Tramadol Hydrochloride Tablets (new) 31 2 462
Travoprost (new) 32 4 1115
Travoprost Ophthalmic Solution (new) 32 4 1118
Triamcinolone Acetonide—USP Reference standards, Assay 31 3 800
Triamcinolone Diacetate—Definition, Identification 32 4 1120
Tricitrates Oral Solution—USP Reference standards (add), 31 2 465
Triclosan—Assay 32 2 377
Trimipramine Maleate (new) 32 6 1759
Crystallized Trypsin—Definition 32 3 779
Tyrosine—Sulfate 32 6 1761
Ursodiol Capsules—Dissolution 31 3 800
Valganciclovir Hydrochloride (new) 32 2 379
Valganciclovir Tablets (new) 32 2 384
Valsartan (new) 32 1 150
Valsartan and Hydrochlorothiazide Tablets (new) 31 4 1123
Valproic Acid Injection (new)—Title 32 2 387
(delayed implementation to October 1, 2008)
Vancomycin Hydrochloride—USP Reference standards, 30 6 2055
Limit of monodechlorovancomycin (add)
Vasopressin—Identification 31 4 1127
Verapamil Hydrochloride—USP Reference standards 32 2 389
Verapamil Hydrochloride Injection—USP Reference standards, 32 6 1762
Verapamil Hydrochloride Oral Solution (new) 32 1 155
Verapamil Hydrochloride Oral Suspension (new) 32 1 156
Verapamil Hydrochloride Tablets—USP Reference standards, 32 6 1763
Vinblastine Sulfate—USP Reference standards 32 5 1470
Vinblastine Sulfate for Injection—USP Reference standards 32 5 1470
Vincristine Sulfate—USP Reference standards 32 5 1470
Vincristine Sulfate Injection—USP Reference standards 32 5 1470
Vincristine Sulfate for Injection—USP Reference standards 32 5 1470
Vinorelbine Injection—Related compounds, Assay 32 5 1471
Vinorelbine Tartrate—Related compounds, Assay 32 5 1471
Pure Steam (new) 31 2 467
Water for Hemodialysis—Bacterial endotoxins 31 2 468
Sterile Water for Inhalation—pH (delete), Ammonia (delete), 31 3 802
Calcium (delete), Carbon dioxide (delete), Chloride
(delete), Sulfate (delete), Conductivity (add),
Oxidizable substances
Sterile Water for Injection—pH (delete), Ammonia (delete), 31 3 803
In-Process Revision
Sterile Water for Irrigation—pH (delete), Ammonia (delete), 31 3 804
Sterile Purified Water—pH (delete), Ammonia (delete), 31 3 804
Zidovudine Tablets—USP Reference standards, 32 1 158
Zinc Chloride Injection—Assay 32 5 1473
Dietary Supplements Monographs
Ademetionine Disulfate Tosylate (new) 31 2 469
Acesulfame Potassium—Packaging and storage (add), 31 3 811
Limit of fluoride
Alpha Lipoic Acid Capsules—Content of alpha lipoic acid 32 6 1764
Calcium Glycerophosphate (new) 32 6 1765
Cat’s Claw (new) 32 4 1120
Pharmacopeial Forum
Powdered Cat’s Claw (new) 32 4 1124
Powdered Cat’s Claw Extract (new) 32 4 1124
Cat’s Claw Capsules (new) 32 4 1126
Cat’s Claw Tablets (new) 32 4 1127
Black Cohosh (new) 32 4 1128
Powdered Black Cohosh (new) 32 4 1132
Powdered Black Cohosh Extract (new) 32 4 1133
Black Cohosh Fluidextract (new) 32 4 1134
Black Cohosh Tablets (new) 32 4 1135
Fish Oil Containing Omega-3 Acids (new) (entire submission) 31 2 474
Fish Oil Containing Omega-3 Acids Capsules (new) (entire submission) 31 2 481
Ginger—Packaging and storage, Labeling, USP Reference standards, 32 1 160
Identification, Microbial enumeration, Alcohol-soluble extractives,
Limit of shogaols, Content of gingerols and gingerdiones
Powdered Ginger—Packaging and storage, USP Reference standards 32 1 162
Ginger Capsules—USP Reference standards, Content of 32 1 163
gingerols, gingerdiones, and shogaols
Ginger Tincture—USP Reference standards, Thin-layer 32 1 163
chromatographic identification test, Microbial enumeration,
Content of gingerols
Ginkgo—Definition, Packaging and storage, USP Reference 32 1 164
standards, Thin-layer chromatographic identification test,
Microbial enumeration, Content of terpene lactones
Powdered Ginkgo Extract (new) 32 1 166
Ginkgo Capsules (new) 32 1 172
Ginkgo Tablets (new) 32 1 174
Glucosamine Tablets—Disintegration and dissolution 32 4 1137
Glucosamine and Methylsulfonylmethane Tablets (new) 32 4 1137
Glucosamine, Chondroitin Sulfate Sodium and 32 4 1138
Methylsulfonylmethane Tablets (new)
Tomato Extract Containing Lycopene—Microbial 30 2 578
enumeration, Limit of aflatoxins
Maleic Acid—Identification 31 3 815
Maltose—Water 31 3 815
Maritime Pine—Identification, Content of procyanidins 32 4 1140
Maritime Pine Extract—Identification, microbial enumeration, 32 4 1142
Content of procyanidins
Methylsulfonylmethane (new) 32 3 826
Methylsulfonylmethane Tablets (new) 32 3 827
Minerals Capsules—Definition 32 5 1474
Minerals Tablets—Definition 32 5 1474
Olive Oil—Definition, Labeling (add), Teaseed oil 31 3 815
Phenoxyethanol—Chromatographic purity, Assay 31 3 816
Polyethylene Glycol (new)—Harmonization 31 3 897
Polyoxyl 10 Oleyl Ether—Free ethylene oxide 31 3 816
Polyoxyl 20 Oleyl Cetostearyl Ether—Free ethylene oxide 31 3 817
Sodium Benzoate—USP Reference standards (add), 31 3 818
Identification
Sucrose (new)—Harmonization 31 3 902
Sugar Spheres—Identification, Specific rotation 31 3 819
In-Process Revision
Tagatose (new) 31 3 819

Thymol—USP Reference standards (add), Identification 31 3 821
Ubidecarenone—USP Reference standards, Assay 31 1 86
Ubidecarenone Capsules—USP Reference standards, Assay 31 1 86
Valerian—Packaging and storage, Extractable matter, 32 2 394
Microbial enumeration
Powdered Valerian—Packaging and storage, Labeling, 32 2 395
Botanic characteristics
Valerian Capsules (new) (entire submission) 27 1 1825
Valerian Tablets—Packaging and storage, USP Reference standards 32 2 395
Oil- and Water-Soluble Vitamins with Minerals Capsules— 32 5 1474
Definition
Oil- and Water-Soluble Vitamins with Minerals Oral Solution— 32 5 1475
Definition
Oil- and Water-Soluble Vitamins with Minerals Tablets— 32 5 1476
Definition
Water-Soluble Vitamins with Minerals Capsules— 32 5 1476
Definition
Water-Soluble Vitamins with Minerals Oral Solution— 32 5 1477
Definition
Pharmacopeial Forum
Water-Soluble Vitamins with Minerals Tablets— 32 5 1477
Definition
Xanthan Gum—Assay 31 3 821
USP General Test Chapters
h1i Injections—Labels and Labeling, Packaging 32 2 402
h1i Injections—Packaging—Printing on Ferrules and 32 2 406
Cap Overseals (delayed implementation to February 1, 2009)
h11i USP Reference Standards— 27 1 1832
28 2 433
28 3 839
28 5 1468
29 3 710
29 5 1601
29 6 2022
30 2 613
30 4 1338
30 5 1674
30 6 2092
31 1 99
31 2 507
31 3 822
31 5 1433
31 6 1680
32 1 181
32 2 407
32 3 829
32 4 1161
32 5 1491
32 6 1779
h31i Volumetric Apparatus—Standards of Accuracy 32 6 1780
h41i Weights and Balances—Introduction, Repeatability (add), 32 6 1781
Verification of Accuracy (add), Calibration Check (add)
h55i Biological Indicators—Resistance Performance 30 1 212
Tests—Total Viable Spore Count, D-Value Determination
h121i Insulin Assays—Appendix (add) 30 5 1675
h231i Heavy Metals—Method II 32 1 182
h267i Porosimetry by Mercury Intrusion (new)—Harmonization 31 3 905
h311i Alginates Assay—System Suitability 32 2 516
h345i Assay for Citric Acid/Citrate and Phosphate (new) 31 2 514
h381i Elastomeric Closures for Injections—Introduction, 30 1 220
Characteristics, Identification Tests, Test Procedures
h401i Fats and Fixed Oils—Acid Value (Free Fatty Acids) 32 5 1492
h429i Light Diffraction Measure of Particle Size (new)— 31 4 1234
Harmonization
h466i Ordinary Impurities—Introduction, Reporting 32 5 1493
and Specifications (add), Methodology (add),
Procedure
h467i Residual Solvents—Introduction; 32 5 1494
In-Process Revision
Classification of Residual Solvents by Risk Assessment;
Methods for Establishing Exposure Limits; Options for Describing
Limits of Class 2 Residual Solvents; Analytical Procedures (add);
Reporting Levels of Residual Solvents (add); Limits of
Residual Solvents; Identification, Control, and Quantification of
Residual Solvents; Glossary
h611i Alcohol Determination—Introduction, Method IIa, Method IIb 32 3 830
h616i Bulk Density and Tapped Density—Harmonization 31 3 909
h621i Chromatography—Introduction, Thin-Layer Chromatography, 32 4 1163
Interpretation of Chromatograms, System Suitability,
Chromatographic Reagents
h644i Conductivity (new) (entire submission) 31 3 841
h660i Containers—Glass (new) 32 4 1171
h661i Containers—Plastics (entire chapter revised) 32 4 1176
h671i Containers—Performance Testing— 32 4 1193
Introduction, Multiple-Unit Containers for Capsules and Tablets,
Multiple-Unit Containers for Capsules and Tablets (Without
Closure)(add), Multiple-Unit Containers and Unit-Dose Containers
for Liquids (add), Light Transmission Test (add)
h681i Repackaging into Single-Unit Containers and Unit-Dose 32 4 1197
Containers for Nonsterile Solid and Liquid Dosage Forms (new)
Pharmacopeial Forum
h699i Density of Solids (new)—Harmonization 31 3 912
h721i Distilling Range—Method II 32 4 1200
h729i Globule Size Distribution in Lipid Injectable 31 5 1448
Emulsions (new)
h730i Plasma Spectrochemistry—Sample Preparation, 32 3 836
Sample Introduction, Standard Preparation, ICP,
ICP–AES, ICP–MS, Glossary
h785i Osmolality and Osmolarity—Osmolarity, 32 3 850
Measurement of Osmolality
h797i Pharmaceutical Compounding—Sterile Preparations— 32 3 852
Introduction; Organization of This Chapter, Definitions (add);
Responsibility of Compounding Personnel; CSP Microbial
Contamination Risk Levels; Immediate Use CSPs (add);
Single-Dose and Multiple-Dose Containers (add);
Hazardous Drugs as CSPs (add); Radiopharmaceuticals
as CSPs (add); Verification of Compounding Accuracy and
Sterility; Personnel Training and Evaluation in Aseptic
Manipulation Skills; Environmental Quality and Control;
Suggested Standard Operating Procedures; Environmental
Monitoring (add); Processing; Finished Preparation
Release Checks and Tests; Storage and Beyond-Use
Dating; Maintaining Sterility, Purity, and Stability of
Dispensed and Distributed CSPs; Acronyms (add), Appendix
h811i Powder Fineness—Harmonization 31 1 228
h921i Water Determination—Method I (Titrimetric) 31 2 517
h941i X-Ray Diffraction (new)—Harmonization 31 4 1241
General Information Chapters

h1005i Acoustic Emission (new) 32 5 1504
h1047i Biotechnology-Derived Articles—Tests (delete) 32 2 516
h1052i Biotechnology-Derived Articles— 32 2 542
Amino Acid Analysis (new)
Capillary Electrophoresis (new)
Isoelectric Focusing (new)
Peptide Mapping (new)
Polyacrylamide Gel Electrophoresis (new)
Total Protein Assay (new)
h1058i Analytical Instrument Qualification (new) 32 6 1784
h1065i Ion Chromatography—Apparatus 32 3 899
h1070i Emergency Medical Services Vehicles and 32 2 605
Ambulances—Storage of Preparations (new)
h1079i Good Storage and Shipping Practices— 32 4 1208
Storage in Warehouses, Pharmacies, Trucks, Shipping Docks, and
Other Locations; Special Handling; Shipment from Manufacturer
to Wholesaler; Shipment from Manufacturer or Wholesaler
In-Process Revision
to Pharmacy; Shipment from Pharmacy to Patient or

Customer; Storage of Physician Samples Handled by
Sales Representatives in Automobiles; Statements/Labeling
of the Immediate Containers or Package Insert
h1080i Bulk Pharmaceutical Excipients—Certificate of 31 4 1167
Analysis (new)
h1082i Genotoxicity Testing (new) (entire submission) 30 1 264
h1086i Impurities in Official Articles—Introduction, 32 5 1509
Initial IND Filing, NDA Filing, Post NDA Approval,
ANDA Filing, Definitions
h1087i Intrinsic Dissolution—Title, Introduction, Experimental 30 6 2130
Procedure, Data Analysis and Interpretation
Pharmacopeial Forum
h1116i Microbiological Evaluation of Clean Rooms and 31 2 524
Other Controlled Environments—Title, Introduction,
Establishment of Clean Room Classifications,
Importance of a Microbiological Evaluation Program for
Controlled Environments, Physical Evaluation of
Contamination Control Effectiveness (add),Training of
Personnel, Critical Factors Involved in the Design and
Implementation of a Microbiological Environmental
Control Program, Establishment of Sampling Plan and
Sites, Establishment of Microbiological Alert and Action
Levels in Controlled Environments, Microbial
Considerations and Action Levels for Controlled
Environments, Methodology and Instrumentation for
Quantitation of Viable Airborne Microorganisms,
Methodology and Equipment for Sampling of Surfaces
for Quantitation of Viable Microbial Contaminants
in Controlled Environments, Culture Media and Diluents
Used for Sampling or Quantitation, Identification of
Microbial Isolates from the Environmental Control
Program, Operational Evaluation of the Microbiological
Status of Aseptically Filled Products in Clean Rooms
and Other Controlled Environments (delete),
An Overview of the Emerging Technologies for Advanced
Aseptic Processing (delete), Conclusion (add), Glossary
h1118i Monitoring Devices—Time, Temperature, and Humidity— 32 3 900
Electronic Time–Temperature History Recorders
h1120i Raman Spectrometry (entire chapter revised) 32 4 1211
h1121i Nomenclature—Introduction, 32 4 1228
General Nomenclature Forms (add), Salt Nomenclature
Policy (add), Policy for Postponement Schedules (add)
h1150i Pharmaceutical Stability—Controlled Room 32 4 1232
Temperature and Controlled Cold Temperature
h1160i Pharmaceutical Calculations in Prescription 31 3 847
Compounding—Basic Pharmaceutical Calculations
h1163i Quality Assurance in Pharmaceutical Compounding (new) 32 5 1517
h1178i Good Repackaging Practices (entire chapter revised) 32 5 1523
h1184i Sensitization Testing (new) 30 1 289
h1195i Significant Change Guide for Bulk Pharmaceutical 31 4 1180
Excipients (new)
h1208i Sterility Testing—Validation of Isolator Systems— 30 6 2162
Introduction, Isolator Design and Construction,
Validation of the Isolator System, Package Integrity
Verification, Maintenance of Asepsis Within the Isolator
Environment, Interpretation of Sterility Test Results,
Training and Safety
h1211i Sterilization and Sterility Assurance of Compendial Articles— 30 5 1729
Introduction; Methods of Sterilization; Sterility Testing of Lots;
Performance, Observation, and Interpretation
h1217i Tablet Breaking Force (new) 31 6 1695
h1222i Terminally Sterilized Pharmaceutical Products— 30 5 1741
In-Process Revision
Parametric Release—Introduction, General Review,
Modes of Sterilization, Summary
h1226i Verification of Compendial Procedures (new) 32 4 1232
h1231i Water for Pharmaceutical Purposes—Types of Water 32 5 1528
h1232i Instrumentation for Analysis of High Purity Pharmaceutical 30 5 1806
Waters (new) (entire submission)
Dietary Supplement Chapters
h2040i Disintegration and Dissolution of Dietary Supplements— 32 6 1795
Introduction (add), Disintegration, Rupture Test for
Soft Shell Capsules (add), Dissolution
Reagent Specifications
Acetaldehyde 32 2 607
Acetanilide 32 2 608
Acetic Acid, Glacial 32 2 608
Acetic Anhydride 32 2 608
Acetone 32 2 608
Acetonitrile 32 2 608
Acetophenone 32 2 609
p-Acetotoluidide 32 2 609
Pharmacopeial Forum
Acetylacetone 32 2 609
Acetyl Chloride 32 2 609
Acetylcholine Chloride 32 2 610
Acrylic Acid 32 2 610
Adipic Acid 32 2 610
Alprenolol Hydrochloride 32 2 610
Alum 32 2 611
Alumina, Activated 32 2 611
Alumina, Anhydrous 32 2 611
Aluminon 32 2 611
Aluminum 32 2 611
Aluminum Oxide, Acid-Washed 32 2 611
Aluminum Potassium Sulfate 32 2 612
Amaranth 32 2 612
Aminoacetic Acid 32 2 612
4-Aminoantipyrine 32 2 612
4-Amino-6-chloro-1,3-benzenedisulfonamide 32 2 613
4-Amino-2-chlorobenzoic Acid 32 2 613
2-Amino-5-chlorobenzophenone 32 2 613
1-(2-Aminoethyl)piperazine 32 2 613
Aminoguanidine Bicarbonate 32 2 613
N-Aminohexamethyleneimine 32 2 614
4-Amino-3-hydroxy-1-naphthalenesulfonic Acid 32 2 614
m-Aminophenol 32 2 614
p-Aminophenol 32 2 614
3-Amino-1-propanol 32 2 614
Ammonia Water, Stronger 32 2 615
Ammonia Water, 25 Percent 32 2 615
Ammonium Acetate 32 2 615
Ammonium Bisulfate 32 2 615
Ammonium Bromide 32 2 615
Ammonium Carbonate 32 2 615
Ammonium Chloride 32 2 616
Ammonium Citrate, Dibasic 32 2 616
Ammonium Fluoride 32 2 616
Ammonium Hydroxide 32 2 616
Ammonium Molybdate 32 2 616
Ammonium Nitrate 32 2 616
Ammonium Oxalate 32 2 617
Ammonium Persulfate 32 2 617
Ammonium Phosphate, Dibasic 32 2 617
Ammonium Phosphate, Monobasic 32 2 617
Ammonium Reineckate 32 2 617
Ammonium Sulfamate 32 2 617
Ammonium Sulfate 32 2 618
Ammonium Thiocyanate 32 2 618
Ammonium Vanadate 32 2 618
Amyl Acetate 32 2 618
Amyl Alcohol 32 2 618
tert-Amyl Alcohol 32 2 619
In-Process Revision
Aniline 32 2 619
Aniline Blue 32 2 619
Anion-Exchange Resin, Strong, Lightly Cross-Linked, 31 3 858
in the Chloride Form
Anisole 32 2 619
Anthracene 32 2 619
Anthrone 32 2 620
Antimony Pentachloride 32 2 620
Antimony Trichloride 32 2 620
Aprobarbital 32 2 620
Arsenazo III Acid 32 2 621
Arsenic Trioxide 32 2 621
L-Asparagine 32 2 621
Bacterial Alkaline Protease Preparation 30 2 644
Barium Chloride 32 2 621
Barium Chloride, Anhydrous 32 2 622
Barium Hydroxide 32 2 622
Barium Nitrate 32 2 622
Benzaldehyde 32 2 622
Benzamidine Hydrochloride Hydrate 32 2 622
Benzanilide 32 2 623
Pharmacopeial Forum
Benzene 32 2 623
Benzenesulfonamide 32 2 623
Benzenesulfonyl Chloride 32 2 623
Benzhydrol 32 2 623
Benzoic Acid 32 2 623
Benzophenone 32 2 624
p-Benzoquinone 32 2 624
3-Benzoylbenzoic Acid 32 2 624
Benzoyl Chloride 32 2 624
Benzoylformic Acid 32 2 624
Benzphetamine Hydrochloride 32 2 624
2-Benzylaminopyridine 32 2 625
1-Benzylimidazole 32 2 625
Benzyltrimethylammonium Chloride 32 2 625
Bibenzyl 32 2 625
Biphenyl 32 2 625
2,2’-Bipyridine 32 2 626
4,4’-Bis(4-amino-1-naphthylazo)-2,2’- 32 2 626
stilbenedisulfonic Acid
Bis(2-ethylhexyl) Maleate 32 2 626
Bis(2-ethylhexyl) Phthalate 32 2 626
Bis(2-ethylhexyl) Sebacate 32 2 626
Bis(2-ethylhexyl)phosphoric Acid 32 2 627
Bis(trimethylsilyl)acetamide 32 2 627
Bis(trimethylsilyl)trifluoroacetamide 32 2 627
Bis(trimethylsilyl)trifluoroacetamide with 32 2 627
Trimethylchlorosilane
Blue Tetrazolium 32 2 627
Boric Acid 32 2 628
Boron Trifluoride 32 2 628
14% Boron Trifluoride–Methanol 32 2 628
Brilliant Green 32 2 628
Bromine 32 2 629
p-Bromoaniline 32 2 629
N-Bromosuccinimide 32 2 629
Brucine Sulfate 32 2 629
1,3-Butanediol 32 2 629
2,3-Butanedione 32 2 630
Butyl Acetate, Normal 32 2 630
Butyl Alcohol 32 2 630
Butyl Alcohol, Secondary 32 2 630
Butyl Alcohol, Tertiary 32 2 630
Butyl Benzoate 32 2 631
Butyl Ether 32 2 631
n-Butyl Chloride 32 4 1239
tert-Butyl Methyl Ether 32 2 631
Butyl Methacrylate (new) 31 4 1189
n-Butylamine 32 2 631
tert-Butylamine 32 2 632
4-tert-Butylphenol 32 2 632
In-Process Revision
Butyraldehyde 32 2 632
Butyric Acid 32 2 632
Butyrolactone 32 2 633
Cadmium Acetate 32 2 633
Cadmium Nitrate 32 2 633
Calcium Acetate 32 2 634
Calcium Carbonate 32 2 634
Calcium Carbonate, Chelometric Standard 32 2 634
Calcium Chloride 32 2 634
Calcium Chloride, Anhydrous 32 2 634
Calcium Citrate 32 2 634
Calcium Hydroxide 32 2 635
Calcium Lactate 32 2 635
Calcium Nitrate 32 2 635
Calcium Sulfate 32 2 635
dl-10-Camphorsulfonic Acid 32 2 636
Capric Acid 32 2 636
Carbazole 32 2 636
Carbon Disulfide, CS 32 2 636
Carbon Tetrachloride 32 2 636
Carboxymethoxylamine Hemihydrochloride 32 2 637
Pharmacopeial Forum
Casein 32 2 637
Casein, Hammersten (new) 32 4 1239
Catechol 32 2 637
Cedar Oil 32 2 637
Ceric Sulfate 32 2 638
Chenodeoxycholic Acid 32 2 638
Chloramine T 32 2 638
Chlorine 32 2 638
1-Chloroadamantane 32 2 639
3-Chloroaniline 32 2 639
Chlorobenzene 32 2 639
m-Chlorobenzoic Acid 32 2 639
4-Chlorobenzoic Acid 32 2 639
4-Chlorobenzophenone 32 2 640
Chloroform 32 2 640
Chlorogenic Acid 32 2 640
1-Chloronaphthalene 32 2 640
2-Chloronicotinic Acid 32 2 640
2-Chloro-4-nitroaniline, 99% 32 2 641
Chloroplatinic Acid 32 2 641
5-Chlorosalicylic Acid 32 2 641
Chlorotrimethylsilane 32 2 641
Cholestane 32 2 641
Cholesteryl Benzoate 32 2 641
Choline Chloride 32 2 642
Chromium Trioxide 32 2 642
Chromotropic Acid 32 2 642
Chromotropic Acid Disodium Salt 32 2 642
Cinchonidine 32 2 642
Cinchonine 32 2 643
Citric Acid, Anhydrous 32 2 643
Cobalt Chloride 32 2 643
Cobalt Nitrate 32 2 643
Cobaltous Acetate 32 2 643
Congo Red 32 2 643
Coomassie Brilliant Blue R-250 32 2 644
Copper 32 2 644
Cortisone 32 2 644
m-Cresol Purple 32 2 644
Cupric Acetate 32 2 644
Cupric Chloride 32 2 645
Cupric Citrate 32 2 645
Cupric Sulfate, Anhydrous 32 2 645
Cyanoacetic Acid 32 2 645
Cyanogen Bromide 32 2 645
Cyclohexane 32 2 645
Cyclohexanol 32 2 646
L-Cystine 32 2 646
Decanol 32 2 646
Deuterated Methanol (new) 29 6 2054
In-Process Revision
Deuterium Oxide 32 2 646

Devarda’s Alloy 32 2 646
Dextran, High Molecular Weight 32 2 646
Dextrin 32 2 647
3,3’-Diaminobenzidine Hydrochloride 32 2 647
2,3-Diaminonaphthalene 32 2 647
Diatomaceous Earth, Flux-Calcined 32 2 648
Diatomaceous Earth, Silanized 32 2 648
Diatomaceous Silica, Calcined 32 2 648
Diaveridine (new) 32 4 1239
2,6-Dibromoquinone-chlorimide 32 2 648
Dibutylamine 32 2 648
Dibutyl Phthalate 32 2 649
2,5-Dichloroaniline 32 2 649
o-Dichlorobenzene 32 2 649
2,8-Dichlorodibenzo-p-dioxin (delete) 30 6 2168
2,8-Dichlorodibenzofuran (delete) 30 6 2168
Dichlorofluorescein 32 2 650
Dichlorofluoromethane 32 2 650
2,4-Dichloro-1-naphthol 32 2 650
Pharmacopeial Forum
2,4-Dichlorophenol (delete) 30 6 2168
2,6-Dichlorophenol-indophenol Sodium 32 2 650
2,6-Dichlorophenylacetic Acid 32 2 650
Dicyclohexyl 31 3 858
Dicyclohexylamine 32 6 1803
Diethylamine 32 2 651
N,N-Diethylaniline 32 2 651
Diethylene Glycol 32 2 651
Diethylene Glycol Succinate Polyester 32 2 652
Diethylenetriamine 32 2 652
Di(2-ethylhexyl)phthalate 32 2 652
Digitonin 32 2 652
Digoxigenin (new) 32 6 1803
Digoxigenin Bisdigitoxoside (delete) 32 6 1803
10,11-Dihydrocarbamazepine (delete) 32 2 652
Dihydroquinidine Hydrochloride 32 2 653
Dihydroquinine 32 2 653
2,5-Dihydroxybenzoic Acid 32 2 653
Diiodofluorescein 32 2 653
Diisodecyl Phthalate 32 2 654
Diisopropyl Ether 32 3 901
Diisopropylamine 32 2 654
Diisopropylethylamine 32 2 654
2,5-Dimethoxybenzaldehyde 32 2 654
1,2-Dimethoxyethane 32 2 655
(3,4-Dimethoxyphenyl)acetonitrile 32 2 655
Dimethyl Phthalate 32 2 655
Dimethyl Sulfone 32 2 655
Dimethyl Sulfoxide, Spectrophotometric Grade 32 2 655
N,N-Dimethylacetamide 32 5 1535
p-Dimethylaminoazobenzene 32 2 656
p-Dimethylaminobenzaldehyde, 32 2 656
2-Dimethylaminoethyl Methacrylate (new) 31 4 1190
2,6-Dimethylaniline 32 2 656
N,N-Dimethylaniline 32 2 656
3,4-Dimethylbenzophenone 32 2 657
5,5-Dimethyl-1,3-cyclohexanedione 32 2 657
N,N-Dimethyldodecylamine-N-oxide (new) 27 4 2837
Dimethylformamide 32 2 657
N,N-Dimethylformamide Diethyl Acetal (delete) 32 2 657
N,N-Dimethyl-1-naphthylamine 32 2 657
N,N-Dimethyloctylamine 32 2 658
2,6-Dimethylphenol 32 2 658
N,N-Dimethyl-p-phenylenediamine Dihydrochloride 32 2 658
m-Dinitrobenzene 32 2 658
3,5-Dinitrobenzoyl Chloride 32 2 659
2,4-Dinitrochlorobenzene 32 2 659
2,4-Dinitrofluorobenzene 32 2 659
2,4-Dinitrophenylhydrazine 32 5 1535
Dioxane 32 3 902
In-Process Revision
Diphenyl Ether 32 3 902
Diphenylamine 32 3 902
Diphenylcarbazide 32 3 902
Diphenylcarbazone 32 3 902
2,2-Diphenylglycine 32 3 902
Dipropyl Phthalate 32 3 903
4,4’-Dipyridyl Dihydrochloride 32 3 903
5,5’-Dithiobis(2-nitrobenzoic Acid) 32 3 903
Dithiothreitol 32 3 903
Dithizone 32 3 903
Docusate Sodium (new) 31 4 1190
1-Dodecanol 32 3 903
n-Eicosane 32 3 904
Eicosanol 32 3 904
Eosin Y (Eosin Yellowish Y) 32 3 904
Epiandrosterone 32 3 904
Equilenin 32 3 904
Eriochrome Cyanine R 32 3 904
Eriochrome Black T–Sodium Chloride Indicator (new) 32 4 1239
Ethanesulfonic Acid 32 3 905
2-Ethoxyethanol 32 3 905
Pharmacopeial Forum
Ethyl Acetate 32 3 905
Ethyl Acrylate 32 3 905
Ethyl Benzoate 32 3 905
Ethyl Cyanoacetate 32 3 906
Ethyl Ether 32 3 906
Ethyl Ether, Anhydrous 32 3 906
Ethyl Salicylate 32 3 906
2-Ethylaminopropiophenone Hydrochloride 32 3 906
4-Ethylbenzaldehyde 32 3 906
Ethylbenzene 32 3 907
Ethylene Dichloride 32 3 907
Ethylene Glycol 32 3 907
Ethylene Oxide in Methylene Chloride (50 mg/mL) (new) 31 3 859
1-Ethylquinaldinium Iodide 32 3 907
Fast Blue B Salt 32 3 907
Fast Blue BB Salt 32 3 908
Ferric Chloride 32 3 908
Ferric Nitrate 32 3 908
Ferric Sulfate 32 3 908
Ferrous Sulfate 32 3 909
Fluorene 32 3 909
9-Fluorenylmethyl Chloroformate 32 3 909
Fluorescamine 32 3 909
4’-Fluoroacetophenone 32 3 909
Formamide 32 3 909
Formic Acid 32 3 910
Formic Acid, 96 Percent 32 3 910
Fuchsin, Basic 32 3 910
Gadolinium (Gd III) Acetate Hydrate 32 3 910
Geneticin (new) 31 6 1700
Gitoxin 32 3 910
D-Gluconic Acid, 50 Percent in Water 32 3 911
Glucose 32 3 911
D-Glucuronolactone 32 3 911
Glycerin 32 3 911
Glycolic Acid 32 3 911
Gold Chloride 32 3 911
Guaiacol 32 3 912
Guanidine Hydrochloride 32 6 1803
Guanine Hydrochloride 32 3 912
Hematein 32 3 912
Hematoxylin 32 3 912
n-Heptane, Chromatographic 32 2 659
Hexadecyl Hexadecanoate 32 3 913
Hexamethyldisilazane 32 3 913
Hexamethyleneimine 32 3 913
n-Hexane 32 3 913
Hexane, Solvent 32 3 913
Hexanitrodiphenylamine 32 3 914
Hexanophenone 32 3 914
In-Process Revision
Hydrazine Dihydrochloride 32 3 914

Hydrazine Hydrate, 85% in Water 32 3 914
Hydriodic Acid 32 3 914
Hydrochloric Acid 32 3 915
Hydrochloric Acid, Diluted 32 3 915
Hydrofluoric Acid 32 3 915
Hydrogen Peroxide, 10 Percent (new) 32 5 1535
Hydrogen Peroxide, 30 Percent 32 3 915
Hydrogen Sulfide 32 3 915
Hydroquinone 32 3 915
3’-Hydroxyacetophenone 32 3 916
p-Hydroxybenzoic Acid 32 3 916
4-Hydroxybenzoic Acid Isopropyl Ester 32 3 916
1-Hydroxybenzotriazole Hydrate 32 3 916
2-Hydroxybenzyl Alcohol 32 3 916
4-Hydroxyisophthalic Acid 32 5 1536
Hydroxylamine Hydrochloride 32 3 917
Hydroxy Naphthol Blue 32 3 917
D-a-Hydroxyphenylglycine 32 3 917
4-(4-Hydroxyphenyl)-2-butanone 32 3 917
Pharmacopeial Forum
Hydroxypropyl-b-cyclodextrin (new) 32 6 1804
8-Hydroxyquinoline 32 3 918
Hypophosphorous Acid, 50 Percent 32 3 918
Imidazole 32 3 918
Iminostilbene (delete) 32 2 659
Indene 32 3 918
Inosine 32 3 918
Inositol 32 3 918
Iodic Acid 32 3 919
Iodine 32 3 919
Iodine Monobromide 32 3 919
Iodine Monochloride 32 3 919
Isobutyl Acetate 32 3 919
Isobutyl Alcohol 32 3 919
Isonicotinic Acid 32 3 920
Isopropyl Alcohol 32 3 920
Isopropyl Alcohol, Dehydrated 32 3 920
Isopropyl Iodide 31 6 1701
Isopropyl Myristate 32 3 920
Isopropylamine 32 3 920
Kerosene 32 3 921
Lactose 32 3 921
Lanthanum Chloride 32 3 921
Lead Acetate 32 3 921
Lead Monoxide 32 3 921
Lead Nitrate 32 3 922
Lithium Chloride 32 3 922
Lithium Hydroxide 32 3 922
Lithium Metaborate 32 3 922
Lithium Nitrate 32 3 922
Lithium Percholate 32 3 922
Lithium Sulfate 32 3 922
Lithocholic Acid 32 3 923
Litmus 32 3 923
L-Lysine 32 3 923
Magnesium 32 3 923
Magnesium Acetate 32 3 923
Magnesium Chloride 32 3 923
Magnesium Nitrate 32 3 924
Magnesium Oxide 32 3 924
Magnesium Perchlorate, Anhydrous 32 3 924
Magnesium Sulfate 32 3 924
Magnesium Sulfate, Anhydrous 32 3 924
Maleic Acid 32 3 924
Manganese Dioxide, Activated 32 3 925
Mercuric Acetate 32 3 925
Mercuric Bromide 32 3 925
Mercuric Chloride 32 3 925
Mercuric Iodide, Red 32 3 925
Mercuric Nitrate 32 3 925
In-Process Revision
Mercuric Oxide, Yellow 32 3 926
Mercuric Sulfate 32 3 926
Mercuric Thiocyanate 32 3 926
Mercury 32 3 926
Mesityl Oxide 32 3 926
Metaphosphoric Acid 32 3 926
Methacrylic Acid 32 3 927
Methanesulfonic Acid 32 3 927
Methanol 32 3 927
Methoxyethanol 32 3 927
2-Methoxyethanol 32 3 927
5-Methoxy-2-methyl-3-indoleacetic Acid 32 3 927
Methyl Acetate 32 3 927
Methyl 4-Aminobenzoate 32 3 928
Methyl Arachidate 32 3 928
Methyl Behenate 32 3 928
Methyl Caprate 32 3 928
Methyl Caprylate 32 3 928
Methyl Carbamate 32 3 929
Methyl Chloroform 32 3 929
Methyl Erucate 32 3 929
Pharmacopeial Forum
Methyl Ethyl Ketone 32 3 929
Methyl Green 32 5 1536
Methyl Heptadecanoate 32 3 929
Methyl Iodide 32 5 1536
Methyl Laurate 32 3 930
Methyl Lignocerate 32 3 930
Methyl Linoleate 32 3 930
Methyl Linolenate 32 3 930
Methyl Methacrylate 32 3 931
Methyl Myristate 32 3 931
Methyl Oleate 32 3 931
Methyl Palmitate 32 3 931
Methyl Stearate 32 3 931
Methyl Sulfoxide 32 3 932
Methylamine, 40 Percent in Water 32 3 932
p-Methylaminophenol Sulfate 32 3 932
Methylene Blue 32 3 932
Methylene Chloride 32 3 932
5-5’-Methylenedisalicylic Acid 32 3 932
4-Methyl-2-pentanone 32 3 933
2-Methyl-2-propyl-1,3-propanediol 32 3 933
N-Methylpyrrolidine 32 2 659
Molybdic Acid 32 3 933
Monochloroacetic Acid 32 3 933
Morpholine 32 3 933
Naphthalene 32 3 933
1,3-Naphthalenediol 32 3 934
2-Naphthalenesulfonic Acid 32 3 934
1-Naphthol 32 3 934
2-Naphthol 32 3 934
p-Naphtholbenzein 32 3 935
Naphthoresorcinol 32 3 935
1-Naphthylamine Hydrochloride 32 3 935
2-Napthyl Chloroformate 32 3 935
N-(1-Naphthyl)ethylenediamine Dihydrochloride 32 3 935
Nickel 32 3 935
Nickel Sulfate 32 3 936
b-Nicotinamide Adenine Dinucleotide 32 3 936
Ninhydrin 32 3 936
Nitric Acid 32 3 936
Nitric Acid, Diluted 32 3 936
Nitric Acid, Fuming 32 3 936
Nitrilotriacetic Acid 32 3 937
4’-Nitroacetophenone 32 3 937
o-Nitroaniline 32 3 937
p-Nitroaniline 32 3 937
Nitrobenzene 32 3 937
p-Nitrobenzenediazonium Tetraflouroborate 32 3 937
4-(p-Nitrobenzyl)pyridine 32 3 938
In-Process Revision
Nitromethane 32 3 938
5-Nitro-1,10-phenanthroline 32 3 938
1-Nitroso-2-naphthol 32 3 938
Nitroso R Salt 32 3 939
Nitrous Oxide Certified Standard 32 3 939
Nonadecane 32 3 939
Nonanoic Acid 32 3 939
1-Nonyl Alcohol 32 4 1239
n-Octadecane (new) 32 5 1537
Octadecyl Silane 32 4 1240
1-Octanol (new) 32 6 1804
Octanophenone 32 4 1240
Orange G 32 4 1240
Orcinol 32 4 1240
Osmium Tetroxide 32 4 1241
Oxalic Acid 32 4 1241
3,3’-Oxydipropionitrile 32 4 1241
Palladium Chloride 32 4 1241
Pancreatin 32 4 1241
Para-aminobenzoic Acid 32 4 1241
Paraformaldehyde 32 4 1242
Pharmacopeial Forum
Pentadecane 32 4 1242
Pentane 32 4 1242
Pepsin 32 4 1242
Perchloric Acid 32 4 1242
Periodic Acid 32 4 1243
Phenacetin 32 4 1243
1,10-Phenanthroline 32 4 1243
Phenol 32 4 1243
Phenoxybenzamine Hydrochloride 32 4 1243
2-Phenoxyethanol 32 4 1243
Phenylhydrazine Hydrochloride 32 2 660
Phenyl Isocyanate 32 4 1244
dl-Phenylalanine 32 4 1244
Phenylhydrazine 32 4 1244
3-Phenylphenol 32 4 1245
Phloroglucinol 32 4 1245
Phosphomolybdic Acid 32 4 1245
Phosphoric Acid 32 4 1245
Phosphorous Pentoxide 32 4 1245
Phthalazine 32 4 1245
Phthalic Acid 32 4 1246
Phthalic Anhydride 32 4 1246
Phthalimide 32 4 1246
2-Picoline 32 4 1246
Picric Acid 32 4 1246
Picrolonic Acid 32 4 1246
Pipemidic Acid 32 4 1247
Piperidine 32 4 1247
Platinic Chloride 32 4 1247
Polyethylene Glycol 600 32 4 1247
Polyethylene Glycol 20,000 32 4 1247
Polysaccharide Molecular Weight Standards 32 6 1804
Polyvinyl Alcohol 32 4 1247
Potassium Acetate 32 4 1248
Potassium Bicarbonate 32 4 1248
Potassium Biphthalate 32 4 1248
Potassium Bisulfate 32 4 1248
Potassium Bromate 32 4 1248
Potassium Bromide 32 4 1249
Potassium Carbonate, Anhydrous 32 4 1249
Potassium Chlorate 32 4 1249
Potassium Chloride 32 4 1249
Potassium Chromate 32 4 1249
Potassium Cyanide 32 4 1249
Potassium Dichromate 32 4 1249
Potassium Ferricyanide 32 4 1250
Potassium Ferrocyanide 32 4 1250
Potassium Hydroxide 32 4 1250
Potassium Iodate 32 4 1250
In-Process Revision
Potassium Iodide 32 4 1250
Potassium Nitrate 32 4 1250
Potassium Nitrite 32 4 1250
Potassium Perchlorate 32 4 1251
Potassium Periodate 32 4 1251
Potassium Permanganate 32 4 1251
Potassium Persulfate 32 4 1251
Potassium Phosphate, Dibasic 32 4 1251
Potassium Phosphate, Monobasic 32 4 1251
Potassium Phosphate, Tribasic 32 4 1252
Potassium Pyroantimonate 32 4 1252
Potassium Pyrophosphate 32 4 1252
Potassium Pyrosulfate 32 4 1252
Potassium Sodium Tartrate 32 4 1252
Potassium Sulfate 32 4 1252
Potassium Tellurite 32 4 1253
Potassium Thiocyanate 32 4 1253
Propionaldehyde 32 4 1253
Propionic Anhydride 32 4 1253
n-Propyl Alcohol 32 4 1253
Pullulan Standards (new) 32 5 1537
Pharmacopeial Forum
Purine 32 4 1253
Pyrazole 32 4 1254
Pyrene 32 4 1254
Pyridine 32 4 1254
Pyridine, Dried 32 4 1254
Pyridoxal Hydrochloride 32 4 1254
Pyridoxal 5-Phosphate 32 4 1254
Pyridoxamine Dihydrochloride 32 4 1255
1-(2-Pyridylazo)-2-naphthol 32 4 1255
Pyrogallol 32 4 1255
Pyrrole 32 4 1255
Pyruvic Acid 32 4 1255
Quinhydrone 32 4 1256
Resazurin (Sodium) 32 4 1256
Anion-Exchange Resin, Styrene-Divinylbenzene 30 3 1043
Cation-Exchange Resin, Styrene-Divinylbenzene 30 3 1043
Rhodamine B 32 4 1256
Rose Bengal Sodium 32 4 1256
Ruthenium Red 32 4 1257
Safranin O 32 4 1257
Salicylaldehyde 32 4 1257
Selenious Acid 32 4 1257
Selenium 32 4 1258
Selenomethionine 32 4 1258
Silica Gel, Octadecylsilanized Chromatographic 32 2 660
Silicic Acid 32 4 1258
Silicon Carbide 32 4 1259
Silicotungstic Acid, n-Hydrate 32 4 1259
Silver Diethyldithiocarbamate 32 4 1259
Silver Nitrate 32 4 1259
Silver Oxide 32 4 1259
Sodium 32 4 1260
Sodium Acetate 32 4 1260
Sodium Acetate, Anhydrous 32 4 1260
Sodium Arsenite 32 4 1260
Sodium Azide 32 4 1260
Sodium Bicarbonate 32 4 1261
Sodium Bisulfite 32 4 1261
Sodium Bitartrate 32 4 1261
Sodium Borate 32 4 1261
Sodium Borohydride 32 4 1261
Sodium Bromide 32 4 1262
Sodium Carbonate, Anhydrous 32 4 1262
Sodium Carbonate, Monohydrate (new) 31 6 1701
Sodium Chloride 32 4 1262
Sodium Chromate 32 4 1262
Sodium Citrate Dihydrate (new) 32 5 1537
Sodium Cobaltinitrite 32 4 1262
Sodium Cyanide 32 4 1263
Sodium 1-Decanesulfonate 32 4 1263
In-Process Revision
Sodium Dichromate 32 4 1263

Sodium Diethyldithiocarbamate 32 4 1263
Sodium Dodecyl Sulfate 32 4 1263
Sodium Ferrocyanide 32 4 1263
Sodium Fluoride 32 4 1264
Sodium Glycocholate 32 4 1264
Sodium 1-Heptanesulfonate 32 4 1264
Sodium 1-Hexanesulfonate 32 4 1264
Sodium Hydrosulfite 32 4 1264
Sodium Hydroxide 32 4 1265
Sodium Hypochlorite Solution 32 4 1265
Sodium Metabisulfite 32 4 1265
Sodium Metaperiodate 32 4 1265
Sodium Methoxide 32 4 1265
Sodium Molybdate 32 4 1266
Sodium Nitrate 32 4 1266
Sodium Nitrite 32 4 1266
Sodium Nitroferricyanide 32 4 1266
Sodium 1-Octanesulfonate 32 4 1266
Sodium Oxalate 32 4 1266
Sodium (tri) Pentacyanoamino Ferrate 32 4 1267
Pharmacopeial Forum
Sodium 1-Pentanesulfonate 32 4 1267
Sodium Perchlorate 32 4 1267
Sodium Peroxide 32 4 1267
Sodium Phosphate, Dibasic 32 4 1267
Sodium Phosphate, Dibasic, Anhydrous 32 4 1268
Sodium Phosphate, Dibasic, Dodecahydrate 32 4 1268
Sodium Phosphate, Monobasic 32 4 1268
Sodium Phosphate, Tribasic 32 4 1268
Sodium Pyrophosphate 32 4 1268
Sodium Pyruvate 32 4 1268
Sodium Salicylate 32 4 1269
Sodium Selenite 32 4 1269
Sodium Sulfate 32 4 1269
Sodium Sulfate, Anhydrous 32 4 1269
Sodium Sulfide 32 4 1270
Sodium Sulfite, Anhydrous 32 4 1270
Sodium Tartrate 32 4 1270
Sodium Tetraphenylborate 32 4 1270
Sodium Thioglycolate 32 4 1270
Sodium Thiosulfate 32 4 1270
Sodium Tungstate 32 4 1271
Stachyose Tetrahydrate (new) 32 5 1537
Stannous Chloride 32 4 1271
Starch, Soluble 32 4 1271
Stearic Acid 32 4 1271
Stearyl Alcohol 32 4 1271
Strontium Acetate 32 4 1271
Strontium Hydroxide 32 4 1272
Strychnine Sulfate 32 4 1272
Sudan III 32 4 1273
Sudan IV 32 4 1273
Sulfamic Acid 32 4 1273
Sulfanilamide 32 4 1273
Sulfanilic Acid 32 4 1273
Sulfosalicylic Acid 32 4 1273
Sulfuric Acid 32 4 1274
Sulfuric Acid, Fuming 32 4 1274
Sulfurous Acid 32 4 1274
Tannic Acid 32 4 1274
Tetrabutylammonium Bromide 32 4 1274
Tetrabutylammonium Hydrogen Sulfate 32 4 1274
Tetrabutylammonium Hydroxide, 1.0 M in Methanol 32 4 1275
Tetrabutylammonium Hydroxide, 40 Percent in Water 32 4 1275
Tetrabutylammonium Iodide 32 6 1804
Tetrabutylammonium Phosphate 32 4 1275
Tetracosane 32 4 1275
Tetradecane 32 4 1275
Tetraethylene Glycol 32 4 1276
Tetraethylenepentamine 32 4 1276
Tetraheptylammonium Bromide 32 4 1276
In-Process Revision
Tetrahydrofuran 32 4 1276
Tetrahydro-2-furnancarboxylic Acid 32 4 1276
1,2,3,4-Tetrahydronaphthalene 32 4 1277
Tetramethylammonium Bromide 32 4 1277
Tetramethylammonium Chloride 32 4 1277
Tetramethylammonium Hydroxide 32 4 1277
Tetramethylammonium Hydroxide, Pentahydrate 32 4 1277
Tetramethylammonium Hydroxide Solution in Methanol 32 4 1278
Tetramethylammonium Nitrate 32 4 1278
4-4’-Tetramethyldiaminodiphenylmethane 32 4 1278
Tetramethylsilane 32 4 1278
Theobromine 32 4 1278
Thiazole Yellow 32 4 1278
Thioacetamide 32 4 1279
2-Thiobarbituric Acid 32 4 1279
2,2’-Thiodiethanol 32 4 1279
Thiourea 32 4 1279
Thorium Nitrate 32 4 1279
Thrombin Human (new) 29 6 2055
Thromboplastin 32 4 1279
Thymol 32 4 1280
Pharmacopeial Forum
Tin 32 4 1280
Titanium Tetrachloride 32 4 1280
Titanium Trichloride 32 4 1280
o-Tolidine 32 4 1280
Tolualdehyde 32 4 1281
p-Tolualdehyde 32 4 1281
Toluene 32 4 1281
p-Toluenesulfonic Acid 32 4 1281
p-Toluenesulfonyl-L-arginine Methyl Ester Hydrochloride 32 1 186
p-Toluic Acid 32 4 1281
o-Toluidine 32 4 1282
p-Toluidine 32 4 1282
n-Triacontane 32 4 1282
Tributyl Phosphate 32 4 1282
Tributyrin 32 4 1282
Trichloroacetic Acid 32 4 1282
2,4,8-Trichlorodibenzofuran (delete) 30 6 2169
1,3,7-Trichlorodibenzo-p-dioxin (delete) 30 6 2169
Trichlorofluoromethane 32 4 1283
n-Tricosane 32 4 1283
Triethylamine 32 4 1283
Triethylamine Hydrochloride 32 4 1283
Triethylene Glycol 32 4 1284
Trifluoroacetic Acid 32 4 1284
Trifluoroacetic Anhydride 32 4 1284
2,2,2-Trifluoroethanol 32 4 1284
5-(Trifluoromethyl)uracil 32 4 1285
Trimethylacethydrazide Ammonium Chloride 32 4 1285
2,2,4-Trimethylpentane 32 4 1285
2,4,6-Trimethylpyridine 32 4 1285
N-(Trimethylsilyl)-imidazole 32 4 1285
2,4,6-Trinitrobenzenesulfonic Acid 32 4 1285
Trioctylphosphine Oxide 32 4 1286
1,3,5-Triphenylbenzene 32 4 1286
Triphenylmethane 32 4 1286
Triphenylmethanol 32 4 1286
Triphenyltetrazolium Chloride 32 4 1286
Tris(2-aminoethyl)amine 32 4 1287
Tris(hydroxymethyl)aminomethane 32 4 1287
Tropaeolin OO 32 4 1287
L-Tryptophane 32 4 1287
Tubocurarine Chloride (new) 32 4 1287
Tungstic Acid (new) 32 5 1538
Uracil 32 4 1288
Uranyl Acetate 32 4 1288
Urea 32 4 1288
Urethane 32 4 1288
Uridine 32 4 1288
Valeric Acid 32 4 1288
Valerophenone 32 4 1289
In-Process Revision
Vanadium Pentoxide 32 4 1289

Vanadyl Sulfate 32 4 1289
Vinyl Acetate 32 4 1289
1-Vinyl-2-pyrrolidone 32 4 1290
Wright’s Stain 32 4 1290
Xanthine 32 4 1290
Xanthydrol 32 4 1290
Xylene 32 4 1290
o-Xylene 32 4 1291
p-Xylene 32 4 1291
Xylene Cyanole FF 32 4 1291
Xylose 32 4 1291
Zinc 32 4 1291
Zinc Acetate 32 4 1291
Zirconyl Nitrate 32 4 1292
Indicator and Test Papers

Methyl Green–Iodomercurate Paper (new) 32 5 1538
Test Solutions
Acetic Acid, Strong, TS (new) 32 5 1538
Pharmacopeial Forum
Ammonium Pyrrolidinedithiocarbamate, Saturated, TS (new) 32 5 1538
Dicyclohexylamine Acetate TS (delete) 32 6 1805
Bismuth Nitrate (new) 32 4 1292
Magnesium Chloride, 0.01 M (new) 32 4 1292
Mercuric Nitrate, Tenth Molar 32 6 1805
Potassium Hydroxide, Normal (1 N) 32 4 1292
Sodium Hydroxide, Normal (1 N) 32 3 940
Sodium Tetraphenylboron, Fiftieth Molar 32 6 1807
Sodium Thiosulfate, Tenth-Normal (0.1 N) 32 3 940
Chromatographic Reagents (new) 32 4 1293
Reference Tables
Container Specifications for Capsules and Tablets 32 6 1809
Excipients, USP and NF Excipients, Listed by Category 32 6 1768
Description and Solubility 25 4 8589
26 4 1135
27 1 1908
28 2 554
28 6 1953
29 1 266
29 3 812
29 5 1684
30 4 1405
30 5 1822
30 6 2183
31 1 122
31 2 591
31 3 861
31 4 1193
31 5 1491
31 6 1703
32 1 188
32 2 662
32 3 942
32 4 1301
32 5 1541
32 6 1811
NF Monographs
Acetyltributyl Citrate—Assay 32 1 177
Acetyltriethyl Citrate—Assay 32 1 178
Alfadex—Definition, Packaging and storage (add), 32 2 395
Loss on drying (delete), Water, Method I (add),
Reducing sugars, Light-absorbing impurities, Organic volatile
impurities, Method IV (delete), Residual solvents (delete),
Assay
In-Process Revision
Almond Oil—Definition, Packaging and storage, Labeling (add), 32 4 1147
Identification (add), Foreign kernel oils (delete), Cottonseed oil
(delete), Sesame oil (delete), Mineral oil and foreign fatty oils (delete),
Foreign oils (delete), Free fatty acids (delete),
Iodine value (delete), Saponification value (delete), Acid value
(add), Peroxide value (add), Unsaponifiable matter (add),
Fatty acid composition (add), Sterol composition (add),
Residual solvents (delete)
Amino Methacrylate Copolymer (new) 31 4 1137
Canola Oil (new) 31 6 1667
Carbomer Copolymer—Limit of ethyl acetate and cyclohexane 32 5 1481
Carboxymethylcellulose Calcium—Heavy metals 31 5 1420
Carboxymethylcellulose Sodium 12—Labeling, Viscosity, Heavy metals 31 5 1420
Cellacefate—USP Reference standards 32 1 179
Coconut Oil (new) 32 2 397
Copovidone—Harmonization 32 6 1843
Corn Syrup Solids (new) (entire submission) 28 6 1894
Crospovidone—Harmonization 28 4 1257
Erythritol (new) 31 5 1422
Ethyl Acrylate and Methyl Methacrylate Copolymer 31 4 1141
Dispersion (new)
Pharmacopeial Forum
Ethylcellulose Aqueous Dispersion—Labeling, Identification 31 6 1668
High Fructose Corn Syrup (new) 32 4 1151
Gamma Cyclodextrin (new) (entire submission) 31 3 812
Glyceryl Monostearate—Labeling, USP Reference standards 31 6 1669
(delete), Assay for monoglycerides
Hydroxyethyl Cellulose (new)—Harmonization 30 2 709
Hydroxypropyl Betadex (new) 32 5 1481
Low-Substituted Hydroxypropyl Cellulose— 30 1 338
Harmonization
Isomalt—Identification, Related compounds 32 4 1154
Anhydrous Lactose—Harmonization 32 6 1847
Magnesium Stearate—Harmonization 30 1 340
Nitrogen—Definition, Packaging and storage, Assay 31 4 1145
Nitrogen 97 Percent—Definition, Packaging and storage, Assay 31 4 1146
Oleic Acid—USP Reference standards (add), Identification (add) 32 6 1771
Oleyl Oleate (new) 31 6 1670
Palm Kernel Oil (new) 32 5 1486
Polacrilin Potassium—CAS number, Chemical name 31 6 1671
Polydextrose (new) 32 4 1155
Polyethylene Glycol—Harmonization 31 3 897
Polyethylene Oxide—Packaging and storage, USP Reference standards, 32 2 398
Identification, Heavy metals (delete), Heavy metals (add),
Limit of free ethylene oxide, Organic volatile impurities, Method I
(delete), Residual solvents (delete)
Polyisobutylene—Loss on drying 32 3 828
Polyoxyl 10 Oleyl Ether—Definition, Average polymer length 32 5 1488
Polyoxyl 35 Castor Oil—Viscosity 31 6 1671
Polyvinyl Acetate (new) 32 2 400
Fully Hydrogenated Rapeseed Oil (new) 32 6 1771
Superglycerinated Fully Hydrogenated Rapeseed Oil (new) 32 6 1773
Silicon Dioxide (new)—Harmonization 31 4 1229
Colloidal Silicon Dioxide (new)—Harmonization 31 4 1233
Tribasic Sodium Phosphate—Loss on ignition 32 2 402
Sodium Tartrate—Limit of oxalate (delete) 32 6 1776
Rice Starch (new)—Harmonization 30 2 721
Sucrose—Harmonization 31 3 902
Stearyl Alcohol—Assay 32 6 1777
Strawberry Syrup (new) 32 1 179
Succinic Acid—Identification 32 6 1777
Sugar Spheres—Particle size 32 6 1777
Tetrafluoroethane (new) 31 6 1672
Tributyl Citrate—Assay 32 1 179
Triethyl Citrate—Assay 32 1 180
In-Process Revision
Pharmacopeial Forum
Proposed Revisions and New Text Previously Presented in PF but Now Canceled
(Canceled proposals may be republished at any time in a future number of Pharmacopeial Forum.)
[PF 33(1)–PF 33(6)]
PF Volume, Issue, and Page Numbers of Canceled Proposals
USP Monographs
{Ensulizole—Assay 31 6 1617
{New cancellation in PF 33(1).
In-Process Revision
In-Process Revision
HARMONIZATION
This section contains monographs or chapters undergoing harmonization by the Pharmacopeial Discussion Group (PDG). The PDG
consists of the United States Pharmacopeia (USP), the European Pharmacopoeia (EP), and the Japanese Pharmacopoeia (JP). The
process of harmonization is composed of several steps (Stages).
Stage 1: Identification The PDG identifies items to be harmonized and designates a coordinating pharmacopeia for each item.
The PDG distributes the work by consensus among the three participating pharmacopeias. Harmonization may be carried out retro-
spectively for existing monographs or chapters, or prospectively for new monographs or chapters.
Stage 2: Investigation The investigation process conducted by the coordinating pharmacopeia results in the preparation of a
Stage 3 draft monograph or chapter accompanied by a report giving the rationale for the proposal and including validation data
where appropriate. This report is based on input that comes from users, authorities, producers, associations, literature, experts, and
staff.
Stage 3: Proposal The Stage 3 draft is reviewed and commented on by the other two pharmacopeias. The coordinating pharma-
copeia reviews those comments, prepares a harmonized Stage 4 draft, and sends it to the other two participating pharmacopeias.
Stage 4: Official Inquiry The Stage 4 draft is published in the Forum of each pharmacopeia. In PF, this stage appears as OFFI-
CIAL INQUIRY STAGE 4 in the Harmonization section. Each pharmacopeia analyzes the comments it receives and submits the
consolidated comments to the coordinating pharmacopeia, which then reviews those comments, prepares a harmonized Stage 5A
draft, and sends it to the other two participating pharmacopeias.
Stage 5: Consensus
A. Provisional
The Stage 5A draft is reviewed and commented on by the other two pharmacopeias. When consensus is reached, a
CONSENSUS STAGE 5B document is prepared by the coordinating pharmacopeia.
B. Final
The Stage 5B draft (consensus document) is sent by the coordinating pharmacopeia to the other two participating
pharmacopeias for final approval.
Stage 6: Adoption Each pharmacopeia incorporates the harmonized Stage 5B draft according to its own procedure. Adopted
items are published by the three pharmacopeias in their Supplements or, where applicable, in a new edition of their Pharmacopeias.
Stage 7: Date of Implementation The pharmacopeias inform each other of the date of implementation in the particular region.
Harmonization
Pharmacopeial Forum
140 HARMONIZATION Vol. 33(1) [Jan.–Feb. 2007]
HARMONIZATION ...................................................................... 139

Harmonization
Pharmacopeial Previews
PHARMACOPEIAL PREVIEWS
This section contains potential revisions not yet targeted for official adoption. These may include drafts for new monographs or
chapters; drafts for standards that would require new or unusual technology; drafts for which more data are required; or changes that
would affect numerous monographs, thus having a broad impact on individual products. Readers should review the drafts in this
section and provide comments to the appropriate staff liaison whose name is cited in the Briefing (use the Staff Directory to find the
contact information).
Briefings Each Preview is preceded by a Briefing in the following format:

BRIEFING
revision. Other relevant information. (For example, if a chromatographic method is being used, column specifica-
tions and retention times for compounds of interest.) Finally, the Committee designation (see How To Use PF), the
name of the scientific staff liaison who handled this item, and the USP tracking correspondence number, as shown
in the example below:
(DSN: L. Evans) RTS—55678-1
Symbols No symbols are used in this section, as Previews are not yet targeted for official adoption.
Pharmacopeial Forum
142 PHARMACOPEIAL PREVIEWS Vol. 33(1) [Jan.–Feb. 2007]
PHARMACOPEIAL PREVIEWS ........................................................... 141
STIMULI TO THE

REVISION PROCESS
This section may contain the following:
reports or statements of authoritative committees
original research reports
evaluations of new and existing pharmacopeial methods
commentaries
articles relevant to compendial issues
These items are published to stimulate discussion and continual review of Pharmacopeial standards. Generally, if an Expert Com-
mittee publishes an article on which they are specifically seeking comment, this will be clearly stated in the article. Readers may
submit comments on issues raised in this section, but comment is not as critical as that for the In-Process Revision and Pharma-
copeial Previews sections. Readers interested in submitting comments should see Instructions to Authors.
STIMULI TO THE REVISION PROCESS
Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum
144 of the USPC or the USP Council of Experts Vol. 33(1) [Jan.–Feb. 2007]
Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies
Vol. 33(1) [Jan.–Feb. 2007] of the USPC or the USP Council of Experts 145
Instructions to Authors
Contributions in the form of original research reports, evaluations of new and existing compendial methods, and other com-
mentaries and articles relevant to drug standards or to USP–NF revision will be considered for publication in the Pharmacopeial
Forum under the section Stimuli to the Revision Process. Manuscripts are received with the explicit understanding that they have
not been published previously and that they are not simultaneously under consideration by any other publication.

All manuscripts are subject to review by USP headquarters staff, Committee members, or qualified outside referees, and if
accepted for publication will be subject to editing by USP staff. Accepted manuscripts become the property of the USP Conven-
tion (USPC) and may not be published elsewhere without written permission from the USPC. Authors are also
responsible for obtaining permission for reprinting any illustrations that have been published elsewhere.
Abstract—Include an abstract of not more than 250 words stating the purpose and the results or conclusions of the article.
References—Consult a current copy of the Pharmacopeial Forum and the ACS Style Guide for assistance with reference style.
Copyright—Copyright transfer documents will be sent to authors after manuscripts have been accepted for publication.
Contact Person—When submitting a manuscript, designate one author of the article as correspondent and include that author’s
full address, telephone number, fax number, and e-mail address.
Submission Instructions—Manuscripts must be submitted both as an electronic file and as a printed copy of the electronic file.
Submit the text in Microsoft1 Word or another current word-processing application. The preferred format for graphics submitted
electronically is tagged image file format (TIFF). Graphics that cannot be submitted electronically must be camera-ready, of easily
reproducible quality and size, and clearly labeled. Photocopies are not acceptable. Manuscripts submitted for publication should
be addressed to:
Pharmacopeial Forum
Executive Secretariat, USP
12601 Twinbrook Pkwy.
Rockville, MD 20852
NOMENCLATURE
This section includes supplements to the latest edition of the USP Dictionary of USAN and International Drug Names that incor-
porate new United States Adopted Names (USAN) and revisions to existing Dictionary names. Also listed are Proposed and Rec-
ommended International Nonproprietary Names (INN) when they have been announced by the World Health Organization.
Possible names suggested for use as USAN and INN are listed for public review and comment along with information on how
nonproprietary names are devised. In addition, readers may find articles relevant to current compendial nomenclature issues that
also occasionally report on related matters pertaining to USAN and INN.
Nomenclature
Nomenclature
INDEX
This is a cumulative directory for the content of all issues of PF beginning with PF 33(1).
Index
Pharmacopeial Forum
150 INDEX Vol. 33(1) [Jan.–Feb. 2007]
[Note—This index covers Vol. 33 No. 1, pp. 1–150] GENERAL SUBJECTS
Canceled Revision Proposals . . . . . . . . . . . . . . . . . . . . . 137
MONOGRAPHS Catalog to be Removed from Pharmacopeial Forum Print
Alprazolam Tablets . . . . . . . . . . . . . . . . . . . . . . .... 41 Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Bismuth Subsalicylate Oral Suspension (USP) . . . . . . . .... 41 Errata List for USP 30–NF 25
Bupropion Hydrochloride Extended-Release Tablets (USP) ... 42 Ginkgo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Calcitriol (USP) . . . . . . . . . . . . . . . . . . . . . . . . .... 44 Magnesium Chloride . . . . . . . . . . . . . . . . . . . . . . . . 37
Citalopram Tablets (USP) . . . . . . . . . . . . . . . . . . . .... 46 Methdilazine Hydrochloride Oral Solution . . . . . . . . . . . 37
Cladribine (USP) . . . . . . . . . . . . . . . . . . . . . . . . .... 49 Pygeum Extract . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Clopidogrel Tablets (USP) . . . . . . . . . . . . . . . . . . .... 50 Ramipril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Cytarabine for Injection (USP) . . . . . . . . . . . . . . . . .... 51 Expert Committee Designations . . . . . . . . . . . . . . . . . . . 12
Dimethyl Sulfoxide Gel (USP) . . . . . . . . . . . . . . . . .... 52 Interim Revision Announcement . . . . . . . . . . . . . . . . . . . 31
Enoxaparin Sodium (USP) . . . . . . . . . . . . . . . . . . .... 52 Harmonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Enoxaparin Sodium Injection (USP) . . . . . . . . . . . . . .... 58 How to Submit Comments . . . . . . . . . . . . . . . . . . . . . . 20
Eprinomectin (USP) . . . . . . . . . . . . . . . . . . . . . . .... 60 How to Use PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Conjugated Estrogens Tablets (USP) . . . . . . . . . . . . .... 35 Implemenation Period for Official Revisions to USP–NF
Fluvastatin Sodium (USP) . . . . . . . . . . . . . . . . . . .... 64 Extended . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Fosinopril Sodium and Hydrochlorothiazide Tablets (USP) ... 66 In Memoriam: Joseph Robinson, Ph.D. . . . . . . . . . . . . . . . 18
Ginkgo (USP) . . . . . . . . . . . . . . . . . . . . . . . . . .... 37 International Correspondence . . . . . . . . . . . . . . . . . . . . . 20
Hydrocortisone Tablets (USP) . . . . . . . . . . . . . . . . .... 72 First Interim Revision . . . . . . . . . . . . . . . . . . . . . . . 31
Isosorbide Dinitrate Extended-Release Tablets (USP) . . . .... 73 Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Levalbuterol Hydrochloride (USP) . . . . . . . . . . . . . .... 75 Pharmacopeial Education Courses . . . . . . . . . . . . . . . . . . 19
Levalbuterol Inhalation Solution (USP) . . . . . . . . . . . .... 79 Pharmacopeial Forum Public Review and Comment Period
Magnesium Chloride (USP) . . . . . . . . . . . . . . . . . .... 37 Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Methdilazine Hydrochloride Oral Solution (USP) . . . . . .... 37 Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . . . 18
Norethindrone Acetate and Ethinyl Estradiol Tablets (USP) ... 81
Pamidronate Disodium for Injection (USP) . . . . . . . . . .... 81 Policies and Announcements
Phenylbutazone Boluses (USP) . . . . . . . . . . . . . . . .... 82 Catalog to be Removed from Pharmacopeial Forum Print
Phenylbutazone Tablets (USP) . . . . . . . . . . . . . . . . .... 82 Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
How to Submit Comments . . . . . . . . . . . . . . . . . . . . 20
Progesterone Vaginal Suppositories (USP) . . . . . . . . . .... 82
Implemenation Period for Official Revisions to USP–NF
Pygeum Extract (USP) . . . . . . . . . . . . . . . . . . . . .... 37
Ramipril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 37 Extended . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Salicylic Acid (USP) . . . . . . . . . . . . . . . . . . . . . .... 83 In Memoriam: Joseph Robinson, Ph.D. . . . . . . . . . . . . . 18
Ubidecarenone Capsules (USP) . . . . . . . . . . . . . . . .... 93 International Correspondence . . . . . . . . . . . . . . . . . . . 20
Ubidecarenone Tablets (USP) . . . . . . . . . . . . . . . . .... 94 Pharmacopeial Education Courses . . . . . . . . . . . . . . . . 19
Pharmacopeial Forum Public Review and Comment Period
Valganciclovir Hydrochloride (USP) . . . . . . . . . . . . .... 84
Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Valganciclovir Tablets (USP) . . . . . . . . . . . . . . . . . .... 89
Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . 18
GENERAL CHAPTERS Priority New Monograph Items . . . . . . . . . . . . . . . . . . 22
h11i USP Reference Standards (USP) . . . . . . . . ........ 95 Publication Schedules . . . . . . . . . . . . . . . . . . . . . . . 21
h1225i Validation of Compendial Procedures (USP) ....... 96 Stimuli Articles to be Posted on the USP’s Website . . . . . . 19
USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . 19
REAGENTS, INDICATORS, AND SOLUTIONS USP Forms Stakeholder Forum to Address the Food Chemicals
Codex; First Meeting Set for February 2007 . . . . . . . . . 18
2-Aminoheptane (USP) . . . . . . . . . . . . . . . . . . . . .. 100 USP Seeks Candidates for Three Expert Committees . . . . . 18
Index
Calconcarboxylic Acid (USP) . . . . . . . . . . . . . . . . . .. 100 Vice President of Pharmacopeial Education Named . . . . . . 18

Calconcarboxylic Acid Triturate (USP) . . . . . . . . . . . .. 100 Visit the USP Website at hhttp://www.usp.orgi . . . . . . . . . 20
Dimethicone, Viscosity 500 Centistokes (USP) . . . . . . . .. 100 Pending Proposals . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Previews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Lactose (USP) . . . . . . . . . . . . . . . . . . . . . . . . . .. 100
Priority New Monograph Items . . . . . . . . . . . . . . . . . . . 22
Propylamine Hydrochloride (USP) . . . . . . . . . . . . . . .. 101
Sodium Phosphate Dibasic Dihydrate (USP) . . . . . . . . .. 101 Publication Schedules . . . . . . . . . . . . . . . . . . . . . . . . . 21
Triethylamine (USP) . . . . . . . . . . . . . . . . . . . . . . .. 101 Section Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Volumetric Solutions Standards Development . . . . . . . . . . . . . . . . . . . . . . . . 5
Ceric Sulfate, Tenth-Normal (0.1 N) (USP) . . . . . . . .... 102
Potassium Permanganate, Tenth-Normal (0.1 N) (USP) .... 103
Instructions to Authors . . . . . . . . . . . . . . . . . . . . . . . 145
Chromatographic Reagents (USP) . . . . . . . . . . . . ..... 104 Stimuli Articles to be Posted on the USP’s Website . . . . . . . . 19
USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . . . 19
REFERENCE TABLES USP Forms Stakeholder Forum to Address the Food Chemicals
Description and Solubility (USP) .................. 110 Codex; First Meeting Set for February 2007 . . . . . . . . . . . 18
USP Seeks Candidates for Three Expert Committees . . . . . . . 18
Vice President of Pharmacopeial Education Named . . . . . . . . 18
Visit the USP Website at hhttp://www.usp.orgi . . . . . . . . . . . 20
Table of Contents*
PHARMACOPEIAL FORUM VOL. 33 NO. 2 MAR.–APR. 2007

HOW TO USE PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
USP to Establish Office and Laboratory Facility in China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
USP to Verify the Quality of Pharmaceutical Ingredients Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
USP Annual Scientific Meeting 2007 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Revision Bulletins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Extractable Volume, USP–NF General Chapter h1i, Injections: Notice of Harmonized Text . . . . . . . . . . . . . . . . . . . 168
Harmonized Microbiology General Chapters: Notice of Postponement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
USP Catalog Available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Stimuli Articles Posted on USP’s Website . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
2007 USP Dictionary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Visit the USP Web Site at http://www.usp.org . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Food Chemicals Codex Public Notice and Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Acetaminophen Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Bisoprolol Fumarate Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Bupropion Hydrochloride Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Diltiazem Hydrochloride Extended-Release Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Metformin Hydrochloride Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
GENERAL CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
h1i Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
h61i Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests . . . . . . . . . . . . . . . . . . . . . 189
h62i Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms . . . . . . . . . . . . . . . . 193
h788i Particulate Matter in Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
h1111i Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and
Substances for Pharmaceutical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Baclofen (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Bupropion Hydrochloride (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Bupropion Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Calcium Carbonate and Magnesia Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Calcium Carbonate and Magnesia Chewable Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Carbachol (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Carbachol Intraocular Solution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Carbachol Ophthalmic Solution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Citalopram Hydrobromide (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Diclofenac Sodium Extended-Release Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Enalapril Maleate and Hydrochlorothiazide Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Estradiol and Norethindrone Acetate Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Estradiol Transdermal System [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Estradiol Benzoate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Pharmacopeial Forum
152 Contents* Vol. 33(2) [Mar.–Apr. 2007]
Fludarabine Phosphate Injection [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

Flumazenil Injection (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Galantamine Hydrobomide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Heparin Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Ipratropium Bromide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Letrozole Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Meclizine Hydrochloride (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Meclizine Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Methylphenidate Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Octinoxate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Oxandrolone (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Paclitaxel (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Paricalcitol (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Sucralfate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Sulfadimethoxine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
DIETARY SUPPLEMENT–MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Lutein (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Lutein Preparation (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Excipients, USP and NF Excipients, Listed by Category (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Propylene Glycol Monocaprylate [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Trehalose [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
h11i USP Reference Standards (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
h503i Acetic Acid in Peptides [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
h1087i Intrinsic Dissolution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
a-Cyclodextrin [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Sodium Phosphate, Monobasic, Anhydrous [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Sodium Phosphate, Monobasic, Dihydrate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Tetrapropylammonium Chloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Chromatographic Reagents [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Container Specifications for Capsules and Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Description and Solubility (1st Supp to USP 31 and to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
PENDING PROPOSALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Propylene Glycol [new] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
A New Validated Differential Scanning Calorimetric Procedure for Monitoring the Less Active R,S Isomer of
Ethambutol Dihydrochloride in Bulk Drug Samples and Anti-tuberculosis Formulations, Bhagwat Prasad, Hemant
Bhutani, Vijay Kumar, and Saranjit Singh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
NOMENCLATURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] Contents* 153
Nancy Blum, M.P.H.
Director, Information Programs and pharmacy. It publishes the U.S. Pharmacopeia and National For-
Deborah G. Perfetto, Pharm.D. mulary, the legally recognized compendia of standards for drugs and
Director, Publications products of other health care technologies. The USP and NF include
Linda M. Guard assays and tests for the determination of strength, quality, and purity
Director, Scientific Reports and requirements for packaging and labeling.
Manager, Editorial Services This publication was paginated using Advent 3B2 Publishing Soft-
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Kate Meringolo
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Debbie Miller Printed in USA by Port City Press, Baltimore, Maryland
Senior Production Coordinators
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Senior Editors generated. Please send your new address, and your latest label, or an
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Pharmacopeial Forum
156 STANDARDS DEVELOPMENT Vol. 33(2) [Mar.–Apr. 2007]
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USP welcomes comments and data on potential, proposed, or official standards.* Comments, along with USP’s responses, will be
*
If you are not immediately able to submit comments but you intend to do so,
please notify USP by using the Intent to Comment form provided before the
section Chromatographic Reagents Used in USP–NF and PF.
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] STANDARDS DEVELOPMENT 157
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How to Use PF
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the beginning of that section. A general description of the types and amount of information expected in a Request for
Revision is available in the Guideline for Submitting Requests for Revision to the USP–NF on the USP website
(www.usp.org/USPNF/submitMonograph/subGuide.html).

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Manager
Biotechnology
Scientific Fellow,
Patient Safety
American Liaison
Scientific Fellow
Pharmacopeial Forum

Statistics (STAT)
How to Use PF

Senior Scientist
Catherine M. Sheehan, cxs@usp.org (301) 816-8262 Food Additives (FA)
Tom Sigambris, M.S. tzs@usp.org (301) 816-6789
Chapters (EGC)
Information (RI)
POLICIES AND
ANNOUNCEMENTS
processes and announcements about issues being considered by USP. This section also includes publication and comment sched-
ules.

Pharmacopeial Forum
168 POLICIES AND ANNOUNCEMENTS Vol. 33(2) [Mar.–Apr. 2007]
USP TO ESTABLISH OFFICE AND LABORATORY Manufacturers seeking USP Verification for a pharmaceutical
FACILITY IN CHINA. USP’s Board of Trustees has ingredient should contact Eric Sheinin, Vice President, Phar-
approved the establishment of a USP facility in China. The maceutical Ingredient Verification Program (es@usp.org or
USP-China facility will be the second international office 301-816-8103) for further information.
and laboratory facility established by USP. USP-India
Limited opened in February 2006. USP ANNUAL SCIENTIFIC MEETING 2007. Hold the
The establishment of the USP-China facility supports USP’s date! The USP Annual Scientific Meeting will be held in
international public health strategy and mission. The USP of- Tampa, Florida, at the Hyatt Regency Tampa on September
fice and laboratory facility in China will enable USP to work 25–28, 2007. Information is available on USP’s website at
with Chinese manufacturers, the Chinese Pharmacopoeia, and www.usp.org.
other constituencies to ensure the quality of medicines. Contact Ms. Kelly Coates (ktc@usp.org or 301-816-8510) for
The facility, located in Zhangjiang Hi-Tech Park in Shanghai, further information.
will support collaborative testing, technical assistance,
customer service, and training. John Hu, Ph.D., international REVISION BULLETINS. In accordance with Section 9.01
vice president-China, currently oversees the site and projects of the Rules and Procedures of the Council of Experts, a
hiring approximately 15 people to work in the facility. A Feb- Revision Bulletin is an official publication of the United
ruary 2007 opening date is planned. States Pharmacopeia and the National Formulary. Revision
Bulletins are posted on USP’s website and sent to affected
In addition to USP-India Limited (Hyderabad, India), USP has manufacturers via mail and e-mail, and are used to make
a European sales office (Basel, Switzerland). The USP-China revisions effective immediately when the need arises.
office and laboratory facility in Shanghai will further expand
USP’s capacity to reach those in the 130 countries around the EXTRACTABLE VOLUME, USP–NF GENERAL
world that rely upon USP standards. C H A P T E R h1 i, I N J E C T I O N S : N O T I C E O F
HARMONIZED TEXT.Effective November 14, 2006, re-
USP TO VERIFY THE QUALITY OF vised text on Extractable Volume has been approved by the
PHARMACEUTICAL INGREDIENTS WORLDWIDE. Parenteral Products—Industrial Expert Committee, Dr. Steven
USP has announced a new service to verify the quality of L. Nail, Chair. The changes to General Chapter h1i, Injections,
pharmaceutical ingredients. USP will offer this service to include verbatim harmonized text as proposed in the European
manufacturers of drug substances and excipients worldwide. and Japanese pharmacopoeias and reflect alignment with the
The verification service will identify those pharmaceutical June 2004 signed-off text of the Pharmacopoeial Discussion
ingredients that meet USP’s world class quality standards. Group (PDG). Questions should be directed to Dr. Desmond
Hunt, Scientific Liaison, PPI Expert Committee (dgh@usp.org
‘‘USP Verified’’ pharmaceutical ingredients will receive a Cer-
or 301-816-8341).
tificate of Standards Compliance and will be awarded the dis-
tinctive USP Verified Pharmaceutical Ingredients mark to HARMONIZED MICROBIOLOGY GENERAL
display on the shipping container. USP will award the certifi- CHAPTERS: NOTICE OF POSTPONEMENT. Effective
cate and mark to drug substances and excipients that pass a November 14, 2006, the implementation of the following har-
rigorous audit, testing, and review process, which includes: monized microbiological quality USP–NF General Chapters
Evaluation of an ingredient manufacturer’s quality sys- has been postponed until May 1, 2009:
tems through an audit for compliance with Good Manu- h61i Microbiological Examination of Nonsterile Prod-
facturing Practices (GMPs) ucts: Microbial Enumeration Tests
Review of manufacturing and quality control documents h62i Microbiological Examination of Nonsterile Prod-
for ingredients submitted for verification ucts: Tests for Specified Microorganisms
Laboratory testing of ingredient samples from USP- h1111i Microbiological Examination of Nonsterile Prod-
selected lots for compliance with USP’s FDA-enforceable ucts: Acceptance Criteria for Pharmaceutical Prepara-
standards for purity, potency, and quality tions and Substances for Pharmaceutical Use
Post-verification surveillance testing of ingredients bear- These USP–NF General Chapters were originally scheduled to
ing the USP Verified mark be effective on August 1, 2007. Implementation of the post-
This service will assure drug product manufacturers and reg- poned harmonized General Chapters prior to the May 2009
ulatory agencies that the substances with the USP Verified date is at the discretion of the user and may be subject to reg-
mark have met the highest standards in the world for strength, ulatory consideration.
quality, and purity. USP wants to raise the quality of medicines
by calling attention to the best ingredients. Drug product man-
ufacturers and patients worldwide will benefit as a result.
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] POLICIES AND ANNOUNCEMENTS 169
The currently official USP–NF General Chapters h61i Micro- PHARMACOPEIAL EDUCATION COURSES. The USP
bial Limit Tests and h1111i Microbiological Attributes of Non- Pharmacopeial Education (PE) courses offer specialized
sterile Pharmaceutical Products will remain effective until instruction for chemists, other scientists, and professionals in
May 1, 2009. the pharmaceutical and allied industries. USP scientists and
USP science experts, who play a key role in establishing
Questions should be directed to Dr. Radhakrishna Tirumalai, official USP standards, teach these courses and provide
Senior Scientist (rst@usp.org or 301-816-8339). expert insights into the practical applications of official test
procedures and best practices in using the USP–NF and
USP CATALOG AVAILABLE. While no longer included in
opportunity to learn how to get involved in USP’s
the back of this publication, the USP Catalog is still available
standards-setting processes and the benefits of participating
in online and stand-alone print versions. Online bi-monthly in standards development. Courses offered in 2007 are listed
and daily catalogs can be accessed at www.usp.org/ below. For more information and to register, visit
referenceStandards/catalog.html. You can also sign up to www.usp.org/goto/pe. To discuss how USP can bring
receive the USP Catalog in print (via postal mail) along with courses to a location of your choice or design a custom
monthly email alerts—which will keep you informed about course package for you, call 301-816-8589, or e-mail
new Reference Standards, availability, and current lots—by PharmacopeialEducation@usp.org.
sending an email to marketing@usp.org or calling 301-816-
Beginning in the 2007 calendar year, USP’s PE program will
8237.
be initiating a significant expansion. Both the depth and

breadth of course offerings will grow as the Pharmacopeial
STIMULI ARTICLES POSTED ON USP’S WEBSITE.
Education staff works to make the science behind the stan-
Starting in March 2007, the Stimuli articles that are dards more accessible. As this process begins, the PE program
published in Pharmacopeial Forum will be simultaneously
invites you to participate by suggesting titles, developing
published on USP’s website. Look for them at www.usp.org.
course objectives, or even joining the teaching staff.
For more information about Stimuli articles, please contact
Stefan Schuber, Ph.D., Director, Scientific Reports (301-
816-8551 or sps@usp.org).
Calendar of Forthcoming Pharmacopeial Education Courses

The Americas
6-Mar-07 Navigating Chapter h467i Residual Solvents (new) East Brunswick, NJ (half-day seminar) $245*
15-Mar-07 Essentials of USP Microbiological Testing (new) Raleigh, NC $595
20-Mar-07 Navigating Chapter h467i Residual Solvents (new) San Francisco, CA (half-day seminar) $245*
22-Mar-07 Navigating Chapter h467i Residual Solvents (new) Fullerton, CA (half-day seminar) $245*
27-Mar-07 Navigating Chapter h467i Residual Solvents (new) Montreal, Canada (half-day seminar) (1)
19-Apr-07 Navigating Chapter h467i Residual Solvents (new) Rockville, MD (USP Headquarters, $245
half-day seminar)
8–9 May-07 Fundamentals of Dissolution North Brunswick, NJ (with Distek, $1,500
2-day)
17-May-07 Analytical Method Validation (in Spanish) Mexico City, Mexico (2)
22-May-07 Analytical Method Validation Raleigh, NC $595
19-Jun-07 Effectively Using the USP–NF—Sessions I & II Raleigh, NC $595
Europe/Middle East/Africa/India
23-Apr-07 Navigating Chapter h467i Residual Solvents (new) Munich, Germany
24-Apr-07 Navigating Chapter h467i Residual Solvents (new) Berlin, Germany
26-Apr-07 Navigating Chapter h467i Residual Solvents (new) Liverpool, United Kingdom
27-Apr-07 Navigating Chapter h467i Residual Solvents (new) Brussels, Belgium
7–8 May 07 Fundamentals of Dissolution (2-day) (in English Milan, Italy
with assistance for Italian)
10–11 May 07 Fundamentals of Dissolution (2-day) (in English Rome, Italy
with assistance for Italian)
Pharmacopeial Forum
Calendar of Forthcoming Pharmacopeial Education Courses (Continued)

30-May-07 Analytical Method Validation Johannesburg, South Africa
31-May-07 Fundamentals of Dissolution (Lectures) Johannesburg, South Africa
11-Jun-07 Effectively Using the USP–NF—Sessions I and II (in Milan, Italy
English with assistance for Italian)
12-Jun-07 Analytical Method Validation (in English with assis- Rome, Italy
tance for Italian)
To receive further information on all courses in Europe/Middle East/Africa,contact USP, Münchensteinerstrasse 41, CH-4052 Basel, Swit-
zerland, +41 (0)61 316 3010, or AP@usp.org
* Two identical half-day seminars, morning and afternoon, will be offered. To register, send your contact information by e-mail to
PharmacopeialEducation@usp.org to receive a flyer/registration form by return e-mail. If space permits, registrations accepted later than 14
days before each seminar date will be $295.
(1) For registration information, contact custserv@acamchem.com (2) For registration information, contact ventas@proquifa.com.mx
2007 USP DICTIONARY. The new 2007 edition of the USP HOW TO SUBMIT COMMENTS. The USP welcomes and
Dictionary will publish in April. It features more than 3,700 encourages interested parties to submit comments and data
new and revised chemical formulas, over 1,000 new regarding potential, proposed, or adopted (official)
pronunciations, and hundreds of new USAN and INN standards. Submissions concerning a particular item that has
names. Available in print or online. USP is now accepting appeared in an issue of PF should be submitted to the
orders. Please contact Customer Service at 301-881-0666 or appropriate USP scientific staff liaison identified at the end
1-800-227-8772. You may also visit our Online Store at of the Briefing accompanying each item. To submit
http://www.usp.org/products/. comments and data to a liaison, use the e-mail address and
telephone number listed in the Staff Directory included in
VISIT THE USP WEBSITE AT http://www.usp.org. every PF.
Various resources related to Pharmacopeial standards are
presented, including highlights from PF. Please note that USP–NF is being published in an annual edi-
tion, with one three-volume primary publication and two Sup-
INTERNATIONAL CORRESPONDENCE. Individuals plements a year. In addition, the schedule provided below will
who wish to correspond with the European and Japanese repeat every year so that users will know what to expect and
pharmacopoeias concerning monographs in the Official will become familiar with the deadlines.
Inquiry and Consensus stages of international harmonization For general inquiries or in cases where a particular liaison is
should address their comments to the coordinating not identified, use the general USP telephone number 301-
pharmacopoeia, with a copy to USP, for a given article. The 881-0666 or fax number 301-816-8373.
addresses for the European and Japanese pharmacopeias are
as follows: PHARMACOPEIAL FORUM PUBLIC REVIEW AND
Technical Secretariat of the European COMMENT PERIOD DEADLINES.The full year’s
Pharmacopoeia Commission listing of comment period deadlines and the targeted official
B.P. 907
publications appears below. In accordance with the Rules
F 67029 Strasbourg Cedex 1
France and Procedures of the 2005–2010 Council of Experts, USP
has implemented a 90-day comment period by providing a
NAKASHIMA Nobumasa deadline for each issue of PF unless otherwise stated in the
Evaluation and Licensing Division individual Briefing. As previously stated, as a result of the
Pharmaceutical and Medical Safety Bureau
Ministry of Health, Labour and Welfare, Japan comment deadline extension, the ‘‘Intent to Comment’’ form
Tel. +81-3-3595-2431, Fax +81-3-3597-9535 will no longer be used and will be removed from PF. The
E-mail: nakashima-nobumasa@mhlw.go.jp listing of comment period deadlines and the targeted official
publications appears below.
Targeted Official
PF 33(1) April 16, 2007
Pharmacopeial Forum
Targeted Official
PF 34(1) April 15, 2008
in the upcoming Supplement. The official publication in which and official dates, and the book or Supplement that supersedes

USP 30–NF 25 Nov. 1, 2006* May 1, 2007* 1st Supplement
IRA [PF 33(1)] Jan. 1, 2007* Feb. 1, 2007* 2nd Supplement
USP 31–NF 26
USP 31–NF 26
USP 31–NF 26
* Tentative.
FOOD CHEMICALS CODEX. PUBLIC NOTICE AND PRIORITY NEW MONOGRAPH ITEMS. USP is seeking
COMMENT. USP aquired the Food Chemicals Codex monographs for the following drug substances and drug prod-
(FCC) in August, 2006 and intends to publish the Sixth Edi- ucts that are or soon will be off patent and thus are of the high-
tion in February, 2008. USP plans to create an FCC page on est priority. USP also is seeking monographs for the excipients
the USP website (www.usp.org/fcc), at which FCC users will listed below. Monographs are marked received upon receipt of
have the opportunity to provide public comment on proposed the monograph proposal. Received monographs are removed-
revisions of FCC content prior to publication. The FCC web- from this list upon publication in Pharmacopeial Forum. (This
site is expected to be available in June, 2007. list has been updated as of December 21, 2006.) For additional
FCC stakeholders and users are encouraged to assist USP in information, contact Karen A. Russo, Ph.D., kar@usp.org.
developing a "Priority List" of monographs needing revision Monograph sponsors should consult USP’s Guideline for Sub-
that will be posted to the FCC website after review by USP’s mitting Requests for Revision to the USP–NF (http://
Food Additives Expert Committee. Submit priority mono- www.usp.org/USPNF/submitMonograph/subGuide.html).
graphs to Catherine Sheehan, Director, Excipients and Food
Additives, Standards Division (cxs@usp.org).
Small Molecules (Drug Substances)
Acarbose Alatrofloxacin Mesylate Alfuzosin Hydrochloride
Allopurinol Sodium Aminopromazine Fumarate Aminopterin Sodium
Anagrelide Hydrochloride Arsenic Trioxide Auranfoin
Azelaic Acid Balsalazide Disodium Bentoquatam
Pharmacopeial Forum
Small Molecules (Drug Substances) (Continued)
Benzphetamine Hydrochloride Bepridil Hydrochloride Bivalirudin

Cabergoline Calcipotriene Calcium Trisodium Pentetate
(Received)
Calfactant Candesartan Cilexetil Carmustine
(Received)
Cefdinir Cefditoren Pivoxil Ceftibuten
(Received)
Ceftiofur Hydrochloride Cysteamine Bitartrate Cetrorelix
Colfosceril Cytarabine Liposome Dalfopristin
(Received)
Difloxacin Hydrochloride Diltiazem Malate Doxacurium Chloride
Entacapone Epoprostenol Sodium Erythromycin Phosphate
(Received)
Erythromycin Thiocyanate Esmolol Hydrochloride Esomeprazole Magnesium
(Received)
Estazolam Estradiol Benzoate Estramustine Phosphate Sodium

(Received)
Ethanolamine Oleate Etomidate Etoposide
(Received)
Gadobenate Dimeglumine Gadopentetic Acid Galantamine Hydrobromide
(Received)
Gallium Nitrate Ganirelix Glyceryl Aminobenzoate
Granisetron Hydrochloride Guanidine Hydrochloride Halobetasol Propionate
Haloperidol Decanoate Hydrocodone Polistirex Ibandronate Sodium
(Received)
Imipramine Pamoate Imiquimod Irinotecan
Isosulfan Blue Itraconazole Lamotrigine
Latanoprost Levetriacepam Levobetaxolol
Levomethadyl Acetate Lomustine Lopinavir
(Received)
(Received)
Mivacurium Chloride Moexipril Hydrochloride Nalbuphine Hydrochloride
Nalmefene Hydrochloride Nateglinide Nedocromil Sodium
(Received)
Nicardipine Hydrochloride Nilutamide Nisoldipine
Olopatadine Olsalazine Sodium Orbifloxacin
Orlistat Oxcarbazepine Oxiconazole Nitrate
Pantoprazole Sodium Pemirolast Potassium Pemoline
(Received)
Pentamidine Isethionate Piperonyl Butoxide Pirbuterol Acetate
(Received)
Poractant Alpha Porfimer Sodium Pramiprexole Dihydrochloride
Proguanil Hydrochloride Quetiapine Fumarate Ranitidine
Rivastigmine Tartrate Rose Bengal Rosiglitazone Maleate
Salmeterol Xinafoate Sertraline Hydrochloride Sirbutramine Hydrochloride
Sodium Phenylbutyrate Sodium Phosphates Spectinomycin Sulfate
Streptozocin Sulfacytine Tacrolimus
Pharmacopeial Forum
Tenofovir Disoproxil Fumarate Terbinafine Hydrochloride Terconazole

Tiludronate Disodium Tiopronin Trandolapril
Tranexamic Acid Tranylcypromine Sulfate Trimetrexate Glucuronate
(Received)
Trovafloxacin Mesylate Unoprostone Isopropyl Venlafaxine Hydrochloride
Voriconazole Zinc Tridosium Pentetate Zoledronic Acid
Small Molecules (Drug Products)

Abacavir Sulfate, Lamivudine, and Zido- Acarbose Tablets Acetaminophen, Butalbital, Caffeine, and Co-
vudine Tablets deine Phosphate Capsules
Albuterol for Inhalation Albuterol Inhalation Aerosol Alendronate Sodium Oral Solution
Alfuzosin Tablets Allopurinol for Injection Alprazolam Extended-Release Tablets
Alprostadil Urethral Suppository Aminopromazine Fumarate and Neomycin Aminopromazine Fumarate Injection
Sulfate Tablets

Aminopromazine Fumarate Tablets Aminopterin Sodium Tablets Amlodipine and Benazepril Hydrochloride
Capsules
Amphotericin B Injection Anagrelide Hydrochloride Capsules Arsenic Trioxide Injection
Atovaquone and Proguanil Hydrochloride Atovaquone Tablets Auranofin Capsules
Tablets
Azatadine Maleate and Pseudoephedrine Azelaic Acid Cream Azithromycin for Injection
Sulfate Extended-Release Tablets (Received)
Azithromycin Tablets Baclofen Injection Balsalazide Disodium Capsules
Beclomethasone Dipropionate Inhalation Beclomethasone Dipropionate Nasal Sus- Bentoquatam Topical Suspension
Aerosol pension
Benzocaine and Cetylpyridinium Chloride Benzocaine and Menthol Lotion Benzphetamine Hydrochloride Tablets
Lozenges
Bepridil Tablets Bicalutamide Tablets Bivalirudin Injection
Brompheniramine Maleate, Dextromethor- Budesonide Inhalation Aerosol Bupivacaine and Lidocaine Hydrochlorides
phan Hydrobromide, and Pseudoephedrine Injection
Buprenorphine Hydrochloride Injection Butalbital and Acetaminophen Capsules Butalbital and Acetaminophen Tablets
Calcipotriene Cream Calcipotriene Ointment Calcipotriene Topical Solution
Cabergoline Tablets Calcitriol Capsules Calcitriol Oral Solution
Calcium Acetate Capsules Calcium Trisodium Pentetate Injection Calfactant Intratracheal Suspension
Carbidopa and Levodopa Extended-Release Carbidopa and Levodopa Tablets for Oral Carbidopa, Levidopa, and Entacapone
Tablets Suspension Tablets
Carmustine for Injection Carmustine Implant Carvedilol Tablets
Cefdinir Tablets Cefditoren Pivoxil Tablets Ceftibuten Capsules
Ceftibuten for Oral Suspension Ceftiofur Hydrochloride Oral Suspension Cetirizine Hydrochloride Oral Solution
Cetirizine Hydrochloride Tablets Cetrorelix Injection Cevimeline Hydrochloride Capsules
(Received)
Chloroxine Cream Chlorpromazine Hydrochloride Extended- Choline and Magnesium Salicylates Oral So-
Release Capsules lution
Choline and Magnesium Salicylates Tablets Choline Salicylate Oral Solution Ciclopirox Shampoo
(Received)
Ciclopirox Topical Gel Ciclopirox Topical Solution Cilostazol Tablets
Cimetidine Oral Solution Ciprofloxacin Hydrochloride and Hydrocor- Ciprofloxacin Otic Solution
tisone Otic Suspension
Citalopram Hydrobromide Oral Solution Citric Acid, Gluconolactone, and Magne- Cladribine Injection
sium Carbonate Irrigation
Clemastine Fumarate Syrup Clobetasol Propionate Gel Clonazepam Orally Disintegrating Tablets
Clorazepate Dipotassium Capsules Clorazepate Dipotassium Extended-Release Clotrimazole and Betamethasone Dipropio-
Tablets nate Lotion
Colestipol Hydrochloride Tablets Colfosceril and Tyloxapol Suspension Compound Undecylenic Acid Cream
Pharmacopeial Forum
Small Molecules (Drug Products) (Continued)

Release Tablets
Difloxacin Hydrochloride Tablets Dihydroergotamine Mesylate Metered Diltiazem Malate Extended-Release Tablets
Spray
Dinoprostone Vaginal Suppositories Diphenhydramine Hydrochloride and Acet- Divalproex Sodium Delayed-Release Cap-
aminophen Tablets sules
Dorzolamide and Timolol Ophthalmic So- Dorzolamide Ophthalmic Solution Doxacurium Chloride Injection
lution
Doxepin Hydrochloride Cream Doxycycline Oral Gel Econazole Nitrate Cream
Edrophonium Chloride and Atropine Sul- Enalapril Maleate and Diltiazem Malate Enalapril Maleate and Felodipine Extended-
fate Injection Extended-Release Tablets Release Tablets
Enalaprilat Injection Entacapone Tablets Ephedrine Sulfate and Guaifenesin Tablets
(Received)
Epoprostenol for Injection Epoprostenol Injection Esmolol Hydrochloride Injection

Esomeprazole Magnesium Capsules Estazolam Tablets Estramustine Phosphate Sodium Capsules
Ethanolamine Oleate Injection Etidronate Disodium Injection Concentrate Etomidate Injection
Exemestane Tablets Famotidine Orally Disintegrating Tablets Felbamate Oral Suspension
Felbamate Tablets Fentanyl Lozenges Fentanyl Transdermal System
(Received)
Ferrous Fumarate and Docusate Sodium Flavoxate Hydrochloride Tablets Fluconazole Injection
Extended-Release Capsules (Received)
Fluconazole Tablets Flunisolide Inhalation Aerosol Flunisolide Nasal Spray
Fluocinolone Acetonide Shampoo Fluorescein Sodium Ophthalmic Solution Fluorometholone Ointment
Fluticasone Propionate Cream Fluticasone Propionate Inhalation Powder Fluticasone Propionate Ointment
Fluticasone Propionate Pressurized Inhaler Foscarnet Sodium Injection Fosfomycin for Oral Solution
Gabapentin Oral Solution Gadobenate Dimeglumine Injection Galantamine Tablets
(Received)
Gallium Nitrate Injection Ganciclovir Capsules Ganirelix Acetate Injection
Gatifloxacin Injection Gatifloxacin Tablets Gentamicin Sulfate Oral Solution
Gentamicin Sulfate Soluble Powder Glimepiride Tablets Glipizide Extended-Release Tablets
(Received)
Granisetron Injection Granisetron Tablets Guaifenesin and Salts of Dextromethorphan
(Received) (Received) and Pseudoephedrine Oral Solution
Guaifenesin and Pseudoephedrine Hydro- Guanidine Hydrochloride Tablets Halobetasol Propionate Cream
chloride Extended-Release Tablets
Halobetasol Propionate Ointment Haloperidol Decanoate Injection Haloperidol Lactate Injection
Haloperidol Lactate Oral Concentrate Hydralazine Hydrochloride and Hydro- Hydrochlorothiazide Capsules
chlorothiazide Capsules
Hydrochlorothiazide Oral Solution Concen- Hydrocodone Bitartrate and Acetaminophen Hydrocodone Bitartrate and Aspirin Tablets
trate Oral Solution
Hydrocodone Bitartrate and Guaifenesin Hydrocodone Bitartrate and Homatropine Hydrocodone Bitartrate and Homatropine
Oral Solution Methylbromide Syrup Methylbromide Tablets
Hydrocortisone Acetate Dental Paste Hydrocortisone Acetate Rectal Foam Aero- Hydrocortisone Butyrate Lotion
sol
Hydroflumethiazide and Reserpine Tablets Hydromorphone Hydrochloride Oral Solu- Hydroquinone Lotion
tion
(Received)
Ibandronate Sodium Tablets Ibuprofen Capsules Idarubicin Hydrochloride Injection
Imipramine Pamoate Capsules Imiquimod Topical Cream Ipratropium Bromide Inhalation Aerosol
Ipratropium Bromide Inhalation Solution Irinotecan Hydrochloride Injection Isosulfan Blue Injection
Isradipine Extended-Release Tablets Itraconazole Injection Itraconazole Oral Solution
Ketoconazole Cream Ketoconazole Shampoo Ketoprofen Capsules
(Received)
Ketoprofen Extended-Release Capsules Ketoprofen Tablets Ketotifen Fumarate Ophthalmic Solution
Pharmacopeial Forum

Lactic Acid Lotion Lamivudine Tablets Lamotrigine Tablets
(Received)
Latanoprost Ophthalmic Solution Leucovorin Calcium for Injection Levetriacepam Tablets
Levobetaxolol Ophthalmic Suspension Levocabastine Ophthalmic Suspension Levofloxacin Solution
Levomethadyl Acetate Hydrochloride Oral Lincomycin Hydrochloride and Spectino- Liothyronine Injection
Concentrate mycin Sulfate Soluble Powder
Lisinopril and Hydrochlorothiazide Tablets Lomustine Capsules Lopinavir and Ritonavir Solution
(Received)
Lopinavir Capsules Lopinavir Solution Loratadine Orally Disintegrating Tablets
Losartan Potassium Tablets Mefloquine Hydrochloride Tablets Melphalan for Injection
Mesalamine Suppositories Mesoridazine Besylate Concentrate Metaraminol Bitartrate Injection
Methacholine Chloride for Inhalation Solu- Methadone Hydrochloride Oral Concentrate Methocarbamol and Aspirin Tablets
tion
Methoxsalen Softgels Methyclothiazide and Deserpidine Tablets Methylphenidate Hydochloride Chewable
Tablets
Metipranolol Ophthalmic Solution Metronidazole Capsules Metronidazole Cream
Metronidazole Extended-Release Tablets Metronidazole Hydrochloride for Injection Metronidazole Lotion
Miconazole Nitrate Topical Aerosol Midazolam Injection Mifepristone Tablets

(Received)
Miglitol Tablets Milrinone Injection Misoprostol Tablets
(Received)
Mivacurium in Dextrose Injection Mivacurium Injection Moexipril Hydrochloride and Hydrochlor-
othiazide Tablets
Moexipril Hydrochloride Tablets Molindone Hydrochloride Oral Solution Morphine Sulfate for Injection Concentrate
Morphine Sulfate Oral Solution Morphine Sulfate Oral Solution Concentrate Morphine Sulfate Tablets
Mycophenolate Mofetil Capsules Mycophenolate Mofetil Oral Solution Mycophenolate Mofetil Tablets
Nalbuphine Hydrochloride Injection Nalmefene Hydrochloride Injection Naphazoline Hydrochloride and Pheniramine
Maleate Ophthalmic Solution
Naphazoline Hydrochloride and Phenira- Naproxen Extended-Release Tablets Nateglinide Tablets
mine Maleate Ophthalmic Solution
Nedocromil Sodium Inhalation Aerosol Neomycin Sulfate Oral Powder Nicardipine Hydrochloride Capsules
Nilutamide Tablets Nimodipine Capsules Nisoldipine Extended-Release Tablets
Nitroglycerin Extended-Release Transder- Nitroglycerin Transdermal System Nitroglycerin Solution in Acrylic Adhesive
mal Film
Nizatidine Tablets Ofloxacin in Dextrose Injection Ofloxacin Injection
(Received)
Orbifloxacin Tablets Orphenadrine Citrate Extended-Release Orphenadrine Citrate, Aspirin, and Caffeine
(Received) Tablets Tablets
(Received)
Oxcarbazepine Suspension Oxcarbazepine Tablets Oxiconazole Cream
Pantoprazole Sodium for Injection Pantoprazole Sodium Tablets Paroxetine Hydrochloride Extended-Release
Tablets
Paroxetine Oral Suspension Pemirolast Potassium Ophthalmic Solution Pemoline Tablets
Penicillin G Potassium Tablets for Oral So- Pentamidine Isethionate for Inhalation Pentamidine Isethionate Injection
lution (Received)
Pentazocine Hydrochloride and Acetamino- Phendimetrazine Tartrate Extended-Release Phenobarbital Capsules
phen Tablets Capsules
Phentermine Resin Complex Capsules Phenylephrine Hydrochloride and Chlor- Phenylephrine Hydrochloride, Chlorphenira-
pheniramine Maleate Extended-Release mine Maleate, and Acetaminophen Extended-
Capsules Release Tablets
Pilocarpine Hydrochloride Ophthalmic Gel Pilocarpine Hydrochloride Ophthalmic Pilocarpine Hydrochloride Tablets
Ointment
Piperonyl Butoxide and Pyrethrins Aerosol Pirbuterol Acetate Inhalation Aerosol Poractant Alpha Supension
Foam
Porfimer Sodium for Injection Povacrylate Solution Povacrylate-Iodine Topical Solution
Povidone-Iodine Gauze Povidone-Iodine Swabsticks Povidone-Iodine Topical Aerosol Foam
Povidone-Iodine Vaginal Suppositories Pramipexole Dihydrochloride Tablets Prednisolone Sodium Phosphate Oral Solu-
tion
Prochlorperazine Maleate Extended- Progesterone Capsules Promethazine and Phenylephrine Hydro-
Release Capsules chlorides and Codeine Phosphate Syrup
Promethazine and Phenylephrine Hydro- Promethazine Hydrochloride and Codeine Promethazine Hydrochloride and Dextro-
chlorides Syrup Phosphate Oral Solution methorphan Hydrobromide Syrup
Pharmacopeial Forum

Propafenone Hydrochloride Tablets Pseudoephedrine Hydrochloride and Brom- Pseudoephedrine Hydrochloride and Naprox-
pheniramine Maleate Extended-Release en Sodium Extended-Release Tablets
Tablets
Pseudoephedrine Hydrochloride, Chlor- Pseudoephedrine Hydrochloride, Guaifene- Pseudoephedrine Sulfate and Dexbromphe-
pheniramine Maleate, and Codeine Phos- sin, and Codeine Phosphate Oral Solution niramine Maleate Extended-Release Tablets
phate Oral Solution
Pseudoephedrine Sulfate and Dexbrom- Pseudoephedrine Sulfate, Dexbromphenira- Pyrilamine Maleate Injection
pheniramine Maleate Oral Solution mine Maleate, and Acetaminophen Quinidine Sulfate Injection
Ramipril Capsules Ranitidine Capsules Rauwolfia Serpentina and Endroflumethia-
zide Tablets
Reserpine and Polythiazide Tablets Rimantadine Hydrochloride Oral Solution Risperidone Oral Solution
Risperidone Orally Disintegrating Tablets Rivastigmine Tartrate Capsules Rivastigmine Tartrate Oral Solution
(Received)
Rocuronium Bromide Injection Ropinirole Hydrochloride Tablets Rose Bengal Ophthalmic Solution
Rosiglitazone Maleate Tablets Salicylic Acid and Sulfur Cleansing Lotion Salicylic Acid and Sulfur Lotion
Salicylic Acid and Sulfur Shampoo Salicylic Acid Cream Salicylic Acid Ointment
Salmeterol Inhalation Aerosol Salmeterol Xinafoate Inhalation Powder Scopolamine Transdermal System
Selegiline Hydrochloride Capsules Sertraline Hydrochloride Oral Solution Sibutramine Hydrochloride Capsules
Sodium Bicarbonate and Sodium Citrate for Sodium Bicarbonate, Sodium Citrate, and Sodium Iodide Injection
Oral Solution Sodium Tartrate for Oral Suspension
Sodium Phenylbutyrate Oral Powder Sodium Phenylbutyrate Tablets Sodium Phosphates for Oral Suspension
Sodium Phosphates Tablets Sodium Salicylate and Sulfur Shampoo Sterile Talc Aerosol
Streptozocin for Injection Sucralfate Oral Suspension Sulconazole Nitrate Cream
Sulfacetamide Sodium and Fluorometho- Sulfacetamide Sodium and Prednisolone Sulfacytine Tablets
lone Ophthalmic Suspension Sodium Phosphate Ophthalmic Solution
Sulfasalazine Oral Suspension Sulisobenzone Lotion Sumatriptan Injection
Sumatriptan Tablets Tacrolimus Capsules Tacrolimus Injection
Tacrolimus Ointment Tamsulosin Hydrochloride Capsules Technetium Tc 99M Teboroxime Injection
(Received)
Tenofovir Disoproxil Fumarate Tablets Terbinafine Hydrochloride Cream Terbinafine Tablets
(Received)
Terbinafine Topical Solution Terconazole Vaginal Cream Terconazole Vaginal Suppositories
Testosterone Transdermal System Tetracycline Hydrochloride Periodontal Fi- Theophylline Extended-Release Tablets
ber
Tioconazole Vaginal Ointment Tiopronin Tablets Tolnaftate Topical Aerosol Solution
Topiramate Capsules Topiramate Tablets Torsemide Injection
Torsemide Tablets Trandolapril and Verapamil Hydrochloride Trandolapril Tablets
Tranexamic Acid Injection Tranylcypromine Sulfate Tablets Tretinoin Capsules
Tretinoin Microsphere Gel Triamcinolone Acetonide Nasal Suspension Trifluridine Ophthalmic Solution
Trimetrexate for Injection Trimipramine Maleate Capsules Triprolidine and Pseudoephedrine Hydro-
Trolamine Salicylate Cream Trolamine Salicylate Gel Trolamine Salicylate Topical Emulsion
Trovafloxacin Injection Trovafloxacin Mesylate for Injection Undecylenic Acid Topical Foam Aerosol
Unoprostone Isopropyl Ophthalmic Solu- Urea Cream Vecuronium Bromide for Injection
tion
Venlafaxine Extended-Release Capsules Venlafaxine Tablets Verapamil Hydrochloride Capsules
(Received)
Verapamil Hydrochloride Extended- Voriconazole Injection Voriconazole Oral Suspension
Release Capsules
Voriconazole Tablets Yttrium Y-90 Chloride Solution Yttrium Y-90 Glass Microspheres
Yttrium Y-90 Microspheres Injection Zidovudine and Lamivudine Tablets Zinc Acetate Capsules
(Received)
Zinc Tridosium Pentetate Injection Ziprasidone Hydrochloride Capsules Zoledronic Acid for Injection
Excipients
Acrylic Acid-Octyl Acrylate Copolymer Albumin Colloidal Aliphatic Polyesters
Allantoin-Sodium Pyrrolidone Carboxylate Aluminum Ammonium Sulfate Aluminum Lactate
Pharmacopeial Forum
Butadiene-Styrene Rubber Butylated Hydromethylphenol Butylene Glycol
Calcium Glycerophosphate Calcium Phosphate Monobasic Calcium Propionate
(Received)
Calcium Pyrophosphate Calcium Sorbate Calcium Stearoyl Lactylate
Caldiamide Sodium Calteridol Calcium Canola Oil
Capric Acid Caprylic/Capric Diglyceryl Succinate Carbon
Carboxymethyl Starch Carboxymethylamylopectin Sodium Carboxymethylcellulose Potassium
Cetostearyl Isononanoate Chlorodifluoroethane Cholic Acid
Cinnamaldehyde Cocamide Diethanolamine Cocamide Oxide
Cocoyl Caprylocaprate Crystal Gum Cutina

Cystine Dammar Gum Decanoic Acid
Decyl Oleate Dehydroacetic Acid Desoxycholic Acid
(Received)
Dextrin Palmitate Dextrins Modified Diacetyl Tartaric Acid Esters of Mono- and
Diglycerides
Dicetyl Phosphate Dichlorofluoromethane Diethyl Sebacate
Difluoroethane Diglycol Stearate Diisobutyl Adipate
Diisopropyl Adipate Diisopropylbenzothiazyl-2-Sulfenamide Dilauryl Thiodipropionate
Dimethyl Dicarbonate Dimyristoyl Lecithin Dimyristoyl Phosphatidylglycerol
Dipropylene Glycol Disodium Edisylate Disodium Guanylate
Disodium Inosinate Disodium Monooleamide Sulfasuccinate D-Mannose
Docusate Sodium/Sodium Benzoate Erythorbic Acid Erythrosine
Ethoxylated Mono- and Diglycerides Ethoxyquin Ethyl Hexanediol
Ethyl Linoleate Ethyl Maltol Ethylene Dichloride
Ethylurea Ferric Ammonium Citrate Ferric Citrate
Ferric Oxide, Brown Ferric Phosphate Ferric Pyrophosphate
Ferrous Citrate Ferrous Glycinate Ferrous Lactate
Fluorochlorohydrocarbons Formic Acid Furcelleran
Gamma Cyclodextrin Gentistic Acid Geraniol
(Received)
Glutamic Acid Hydrochloride Gluten Glycerol Ester of Gum Rosin (Ester Gum)
Hydroxylated Lecithin Hydroxypropyl Beta Cyclodextrin Indigotine
Inositol Iron Carbonyl Iron Subcarbonate
(Received)
Isobutylated-Isoprene Copolymer Isooctylacrylate Isopropyl Isostearate
Isopropyl Stearate Isostearic Acid Isostearyl Alcohol
Lactobionic Acid Lactose Ferrin, Bovine Lactylated Fatty Acid Esters of Glycerol and
Propylene Glycol
Lactylic Esters of Fatty Acids Lanolin (Wool Fat), Hydrogenated Lanolin Alcohols, Acetylated
Lanolin Hydrous L-Ascorbyl Stearate Lauramine Oxide
Lauric Myristic Diethanolamide Lauric Acid Lauric Diethanolamide
Lavender Oil L-Cysteine Monohydrochloride Lecithin, Hydroxylated
L-Glutamic Acid Linoleic Acid L-Leucine
Macrogol Sorbitan Tristearate Macrogolglycerol Cocoates Macrogolglycerol Triisostearate
Magnesium Aluminum Silicate Hydrate Magnesium Aspartame Dihydrate Magnesium Aspartate
Magnesium Phosphate, Dibasic, Trihydrate Magnesium Phosphate Tribasic Magnesium Tartrate
Malt Syrup Maltitol Syrup Maltol Isobutyrate
Pharmacopeial Forum
Manganese Chloride Manganese Citrate Manganese Glycerophosphate
Manganese Hypophosphite Medical Antifoam Emulsion C Medronate Disodium
Medronic Acid Methyl Chloride Methylchloroisothiazolinone
Methylisothiazolinone Microcrystalline Cellulose, Silicified Mineral Spirits
(Received)
Monoisostearyl Glyceryl Ester Monopotassium Glutamate Monohydrate Monosodium Citrate
Mullein Leaf Myristyl Gamma-Picolinium Chloride Myristyl Lactate
N,N-Bis(2-Hydroxyethyl)Stearamide N-Acetyl-L-Methionine Naphtha
N-Methylpyrrolidone Non-Pareil Seeds Nutmeg Oil
(Received)
Octanoic Acid Oxystearin Palm Oil
Pentasodium Triphosphate Pentetate Calcium Trisodium Pentetate Pentasodium
Phenprobamate Phenylmercuric Acetate Phenylmercuric Nitrate
Pine Oil Polacrilin Polydextrose Solution
Polyglycerol Esters of Fatty Acids Polyglycerol Polyricinoleic Acid Polyoxyethylene Castor Oil (USP Has 35)
Polyoxyl Stearate (USP Has 40) Polypropylene Oleate Polypropylene Stearyl Ether
Polysorbate 65 Polyvinylacetal Polyvinylacetal Diethylanoacetate
Polyvinylpolypyrrolidone Polyvinylpyrrolidone Ethylcellulose Potassium Acid Tartrate
Potassium Bromate Potassium Carbonate Solution Potassium Dichloroisocyanurate

Potassium Gibberellate Potassium Glycerophospate Potassium Iodate
Potassium Nitrite Potassium Phosphate Potassium Phosphate Tribasic
Potassium Polymetaphosphate Potassium Pyrophosphate Potassium Stearate
Potassium Sulfate Potassium Sulfite Potassium Tripolyphosphate
Propyl Propionate Propylene Glycol Diacetate Propylene Glycol Mono- and Diesters
Purified Polyoxyl 35 Castor Oil Rice Bran Wax Rosin
(Received)
Silicone Sodium Acid Pyrophosphate Sodium Aluminosilicate
Sodium Aluminum Phosphate Acidic Sodium Aluminum Phosphate Basic Sodium Aspartate
Sodium Bisulfate Sodium Bisulfite Sodium Carbonate Hydrate
Sodium Carboxymethyl Betaglucan Sodium Caseinate Sodium Chlorate
Sodium Citrate, Dibasic Sodium Citrate, Monobasic Sodium Dehydroacetate
Sodium Diacetate Sodium Erythorbate Sodium Ferric Pyrophosphate
Sodium Ferrocyanide Sodium Hypophosphite Sodium Laureth Sulfate
Sodium Lauroyl Sarcosinate Sodium Lauryl Sulfoacetate Sodium Magnesium Aluminosilicate
Sodium Magnesium Silicate Sodium Malate Sodium Metaphosphate, Insoluble
Sodium Metasilicate Sodium Methylate Sodium Polyphosphates Glassy
Sodium Potassium Tripolyphosphate Sodium Pyrophosphate Sodium Pyrrolidone Carboxylate
Sodium Sesquicarbonate Sodium Sesquinoleate Sodium Stearoyl Lactylate
Sodium Thiomalate Sodium Trimetaphosphate Sodium Trioleate
Sodium Tripolyphosphate Soy Polysaccharides Stannous Chloride
Stannous Tartrate Starch, Pregelatinized Corn Starch, Pregelatinized Tapioca
Stearalkonium Chloride Stearyl Citrate Stearyl Monoglyceridyl Citrate
Succinylated Monoglycerides Sucrose Acetate Isobutyrate Sucrose Fatty Acid Esters
Sucrose Stearate Sugar Fruit Fine Sulfobutyl Ether Beta Cyclodextran
Tallow Tallow Glycerides Tallow Oil
Tetrafluoroethane Thioglycerol Thyme Oil
Tribehenin Triceteareth-4 Phosphate Trichloroethylene
Trimyristin Trisodium Citrate Trolamine Lauryl Sulfate
Vegetable Oil Wheat Flour Wheat Germ Oil
Wheat Gluten Whey
(Received)
INTERIM REVISION
ANNOUNCEMENT
next page.)

Pharmacopeial Forum
180 INTERIM REVISION ANNOUNCEMENT Vol. 33(2) [Mar.–Apr. 2007]
INTERIM REVISION ANNOUNCEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Acetaminophen Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Bisoprolol Fumarate Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Bupropion Hydrochloride Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Diltiazem Hydrochloride Extended-Release Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Metformin Hydrochloride Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
h1i Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
h61i Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests . . . . . . . . . . . . . . . . . . . 189
h62i Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms . . . . . . . . . . . . . . 193
h788i Particulate Matter in Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
h1111i Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and
Substances for Pharmaceutical Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] INTERIM REVISION ANNOUNCEMENT 181
INTERIM REVISION
ANNOUNCEMENT


Official April 1, 2007 Released March 1, 2007

Pharmacopeial Forum
New USP Reference Standards USP Amifostine RS

USP Amifostine Thiol RS
The following USP Reference Standards, which were not USP Antithrombin III Human RS
USP Aprotinin RS
available when the associated monograph was made official, USP Aprotinin System Suitability RS
have since become available. The respective official date of USP Cetrimonium Bromide RS
each USP 29 or NF 24 standard, test, or assay requiring the USP Cladribine Related Compound A RS
USP Copolymer Polypropylene RS
use of the following USP Reference Standards is indicated USP Decoquinate RS
in parentheses after the name of the Reference Standard. USP Cryopreserved Human Fibroblast-Derived Dermal Substitute
Reference Photomicrographs RS
USP Cladribine RS (August 1, 2007) USP Diethylstilbestrol Diphosphate RS
USP Citalopram Hydrobromide RS (May 1, 2007) USP Docosyl Ferulate RS
USP Fluvastatin Sodium RS (March 1, 2007) USP Powdered Echinacea pallida Extract RS
USP Gabapentin Related Compound B RS (June 1, 2007) USP Eucatropine Hydrochloride RS
USP Glyceryl Monooleate RS (August 1, 2007) USP Fluvastatin Related Compound A RS
USP Hexacosanol RS (March 1, 2007) USP Ginkgo Terpene Lactones RS
USP Irbesartan RS (August 1, 2007) USP Powdered American Ginseng Extract RS
USP Mecamylamine Related Compound A RS (March 1, 2007) USP Glyceryl Monolinoleate RS
USP Naratriptan Resolution Mixture RS (May 1, 2007) USP Gonadorelin Hydrochloride RS
USP Nimodipine RS (June 1, 2007) USP Hemoglobin RS
USP Nimodipine Related Compound A RS (June 1, 2007) USP Irbesartan Related Compound A RS
USP Cultured Rat Pheochromocytoma Reference Photomicrographs USP Isosorbide Mononitrate RS
RS (May 1, 2007) USP Isosorbide Mononitrate Related Compound A RS
USP Polyoxyl 10 Oleyl Ether RS (August 1, 2007) USP Alpha Lipoic Acid RS
USP Ramipril Related Compound B RS (May 1, 2007) USP Maritime Pine Extract RS
USP Saccharin Sodium RS (March 1, 2007) USP Menotropins RS
USP Tizanidine Hydrochloride RS (August 1, 2007) USP Methyldopa-Glucose Reaction Product RS
USP Tizanidine Related Compound A RS (June 1, 2007) USP Mibolerone RS
USP Tizanidine Related Compound B RS (June 1, 2007) USP Narasin RS
USP Tizanidine Related Compound C RS (June 1, 2007) USP Near-Infrared Calibrator RS
USP Potassium Perchlorate RS
USP Pyrethrum Extract RS
Unavailable First-Time Official USP USP Quinapril Hydrochloride RS
USP Powdered St John’s Wort Extract RS
USP Sincalide RS
availability of the respective Reference Standards. This listing USP Valrubicin RS
was updated as of December 20, 2006. USP Valrubicin Related Compound A RS
USP Vasopressin RS
USP Albumin Human RS
USP Alteplase RS
Pharmacopeial Forum
MONOGRAPHS (USP) Tolerances—The percentage of the labeled amount of C8H9NO2

Time Amount dissolved
30 minutes between 40% and 60%
Acetaminophen Extended-Release 4 hours not less than 80%
Tablets
TEST 2—If the product complies with this test, the labeling
Medium, Apparatus, and Procedure—Proceed as directed for Test
Change to read: 1.
Tolerances—The percentages of the labeled amount of C8H9NO2
Labeling—Where the Tablets are gelatin-coated, the label so states. dissolved at the times specified conform to Acceptance Table 2.
.When more than one Dissolution test is given, the labeling states
Time Amount dissolved
the Dissolution test used only if Test 1 is not used..2
1 hour between 55% and 75%
Delete the following: 3 hours not less than 80%
.Drug release h724i— .2
Medium: simulated gastric fluid TS (without enzyme); 900 mL.
Times: 15 minutes, 1 hour, and 3 hours.
Procedure—Determine the amount of C8H9NO2 dissolved from Bisoprolol Fumarate Tablets
UV absorbances at 243 nm, using a filtered portion of the solution
under test in comparison with a Standard solution having a known
concentration of USP Acetaminophen RS in the same Medium.
Tolerances—The percentages of the labeled amount of C8H9NO2
dissolved at the times specified conform to Acceptance Table 1. Add the following:
Time Amount dissolved .Labeling—When more than one Dissolution test is given, the
15 minutes between 45% and 65% labeling states the Dissolution test used only if Test 1 is not used..2
1 hour between 60% and 85%
3 hours not less than 85%
Change to read:

FOR GELATIN-COATED TABLETS— Dissolution h711i—
Medium, Apparatus, and Procedure—Proceed as directed above. .TEST 1—
.2
Times: 30 minutes, 90 minutes, and 4 hours. Medium: water; 900 mL.
Tolerances—The percentage of the labeled amount of C8H9NO2 Apparatus 2: 75 rpm.
dissolved at the times specified conform to Acceptance Table 2. Time: 20 minutes.
Determine the amount of (C18H31NO4)2 C4H4O4 dissolved by
Time Amount dissolved employing the following method.
30 minutes between 40% and 60% Diluent—Prepare a mixture of methanol, water, triethylamine, and
90 minutes between 55% and 85% phosphoric acid (160 : 35 : 5 : 2.5).
4 hours not less than 80% Mobile phase—Mix 20 mL of triethylamine with 1000 mL of
water and 680 mL of methanol, adjust with phosphoric acid to a pH
.2 of 4.0 + 0.1, and mix.
Standard stock solution—Quantitatively dissolve an accurately
Add the following: weighed quantity of USP Bisoprolol Fumarate RS in water to obtain
a solution having a known concentration of about twice the
.Dissolution concentration of bisoprolol fumarate in the Test solution.
h711i— Standard solution—Dilute an accurately measured volume of
TEST 1— Standard stock solution with an equal accurately measured volume
Medium: simulated gastric fluid TS (without enzyme); 900 mL. of Diluent.
Apparatus 2: 50 rpm. Test solution—Withdraw a portion of the solution under test, filter,
Times: 15 minutes, 1 hour, and 3 hours. dilute with an equal volume of Diluent, and mix.
Procedure—Determine the amount of C8H9NO2 dissolved from Chromatographic system (see Chromatography h621i)—The
UV absorbances at 280 nm, using a filtered portion of the solution liquid chromatograph is equipped with a 227-nm detector and
under test in comparison with a Standard solution having a known .
a 4.6-mm 6 33-cm.2 column that contains packing L7. The flow
concentration of USP Acetaminophen RS in the same Medium. rate is about 1 mL per minute. Chromatograph the Standard solution,
Tolerances—The percentages of the labeled amount of C8H9NO2 and record the peak responses as directed for Procedure: the relative
dissolved at the times specified conform to Acceptance Table 2. standard deviation for replicate injections is not more than 2.0%.
Time Amount dissolved Standard solution and the Test solution into the chromatograph,
15 minutes between 45% and 65% record the chromatograms, and measure the peak areas for
1 hour between 60% and 85% bisoprolol. Calculate the quantity, in mg, of bisoprolol fumarate
3 hours not less than 85% [(C18H31NO4)2 C4H4O4] dissolved.
(C18H31NO4)2 C4H4O4 is dissolved in 20 minutes.
FOR GELATIN-COATED TABLETS— .TEST 2—If the product complies with this test, the labeling
Medium, Apparatus, and Procedure—Proceed as directed above. indicates that it meets USP Dissolution Test 2.
Times: 30 minutes, 90 minutes, and 4 hours. Medium: 0.5 M sodium chloride; 900 mL.
Pharmacopeial Forum
Apparatus 2: 75 rpm. Tolerances—The percentages of the labeled amount of

Time: 20 minutes. C13H18ClNO HCl dissolved at the times specified conform to
Determine the amount of (C18H31NO4)2 C4H4O4 dissolved by Acceptance Table 2.
employing the chromatographic method described in Test 1.
Tolerances—Not less than 80% (Q) of the labeled amount of Time (hours) Amount dissolved
(C18H31NO4)2 C4H4O4 is dissolved in 20 minutes..2 1 between 25% and 50%
6 not less than 80%
Bupropion Hydrochloride Extended- indicates that it meets USP Dissolution Test 3.
Release Tablets Medium, Apparatus, and Procedure—Proceed as directed for Test
1, except using the wavelength of about 250 nm.
Times: 1, 2, 4, and 6 hours.
Change to read: Acceptance Table 2.
Dissolution h711i— Time (hours) Amount dissolved

TEST 1— 1 between 30% and 55%
Medium: water; 900 mL. 2 between 50% and 75%
Apparatus 2: 50 rpm. 4 between 70% and 90%
Times: 1, 4, and 8 hours. 6 not less than 80%
Procedure—Determine the amount of C13H18ClNO HCl dissolved
absorbance at about 298 nm, using a 1.0-cm cell, on filtered portions .TEST 5—If the product complies with this test, the labeling
of the solution under test, suitably diluted with Medium, if necessary, indicates that it meets USP Dissolution Test 5.
in comparison with a Standard solution having a known concentra- Medium and Procedure—Proceed as directed for Test 1.
tion of USP Bupropion Hydrochloride RS in the same Medium. Apparatus—Proceed as directed for Test 1, except to use a 0.5-cm
Tolerances—The percentages of the labeled amount of cell.
C13H18ClNO HCl dissolved at the times specified conform to Times: 1, 3, and 6 hours.
Acceptance Table 2. Tolerances—The percentages of the labeled amount of
Time (hours) Amount dissolved Acceptance Table 2.

4 between 60% and 85% Time (hours) Amount dissolved
8 not less than 80% 1 between 35% and 55%
6 not less than 80%
indicates that it meets USP Dissolution Test 2. .2
Medium: 0.1 N hydrochloric acid, pH 1.5; 900 mL.
Determine the percentages of the labeled amount of
C13H18ClNO HCl dissolved by employing the following method.
Buffer solution—Dissolve 3.45 g of sodium phosphate monobasic
monohydrate in 996 mL of water, add 4.0 mL of triethylamine, and Diltiazem Hydrochloride Extended-
mix. Adjust with phosphoric acid to a pH of 2.80 + 0.05. Release Capsules
Mobile phase—Prepare a filtered and degassed mixture of Buffer
solution and methanol (65 : 35). Make adjustments if necessary (see
System Suitability under Chromatography h621i).
USP Bupropion Hydrochloride RS in Medium, and dilute quantita- Change to read:
tively, and stepwise if necessary, with Medium to obtain a solution
having a known concentration similar to the one expected in the Test Dissolution h711i—
solution.
through a 0.45-mm nylon filter.
Chromatographic system (see Chromatography h621i)—The indicates that it meets USP Dissolution Test 1. Proceed as directed
liquid chromatograph is equipped with a 298-nm detector and for Extended-Release Dosage Forms.
a 4.6-mm 6 15-cm column that contains packing L1. The flow rate Medium: water; 900 mL.
is about 1.0 mL per minute. Chromatograph the Standard solution, Apparatus 2: 100 rpm.
and record the peak responses as directed for Procedure: the column Times: 3, 9, and 12 hours.
efficiency is not less than 2000 theoretical plates; the tailing factor is Procedure—Determine the amount of C22H26N2O4S HCl dis-
not more than 2.0; and the relative standard deviation for replicate solved by employing UV absorption at the wavelength of maximum
injections is not more than 2.0%. absorbance at about 237 nm on filtered portions of the solution under
Procedure—Separately inject equal volumes (about 20 mL) of the test, suitably diluted with Medium, if necessary, in comparison with
Standard solution and the Test solution into the chromatograph, a Standard solution having a known concentration of USP Diltiazem
record the chromatograms, and measure the peak responses. Hydrochloride RS in the same Medium.
Calculate the percentage of bupropion hydrochloride dissolved at
each time point.
Pharmacopeial Forum

C22H26N2O4S HCl dissolved at the times specified conform to the Time (hours) Amount dissolved
Acceptance Table given.
8 not less than 80%
3 between 10% and 25% TEST 10—If the product complies with this test, the labeling
9 between 45% and 85% indicates that it meets USP Dissolution Test 10.
12 not less than 70% Medium: 0.05 M phosphate buffer, pH 6.5; 900 mL. Prepare the
buffer employing the following method. Dissolve 7.1 g of anhydrous
dibasic sodium phosphate in 1000 mL of water, and adjust with
phosphoric acid to a pH of 6.5.
Acceptance Table Apparatus 1: 100 rpm.
Procedure—Proceed as directed under Test 1.
Number Times: 1, 6, 9, and 24 hours.
Level Tested Criteria Tolerances—The percentages of the labeled amount of
L1 6 No individual value lies outside each of the C22H26N2O4S HCl dissolved at the times specified conform to
stated ranges, and no individual value is less Acceptance Table 2.
than the stated amount at the final test time.
L2 6 The average value of the 12 units (L1 + L2) Time (hours) Amount dissolved
lies within each of the stated ranges and is 1 not more than 10%
not less than the stated amount at the final 6 between 10% and 30%
test time. At 3 hours none of the units is 9 between 34% and 60%
outside the range of 10% to 35% of labeled 24 not less than 80%
content; at 9 hours none of the units is
outside the range of 45% to 95% of labeled
content; and at 12 hours none of the units is FOR PRODUCTS LABELED FOR DOSING EVERY 24 HOURS—
less than 65% of labeled content at the final TEST 2—If the product complies with this test, the labeling
test time. indicates that it meets USP Dissolution Test 2.
L3 12 The average value of the 24 units (L1 + L2 + Medium, Apparatus, and Procedure—Proceed as directed under
L3) lies within each of the stated ranges and Test 1.
is not less than the stated amount at the final Times: 1, 4, 10, and 15 hours.
test time. At 3 hours not more than 2 of the Tolerances—The percentages of the labeled amount of
24 units are outside the range of 10% to 35% C22H26N2O4S HCl dissolved at the times specified conform to
of labeled content, and these two units must Acceptance Table 2.
be within the range of 5% to 45% of labeled
content; at 9 hours not more than 2 of the 24 Time (hours) Amount dissolved
units are outside the range of 45% to 95% of

labeled content, and these two units must be
within the range of 35% to 100% of labeled 4 between 30% and 50%
content; at 12 hours not more than 2 of the 10 between 70% and 90%
24 units are less than 65% of labeled content 15 not less than 80%
at the final test time, and these two units
cannot be less than 60% of labeled content at
the final test time.
Medium: 0.1 N hydrochloric acid; 900 mL.
indicates that it meets USP Dissolution Test 4. Times: 6, 12, 18, 24, and 30 hours.
Medium, Apparatus, and Procedure—Proceed as directed under Procedure—Determine the amount of C22H26N2O4S HCl dis-
Test 1. solved by employing UV absorption at the wavelength of maximum
Times: 4, 8, 12, and 24 hours. absorbance at about 237 nm on filtered portions of the solution under
Tolerances—The percentages of the labeled amount of test, suitably diluted with Medium, if necessary, in comparison with
C22H26N2O4S HCl dissolved at the times specified conform to a Standard solution having a known concentration of USP Diltiazem
Acceptance Table 2. Hydrochloride RS in the same Medium.
Time (hours) Amount dissolved C22H26N2O4S HCl dissolved at the times specified conform to
Acceptance Table 2.
8 between 35% and 60% Time (hours) Amount dissolved
24 not less than 80% 6 between 20% and 45%
indicates that it meets USP Dissolution Test 5. 30 not less than 85%
Medium: 0.05 M phosphate buffer, pH 7.2; 900 mL.
Procedure—Proceed as directed under Test 1.
Times: 1, 3, and 8 hours. indicates that it meets USP Dissolution Test 6.
Tolerances—The percentages of the labeled amount of Medium and Procedure—Proceed as directed under Test 1.
C22H26N2O4S HCl dissolved at the times specified conform to Apparatus 1: 100 rpm.
Acceptance Table 2. Times: 2, 4, 8, 12, and 16 hours.

1 not more than 15%
Pharmacopeial Forum
Tolerances—The percentages of the labeled amount of Tolerances—The percentages of the labeled amount of
C22H26N2O4S HCl dissolved at the times specified conform to C22H26N2O4S HCl dissolved at the times specified conform to
Acceptance Table 2. Acceptance Table 2.
Time (hours) Amount dissolved Time Amount dissolved Amount dissolved
2 not more than 25% (hours) (Medium 1) (Medium 2)
4 between 25% and 50% 2 between 0% and 5% between 20% and 45%
TEST 7—If the product complies with this test, the labeling TEST 11—If the product complies with this test, the labeling
indicates that it meets USP Dissolution Test 7. indicates that it meets USP Dissolution Test 11.
Medium: pH 4.2 acetate buffer; 900 mL. Prepare the buffer by Medium, Apparatus, and Procedure—Proceed as directed under
employing the following method. Transfer 115 mL of acetic acid to Test 3.
a 10-L volumetric flask, dilute with water to volume, and mix Times: 1, 6, 12, and 18 hours.
(Solution A). Transfer 165.4 g of anhydrous sodium acetate to a 10-L Tolerances—The percentages of the labeled amount of
volumetric flask, dilute with water to volume, and mix (Solution B). C22H26N2O4S HCl dissolved at the times specified conform to
Mix 4410 mL of Solution A with 1590 mL of Solution B. Adjust, if Acceptance Table 2.
necessary, with the addition of Solution A or Solution B to a pH of
4.2 + 0.05. Time (hours) Amount dissolved
Apparatus 2: 100 rpm. 1 not more than 10%
Times: 1, 4, 10, and 15 hours. 6 between 30% and 40%
Procedure—Determine the amount of C22H26N2O4S HCl dis- 12 between 36% and 58%
solved by employing UV absorption at the wavelength of maximum 18 not less than 85%
absorbance at about 237 nm on filtered portions of the solution under
test, suitably diluted with Medium, if necessary, in comparison with
a Standard solution having a known concentration of USP Diltiazem TEST 12—If the product complies with this test, the labeling
Hydrochloride RS in the same Medium. indicates that it meets USP Dissolution Test 12. Proceed as directed
Tolerances—The percentages of the labeled amount of for Extended-Release Dosage Forms.
C22H26N2O4S HCl dissolved at the times specified conform to Medium and Procedure—Proceed as directed under Test 1.
Acceptance Table 2. Apparatus 1: 100 rpm.
Time (hours) Amount dissolved Tolerances—The percentages of the labeled amount of
1 not more than 10% C22H26N2O4S HCl dissolved at the times specified conform to
4 between 15% and 35% Acceptance Table 2.

15 not less than 80% Time (hours) Amount dissolved
2 not more than 20%
TEST 8—If the product complies with this test, the labeling 14 not less than 65%
indicates that it meets USP Dissolution Test 8. 24 not less than 80%
Medium, Apparatus, and Procedure—Proceed as directed under
Test 1.
Times: 1, 4, 10, and 15 hours. TEST 13—If the product complies with this test, the labeling
Tolerances—The percentages of the labeled amount of indicates that it meets USP Dissolution Test 13. Proceed as directed
C22H26N2O4S HCl dissolved at the times specified conform to for Extended-Release Dosage Forms.
Acceptance Table 2. Medium and Procedure—Proceed as directed under Test 1.
Time (hours) Amount dissolved Times: 2, 8, 14, and 24 hours.
1 between 5% and 20% Tolerances—The percentages of the labeled amount of
4 between 30% and 50% C22H26N2O4S HCl dissolved at the times specified conform to
10 between 60% and 90% Acceptance Table 2.
2 not more than 20%
TEST 9—If the product complies with this test, the labeling 8 between 30% and 55%
indicates that it meets USP Dissolution Test 9. 14 between 60% and 80%
NOTE—Perform the test separately in each of the two media. 24 not less than 80%
Medium 1: 0.1 N hydrochloric acid; 900 mL.
Medium 2: simulated intestinal fluid TS, prepared without
enzyme and adjusted to a pH of 7.5 + 0.1; 900 mL. TEST 14—If the product complies with this test, the labeling
Apparatus 2: 75 rpm. indicates that it meets USP Dissolution Test 14. Proceed as directed
Time for Medium 1: 2 hours. for Extended-Release Dosage Forms.
Times for Medium 2: 2, 12, 18, and 24 hours. Medium, Apparatus, Times, and Procedure—Proceed as directed
Procedure—Determine the amount of C22H26N2O4S HCl dis- under Test 3.
solved by employing UV absorption at the wavelength of maximum Tolerances—The percentages of the labeled amount of
absorbance at about 237 nm on filtered portions of the solution under C22H26N2O4S HCl dissolved at the times specified conform to
test, suitably diluted with the appropriate Medium, if necessary, in Acceptance Table 2.
comparison with a Standard solution having a known concentration
of USP Diltiazem Hydrochloride RS in the same Medium. Time (hours) Amount dissolved
Pharmacopeial Forum
Time (hours) Amount dissolved Time: 30 minutes.
Procedure—Proceed as directed for Test 1.
18 between 35% and 70% Tolerances—Not less than 75% (Q) of the labeled amount of
24 not less than 70% C4H11N5 HCl is dissolved in 30 minutes.
30 not less than 80% .TEST 3—If the product complies with this test, the labeling
.TEST 15—If the product complies with this test, the labeling Medium: pH 6.8 phosphate buffer; 1000 mL.
indicates that it meets USP Dissolution Test 15. Proceed as directed Time: 60 minutes.
for Extended-Release Dosage Forms. Determine the amount of C4H11N5 HCl dissolved by employing
Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL. the following method.
Apparatus 2: 75 rpm. 0.05 M Sodium phosphate with 1-pentanesulfonic acid solution—
Times: 2, 4, 8, 12, and 16 hours. Dissolve 1.38 g of monobasic sodium phosphate in about 1800 mL
Procedure—Proceed as directed under Test 1. of water. Add 3.484 g of 1-pentanesulfonic acid sodium salt, and
Tolerances—The percentages of the labeled amount of mix. Adjust with diluted phosphoric acid to a pH of 3.00 + 0.05.
C22H26N2O4S HCl dissolved at the times specified conform to Add water to make 2000 mL, and mix.
Acceptance Table 2. Mobile phase—Prepare a filtered and degassed mixture of 0.05 M
Time (hours) Amount dissolved Sodium phosphate with 1-pentanesulfonic acid solution and
acetonitrile (19 : 1). Make adjustments if necessary (see System
2 not more than 25% Suitability under Chromatography h621i).
4 between 20% and 40% Standard stock solution—Transfer about 25 mg, accurately
8 between 60% and 85% weighed, of USP Metformin Hydrochloride RS to a 100-mL
12 not less than 70% volumetric flask, and add about 50 mL of Medium. Sonicate until
16 not less than 80% dissolved, and dilute with Medium to volume.
Standard solution—Transfer 10.0 mL of the Standard stock
.2 solution to a 50-mL volumetric flask, and dilute with Medium to
volume.
Test solution—Withdraw a portion of the solution under test, and
pass through a 0.45-mm nylon filter. Dilute with Medium, if
Metformin Hydrochloride Tablets necessary, to obtain a concentration similar to that of the Standard
solution.
with a 230-nm detector and a 4.6-mm 6 25-cm column that contains
5-mm packing L1. The flow rate is about 1.0 mL per minute.
Change to read: Chromatograph replicate injections of the Standard solution, and
record the peak responses as directed for Procedure: the tailing
Dissolution h711i— factor is not more than 2.0; the column efficiency is not less than

TEST 1— 1500 theoretical plates; and the relative standard deviation for
Medium: pH 6.8 phosphate buffer; 1000 mL. replicate injections is not more than 2.0%.
Apparatus 1: 100 rpm. Procedure—Separately inject equal volumes (about 40 mL) of the
Time: 45 minutes. Standard solution and the Test solution into the chromatograph,
Procedure—Determine the amount of C4H11N5 HCl dissolved by record the chromatograms, and measure the responses for the major
employing UV absorption at the wavelength of maximum absor- peaks. Calculate the percentage of metformin released by the
bance at about 233 nm on filtered portions of the solution under test, formula:
suitably diluted with Medium, if necessary, in comparison with
a Standard solution having a known concentration of USP
Metformin Hydrochloride RS in the same Medium.
C4H11N5 HCl is dissolved in 45 minutes.
indicates that it meets USP Dissolution Test 2. in which rU and rS are the peak responses obtained from the Test
FOR PRODUCTS LABELED TO CONTAIN 500 MG OF METFORMIN— solution and the Standard solution, respectively; CS is the
Medium: pH 6.8 phosphate buffer; 1000 mL. concentration, in mg per mL, of metformin in the Standard solution;
Apparatus 2: 50 rpm. 900 is the volume, in mL, of Medium; 100 is the conversion factor to
Time: 30 minutes. percentage; D is the dilution factor of the Test solution; and LC is the
Procedure—Proceed as directed for Test 1. Tablet label claim, in mg.
Tolerances—Not less than 80% (Q) of the labeled amount of Tolerances—Not less than 70% (Q) of the labeled amount of
C4H11N5 HCl is dissolved in 30 minutes. C4H11N5 HCl is dissolved in 60 minutes..2
FOR PRODUCTS LABELED TO CONTAIN 850 MG OR 1000 MG OF
METFORMIN—
Medium: pH 6.8 phosphate buffer; 1000 mL.
Pharmacopeial Forum
Neuromuscular Blocking and Paralyzing Agents

GENERAL CHAPTERS All injectable preparations of neuromuscular blocking agents and
paralyzing agents must be packaged in vials with a cautionary state-
ment printed on the ferrules or cap overseals. Both the container cap
ferrule and the cap overseal must bear in black or white print (which-
General Tests and Assays ever provides the greatest color contrast with the ferrule or cap color)
the words: ‘‘Warning: Paralyzing Agent’’ or ‘‘Paralyzing Agent’’ (de-
pending on the size of the closure system). Alternatively, the overseal
may be transparent and without words, allowing for visualization of
General Requirements for the warning labeling on the closure ferrule.
Tests and Assays Containers for Sterile Solids

Containers, including the closures, for dry solids intended for par-
enteral use do not interact physically or chemically with the prepara-
tion in any manner to alter the strength, quality, or purity beyond the
official requirements under the ordinary or customary conditions of
handling, shipment, storage, sale, and use.
A container for a sterile solid permits the addition of a suitable sol-
vent and withdrawal of portions of the resulting solution or suspen-
h1i INJECTIONS sion in such manner that the sterility of the product is maintained.
Where the Assay in a monograph provides a procedure for the As-
say preparation, in which the total withdrawable contents are to be
withdrawn from a single-dose container with a hypodermic needle
and syringe, the contents are to be withdrawn as completely as pos-
Change to read: sible into a dry hypodermic syringe of a rated capacity not exceeding
three times the volume to be withdrawn and fitted with a 21-gauge
PACKAGING needle not less than 2.5 cm (1 inch) in length, with care being taken
to expel any air bubbles, and discharged into a container for dilution
Containers for Injections and assay.
Containers, including the closures, for preparations for injections

do not interact physically or chemically with the preparations in Volume in Container
any manner to alter the strength, quality, or purity beyond the official
requirements under the ordinary or customary conditions of handling, Each container of an injection is filled with sufficient excess of the
shipment, storage, sale, and use. The container is made of material labeled ‘‘size’’ or that volume which is to be withdrawn. See Injec-
that permits inspection of the contents. The type of glass preferable tions under Pharmaceutical Dosage Forms h1151i.
for each parenteral preparation is usually stated in the individual
monograph. Unless otherwise specified in the individual monograph,
plastic containers may be used for packaging injections (see Con- DETERMINATION OF VOLUME OF INJECTION IN CONTAINERS
tainers h661i).
For definitions of single-dose and multiple-dose containers, see .Suspensions and emulsions must be shaken before withdrawal of
Containers in the General Notices and Requirements. Containers the contents and before the determination of the density. Oily and vis-
meet the requirements under Containers h661i. cous preparations may be warmed according to the instructions on the
Containers are closed or sealed in such a manner as to prevent con- label, if necessary, and thoroughly shaken immediately before remov-
tamination or loss of contents. Validation of container integrity must ing the contents. The contents are then cooled to 208–258C before
demonstrate no penetration of microbial contamination or chemical measuring the volume..2
or physical impurities. In addition, the solutes and the vehicle must .Single-Dose Containers— Select 1 .container if the volume
.2 .2
maintain their specified total and relative quantities or concentrations of the container is 10 mL or more, 3 .containers.2 if the .nominal.2
when exposed to anticipated extreme conditions of manufacturing volume is more than 3 mL and less than 10 mL, or 5 .containers.2 if
and processing, and storage, shipment, and distribution. Closures the .nominal.2 volume is 3 mL or less. .Take up individually the to-
for multiple-dose containers permit the withdrawal of the contents tal.2 contents of each container selected into a dry syringe of a capa-
without removal or destruction of the closure. The closure permits city not exceeding three times the volume to be measured and fitted
penetration by a needle and, upon withdrawal of the needle, closes with a 21-gauge needle not less than 2.5 cm (1 inch) in length. Expel
at once, protecting the container against contamination. Validation any air bubbles from the syringe and needle, and then discharge the
of the multiple-dose container integrity must include verification that contents of the syringe, without emptying the needle, into a standard-
such a package prevents microbial contamination or loss of product ized, dry cylinder (graduated to contain rather than to deliver the des-
contents under anticipated conditions of multiple entry and use. ignated volumes) of such size that the volume to be measured
Piggyback containers are usually intravenous infusion containers occupies at least 40% of .its graduated.2 volume. Alternatively,.the
used to administer a second infusion through a connector of some volume of the contents in mL may be calculated as the mass, in g,
type or an injection port on the administration set of the first fluid, divided by the density..2&For containers with a nominal volume of
thereby avoiding the need for another injection site on the patient’s 2 mL or less, the contents of a sufficient number of containers may
body. Piggyback containers are also known as secondary infusion be pooled to obtain the volume required for the measurement, pro-
containers. vided that a separate, dry syringe assembly is used for each contain-
er.&1S (USP29) The contents of containers holding 10 mL or more may
be determined by means of opening them and emptying the contents
Potassium Chloride for Injection Concentrate directly into the graduated cylinder or tared beaker.
The volume is not less than the .nominal.2 volume in the case of
The use of a black closure system on a vial (e.g., a black flip-off containers examined individually or, in the case of .containers with a
button and a black ferrule to hold the elastomeric closure) or the use nominal volume of 2 mL or less,.2 is not less than the sum of the
of a black band or series of bands above the constriction on an ampul .nominal volumes of the containers taken collectively.
.2
is prohibited, except for Potassium Chloride for Injection Concen-
trate.
Pharmacopeial Forum
.Multi-Dose Containers— For Injections in multiple-dose con-

.2
tainers labeled to yield a specific number of doses of a stated volume,
.select 1 container, and proceed as directed .for single-dose con-
Microbiological Tests
.2
tainers,.2 using the same number of separate.syringe assemblies.2
as the number of doses specified. The volume is such that each sy-
ringe delivers not less than the stated dose. Change to read:
.Injections in Cartridges or Prefilled Syringes—Select 1 con-
tainer if the volume is 10 mL or more, 3 containers if the nominal
volume is more than 3 mL and less than 10 mL, or 5 containers if
the nominal volume is 3 mL or less. If necessary, fit the containers
with the accessories required for their use (needle, piston, syringe) h61i MICROBIOLOGICAL
&
and transfer the entire contents of each container without emptying
the needle into a dry tared beaker by slowly and constantly depressing
EXAMINATION OF NONSTERILE
the piston. Determine the volume in mL, calculated as the mass, in g,
divided by the density.
PRODUCTS: MICROBIAL
The volume measured for each of the containers is not less than the ENUMERATION TESTS
nominal volume..2
.Large-Volume Intravenous Solutions—For intravenous solu-
tions, select 1 container. Transfer the contents into a dry measuring INTRODUCTION
cylinder of such a capacity that the volume to be determined occupies
at least 40% of the nominal volume of the cylinder. Measure the vol- The tests described hereafter will allow quantitative enumeration
ume transferred. of mesophilic bacteria and fungi that may grow under aerobic condi-
The volume is not less than the nominal volume..2 tions.
The tests are designed primarily to determine whether a substance
or preparation complies with an established specification for micro-
&
Printing on Ferrules and Cap Overseals biological quality. When used for such purposes, follow the instruc-
tions given below, including the number of samples to be taken, and
Only cautionary statements are to be printed on the ferrules and cap interpret the results as stated below.
overseals of vials containing an injectable drug product. A cautionary The methods are not applicable to products containing viable mi-
statement is one intended to prevent an imminent life-threatening sit- croorganisms as active ingredients.
uation if the injectable drug is used inappropriately. Examples of such Alternative microbiological procedures, including automated
statements are the following: ‘‘Warning’’, ‘‘Dilute Before Using’’, methods, may be used, provided that their equivalence to the Pharma-
‘‘Paralyzing Agent’’, ‘‘I.M. Use Only’’, ‘‘Chemotherapy’’, etc. copeial method has been demonstrated.
The printing must be in contrasting color and conspicuous under
ordinary conditions of use. The cautionary statement may be printed
solely on the ferrule, provided the cap overseal is constructed so as to GENERAL PROCEDURES
allow the cautionary statement below to be readily legible.
(Postponed indefinitely)&1S (USP29) Carry out the determination under conditions designed to avoid ex-

trinsic microbial contamination of the product to be examined. The
precautions taken to avoid contamination must be such that they do
Packaging and Storage not affect any microorganisms that are to be revealed in the test.
If the product to be examined has antimicrobial activity, this is, in-
The volume of injection in single-dose containers provides the sofar as possible, removed or neutralized. If inactivators are used for
amount specified for parenteral administration at one time and in this purpose, their efficacy and their absence of toxicity for microor-
no case is more than sufficient to permit the withdrawal and admin- ganisms must be demonstrated.
istration of 1 L. If surface-active substances are used for sample preparation, their
Preparations intended for intraspinal, intracisternal, or peridural absence of toxicity for microorganisms and their compatibility with
administration are packaged only in single-dose containers. any inactivators used must be demonstrated.
Unless otherwise specified in the individual monograph, a
multiple-dose container contains a volume of Injection sufficient to
permit the withdrawal of not more than 30 mL. ENUMERATION METHODS
Injections packaged for use as irrigation solutions, for hemofiltra-
tion or dialysis, or for parenteral nutrition are exempt from the 1-L Use the Membrane Filtration method or one of the Plate-Count
restriction of the foregoing requirements relating to packaging. Methods, as directed. The Most-Probable-Number (MPN) Method
Containers for Injections packaged for use as hemofiltration or ir- is generally the least accurate method for microbial counts; however,
rigation solutions may be designed to empty rapidly and may contain for certain product groups with very low bioburden, it may be the
a volume of more than 1 L. most appropriate method.
Injections labeled for veterinary use are exempt from packaging The choice of a method is based on factors such as the nature of the
and storage requirements concerning the limitation to single-dose product and the required limit of microorganisms. The method cho-
containers and the limitation on the volume of multiple-dose con- sen must allow testing of a sufficient sample size to judge compliance
tainers. with the specification. The suitability of the chosen method must be
established.
GROWTH PROMOTION TEST AND

SUITABILITY OF THE COUNTING METHOD
General Considerations
The ability of the test to detect microorganisms in the presence of
product to be tested must be established.
Suitability must be confirmed if a change in testing performance or
a change in the product that may affect the outcome of the test, is
introduced.
Pharmacopeial Forum
Preparation of Test Strains Inoculate portions/plates of Soybean–Casein Digest Broth and

Soybean–Casein Digest Agar with a small number (not more than
Use standardized stable suspensions of test strains or prepare as 100 cfu) of the microorganisms indicated in Table 1, using a separate
stated below. Seed-lot culture maintenance techniques (seed-lot sys- portion/plate of medium for each. Inoculate plates of Sabouraud Dex-
tems) are used so that the viable microorganisms used for inoculation trose Agar with a small number (not more than 100 cfu) of the mi-
are not more than 5 passages removed from the original master seed- croorganisms indicated in Table 1, using a separate plate of medium
lot. Grow each of the bacterial and fungal test strains separately as for each. Incubate according to the conditions described in Table 1.
described in Table 1. For solid media, growth obtained must not differ by a factor greater
Use Buffered Sodium Chloride–Peptone Solution pH 7.0 or Phos- than 2 from the calculated value for a standardized inoculum. For a
phate Buffer Solution pH 7.2 to make test suspensions; to suspend A. freshly prepared inoculum, growth of the microorganisms compara-
niger spores, 0.05% of polysorbate 80 may be added to the buffer. ble to that previously obtained with a previously tested and approved
Use the suspensions within 2 hours, or within 24 hours if stored be- batch of medium occurs. Liquid media are suitable if clearly visible
tween 28 and 88. As an alternative to preparing and then diluting a growth of the microorganisms comparable to that previously obtained
fresh suspension of vegetative cells of A. niger or B. subtilis, a stable with a previously tested and approved batch of medium occurs.
spore suspension is prepared and then an appropriate volume of the
spore suspension is used for test inoculation. The stable spore suspen-
sion may be maintained at 28 to 88 for a validated period of time. Suitability of the Counting Method in the Presence of
Product
Negative Control PREPARATION OF THE SAMPLE
To verify testing conditions, a negative control is performed using The method for sample preparation depends on the physical char-
the chosen diluent in place of the test preparation. There must be no acteristics of the product to be tested. If none of the procedures de-
growth of microorganisms. scribed below can be demonstrated to be satisfactory, a suitable
alternative procedure must be developed.
Growth Promotion of the Media
Test each batch of ready-prepared medium and each batch of me-
dium prepared either from dehydrated medium or from the ingredi-
ents described.
Table 1. Preparation and Use of Test Microorganisms

Suitability of Counting Method in the
Growth Promotion Presence of Product
Preparation of Test Total Aerobic Total Yeasts and Total Aerobic Total Yeasts and
Microorganism Strain Microbial Count Molds Count Microbial Count Molds Count
Staphylococcus aureus Soybean–Casein Digest Soybean–Casein Soybean–Casein
such as ATCC 6538, Agar or Soybean–Casein Digest Agar and Digest Agar/MPN
NCIMB 9518, CIP Digest Broth Soybean–Casein Soybean–Casein
4.83, or NBRC 13276 308–358 Digest Broth Digest Broth
18–24 hours 100 cfu 100 cfu
308–358 308–358
3 days 3 days
Pseudomonas Soybean–Casein Digest Soybean–Casein Soybean–Casein
aeruginosa Agar or Soybean–Casein Digest Agar and Digest Agar/MPN
such as ATCC 9027, Digest Broth Soybean–Casein Soybean–Casein
NCIMB 8626, CIP 308–358 Digest Broth Digest Broth
82.118, or NBRC 18–24 hours 100 cfu 100 cfu
13275 308–358 308–358
3 days 3 days
Bacillus subtilis Soybean–Casein Digest Soybean–Casein Soybean–Casein
such as ATCC 6633, Agar or Soybean–Casein Digest Agar and Digest Agar/MPN
NCIMB 8054, CIP Digest Broth Soybean–Casein Soybean–Casein
52.62, or NBRC 3134 308–358 Digest Broth Digest Broth
18–24 hours 100 cfu 100 cfu
308–358 308–358
3 days 3 days
Candida albicans Sabouraud Dextrose Agar S o y b e a n – C a s e i n Sabouraud S o y b e a n – C a s e i n Sabouraud Dex-
such as ATCC 10231, or Sabouraud Dextrose Digest Agar Dextrose Agar Digest Agar trose Agar
NCPF 3179, IP 48.72, Broth 208–258 100 cfu 100 cfu 100 cfu 100 cfu
or NBRC 1594 2–3 days 308–358 208–258 308–358 208–258
5 days 5 days 5 days 5 days
MPN: not applica-
ble
Aspergillus niger Sabouraud Dextrose Agar S o y b e a n – C a s e i n S a b o u r a u d D e x - S o y b e a n – C a s e i n Sabouraud Dex-
such as ATCC 16404, or Potato–Dextrose Agar Digest Agar trose Agar Digest Agar trose Agar
IMI 149007, IP 208–258 100 cfu 100 cfu 100 cfu 100 cfu
1431.83, or NBRC 9455 5–7 days, or until good 308–358 208–258 308–358 208–258
sporulation is achieved 5 days 5 days 5 days 5 days
MPN: not applica-
ble
Pharmacopeial Forum
Water-Soluble Products—Dissolve or dilute (usually a 1 in 10 (4) A combination of the above measures.

dilution is prepared) the product to be examined in Buffered Sodium Neutralizing Agents—Neutralizing agents may be used to neu-
Chloride–Peptone Solution pH 7.0, Phosphate Buffer Solution pH tralize the activity of antimicrobial agents (see Table 2). They may
7.2, or Soybean–Casein Digest Broth. If necessary, adjust to a pH be added to the chosen diluent or the medium preferably before ster-
of 6 to 8. Further dilutions, where necessary, are prepared with the ilization. If used, their efficacy and their absence of toxicity for mi-
same diluent. croorganisms must be demonstrated by carrying out a blank with
Nonfatty Products Insoluble in Water—Suspend the product to neutralizer and without product.
be examined (usually a 1 in 10 dilution is prepared) in Buffered So-
dium Chloride–Peptone Solution pH 7.0, Phosphate Buffer Solution Table 2. Common Neutralizing Agents/Methods for
pH 7.2, or Soybean–Casein Digest Broth. A surface-active agent such Interfering Substances
as 1 g per L of polysorbate 80 may be added to assist the suspension
of poorly wettable substances. If necessary, adjust to a pH of 6 to 8. Potential Neutralizing Agents/
Further dilutions, where necessary, are prepared with the same dilu- Interfering Substance Method
ent.
Glutaraldehyde, mercurials Sodium hydrogen sulfite
Fatty Products—Dissolve in isopropyl myristate sterilized by fil- (Sodium bisulfite)
tration, or mix the product to be examined with the minimum neces- Phenolics, alcohol, aldehydes, Dilution
sary quantity of sterile polysorbate 80 or another noninhibitory sterile sorbate
surface-active reagent heated, if necessary, to not more than 408 or, in Aldehydes Glycine
exceptional cases, to not more than 458. Mix carefully and if neces- Quaternary ammonium com- Lecithin
sary maintain the temperature in a water bath. Add a sufficient quan- pounds (QACs), parahydroxy
tity of the prewarmed chosen diluent to make a 1 in 10 dilution of the benzoates (parabens), bis-bigua-
original product. Mix carefully, while maintaining the temperature for nides
the shortest time necessary for the formation of an emulsion. Further QACs, iodine, parabens Polysorbate
serial 10-fold dilutions may be prepared using the chosen diluent con- Mercurials Thioglycollate
taining a suitable concentration of sterile polysorbate 80 or another Mercurials, halogens, aldehydes Thiosulfate
noninhibitory sterile surface-active reagent. EDTA (edetate) Mg or Ca ions
Fluids or Solids in Aerosol Form—Aseptically transfer the prod-
uct into a membrane filter apparatus or a sterile container for further
sampling. Use either the total contents or a defined number of me- If no suitable neutralizing method can be found, it can be assumed
tered doses from each of the containers tested. that the failure to isolate the inoculated organism is attributable to the
Transdermal Patches—Remove the protective cover sheets (‘‘re- microbicidal activity of the product. This information serves to indi-
lease liners’’) of the transdermal patches and place them, adhesive cate that the article is not likely to be contaminated with the given
side upwards, on sterile glass or plastic trays. Cover the adhesive sur- species of the microorganism. However, it is possible that the product
face with a suitable sterile porous material (e.g., sterile gauze) to pre- inhibits only some of the microorganisms specified herein, but does
vent the patches from sticking together, and transfer the patches to a not inhibit others not included among the test strains or those for
suitable volume of the chosen diluent containing inactivators such as which the latter are not representative. Then, perform the test with

polysorbate 80 and/or lecithin. Shake the preparation vigorously for the highest dilution factor compatible with microbial growth and
at least 30 minutes. the specific acceptance criterion.
INOCULATION AND DILUTION RECOVERY OF MICROORGANISMS IN THE PRESENCE OF

PRODUCT
Add to the sample prepared as directed above and to a control (with
no test material included) a sufficient volume of the microbial suspen- For each of the microorganisms listed, separate tests are performed.
sion to obtain an inoculum of not more than than 100 cfu. The volume Only microorganisms of the added test strain are counted.
of the suspension of the inoculum should not exceed 1% of the vol- Membrane Filtration—Use membrane filters having a nominal
ume of diluted product. pore size not greater than 0.45 mm. The type of filter material is cho-
To demonstrate acceptable microbial recovery from the product, sen in such a way that the bacteria-retaining efficiency is not affected
the lowest possible dilution factor of the prepared sample must be by the components of the sample to be investigated. For each of the
used for the test. Where this is not possible due to antimicrobial ac- microorganisms listed, one membrane filter is used.
tivity or poor solubility, further appropriate protocols must be devel- Transfer a suitable quantity of the sample prepared as described
oped. If inhibition of growth by the sample cannot otherwise be under Preparation of the Sample, Inoculation and Dilution, and Neu-
avoided, the aliquot of the microbial suspension may be added after tralization/Removal of Antimicrobial Activity (preferably represent-
neutralization, dilution, or filtration. ing 1 g of the product, or less if large numbers of cfu are expected)
to the membrane filter, filter immediately, and rinse the membrane
filter with an appropriate volume of diluent.
NEUTRALIZATION/REMOVAL OF ANTIMICROBIAL ACTIVITY For the determination of total aerobic microbial count (TAMC),
transfer the membrane filter to the surface of the Soybean–Casein Di-
The number of microorganisms recovered from the prepared sam- gest Agar. For the determination of total combined yeasts and molds
ple diluted as described in Inoculation and Dilution and incubated count (TYMC), transfer the membrane to the surface of the Sabour-
following the procedure described in Recovery of Microorganisms aud Dextrose Agar. Incubate the plates as indicated in Table 1. Per-
in the Presence of Product, is compared to the number of microorga- form the counting.
nisms recovered from the control preparation. Plate-Count Methods—Perform plate-count methods at least in
If growth is inhibited (reduction by a factor greater than 2), then duplicate for each medium, and use the mean count of the result.
modify the procedure for the particular enumeration test to ensure Pour-Plate Method—For Petri dishes 9 cm in diameter, add to the
the validity of the results. Modification of the procedure may include, dish 1 mL of the sample prepared as described under Preparation of
for example, the Sample, Inoculation and Dilution, and Neutralization/Removal of
(1) An increase in the volume of the diluent or culture medium; Antimicrobial Activity and 15 to 20 mL of Soybean–Casein Digest
(2) Incorporation of a specific or general neutralizing agents into the Agar or Sabouraud Dextrose Agar, both media maintained at not
diluent; more than 458. If larger Petri dishes are used, the amount of agar me-
(3) Membrane filtration; or dium is increased accordingly. For each of the microorganisms listed
in Table 1, at least two Petri dishes are used.
Pharmacopeial Forum
Incubate the plates as indicated in Table 1. Take the arithmetic

mean of the counts per medium, and calculate the number of cfu in Table 3. Most-Probable-Number Values of Microorganisms
the original inoculum. (Continued)
Surface-Spread Method—For Petri dishes 9 cm in diameter, add 15
to 20 mL of Soybean–Casein Digest Agar or Sabouraud Dextrose Observed Combinations MPN per g or 95%
Agar at about 458 to each Petri dish, and allow to solidify. If larger of Numbers of Tubes per mL of Confidence
Petri dishes are used, the volume of the agar is increased accordingly. Showing Growth in Each Set Product Limits
Dry the plates, for example, in a laminar-airflow cabinet or in an in- 3 1 2 120 30–360
cubator. For each of the microorganisms listed in Table 1, at least two 3 1 3 160 30–380
Petri dishes are used. Spread a measured volume of not less than 0.1 3 2 0 93 18–360
mL of the sample, prepared as directed under Preparation of the Sam- 3 2 1 150 30–380
ple, Inoculation and Dilution, and Neutralization/Removal of Antimi- 3 2 2 210 30–400
crobial Activity over the surface of the medium. Incubate and count 3 2 3 290 90–990
as directed for Pour-Plate Method. 3 3 0 240 40–990
Most-Probable-Number (MPN) Method—The precision and ac- 3 3 1 460 90–1980
curacy of the MPN Method is less than that of the Membrane Filtra- 3 3 2 1100 200–4000
tion method or the Plate-Count Method. Unreliable results are 3 3 3 4 1100
obtained particularly for the enumeration of molds. For these reasons,
the MPN Method is reserved for the enumeration of TAMC in situa-
tions where no other method is available. If the use of the method is RESULTS AND INTERPRETATION
justified, proceed as follows.
Prepare a series of at least three serial 10-fold dilutions of the pro- When verifying the suitability of the Membrane Filtration method
duct as described for Preparation of the Sample, Inoculation and Di- or the Plate-Count Method, a mean count of any of the test organisms
lution, and Neutralization/Removal of Antimicrobial Activity. From not differing by a factor greater than 2 from the value of the control
each level of dilution, three aliquots of 1 g or 1 mL are used to inoc- defined in Inoculation and Dilution in the absence of product must be
ulate three tubes with 9 to 10 mL of Soybean–Casein Digest Broth. If obtained. When verifying the suitability of the MPN Method, the cal-
necessary a surface-active agent such as polysorbate 80, or an inacti- culated value from the inoculum must be within 95% confidence lim-
vator of antimicrobial agents may be added to the medium. Thus, if its of the results obtained with the control.
three levels of dilution are prepared, nine tubes are inoculated. If the above criteria cannot be met for one of more of the organisms
Incubate all tubes at 308 to 358 for not more than 3 days. If reading tested with any of the described methods, the method and test condi-
of the results is difficult or uncertain owing to the nature of the prod- tions that come closest to the criteria are used to test the product.
uct to be examined, subculture in the same broth or in Soybean–Ca-
sein Digest Agar for 1 to 2 days at the same temperature, and use
these results. From Table 3, determine the most probable number of TESTING OF PRODUCTS
microorganisms per g or mL of the product to be examined.
Amount Used for the Test
Table 3. Most-Probable-Number Values of Microorganisms
Unless otherwise directed, use 10 g or 10 mL of the product to be

Observed Combinations MPN per g or 95% examined taken with the precautions referred to above. For fluids or
of Numbers of Tubes per mL of Confidence solids in aerosol form, sample 10 containers. For transdermal patches,
Showing Growth in Each Set Product Limits sample 10 patches.
Number of g or mL of Product The amount to be tested may be reduced for active substances that
per Tube will be formulated in the following conditions: the amount per dosage
unit (e.g., tablet, capsule, injection) is less than or equal to 1 mg, or
0.1 0.01 0.001 the amount per g or mL (for preparations not presented in dose units)
0 0 0 53 0–9.4 is less than 1 mg. In these cases, the amount of sample to be tested is
0 0 1 3 0.1–9.5 not less than the amount present in 10 dosage units or 10 g or 10 mL
0 1 0 3 0.1–10 of the product.
0 1 1 6.1 1.2–17 For materials used as active substances where the sample quantity
0 2 0 6.2 1.2–17 is limited or batch size is extremely small (i.e., less than 1000 mL or
0 3 0 9.4 3.5–35 1000 g), the amount tested shall be 1% of the batch unless a lesser
1 0 0 3.6 0.2–17 amount is prescribed or justified and authorized.
1 0 1 7.2 1.2–17 For products where the total number of entities in a batch is less
1 0 2 11 4–35 than 200 (e.g., samples used in clinical trials), the sample size may
1 1 0 7.4 1.3–20 be reduced to two units, or one unit if the size is less than 100.
1 1 1 11 4–35 Select the sample(s) at random from the bulk material or from the
1 2 0 11 4–35 available containers of the preparation. To obtain the required quan-
1 2 1 15 5–38 tity, mix the contents of a sufficient number of containers to provide
1 3 0 16 5–38 the sample.
2 0 0 9.2 1.5–35
2 0 1 14 4–35
2 0 2 20 5–38 Examination of the Product
2 1 0 15 4–38
2 1 1 20 5–38 MEMBRANE FILTRATION
2 1 2 27 9–94
2 2 0 21 5–40 Use a filtration apparatus designed to allow the transfer of the filter
2 2 1 28 9–94 to the medium. Prepare the sample using a method that has been
2 2 2 35 9–94 shown to be suitable as described in Growth Promotion Test and Suit-
2 3 0 29 9–94 ability of the Counting Method, transfer the appropriate amount to
2 3 1 36 9–94 each of two membrane filters, and filter immediately. Wash each filter
3 0 0 23 5–94 following the procedure shown to be suitable.
3 0 1 38 9–104 For the determination of TAMC, transfer one of the membrane fil-
3 0 2 64 16–181 ters to the surface of Soybean–Casein Digest Agar. For the determi-
3 1 0 43 9–181 nation of TYMC, transfer the other membrane to the surface of
3 1 1 75 17–199 Sabouraud Dextrose Agar. Incubate the plate of Soybean–Casein Di-
Pharmacopeial Forum
gest Agar at 308 to 358 for 3 to 5 days and the plate of Sabouraud Add the following:
Dextrose Agar at 208 to 258 for 5 to 7 days. Calculate the number
of cfu per g or per mL of product.
When examining transdermal patches, separately filter 10% of the
volume of the preparation described for Preparation of the Sample
through each of two sterile filter membranes. Transfer one membrane h62i MICROBIOLOGICAL
&
to Soybean–Casein Digest Agar for TAMC and the other membrane
to Sabouraud Dextrose Agar for TYMC. EXAMINATION OF NONSTERILE
PRODUCTS: TESTS FOR
PLATE-COUNT METHODS SPECIFIED MICROORGANISMS
Pour-Plate Method—Prepare the sample using a method that has
been shown to be suitable as described in Growth Promotion Test and INTRODUCTION
Suitability of the Counting Method. Prepare for each medium at least
two Petri dishes for each level of dilution. Incubate the plates of Soy- The tests described hereafter will allow determination of the ab-
bean–Casein Digest Agar at 308 to 358 for 3 to 5 days and the plates sence of, or limited occurrence of, specified microorganisms that
of Sabouraud Dextrose Agar at 208 to 258 for 5 to 7 days. Select the may be detected under the conditions described.
plates corresponding to a given dilution and showing the highest The tests are designed primarily to determine whether a substance
number of colonies less than 250 for TAMC and 50 for TYMC. Take or preparation complies with an established specification for micro-
the arithmetic mean per culture medium of the counts, and calculate biological quality. When used for such purposes, follow the instruc-
the number of cfu per g or per mL of product. tions given below, including the number of samples to be taken, and
Surface-Spread Method—Prepare the sample using a method interpret the results as stated below.
that has been shown to be suitable as described in Growth Promotion Alternative microbiological procedures, including automated
Test and Suitability of the Counting Method. Prepare at least two Petri methods, may be used, provided that their equivalence to the Pharma-
dishes for each medium and each level of dilution. For incubation and copeial method has been demonstrated.
calculation of the number of cfu, proceed as directed for the Pour-
Plate Method.
GENERAL PROCEDURES
MOST-PROBABLE-NUMBER METHOD The preparation of samples is carried out as described in Microbi-
ological Examination of Nonsterile Products: Microbial Enumera-
Prepare and dilute the sample using a method that has been shown tion Tests h61i.
to be suitable as decribed in Growth Promotion Test and Suitability of If the product to be examined has antimicrobial activity, this is in-
the Counting Method. Incubate all tubes for 3 to 5 days at 308 to 358. sofar as possible removed or neutralized as described in Microbiolog-
Subculture if necessary, using the procedure shown to be suitable. Re- ical Examination of Nonsterile Products: Microbial Enumeration
cord for each level of dilution the number of tubes showing microbial Tests h61i.
growth. Determine the most probable number of microorganisms per If surface-active substances are used for sample preparation, their

g or mL of the product to be examined from Table 3. absence of toxicity for microorganisms and their compatibility with
any inactivators used must be demonstrated as described in Microbi-
ological Examination of Nonsterile Products: Microbial Enumera-
Interpretation of the Results tion Tests h61i.
The total aerobic microbial count (TAMC) is considered to be

equal to the number of cfu found using Soybean–Casein Digest Agar; GROWTH-PROMOTING AND INHIBITORY
if colonies of fungi are detected on this medium, they are counted as PROPERTIES OF THE MEDIA AND
part of TAMC. The total combined yeasts and molds count (TYMC)
is considered to be equal to the number of cfu found using Sabouraud SUITABILITY OF THE TEST
Dextrose Agar; if colonies of bacteria are detected on this medium, The ability of the test to detect microorganisms in the presence of
they are counted as part of TYMC. When the TYMC is expected to the product to be tested must be established. Suitability must be con-
exceed the acceptance criterion due to the bacterial growth, Sabour- firmed if a change in testing performance or a change in the product
aud Dextrose Agar containing antibiotics may be used. If the count is that may affect the outcome of the test is introduced.
carried out by the MPN Method, the calculated value is TAMC.
When an acceptance criterion for microbiological quality is pre-
scribed, it is interpreted as follows:
— 101 cfu: maximum acceptable count = 20; Preparation of Test Strains
— 102 cfu: maximum acceptable count = 200;
— 103 cfu: maximum acceptable count = 2000; and so forth. Use standardized stable suspensions of test strains as stated below.
The recommended solutions and media are described in Microbi- Seed-lot culture maintenance techniques (seed-lot systems) are used
ological Examination of Nonsterile Products: Tests for Specified Mi- so that the viable microorganisms used for inoculation are not more
croorganisms h62i. than five passages removed from the original master seed-lot.
.
Official May 1, 2009.2&2S (USP29)
AEROBIC MICROORGANISMS
Grow each of the bacterial test strains separately in containers con-

taining Soybean–Casein Digest Broth or on Soybean–Casein Digest
Agar at 308 to 358 for 18 to 24 hours. Grow the test strain for Candida
albicans separately on Sabouraud Dextrose Agar or in Sabouraud
Dextrose Broth at 208 to 258 for 2 to 3 days.
Pharmacopeial Forum
Staphylococcus aureus such as ATCC 6538, CLOSTRIDIA

NCIMB 9518, CIP
4.83, or NBRC 13276 Use Clostridium sporogenes such as ATCC 11437 (NBRC 14293,
Pseudomonas aeruginosa such as ATCC 9027, NCIMB 12343, CIP 100651) or ATCC 19404 (NCTC 532 or CIP
NCIMB 8626, CIP 79.3). Grow the clostridial test strain under anaerobic conditions in
82.118, or Reinforced Medium for Clostridia at 308 to 358 for 24 to 48 hours.
NBRC 13275 As an alternative to preparing and then diluting down a fresh suspen-
Escherichia coli such as ATCC 8739, sion of vegetative cells of Cl. sporogenes, a stable spore suspension is
NCIMB 8545, CIP used for test inoculation. The stable spore suspension may be main-
53.126, or tained at 28 to 88 for a validated period.
NBRC 3972
Salmonella enterica such as ATCC 14028
ssp. enterica serotype typhimurium Negative Control
or, as an alternative,
Salmonella enterica such as NBRC 100797, To verify testing conditions, a negative control is performed using
ssp. enterica serotype abony NCTC 6017, or the chosen diluent in place of the test preparation. There must be no
CIP 80.39 growth of microorganisms.
Candida albicans such as ATCC 10231,
NCPF 3179, IP 48.72,
or NBRC 1594 Growth Promotion and Inhibitory Properties
of the Media
Use Buffered Sodium Chloride–Peptone Solution pH 7.0 or Phos- Test each batch of ready-prepared medium and each batch of me-
phate Buffer Solution pH 7.2 to make test suspensions. Use the sus- dium prepared either from dehydrated medium or from ingredients.
pensions within 2 hours or within 24 hours if stored at 28 to 88. Verify suitable properties of relevant media as described in Table 1.
Test for Growth-Promoting Properties, Liquid Media—Inocu-
late a portion of the appropriate medium with a small number (not
more than 100 cfu) of the appropriate microorganism. Incubate at
the specified temperature for not more than the shortest period of time
specified in the test. Clearly visible growth of the microorganism
comparable to that previously obtained with a previously tested and
approved batch of medium occurs.
Table 1. Growth Promoting, Inhibitory, and Indicative Properties of Media
Test/Medium Property Test Strains

Test for bile-tolerant Gram-negative bacteria
Enterobacteria Enrichment Broth Mossel Growth promoting E. coli
P. aeruginosa
Inhibitory S. aureus
Violet Red Bile Glucose Agar Growth promoting + Indicative E. coli
P. aeruginosa
Test for Escherichia coli
MacConkey Broth Growth promoting E. coli
MacConkey Agar Growth promoting + Indicative E. coli
Test for Salmonella
Rappaport Vassiliadis Salmonella Enrichment Broth Growth promoting Salmonella enterica ssp.
enterica serotype typhimur-
ium or
Salmonella enterica ssp.
enterica serotype abony
Xylose Lysine Deoxycholate Agar Growth promoting + Indicative Salmonella enterica ssp.
enterica serotype
typhimurium or
Salmonella enterica ssp.
enterica serotype abony
E. coli
Test for Pseudomonas aeruginosa
Cetrimide Agar Growth promoting P. aeruginosa
Inhibitory E. coli
Test for Staphylococcus aureus
Mannitol Salt Agar Growth promoting + Indicative S. aureus
Inhibitory E. coli
Test for Clostridia
Reinforced Medium for Clostridia Growth promoting Cl. sporogenes
Columbia Agar Growth promoting Cl. sporogenes
Test for Candida albicans
Sabouraud Dextrose Broth Growth promoting C. albicans
Sabouraud Dextrose Agar Growth promoting + Indicative C. albicans
Pharmacopeial Forum
Test for Growth-Promoting Properties, Solid Media—Perform Broth Mossel. Incubate at 308 to 358 for 24 to 48 hours. Subculture
Surface-Spread Method (see Plate-Count Methods under Microbio- on plates of Violet Red Bile Glucose Agar. Incubate at 308 to 358 for
logical Examination of Nonsterile Products: Microbial Enumeration 18 to 24 hours.
Tests h61i), inoculating each plate with a small number (not more The product complies with the test if there is no growth of colonies.
than 100 cfu) of the appropriate microorganism. Incubate at the spec- Quantitative Test—
ified temperature for not more than the shortest period of time spec- Selection and Subculture—Inoculate suitable quantities of Entero-
ified in the test. Growth of the microorganism comparable to that bacteria Enrichment Broth Mossel with the preparation as directed
previously obtained with a previously tested and approved batch of under Sample Preparation and Pre-Incubation and/or dilutions of it
medium occurs. containing respectively 0.1 g, 0.01 g, and 0.001 g (or 0.1 mL, 0.01
Test for Inhibitory Properties, Liquid or Solid Media—Inocu- mL, and 0.001 mL) of the product to be examined. Incubate at 308
late the appropriate medium with at least 100 cfu of the appropriate to 358 for 24 to 48 hours. Subculture each of the cultures on a plate of
microorganism. Incubate at the specified temperature for not less than Violet Red Bile Glucose Agar. Incubate at 308 to 358 for 18 to 24
the longest period of time specified in the test. No growth of the test hours.
microorganism occurs. Interpretation—Growth of colonies constitutes a positive result.
Test for Indicative Properties—Perform Surface-Spread Method Note the smallest quantity of the product that gives a positive result
(see Plate-Count Methods under Microbiological Examination of and the largest quantity that gives a negative result. Determine from
Nonsterile Products: Microbial Enumeration Tests h61i), inoculating Table 2 the probable number of bacteria.
each plate with a small number (not more than 100 cfu) of the appro-
priate microorganism. Incubate at the specified temperature for a pe-
riod of time within the range specified in the test. Colonies are Escherichia coli
comparable in appearance and indication reactions to those previous-
ly obtained with a previously tested and approved batch of medium. Sample Preparation and Pre-Incubation—Prepare a sample us-
ing a 1 in 10 dilution of not less than 1 g of the product to be examined
as described in Microbiological Examination of Nonsterile Products:
Suitability of the Test Method Microbial Enumeration Tests h61i, and use 10 mL or the quantity cor-
responding to 1 g or 1 mL, to inoculate a suitable amount (determined
For each new product to be tested perform sample preparation as as described under Suitability of the Test Method) of Soybean–Casein
described in the relevant paragraph under Testing of Products. At the Digest Broth, mix, and incubate at 308 to 358 for 18 to 24 hours.
time of mixing, add each test strain in the prescribed growth medium. Selection and Subculture—Shake the container, transfer 1 mL of
Inoculate the test strains individually. Use a number of microorga- Soybean–Casein Digest Broth to 100 mL of MacConkey Broth, and
nisms equivalent to not more than 100 cfu in the inoculated test prep- incubate at 428 to 448 for 24 to 48 hours. Subculture on a plate of
aration. MacConkey Agar at 308 to 358 for 18 to 72 hours.
Perform the test as described in the relevant paragraph under Test-
ing of Products using the shortest incubation period prescribed. Interpretation—Growth of colonies indicates the possible pres-
The specified microorganisms must be detected with the indication ence of E. coli. This is confirmed by identification tests.
reactions as described under Testing of Products. The product complies with the test if no colonies are present or if

Any antimicrobial activity of the product necessitates a modifica- the identification tests are negative.
tion of the test procedure (see Neutralization/Removal of Antimicro-
bial Activity under Microbiological Examination of Nonsterile
Products: Microbial Enumeration Tests h61i). Salmonella
For a given product, if the antimicrobial activity with respect to a
microorganism for which testing is prescribed cannot be neutralized, Sample Preparation and Pre-Incubation—Prepare the product
then it is to be assumed that the inhibited microorganism will not be to be examined as described in Microbiological Examination of Non-
present in the product. sterile Products: Microbial Enumeration Tests h61i, and use the
quantity corresponding to not less than 10 g or 10 mL to inoculate
a suitable amount (determined as described under Suitability of the
TESTING OF PRODUCTS Test Method) of Soybean–Casein Digest Broth, mix, and incubate
at 308 to 358 for 18 to 24 hours.
Bile-Tolerant Gram-Negative Bacteria Selection and Subculture—Transfer 0.1 mL of Soybean–Casein
Digest Broth to 10 mL of Rappaport Vassiliadis Salmonella Enrich-
Sample Preparation and Pre-Incubation—Prepare a sample us- ment Broth, and incubate at 308 to 358 for 18 to 24 hours. Subculture
ing a 1 in 10 dilution of not less than 1 g of the product to be examined on plates of Xylose Lysine Deoxycholate Agar. Incubate at 308 to 358
as described in Microbiological Examination of Nonsterile Products: for 18 to 48 hours.
Microbial Enumeration Tests h61i, but using Soybean–Casein Digest Interpretation—The possible presence of Salmonella is indicated
Broth as the chosen diluent, mix, and incubate at 208 to 258 for a time by the growth of well-developed, red colonies, with or without black
sufficient to resuscitate the bacteria but not sufficient to encourage centers. This is confirmed by identification tests.
multiplication of the organisms (usually 2 hours but not more than The product complies with the test if colonies of the types de-
5 hours). scribed are not present or if the confirmatory identification tests are
Test for Absence—Unless otherwise prescribed, use the volume negative.
corresponding to 1 g of the product, as prepared in Sample Prepara-
tion and Pre-Incubation, to inoculate Enterobacteria Enrichment
Table 2. Interpretation of Results

Results for Each Quantity Probable Number
of Product of Bacteria
0.1 g or 0.1 mL 0.01 g or 0.01 mL 0.001 g or 0.001 mL per g or mL of Product
+ + + more than 103
+ + – less than 103 and more than 102
+ – – less than 102 and more than 10
– – – less than 10
Pharmacopeial Forum
Pseudomonas aeruginosa Candida albicans

Sample Preparation and Pre-Incubation—Prepare a sample us- Sample Preparation and Pre-Incubation—Prepare the product
ing a 1 in 10 dilution of not less than 1 g of the product to be examined to be examined as described in Microbiological Examination of Non-
as described in Microbiological Examination of Nonsterile Products: sterile Products: Microbial Enumeration Tests h61i, and use 10 mL
Microbial Enumeration Tests h61i, and use 10 mL or the quantity cor- or the quantity corresponding to not less than 1 g or 1 mL, to inoculate
responding to 1 g or 1 mL to inoculate a suitable amount (determined 100 mL of Sabouraud Dextrose Broth, and mix. Incubate at 308 to
as described under Suitability of the Test Method) of Soybean–Casein 358 for 3 to 5 days.
Digest Broth, and mix. When testing transdermal patches, filter the Selection and Subculture—Subculture on a plate of Sabouraud
volume of sample corresponding to one patch of the preparation Dextrose Agar, and incubate at 308 to 35 8 for 24 to 48 hours.
(see Transdermal Patches under Preparation of the Sample in Micro- Interpretation—Growth of white colonies may indicate the pres-
biological Examination of Nonsterile Products: Microbial Enumera- ence of C. albicans. This is confirmed by identification tests.
tion Tests h61i) through a sterile filter membrane, and place in 100 The product complies with the test if such colonies are not present
mL of Soybean–Casein Digest Broth. Incubate at 308 to 358 for 18 or if the confirmatory identification tests are negative.
to 24 hours.
Selection and Subculture—Subculture on a plate of Cetrimide
Agar, and incubate at 308 to 358 for 18 to 72 hours. RECOMMENDED SOLUTIONS AND
Interpretation—Growth of colonies indicates the possible pres- CULTURE MEDIA
ence of P. aeruginosa. This is confirmed by identification tests.
The product complies with the test if colonies are not present or if [NOTE—This section is given for information.]
the confirmatory identification tests are negative. The following solutions and culture media have been found satis-
factory for the purposes for which they are prescribed in the test for
microbial contamination in the Pharmacopeia. Other media may be
Staphylococcus aureus used if they have similar growth-promoting and inhibitory properties.
Stock Buffer Solution—Transfer 34 g of potassium dihydrogen
Sample Preparation and Pre-Incubation—Prepare a sample us- phosphate to a 1000-mL volumetric flask, dissolve in 500 mL of Pu-
ing a 1 in 10 dilution of not less than 1 g of the product to be examined rified Water, adjust with sodium hydroxide to a pH of 7.2 + 0.2, add
as described in Microbiological Examination of Nonsterile Products: Purified Water to volume, and mix. Dispense in containers, and ster-
Microbial Enumeration Tests h61i, and use 10 mL or the quantity cor- ilize. Store at a temperature of 28 to 88.
responding to 1 g or 1 mL to inoculate a suitable amount (determined
as described under Suitability of the Test Method) of Soybean–Casein Phosphate Buffer Solution pH 7.2—Prepare a mixture of Puri-
Digest Broth, and homogenize. When testing transdermal patches, fil- fied Water and Stock Buffer Solution (800 : 1 v/v), and sterilize.
ter the volume of sample corresponding to one patch of the prepara- Buffered Sodium Chloride–Peptone Solution pH 7.0
tion (see Transdermal Patches under Preparation of the Sample in
Microbiological Examination of Nonsterile Products: Microbial Enu- Potassium Dihydrogen Phosphate 3.6 g
meration Tests h61i) through a sterile filter membrane, and place in Disodium Hydrogen Phosphate Dihydrate 7.2 g (equivalent
100 mL of Soybean–Casein Digest Broth. Incubate at 308 to 358 for to 0.067 M phos-
18 to 24 hours. phate)
Selection and Subculture—Subculture on a plate of Mannitol Salt Sodium Chloride 4.3 g
Agar, and incubate at 308 to 358 for 18 to 72 hours. Peptone (meat or casein) 1.0 g
Interpretation—The possible presence of S. aureus is indicated Purified Water 1000 mL
by the growth of yellow or white colonies surrounded by a yellow
zone. This is confirmed by identification tests. Sterilize in an autoclave using a validated cycle.
The product complies with the test if colonies of the types de-
scribed are not present or if the confirmatory identification tests are Soybean–Casein Digest Broth
negative.
Pancreatic Digest of Casein 17.0 g
Papaic Digest of Soybean 3.0 g
Clostridia Sodium Chloride 5.0 g
Dibasic Hydrogen Phosphate 2.5 g
Glucose Monohydrate 2.5 g
Sample Preparation and Heat Treatment—Prepare the product Purified Water 1000 mL
to be examined as described in Microbiological Examination of Non-
sterile Products: Microbial Enumeration Tests h61i. Take two equal
portions corresponding to not less than 1 g or 1 mL of the product to Adjust the pH so that after sterilization it is 7.3 + 0.2 at 258. Ster-
be examined. Heat one portion at 808 for 10 minutes, and cool rap- ilize in an autoclave using a validated cycle.
idly. Do not heat the other portion.
Selection and Subculture—Transfer 10 mL of each of the mixed
portions to two containers (38 mm 6 200 mm) or other containers Soybean–Casein Digest Agar
containing 100 mL of Reinforced Medium for Clostridia. Incubate Pancreatic Digest of Casein 15.0 g
under anaerobic conditions at 308 to 358 for 48 hours. After incuba- Papaic Digest of Soybean 5.0 g
tion, make subcultures from each tube on Columbia Agar, and incu- Sodium Chloride 5.0 g
bate under anaerobic conditions at 308 to 358 for 48 hours. Agar 15.0 g
Interpretation—The occurrence of anaerobic growth of rods Purified Water 1000 mL
(with or without endospores) giving a negative catalase reaction in-
dicates the presence of Clostridia.
If no anaerobic growth of microorganisms is detected on Columbia Adjust the pH so that after sterilization it is 7.3 + 0.2 at 258. Ster-
Agar or the catalase test is positive, the product complies with the test. ilize in an autoclave using a validated cycle.
Pharmacopeial Forum
Sabouraud Dextrose Agar MacConkey Agar

Dextrose 40.0 g Pancreatic Digest of Gelatin 17.0 g
Mixture of Peptic Digest of Animal 10.0 g Peptones (meat and casein) 3.0 g
Tissue and Pancreatic Digest of Lactose Monohydrate 10.0 g
Casein (1 : 1) Sodium Chloride 5.0 g
Agar 15.0 g Bile Salts 1.5 g
Purified Water 1000 mL Agar 13.5 g
Neutral Red 30.0 mg
Crystal Violet 1 mg
Adjust the pH so that after sterilization it is 5.6 + 0.2 at 258. Ster- Purified Water 1000 mL
ilize in an autoclave using a validated cycle.
Adjust the pH so that after sterilization it is 7.1 + 0.2 at 258. Boil
Potato Dextrose Agar for 1 minute with constant shaking, then sterilize in an autoclave us-
Infusion from potatoes 200 g ing a validated cycle.
Dextrose 20.0 g
Agar 15.0 g Rappaport Vassiliadis Salmonella Enrichment Broth
Purified Water 1000 mL Soya Peptone 4.5 g
Magnesium Chloride Hexahydrate 29.0 g
Sodium Chloride 8.0 g
Adjust the pH so that after sterilization it is 5.6 + 0.2 at 258. Ster- Dipotassium Phosphate 0.4 g
ilize in an autoclave using a validated cycle. Potassium Dihydrogen Phosphate 0.6 g
Malachite Green 0.036 g
Sabouraud Dextrose Broth Purified Water 1000 mL
Dextrose 20.0 g
Mixture of Peptic Digest of Animal 10.0 g Dissolve, warming slightly. Sterilize in an autoclave using a val-
Tissue and Pancreatic Digest of idated cycle, at a temperature not exceeding 1158. The pH is to be
Casein (1 : 1) 5.2 + 0.2 at 258 after heating and autoclaving.
Purified Water 1000 mL
Xylose Lysine Deoxycholate Agar
Adjust the pH so that after sterilization it is 5.6 + 0.2 at 258. Ster- Xylose 3.5 g
ilize in an autoclave using a validated cycle. L-Lysine 5.0 g
Enterobacteria Enrichment Broth Mossel Lactose Monohydrate 7.5 g
Sucrose 7.5 g
Pancreatic Digest of Gelatin 10.0 g Sodium Chloride 5.0 g

Glucose Monohydrate 5.0 g Yeast Extract 3.0 g
Dehydrated Ox Bile 20.0 g Phenol Red 80 mg
Potassium Dihydrogen Phosphate 2.0 g Agar 13.5 g
Disodium Hydrogen Phosphate Dihydrate 8.0 g Sodium Deoxycholate 2.5 g
Brilliant Green 15 mg Sodium Thiosulfate 6.8 g
Purified Water 1000 mL Ferric Ammonium Citrate 0.8 g
Adjust the pH so that after heating it is 7.2 + 0.2 at 258. Heat at
1008 for 30 minutes, and cool immediately. Adjust the pH so that after heating it is 7.4 + 0.2 at 258. Heat to
boiling, cool to 508, and pour into Petri dishes. Do not heat in an au-
toclave.
Violet Red Bile Glucose Agar
Yeast Extract 3.0 g Cetrimide Agar
Pancreatic Digest of Gelatin 7.0 g Pancreatic Digest of Gelatin 20.0 g
Bile Salts 1.5 g Magnesium Chloride 1.4 g
Sodium Chloride 5.0 g Dipotassium Sulfate 10.0 g
Glucose Monohydrate 10.0 g Cetrimide 0.3 g
Agar 15.0 g Agar 13.6 g
Neutral Red 30 mg Purified Water 1000 mL
Crystal Violet 2 mg Glycerol 10.0 mL
Heat to boiling for 1 minute with shaking. Adjust the pH so that
Adjust the pH so that after heating it is 7.4 + 0.2 at 258. Heat to after sterilization it is 7.2 + 0.2 at 258. Sterilize in an autoclave using
boiling; do not heat in an autoclave. a validated cycle.
Mannitol Salt Agar
MacConkey Broth
Pancreatic Digest of Casein 5.0 g
Pancreatic Digest of Gelatin 20.0 g Peptic Digest of Animal Tissue 5.0 g
Lactose Monohydrate 10.0 g Beef Extract 1.0 g
Dehydrated Ox Bile 5.0 g D-Mannitol 10.0 g
Bromocresol Purple 10 mg Sodium Chloride 75.0 g
Purified Water 1000 mL Agar 15.0 g
Phenol Red 0.025 g
Adjust the pH so that after sterilzation it is 7.3 + 0.2 at 258. Ster-
ilize in an autoclave using a validated cycle.
Pharmacopeial Forum
Heat to boiling for 1 minute with shaking. Adjust the pH so that limits. Where for technical reasons the injection cannot be tested by
after sterilization it is 7.4 + 0.2 at 258. Sterilize in an autoclave using light obscuration, microscopic testing may be used exclusively. Doc-
a validated cycle. umentation demonstrating that the light obscuration procedure is in-
capable of testing the injection or produces invalid results is required
Reinforced Medium for Clostridia in each case. It is expected that most articles will meet the require-
Beef Extract 10.0 g ments on the basis of the light obscuration test alone; however, it
Peptone 10.0 g may be necessary to test some articles by the light obscuration test
Yeast Extract 3.0 g followed by the microscopic test to reach a conclusion on confor-
Soluble Starch 1.0 g mance to requirements.
Glucose Monohydrate 5.0 g All large-volume injections for single-dose infusion and those
Cysteine Hydrochloride 0.5 g small-volume injections for which the monographs specify such re-
Sodium Chloride 5.0 g quirements are subject to the particulate matter limits set forth for the
Sodium Acetate 3.0 g test being applied, unless otherwise specified in the individual mono-
Agar 0.5 g graph. Excluded from the requirements of this chapter are injections
Purified Water 1000 mL intended solely for intramuscular and subcutaneous administration.
Not all injection formulations can be examined for particles by one
or both of these tests. Any product that is not a pure solution having a
Hydrate the agar, and dissolve by heating to boiling with continu- clarity and a viscosity approximating those of water may provide er-
ous stirring. If necessary, adjust the pH so that after sterilization it is roneous data when analyzed by the light obscuration counting meth-
about 6.8 + 0.2 at 258. Sterilize in an autoclave using a validated od. Such materials may be analyzed by the microscopic method.
cycle. Emulsions, colloids, and liposomal preparations are examples. Simi-
larly, products that produce air or gas bubbles when drawn into the
Columbia Agar sensor, such as bicarbonate-buffered formulations, may also require
Pancreatic Digest of Casein 10.0 g microscopic testing. Refer to the specific monographs when a ques-
Meat Peptic Digest 5.0 g tion of test applicability occurs. Higher limits are appropriate for cer-
Heart Pancreatic Digest 3.0 g tain articles and will be specified in the individual monographs.
Yeast Extract 5.0 g In some instances, the viscosity of a material to be tested may be
Maize Starch 1.0 g sufficiently high so as to preclude its analysis by either test method. In
Sodium Chloride 5.0 g this event, a quantitative dilution with an appropriate diluent may be
Agar, according to gelling power 10.0–15.0 g made to decrease viscosity, as necessary, to allow the analysis to be
Purified Water 1000 mL performed.
In the tests described below for large-volume and small-volume
injections, the results obtained in examining a discrete unit or group
Hydrate the agar, and dissolve by heating to boiling with continu- of units for particulate matter cannot be extrapolated with certainty to
ous stirring. If necessary, adjust the pH so that after sterilization it is other units that remain untested. Thus, statistically sound sampling
7.3 + 0.2 at 258. Sterilize in an autoclave using a validated cycle. Al- plans based upon known operational factors must be developed if val-
low to cool to 458 to 508; add, where necessary, gentamicin sulfate id inferences are to be drawn from observed data to characterize the
corresponding to 20 mg of gentamicin base, and pour into Petri dish- level of particulate matter in a large group of units. Sampling plans
es. should be based on consideration of product volume, numbers of par-

.(Official May 1, 2009) ticles historically found to be present in comparison to limits, particle
.2&2S (USP29)
size distribution of particles present, and variability of particle counts
between units..2
Physical Tests and Delete the following:
Determinations .LIGHT OBSCURATION PARTICLE COUNT TEST
USP Reference Standards h11i—USP Particle Count RS.

The test applies to large-volume injections labeled as containing
more than 100 mL, unless otherwise specified in the individual mono-
graph. It counts suspended particles that are solid or liquid. This test
h788i PARTICULATE MATTER IN applies also to single-dose or multiple-dose small-volume injections
labeled as containing 100 mL or less that are either in solution or in
INJECTIONS solution constituted from sterile solids, where a test for particulate
matter is specified in the individual monograph. Products for which
the individual monograph specifies that the label states that the prod-
uct is to be used with a final filter are exempt from these requirements.
.Particulate matter consists of mobile, randomly-sourced, extrane- Test Apparatus
ous substances, other than gas bubbles, that cannot be quantitated by The apparatus is an electronic, liquid-borne particle counting sys-
chemical analysis due to the small amount of material that it repre- tem that uses a light-obscuration sensor with a suitable sample-
sents and to its heterogeneous composition. Injectable solutions, in- feeding device. A variety of suitable devices of this type are commer-
cluding solutions constituted from sterile solids intended for cially available. It is the responsibility of those performing the test to
parenteral use, is essentially free from particulate matter that can be ensure that the operating parameters of the instrumentation are appro-
observed on visual inspection. The tests described herein are physical priate to the required accuracy and precision of the test result, and that
tests performed for the purpose of enumerating subvisible extraneous adequate training is provided for those responsible for the technical
particles within specific size ranges. performance of the test.
Microscopic and light obscuration procedures for the determina- It is important to note that for Pharmacopeial applications the ulti-
tion of particulate matter are given herein. This chapter provides a test mate goal is that the particle counter reproducibly size and count par-
approach in two stages. The injection is first tested by the light ob- ticles present in the injectable material under investigation. The
scuration procedure (stage 1). If it fails to meet the prescribed limits, it instruments available range from systems where calibration and other
must pass the microscopic procedure (stage 2) with its own set of test
Pharmacopeial Forum
components of standardization must be carried out by manual proce- SAMPLE FLOW RATE
dures to sophisticated systems incorporating hardware- or software-
based functions for the standardization procedures. Thus, it is not Verify that the flow rate is within the manufacturer’s specifications
possible to specify exact methods to be followed for standardization for the sensor used. This may be accomplished by using a calibrated
of the instrument, and it is necessary to emphasize the required end stopwatch to measure the time required for the instrument to with-
result of a standardization procedure rather than a specific method for draw and count a specific sample volume (i.e., the time between be-
obtaining this result. This section is intended to emphasize the criteria ginning and ending of the count cycle as denoted by instrument
that must be met by a system rather than specific methods to be used indicator lights or other means). Sensors may be operated accurately
in their determination. It is the responsibility of the user to apply the over a range of flow rates. Perform the Test Procedure at the same
various methods of standardization applicable to a specific instru- flow rate as that selected for calibration of the instrument.
ment. Critical operational criteria consist of the following.
Sensor Concentration Limits—Use an instrument that has a con-
centration limit (the maximum number of particles per mL) identified CALIBRATION
by the manufacturer that is greater than the concentration of particles
in the test specimen to be counted. The vendor-certified concentration Use one of the following methods.
limit for a sensor is specified as that count level at which coincidence Manual Method—Calibrate the instrument with a minimum of
counts due to simultaneous presence of two or more particles in the three calibrators, each consisting of near-monosize polystyrene
sensor view volume comprise less than 10% of the counts collected spheres having diameters of about 10, 15, and 25 mm, in an aqueous
for 10-mm particles. vehicle.* The calibrator spheres must have a mean diameter of within
Sensor Dynamic Range—The dynamic range of the instrument 5% of the 10-, 15-, and 25-mm nominal diameters and be standardized
used (range of sizes of particles that can be accurately sized and against materials traceable to NIST standard reference materials. The
counted) must include the smallest particle size to be enumerated in number of spheres counted must be within the sensor’s concentration
the test articles. limit. Prepare suspensions of the calibrator spheres in water at a con-
centration of 1000 to 5000 particles per mL, and determine the chan-
nel setting that corresponds to the highest count setting for the sphere
distribution. This is determined by using the highest count threshold
Instrument Standardization setting to split the distribution into two bins containing equal numbers
The following discussion of instrument standardization emphasiz- of counts, with the instrument set in the differential count mode (mov-
es performance criteria rather than specific methods for calibrating or ing window half-count method). Use only the central portion of the
standardizing a given instrument system. This approach is particular- distribution in this calculation to avoid including asymmetrical por-
ly evident in the description of calibration, where allowance must be tions of the peak. The portion of the distribution, which must be di-
made for manual methods as well as those based on firmware, soft- vided equally, is the count window. The window is bounded by
ware, or the use of electronic testing instruments. Appropriate instru- threshold settings that will define a threshold voltage window of
ment qualification is essential to performance of the test according to +20% around the mean diameter of the test spheres. The window
requirements. Since different brands of instruments may be used in is intended to include all single spheres, taking into account the stan-
the test, the user is responsible for ensuring that the counter used is dard deviation of the spheres and the sensor resolution, while exclud-
operated according to the manufacturer’s specific instructions; the ing noise and aggregates of spheres. The value of 20% was chosen
principles to be followed to ensure that instruments operate within based on the worst-case sensor resolution of 10% and the worst-case

acceptable ranges are defined below. standard deviation of the spheres of 10%. Since the thresholds are
The following information for instrument standardization helps en- proportional to the area of the spheres rather than the diameter, the
sure that the sample volume accuracy, sample flow rate, particle size lower and upper voltage settings are determined by the equations:
response curve, sensor resolution, and count accuracy are appropriate VL = 0.64VS
to performance of the test. Conduct these procedures at intervals of
not more than six months. in which VL is the lower voltage setting and VS is the voltage at the
peak center, and
VU = 1.44VS
SAMPLE VOLUME ACCURACY
in which VU is the upper voltage setting.
Since the particle count from a sample aliquot varies directly with Once the center peak thresholds are determined, use these thresh-
the volume of fluid sampled, it is important that the sampling accu- olds for the standards to create a regression of log voltage versus log
racy is known to be within a certain range. For a sample volume de- particle size, from which the instrument settings for the 10- and
termination, determine the dead (tare) volume in the sample feeder 25-mm sizes can be determined.
with filtered distilled or deionized water that has been passed through Automated Method—The calibration (size response) curve may
a filter having a 1.2-mm or finer porosity. Transfer a volume of filtered be determined for the instrument-sensor system by the use of vali-
distilled or deionized water that is greater than the sample volume to a dated software routines offered by instrument vendors; these may
container, and weigh. Withdraw through the sample feeding device a be included as part of the instrument software or used in conjunction
volume that is appropriate for the specific sampler, and again weigh with a microcomputer interfaced to the counter. The use of these au-
the container. Determine the sample volume by subtracting the tare tomated methods is appropriate if the vendor supplies written certifi-
volume from the combined sample plus tare volumes. Verify that cation that the software provides a response curve equivalent to that
the value obtained is within 5% of the appropriate sample volume attained by the manual method and if the automated calibration is val-
for the test. Alternatively, the sample volume may be determined us- idated as necessary by the user.
ing a suitable Class A graduated cylinder (see Volumetric Apparatus
h31i). [NOTE—Instruments of this type require a variable tare volume. Electronic Method—Using a multichannel peak height analyzer,
This is the amount of sample withdrawn prior to counting. This vol- determine the center channel of the particle counter pulse response for
ume may be determined for syringe-operated samplers by setting the each standard suspension. This peak voltage setting becomes the
sample volume to zero and initiating sampling, so that the only vol- threshold used for calculation of the voltage response curve for the
ume of solution drawn is the tare. Subtract the tare volume from the instrument. The standard suspensions to be used for the calibration
total volume of solution drawn in the sampling cycle to determine the are run in order, and median pulse voltages for each are determined.
sample volume.] These thresholds are then used to generate the size response curve
manually or via software routines. The thresholds determined from
the multichannel analyzer data are then transferred to the counter to
*
ASTM standard F658-87 provides useful discussions pertaining to calibra-
tion procedures applying near-monosize latex spheres.
Pharmacopeial Forum
complete the calibration. If this procedure is used with a comparator- PARTICLE COUNTING ACCURACY
based instrument, the comparators of the counter must be adjusted
accurately beforehand. Determine the particle counting accuracy of the instrument, using
Method 1 (for small-volume injections) or Method 2 (for large-
volume injections).
SENSOR RESOLUTION Method 1—
Procedure—Prepare the suspension and blank using the USP Par-
The particle size resolution of the instrumental particle counter is ticle Count RS. With the instrument set to count in the cumulative
dependent upon the sensor used and may vary with individual sensors (total) mode, collect counts at settings of greater than or equal to
of the same model. Determine the resolution of the particle counter 10 mm and greater than or equal to 15 mm. Mix the blank by inverting
for 10-mm particles using the 10-mm calibrator spheres. The relative 25 times within 10 seconds, and degas the mixture by sonicating (at
standard deviation of the size distribution of the standard particles 80 to 120 watts) for about 30 seconds or by allowing to stand. Re-
used is not more than 5%. Acceptable methods of determining parti- move the closure from the container, and gently stir the contents by
cle size resolution are (1) manual determination of the amount of peak hand-swirling or by mechanical means, taking care not to introduce
broadening due to instrument response; (2) using an electronic meth- air bubbles or contamination. Stir continuously throughout the anal-
od of measuring and sorting particle sensor voltage output with a mul- ysis. Withdraw directly from the container three consecutive volumes
tichannel analyzer; and (3) automated methods. of not less than 5 mL each, obtain the particle counts, and discard the
Manual Method—Adjust the particle counter to operate in the cu- data from the first portion. [NOTE—Complete the procedure within
mulative mode or total count mode. Refer to the calibration curve ob- five minutes.] Repeat the procedure, using the suspension in place
tained earlier, and determine the threshold voltage for the 10-mm of the blank. From the averages of the counts resulting from the anal-
spheres. Adjust 3 channels of the counter to be used in the calibration ysis of the two portions of the suspension at greater than or equal to
procedure as follows: 10 mm and from the analysis of the two portions of the blank at greater
Channel 1 is set for 90% of the threshold voltage. than or equal to 10 mm, calculate the number of particles in each mL
Channel 2 is set for the threshold voltage. by the formula:
Channel 3 is set for 110% of the threshold voltage.
Draw a sample through the sensor, observing the count in Channel (PS – PB) / V
2. When the particle count in that channel has reached approximately in which PS is the average particle count obtained from the suspen-
1000, stop counting, and observe the counts in Channels 1 and 3. sion; PB is the average particle count obtained from the blank; and V is
Check to see if the Channel 1 count and the Channel 3 count are the average volume, in mL, of the 4 portions tested. Repeat the cal-
1.68 + 10% and 0.32 + 10%, respectively, of the count in Channel culations, using the results obtained at the setting of not less than 15
2. If not, adjust Channel 1 and Channel 3 thresholds to meet these mm.
criteria. When these criteria have been satisfied, draw a sample of sus- Interpretation—The instrument meets the requirements for Parti-
pension through the counter until the counts in Channel 2 have cle Counting Accuracy if the count obtained at greater than or equal
reached approximately 10,000, or until an appropriate volume (e.g., to 10 mm and the ratio of the counts obtained at greater than or equal
10 mL) of the sphere suspension has been counted. Verify that Chan- to 10 mm to those obtained at greater than or equal to 15 mm conform
nel 1 and Channel 3 counts are 1.68 + 3% and 0.32 + 3%, respec- to the values that accompany the USP Particle Count RS. If the in-
tively, of the count in Channel 2. strument does not meet the requirements for Particle Counting Accu-
Record the particle size for the thresholds just determined for
racy, repeat the procedure using the remaining suspension and blank.
Channels 1, 2, and 3. Subtract the particle size for Channel 2 from If the results of the second test are within the limits given above, the
the size for Channel 3. Subtract the particle size for Channel 1 from instrument meets the requirements of the test for Particle Counting
the size for Channel 2. The values so determined are the observed Accuracy. If on the second attempt the system does not meet the re-
standard deviations on the positive and negative side of the mean quirements of the test, determine and correct the source of the fail-
count for the 10-mm standard. Calculate the percentage of resolution ures, and retest the instrument.
of the sensor by the formula:
Method 2—
Procedure—Using standard calibrator spheres having a nominal
diameter of 15 to 30 mm, prepare a suspension containing between
50 and 200 particles per mL. Degas the suspension by sonicating
(at 80 to 120 watts) for about 30 seconds or by allowing to stand.
Properly suspend the particles by stirring gently, and perform five
in which SO is the highest observed standard deviation determined for counts on 5-mL volumes of the suspension, using the particle counter
the sphere; SS is the supplier’s reported standard deviation for the 10-mm size threshold. Obtain the mean cumulative particle count per
spheres; and D is the diameter, in mm, of the spheres as specified mL. Pipet a volume of this suspension containing 250 to 500 particles
by the supplier. The resolution is not more than 10%. into a filter funnel prepared as described for Filtration Apparatus un-
Automated Method—Software that allows for the automated de- der Microscopic Particle Count Test. After drying the membrane,
termination of sensor resolution is available for some counters. This count the total number of standard spheres collected on the membrane
software may be included in the instrument or used in conjunction filter. This count should be within 20% of the mean instrumental
with a microcomputer interfaced to the counter. The use of these au- count per mL for the suspension.
tomated methods is appropriate if the vendor supplies written certifi-
cation that the software provides a resolution determination
equivalent to the manual method and if the automated resolution de- Test Environment
termination is validated as necessary by the user.
Electronic Method—Record the voltage output distribution of the Perform the test in an environment that does not contribute any
particle sensor, using a multichannel analyzer while sampling a sus- significant amount of particulate matter. Specimens must be cleaned
pension of the 10-mm particle size standard. To determine resolution, to the extent that any level of extraneous particles added has a negli-
move the cursor of the multichannel analyzer up and down the elec- gible effect on the outcome of the test. Preferably, the test specimen,
tric potential scale from the median pulse voltage to identify a chan- glassware, closures, and other required equipment are prepared in an
nel on each side of the 10-mm peak that has approximately 61% of the environment protected by high-efficiency particulate air (HEPA) fil-
counts observed in the center channel. Use of the counter size re- ters, and nonshedding garments and powder-free gloves are worn
sponse curve to convert the mV values of these two channels to par- throughout the preparation of samples.
ticle sizes provides the particle size at within 1 standard deviation of Cleanse glassware, closures, and other required equipment, prefer-
the 10-mm standard. Use these values to calculate the resolution as ably by immersing and scrubbing in warm, nonionic detergent solu-
described under Manual Method. tion. Rinse in flowing tap water, and then rinse again in flowing
filtered distilled or deionized water. Organic solvents may also be
used to facilitate cleaning. [NOTE—These steps describe one way to
clean equipment; alternatively, particulate-free equipment may be ob-
Pharmacopeial Forum
tained from a suitable vendor.] Finally, rinse the equipment in filtered the light obscuration counter sensor. Discard the data from the first
distilled or deionized water, using a hand-held pressure nozzle with portion. [NOTE—For some products, a pool of 15 or more units may
final filter or other appropriate filtered water source, such as distilled be necessary to achieve a pool volume sufficient for three 5-mL sam-
or deionized water passed through a capsule filter having a 1.2-mm or ple aliquots. Smaller sample aliquots (i.e., less than 5 mL) can be used
finer porosity. if the assay result obtained with the smaller aliquots is validated to
To collect blank counts, use a cleaned vessel of the type and vol- give an assessment of batch suitability equivalent to that obtained
ume representative of that to be used in the test. Place a 50-mL vol- with the 5-mL aliquots specified above.]
ume of filtered distilled or deionized water in the vessel, and agitate Volume in Container 25 mL or More—Prepare the containers as
the water sample in the cleaned glassware by inversion or swirling. directed under Test Preparation. Mix and suspend the particulate
[NOTE—A smaller volume, consistent with the article to be counted, matter in each unit by inverting the unit 20 times. Degas the solution
can be used.] Degas by sonicating (at 80 to 120 watts) for about 30 by sonicating for about 30 seconds or by allowing the solution to
seconds or by allowing to stand. Swirl the vessel containing the water stand undisturbed until it is free from air bubbles. Remove the closure
sample by hand or agitate by mechanical means to suspend particles. of the unit or effect entry by other means so that the counter probe can
Withdraw and obtain the particle counts for three consecutive sam- be inserted into the middle of the solution. Gently stir the contents of
ples of not less than 5 mL each, disregarding the first count. If more the unit by hand-swirling or by mechanical means. Withdraw not
than 10 particles of 10-mm or greater size, or more than 2 particles of fewer than three aliquots, each not less than 5 mL in volume, into
25-mm or greater size are observed in the combined 10-mL sample, the light obscuration counter sensor. Discard the data from the first
the environment is not suitable for particulate analysis: the filtered portion.
distilled or deionized water and glassware have not been properly pre- Dry or Lyophilized Preparations—Prepare the containers as di-
pared or the counter is generating spurious counts. In this case, repeat rected under Test Preparation. Open each container, taking care not to
the preparatory steps until conditions of analysis are suitable for the contaminate the opening or cover. Constitute as directed under Test
test. Preparation, using the specified volume of filtered water or an appro-
priate filtered diluent if water is not suitable. Replace the closure, and
manually agitate the container sufficiently to ensure dissolution of the
Test Procedure drug. [NOTE—For some dry or lyophilized products, it may be neces-
sary to let the units stand for a suitable interval, and then agitate again
TEST PREPARATION to effect complete dissolution.] After the drug in the constituted sam-
ple is completely dissolved, mix and suspend the particulate matter
Prepare the test specimens in the following sequence. Outside of present in each unit by inverting it 20 times prior to analysis. Proceed
the laminar enclosure, remove outer closures, sealing bands, and as directed for the appropriate unit volume under Liquid Prepara-
any loose or shedding paper labels. Rinse the exteriors of the con- tions, and analyze by withdrawing a minimum of three aliquots, each
tainers with filtered distilled or deionized water as directed under Test not less than 5 mL in volume, into the light obscuration counter sen-
Environment. Protect the containers from environmental contamina- sor. Discard the data from the first portion.
tion until analyzed. Withdraw the contents of the containers under test Products Packaged with Dual Compartments Constructed to
in a manner least likely to generate particles that could enter the sam- Hold the Drug Product and a Solvent in Separate Compart-
ple. Contents of containers with removable stoppers may be with- ments—Prepare the units to be tested as directed under Test Prepa-
drawn directly by removing the closures. Sampling devices having ration. Mix each unit as directed in the labeling, activating and
a needle to penetrate the unit closure may also be employed. Products agitating so as to ensure thorough mixing of the separate components

packaged in flexible plastic containers may be sampled by cutting the and drug dissolution. Degas the units to be tested by sonicating or by
medication or administration port tube or a corner from the unit with a allowing the solution to stand undisturbed until it is free from any air
suitably cleaned razor blade or scissors. bubbles. Proceed as directed for the appropriate unit volume under
Dry or lyophilized products may be constituted either by removing Liquid Preparations, and analyze by withdrawing a minimum of
the closure to add diluent or by injecting diluent with a hypodermic three aliquots, each not less than 5 mL in volume, into the light ob-
syringe having a 1.2-mm or finer syringe filter. If test specimens are to scuration counter sensor. Discard the data from the first portion.
be pooled, remove the closure and empty the contents into a clean
container. Products Labeled ‘‘Pharmacy Bulk Package Not for Direct In-
The number of test specimens must be adequate to provide a sta- fusion’’—Proceed as directed for Liquid Preparations where the vol-
tistically sound assessment of whether a batch or other large group of ume is 25 mL or more. Calculate the test result on a portion that is
units represented by the test specimens meets or exceeds the limits. If equivalent to the maximum dose given in the labeling. For example,
the volume in the container is less than 25 mL, test a solution pool of if the total bulk package volume is 100 mL and the maximum dose
10 or more units. Single small-volume injection units may be tested if volume is 10 mL, then the average light obscuration particle count per
the individual unit volume is 25 mL or more. For large-volume injec- mL would be multiplied by 10 to obtain the test result based on the
tions, individual units are tested. For large-volume injections or for 10-mL maximum dose. [NOTE—For the calculations of test results,
small-volume injections where the individual unit volume is 25 mL consider this maximum dose portion to be the equivalent of the con-
or more, fewer than 10 units may be tested, based on the definition of tents of one full container.]
an appropriate sampling plan.
Calculations
PRODUCT DETERMINATION
Pooled Samples (Small-Volume Injections)—Average the counts
Depending upon the dosage form being tested, proceed as directed from the two or more aliquot portions analyzed. Calculate the number
under the appropriate category below. of particles in each container by the formula:
Liquid Preparations— PVT / VAn
Volume in Container Less than 25 mL—Prepare the containers as
directed under Test Preparation. Mix and suspend the particulate in which P is the average particle count obtained from the portions
matter in each unit by inverting the unit 20 times. [NOTE—Because analyzed; VT is the volume of pooled sample, in mL; VA is the volume,
of the small volume of some products, it may be necessary to agitate in mL, of each portion analyzed; and n is the number of containers
the solution more vigorously to suspend the particles properly.] In a pooled.
cleaned container, open and combine the contents of 10 or more units
to obtain a volume of not less than 20 mL. Degas the pooled solution
by sonicating for about 30 seconds or by allowing the solution to
stand undisturbed until it is free from air bubbles. Gently stir the con-
tents of the container by hand-swirling or by mechanical means, tak-
ing care not to introduce air bubbles or contamination. Withdraw a
minimum of three aliquots, each not less than 5-mL in volume, into
Pharmacopeial Forum
Individual Samples (Small-Volume Injections)—Average the to accept and focus an eyepiece graticule. The microscope must have
counts obtained for the 5-mL or greater aliquot portions from each a mechanical stage capable of holding and traversing the entire filtra-
separate unit analyzed, and calculate the number of particles in each tion area of a 25-mm or 47-mm membrane filter.
container by the formula: Illuminators—Two illuminators are required. One is an external,
PV / VA focusable auxiliary illuminator that can be adjusted to give incident
oblique illumination at an angle of 108 to 208. The other is an epi-
in which P is the average particle count obtained from the portions scopic brightfield illuminator internal to the microscope. Both illumi-
analyzed; V is the volume, in mL, of the tested unit; and VA is the nators must be of a wattage sufficient to provide a bright, even source
volume, in mL, of each portion analyzed. of illumination and may be equipped with blue daylight filters to de-
Individual Unit Samples (Large-Volume Injections)—Average crease operator fatigue during use.
the counts obtained for the two or more 5-mL aliquot portions taken Circular Diameter Graticule—Use a circular diameter graticule
from the solution unit. Calculate the number of particles in each mL (see Figure 1) matched to the microscope model objective and eye-
of Injection taken by the formula: piece such that the sizing circles are within 2% of the stated size at the
plane of the stage.
P/V
in which P is the average particle count for an individual 5 mL or
greater sample volume; and V is the volume, in mL, of the portion
taken.
For all types of product, if the tested material has been diluted to
effect a decrease in viscosity, the dilution factor must be accounted
for in the calculation of the final test result.
Interpretation
The injection meets the requirements of the test if the calculated
number of particles present in each discrete unit tested or in each
pooled sample tested does not exceed the appropriate value listed
in Table 1. If the average number of particles exceeds the limit, test
the article by the Microscopic Particle Count Test.
Table 1. Light Obscuration Test Particle Count

10 mm 25 mm
Small-Volume Injections 6000 600 per container
Large-Volume Injections 25 3 per mL
Fig. 1. Circular diameter graticule. The large circle divided by

.2 crosshairs into quadrants is designated the graticule field of view
(GFOV). Transparent and black circles having 10-mm and 25-mm
Delete the following: diameters at 1006 are provided as comparison scales for particle
sizing.
.MICROSCOPIC PARTICLE COUNT TEST
Micrometer—Use a stage micrometer, graduated in 10-mm incre-
The microscopic particulate matter test may be applied to both ments, that is certified by NIST.
large-volume and small-volume injections. This test enumerates sub- Filtration Apparatus—Use a filter funnel suitable for the volume
visible, essentially solid, particulate matter in these products on a per to be tested, having a minimum diameter of about 21 mm. The funnel
volume or per container basis, after collection on a microporous is made of plastic, glass, or stainless steel. Use a filter support made of
membrane filter. Some articles cannot be tested meaningfully by light stainless steel screen or sintered glass as the filtration diffuser. The
obscuration. In such cases, individual monographs specify only this filtration apparatus is equipped with a vacuum source, a solvent dis-
microscopic assay. Solutions exempted from analysis using the mi- penser capable of delivering solvents filtered at 1.2-mm or finer reten-
croscopic assay are identified on a monograph basis. Examples are tion rating at a range of pressures from 10 psi to 80 psi, and
solutions that do not filter readily because of high viscosity (e.g., con- membrane filters (25 mm or 47 mm nongridded or gridded, black
centrated dextrose, starch solutions, or dextrans). In performance of or dark gray, or of suitable material compatible with the product, with
the microscopic assay do not attempt to size or enumerate amorphous, a 1.0-mm or finer porosity). Use blunt forceps to handle membrane
semiliquid, or otherwise morphologically indistinct materials that filters.
have the appearance of a stain or discoloration on the membrane sur-
face. These materials show little or no surface relief and present a ge-
latinous or film-like appearance. Since in solution this material Test Environment
consists of units on the order of 1 mm or less, which may be counted
only after aggregation or deformation on an analytical membrane, in- Use a laminar flow hood or other laminar airflow enclosure, having
terpretation of enumeration may be aided by testing a sample of the a capacity sufficient to envelop the area in which the analysis is pre-
solution by the light obscuration particle count method. pared, and containing HEPA-filtered air having not more than 100
particles (0.5 mm or larger) per cubic foot. For the blank determina-
tion, deliver a 50-mL volume of filtered distilled or deionized water to
Test Apparatus the filtration funnel. Apply vacuum, and draw the entire volume of
water through the membrane filter. Remove the membrane from the
Microscope—Use a compound binocular microscope that corrects filter funnel base, and place atop a strip of double-sided tape in a Petri
for changes in interpupillary distance by maintaining a constant tube slide or Petri dish. After allowing the membrane to dry, examine it
length. The objective and eyepiece combination of lenses must give a microscopically at a magnification of 1006. If not more than 20 par-
magnification of 100 + 106. The objective must be of 106 nominal ticles 10 mm or larger in size and 5 particles 25 mm or larger are pre-
magnification, a planar achromat or better in quality, with a minimum sent within the filtration area, the background particle level is
numerical aperture of 0.25. In addition, the objective must be com- sufficiently low for performance of the microscopic assay.
patible with an episcopic illuminator attachment. The eyepieces must
be of 106 magnification. In addition, one eyepiece must be designed
Pharmacopeial Forum
Throughout this procedure, it is preferable to use powder-free Remove a membrane filter from its container, using ultracleaned
gloves and thoroughly clean glassware and equipment. Prior to con- blunt forceps. Use a low pressurized stream of filtered purified water
ducting the test, clean the work surfaces of the laminar flow enclosure to wash both sides of the filter thoroughly by starting at the top and
with an appropriate solvent. Glassware and equipment should be sweeping back and forth to the bottom. Assemble the cleaned filtra-
rinsed successively with a warm, residue-free solution of detergent, tion apparatus with the diffuser on top of the filtration base, placing
hot water, filtered distilled or deionized water, and isopropyl alcohol. the clean membrane filter on top of the diffuser. Place the funnel as-
[NOTE—Prior to use, pass the distilled or deionized water and the iso- sembly on top of the filtration base, and lock it into place.
propyl alcohol through filters having a 1.2-mm or finer porosity.] Per-
form the rinsing under the laminar flow enclosure equipped with
HEPA filters. Allow the glassware and filtration apparatus to dry un- Test Procedure
der the hood, upstream of all other operations. Preferably, the hood is
located in a separate room that is supplied with filtered air-condi- TEST PREPARATIONS
tioned air and maintained under positive pressure with respect to
the surrounding areas. Proceed as directed for Test Preparation under the Light Obscura-
tion Particle Count Test, beginning with ‘‘Prepare the test specimens
in the following sequence,’’ and ending with ‘‘For large-volume in-
MICROSCOPE PREPARATION jections, individual units are tested.’’ For small-volume injections
containing a volume of 25 mL or more and tested individually and
Place the auxiliary illuminator close to the microscope stage, fo- for large-volume injections, the entire unit volume is tested. For
cusing the illuminator to give a concentrated area of illumination large-volume injections or for small-volume injections where the in-
on a filter membrane positioned on the microscope stage. Adjust dividual unit volume is 25 mL or more, fewer than 10 units may be
the illuminator height so that the angle of incidence of the light is tested, based on the definition of an appropriate sampling plan.
108 to 208 with the horizontal. Using the internal episcopic brightfield
illuminator, fully open the field and aperture diaphragms. Center the
lamp filament, and focus the microscope on a filter containing parti- PRODUCT DETERMINATION
cles. Adjust the intensity of reflected illumination until particles are
clearly visible and show pronounced shadows. Adjust the intensity of Depending upon the dosage form being tested, proceed as directed
episcopic illumination to the lowest setting, then increase the inten- under the appropriate category below.
sity of episcopic illumination until shadows cast by particles show the Liquid Preparations—Thoroughly mix the units to be tested by
least perceptible decrease in contrast. inverting 20 times. Open the units in a manner consistent with the
generation of the lowest possible numbers of background particles.
For products less than 25 mL in volume, open and combine the con-
OPERATION OF CIRCULAR DIAMETER GRATICULE tents of 10 or more units in a cleaned container. Filter large-volume
injection units individually. Small-volume injection units having a
The relative error of the graticule used must initially be measured volume of 25 mL or more may be filtered individually.
with an NIST-certified stage micrometer. To accomplish this, align Transfer to the filtration funnel the total volume of a solution pool
the graticule micrometer scale with the stage micrometer so that they or of a single unit, and apply vacuum. If the volume of solution to be
are parallel. (Compare the scales, using as large a number of gradu- filtered exceeds the volume of the filtration funnel, add, stepwise, a

ations on each as possible.) Read the number of graticule scale divi- portion of the solution until the entire volume is filtered. If the partial
sions, GSD, compared to stage micrometer divisions, SMD. Calculate count procedure is to be used (see Partial Count Procedure under
the relative error by the formula: Enumeration of Particles), do not allow the liquid volume in the fil-
100[(GSD – SMD) / SMD] tration funnel to drop below approximately one-half of the funnel vol-
ume between refills. [NOTE—Use a filter funnel appropriate to the
A relative error of +2% is acceptable. The basic technique of mea- volume of solution if a partial count procedure is to be employed.
surement applied with the use of the circular diameter graticule is to This is necessary to ensure even distribution of particles on the ana-
transform mentally the image of each particle into a circle and then lytical membrane.]
compare it to the 10- and 25-mm graticule reference circles. The siz- After the last addition of solution, begin rinsing the walls of the
ing process is carried out without superimposing the particle on the funnel by directing a low-pressure stream of filtered distilled or de-
reference circles; particles are not moved from their locations within ionized water in a circular pattern along the walls of the funnel, and
the graticule field of view (the large circle) for comparison to the ref- stop rinsing the funnel before the volume falls below about one-
erence circles. Compare the area of the particle being sized to that of fourth of the fill level. Maintain the vacuum until all the liquid in
the black or transparent circles. Use the area of the clear graticule ref- the funnel is gone.
erence circles to size white or transparent particles. Use the area of the Remove the filtration funnel from the filtration base while main-
black reference circles to size dark particles. taining vacuum, then turn the vacuum off, and remove the filter
Rotate the graticule in the right microscope eyepiece so that the membrane with blunt forceps. Place the filter in a Petri dish or similar
linear scale is located at the bottom of the field of view, bringing container, secure in place with double-sided tape, and label with sam-
the graticule into sharp focus by adjusting the right eyepiece diopter ple identification. Allow the filter to air-dry in the laminar-flow enclo-
ring while viewing an out-of-focus specimen. Focus the microscope sure with the cover ajar.
on a specimen, looking through the right eyepiece only. Then, look- Dry or Lyophilized Preparations—To test a dry powder vial or
ing through the left eyepiece, adjust the left eyepiece diopter to bring similar container of drug powder, constitute the material with an ap-
the specimen into sharp focus. propriate diluent, using the method least likely to introduce extrane-
ous contamination, as directed for Test Preparation under Light
Obscuration Particle Count Test. Using a solution pool of 10 or more
PREPARATION OF FILTRATION APPARATUS units, or the desired number of individual units, proceed as directed
for Liquid Preparations.
Preferably, wash the filtration funnel, base, and diffuser in a solu- Products Packaged with Dual Compartments Constructed to
tion of liquid detergent and hot water. Rinse with hot water. Follow- Hold the Drug Product and a Solvent in Separate Compart-
ing the hot water rinse, apply a second rinse with filtered distilled or ments—Activate each unit as directed in the labeling, agitating the
deionized water, using a pressurized jet of water over the entire exte- contents sufficiently to ensure thorough mixing of the separate com-
rior and interior surfaces of the filtration apparatus. Repeat the pres- ponents, and then proceed as directed for Liquid Preparations.
surized rinse procedure using filtered isopropyl alcohol. Finally,
using the pressurized rinser, rinse the apparatus with filtered distilled Pharmacy Bulk Packages or Multiple-Dose Containers—For
or deionized water. Products Labeled ‘‘Pharmacy Bulk Package—Not for Direct Infu-
sion,’’ or for multiple-dose containers, proceed as directed for Liquid
Preparations, filtering the total unit volume.
Pharmacopeial Forum
Calculate the test result on a portion that is equal to the maximum controls to a whole number at the starting position at the center right
dose given in the labeling. Consider this portion to be the equivalent edge of the filtration area, then each GFOV will be one whole divi-
of the contents of one full container. For example, if the total bulk sion of movement of the x-stage positioning control. If the top of the
package volume is 100 mL and the maximum dose listed is 10 mL, filtration area is reached before the desired number of GFOVs is
the microscopic total unit volume count test result would be multi- reached, begin again at the right center edge of the filtration area
plied by 0.1 to obtain the test result for the 10-mL dose volume. one GFOV lower than the first time. This time move downward on
[NOTE—For calculation of the test result, consider this portion to be the membrane when the end of a row of GFOVs is reached. Continue
the equivalent of the contents of one full container.] as before until the number of GFOVs is complete.
For large-volume injections, if a partial count procedure for the
10-mm and 25-mm size ranges is used, calculate the particles
Enumeration of Particles per mL by the formula:
The microscopic test described in this section is flexible in that it PAT / APV
can count, in particles per mL, specimens containing 1 particle per in which P is the number of particles counted; AT is the filtration area,
mL as well as those containing significantly higher numbers of par- in mm2, of the membrane; AP is the partial area counted, in mm2,
ticles per mL. This method may be used where all particles on an based on the number of graticule fields counted; and V is the volume,
analysis membrane surface are counted or where only those particles in mL, of solution filtered. For a solution pool (for small-volume in-
on some fractional area of a membrane surface are counted. jection units containing less than 25 mL) or for a single unit of a
small-volume injection, calculate the number of particles per unit
by the formula:
TOTAL COUNT PROCEDURE
PAT / APn
In performance of a total count, the graticule field of view (GFOV) in which n is the number of units counted (1 in the case of an indi-
defined by the large circle of the graticule is ignored, and the vertical vidual unit); and the other terms are as defined above.
crosshair is used. Scan the entire membrane from right to left in a path For all types of product, if the tested material has been diluted to
that adjoins but does not overlap the first scan path. Repeat this pro- effect a decrease in viscosity, the dilution factor must be accounted
cedure, moving from left to right to left until all particles on the for in the calculation of the final test result.
membrane are counted. Record the total number of particles that
are 10 mm or larger and the number that are 25 mm or larger. For
large-volume injections, calculate the particle count, in particles per
mL, for the unit tested by the formula: Interpretation
P/V The injection meets the requirements of the test if the number of
particles present (actual or calculated) in each discrete unit tested or in
where P is the total number of particles counted; and V is the volume, each pooled sample tested does not exceed the appropriate value list-
in mL, of the solution. For small-volume injections, calculate the pared in Table 2.
ticle count, in particles per container, by the formula:
P/n Table 2. Microscopic Method Particle Count
in which P is the total number of particles counted; and n is the num- 10 mm 25 mm
ber of units pooled (1 in the case of an individual unit).
Small-Volume Injections 3000 300 per container
Large-Volume Injections 12 2 per mL
PARTIAL COUNT PROCEDURE
.2
If a partial count of particles on a membrane is to be performed, the
analyst must first ensure that an even distribution of particles is pre-
sent on the membrane. This is assessed by rapid scanning in order to Add the following:
look for clumps of particles. None should be present. Count the
10-mm or larger particles in one GFOV at the edge of the filtration .Particulate matter in injections and parenteral infusions consists
area as well as those in the center of the membrane. The number of
10-mm or larger particles in the GFOV with the highest total particle of mobile undissolved particles, other than gas bubbles, unintention-
count is not more than twice that of the GFOV with the lowest particle ally present in the solutions.
count. Reject a filter failing these criteria, and prepare another if a For the determination of particulate matter, two procedures, Meth-
partial count procedure is used, or, alternatively, analyze this od 1 (Light Obscuration Particle Count Test) and Method 2 (Micro-
membrane by the total count method. scopic Particle Count Test), are specified hereinafter. When
The normal number of GFOV counted for a partial count is 20. If a examining injections and parenteral infusions for subvisible particles,
smaller confidence interval about the result is desired, a larger number Method 1 is preferably applied. However, it may be necessary to test
of fields and particles may be counted. Count all particles that have a some preparations by the Light Obscuration Particle Count Test fol-
circular area diameter of 10 mm or larger and 25 mm or larger within lowed by the Microscopic Particle Count Test to reach a conclusion
the GFOV and those that are in contact with the right side of the on conformance to the requirements.
GFOV circle. Do not count particles outside of the GFOV. Ignore Not all parenteral preparations can be examined for subvisible par-
those that touch the left side of the GFOV circle. The dividing line ticles by one or both of these methods. When Method 1 is not appli-
between right and left sides of the GFOV circle is the vertical cross cable, e.g., in the case of preparations having reduced clarity or
hair. [NOTE—Make the best possible judgment on particle size without increased viscosity, the test should be carried out according to Method
changing the microscope magnification or illumination.] 2. Emulsions, colloids, and liposomal preparations are examples.
To perform a partial count of the particles on a membrane, start at Similarly, products that produce air or gas bubbles when drawn into
the right center edge of the filtration area and begin counting adjacent the sensor may also require microscopic particle count testing. If the
GFOVs. When the left edge of the filtration area is reached, move one viscosity of the preparation to be tested is sufficiently high so as to
GFOV toward the top of the filter and continue counting GFOVs by preclude its examination by either test method, a quantitative dilution
moving in the opposite direction. Moving from one GFOV to the next with an appropriate diluent may be made to decrease viscosity, as nec-
can be accomplished by one of two methods. One method is to define essary, to allow the analysis to be performed.
a landmark (particle or surface irregularity in the filter) and move over The results obtained in examining a discrete unit or group of units
one GFOV in relation to the landmark. A second method is to use the for particulate matter cannot be extrapolated with certainty to other
vernier on the microscope stage to move 1 mm between GFOVs. To units that remain untested. Thus, statistically sound sampling plans
facilitate the latter, adjust the microscope x-and y-stage positioning
Pharmacopeial Forum
must be developed if valid inferences are to be drawn from observed Powders for parenteral use are reconstituted with particle-free wa-
data to characterize the level of particulate matter in a large group of ter or with an appropriate particle-free solvent when particle-free wa-
units..2 ter is not suitable.
The number of test specimens must be adequate to provide a sta-
tistically sound assessment. For large-volume parenterals or for
Add the following: small-volume parenterals having a volume of 25 mL or more, fewer
than 10 units may be tested, using an appropriate sampling plan.
Remove four portions, not less than 5 mL each, and count the num-
. ber of particles equal to or greater than 10 mm and 25 mm. Disregard
METHOD 1. LIGHT OBSCURATION PARTICLE COUNT the result obtained for the first portion, and calculate the mean number
TEST of particles for the preparation to be examined.
Use a suitable apparatus based on the principle of light blockage
which allows an automatic determination of the size of particles and
the number of particles according to size. The definition for particle- Evaluation
free water is provided in Reagent Specifications under Reagents, In-
dicators and Solutions. For preparations supplied in containers with a nominal volume of
The apparatus is calibrated using dispersions of USP Particle more than 100 mL, apply the criteria of Test 1.A.
Count Reference Standard that consist of spherical particles of For preparations supplied in containers with a nominal volume of
known sizes between 10 mm and 25 mm. These Standard particles less than 100 mL, apply the criteria of Test 1.B.
are dispersed in particle-free water. Care must be taken to avoid ag- For preparations supplied in containers with a nominal volume of
gregation of particles during dispersion. 100 mL, apply the criteria of Test 1.A or those of Test 1.B.
If the average number of particles exceeds the limits, test the prep-
aration by the Microscopic Particle Count Test.
Test 1.A — Solutions for parenteral infusion or solutions for injec-
General Precautions tion supplied in containers with a nominal content of more than 100
mL.
The test is carried out under conditions limiting particulate matter, The preparation complies with the test if the average number of
preferably in a laminar flow cabinet. particles present in the units tested does not exceed 25 per mL equal
Very carefully wash the glassware and filtration equipment used, to or greater than 10 mm and does not exceed 3 per mL equal to or
except for the membrane filters, with a warm detergent solution, greater than 25 mm.
and rinse with abundant amounts of water to remove all traces of de- Test 1.B — Solutions for parenteral infusion or solutions for injec-
tergent. Immediately before use, rinse the equipment from top to bot- tion supplied in containers with a nominal content of less than 100
tom, outside and then inside, with particle-free water. mL.
Take care not to introduce air bubbles into the preparation to be The preparation complies with the test if the average number of
examined, especially when fractions of the preparation are being particles present in the units tested does not exceed 6000 per contain-
transferred to the container in which the determination is to be carried er equal to or greater than 10 mm and does not exceed 600 per con-
out. tainer equal to or greater than 25 mm..2
In order to check that the environment is suitable for the test, that
the glassware is properly cleaned, and that the water to be used is

particle-free, the following test is carried out: determine the particu- Add the following:
late matter in 5 samples of particle-free water, each of 5 mL, accord-
ing to the method described below. If the number of particles of 10
mm or greater size exceeds 25 for the combined 25 mL, the precau-
tions taken for the test are not sufficient. The preparatory steps must .
METHOD 2. MICROSCOPIC PARTICLE COUNT TEST
be repeated until the environment, glassware, and water are suitable
for the test. Use a suitable binocular microscope, filter assembly for retaining
particulate matter, and membrane filter for examination.
The microscope is adjusted to 100 + 10 magnifications and is
Method equipped with an ocular micrometer calibrated with an objective mi-
crometer, a mechanical stage capable of holding and traversing the
Mix the contents of the sample by slowly inverting the container 20 entire filtration area of the membrane filter, and two suitable illumi-
times successively. If necessary, cautiously remove the sealing clo- nators to provide episcopic illumination in addition to oblique illumi-
sure. Clean the outer surfaces of the container opening using a jet nation.
of particle-free water and remove the closure, avoiding any contam- The ocular micrometer is a circular diameter graticule (see Figure
ination of the contents. Eliminate gas bubbles by appropriate mea- 1) and consists of a large circle divided by crosshairs into quadrants,
sures such as allowing to stand for 2 minutes or sonicating. transparent and black reference circles 10 mm and 25 mm in diameter
For large-volume parenterals, single units are tested. For small- at 100 magnifications, and a linear scale graduated in 10-mm incre-
volume parenterals less than 25 mL in volume, the contents of 10 ments. It is calibrated using a stage micrometer that is certified by
or more units are combined in a cleaned container to obtain a volume either a domestic or international standard institution. A relative error
of not less than 25 mL; the test solution may be prepared by mixing of the linear scale of the graticule within +2% is acceptable. The
the contents of a suitable number of vials and diluting to 25 mL with large circle is designated the graticule field of view (GFOV).
particle-free water or with an appropriate particle-free solvent when
particle-free water is not suitable. Small-volume parenterals having a
volume of 25 mL or more may be tested individually.
Pharmacopeial Forum
Powders for parenteral use are constituted with particle-free water

or with an appropriate particle-free solvent when particle-free water
is not suitable.
The number of test specimens must be adequate to provide a sta-
tistically sound assessment. For large-volume parenterals or for
small-volume parenterals having a volume of 25 mL or more, fewer
than 10 units may be tested, using an appropriate sampling plan.
Wet the inside of the filter holder fitted with the membrane filter
with several mL of particle-free water. Transfer to the filtration funnel
the total volume of a solution pool or of a single unit, and apply a
vacuum. If needed, add stepwise a portion of the solution until the
entire volume is filtered. After the last addition of solution, begin
rinsing the inner walls of the filter holder by using a jet of particle-
free water. Maintain the vacuum until the surface of the membrane
filter is free from liquid. Place the membrane filter in a Petri dish,
and allow the membrane filter to air-dry with the cover slightly ajar.
After the membrane filter has been dried, place the Petri dish on the
stage of the microscope, scan the entire membrane filter under the
reflected light from the illuminating device, and count the number
of particles that are equal to or greater than 10 mm and the number
of particles that are equal to or greater than 25 mm. Alternatively, par-
tial membrane filter count and determination of the total filter count
Fig. 1. Circular diameter graticule. The large circle divided by by calculation is allowed. Calculate the mean number of particles for
crosshairs into quadrants is designated the graticule field of view the preparation to be examined.
(GFOV). Transparent and black circles having 10-mm and 25-mm The particle sizing process with the use of the circular diameter
diameters at 1006 are provided as comparison scales for particle graticule is carried out by estimating the equivalent diameter of the
sizing. particle in comparison with the 10 mm and 25 mm reference circles on
the graticule. Thereby the particles are not moved from their initial
Two illuminators are required. One is an episcopic brightfield illu- locations within the graticule field of view and are not superimposed
minator internal to the microscope, the other is an external, focusable on the reference circles for comparison. The inner diameter of the
auxiliary illuminator that can be adjusted to give reflected oblique il- transparent graticule reference circles is used to size white and trans-
lumination at an angle of 108 to 208. parent particles, while dark particles are sized by using the outer di-
The filter assembly for retaining particulate matter consists of a fil- ameter of the black opaque graticule reference circles.
ter holder made of glass or other suitable material, and is equipped In performing the Microscopic Particle Count Test, do not attempt
with a vacuum source and a suitable membrane filter. to size or enumerate amorphous, semiliquid, or otherwise morpholog-
The membrane filter is of suitable size, black or dark gray in color, ically indistinct materials that have the appearance of a stain or dis-
nongridded or gridded, and 1.0 mm or finer in nominal pore size coloration on the membrane filter. These materials show little or no
surface relief and present a gelatinous or film-like appearance. In such
cases, the interpretation of enumeration may be aided by testing a

General Precautions sample of the solution by the Light Obscuration Particle Count Test.
The test is carried out under conditions limiting particulate matter,
preferably in a laminar flow cabinet. Evaluation
Very carefully wash the glassware and filter assembly used, except
for the membrane filter, with a warm detergent solution, and rinse For preparations supplied in containers with a nominal volume of
with abundant amounts of water to remove all traces of detergent. Im- more than 100 mL, apply the criteria of Test 2.A.
mediately before use, rinse both sides of the membrane filter and the For preparations supplied in containers with a nominal volume of
equipment from top to bottom, outside and then inside, with particle- less than 100 mL, apply the criteria of Test 2.B.
free water. For preparations supplied in containers with a nominal volume of
In order to check that the environment is suitable for the test, that 100 mL, apply the criteria of Test 2.A or those of Test 2.B.
the glassware and the membrane filter are properly cleaned, and that Test 2.A — Solutions for parenteral infusion or solutions for injec-
the water to be used is particle-free, the following test is carried out: tion supplied in containers with a nominal content of more than 100
determine the particulate matter of a 50-mL volume of particle-free mL.
water according to the method described below. If more than 20 par- The preparation complies with the test if the average number of
ticles 10 mm or larger in size or if more than 5 particles 25 mm or particles present in the units tested does not exceed 12 per mL equal
larger in size are present within the filtration area, the precautions tak- to or greater than 10 mm and does not exceed 2 per mL equal to or
en for the test are not sufficient. The preparatory steps must be re- greater than 25 mm.
peated until the environment, glassware, membrane filter, and water Test 2.B — Solutions for parenteral infusion or solutions for injec-
are suitable for the test. tion supplied in containers with a nominal content of less than 100
mL.
The preparation complies with the test if the average number of
Method particles present in the units tested does not exceed 3000 per contain-
er equal to or greater than 10 mm and does not exceed 300 per con-
Mix the contents of the samples by slowly inverting the container tainer equal to or greater than 25 mm..2
20 times successively. If necessary, cautiously remove the sealing clo-
sure. Clean the outer surfaces of the container opening using a jet of
particle-free water and remove the closure, avoiding any contamina-
tion of the contents.
For large-volume parenterals, single units are tested. For small-
volume parenterals less than 25 mL in volume, the contents of 10
or more units are combined in a cleaned container; the test solution
may be prepared by mixing the contents of a suitable number of vials
and diluting to 25 mL with particle-free water or with an appropriate
particle-free solvent when particle-free water is not suitable. Small-
volume parenterals having a volume of 25 mL or more may be tested
individually.
Pharmacopeial Forum
health of the patient. Manufacturers have therefore to ensure a low

bioburden of finished dosage forms by implementing current guide-
GENERAL CHAPTERS lines on Good Manufacturing Practice during the manufacture, stor-
age, and distribution of pharmaceutical preparations.
Microbial examination of nonsterile products is performed accord-
ing to the methods given in the texts on Microbiological Examination
General Information of Nonsterile Products: Microbial Enumeration Tests h61i and Mi-
crobiological Examination of Nonsterile Products: Tests for Specified
Microorganisms h62i. Acceptance criteria for nonsterile pharmaceu-
tical products based upon the total aerobic microbial count (TAMC)
and the total combined yeasts and molds count (TYMC) are given in
Tables 1 and 2. Acceptance criteria are based on individual results or
Change to read: on the average of replicate counts when replicate counts are per-
formed (e.g., direct plating methods).
When an acceptance criterion for microbiological quality is pre-
scribed, it is interpreted as follows:
h1111i MICROBIOLOGICAL — 101 cfu: maximum acceptable count = 20;
— 102 cfu: maximum acceptable count = 200;
EXAMINATION OF NONSTERILE — 103 cfu: maximum acceptable count = 2000; and so forth.
Table 1 includes a list of specified microorganisms for which ac-
PRODUCTS: ACCEPTANCE ceptance criteria are set. The list is not necessarily exhaustive, and for
a given preparation it may be necessary to test for other microorga-
CRITERIA FOR nisms depending on the nature of the starting materials and the man-
ufacturing process.
PHARMACEUTICAL
PREPARATIONS AND
SUBSTANCES FOR
PHARMACEUTICAL USE
The presence of certain microorganisms in nonsterile preparations
may have the potential to reduce or even inactivate the therapeutic
activity of the product and has a potential to adversely affect the
Table 1. Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms

Total Aerobic Total Combined
Microbial Count Yeasts/Molds
(cfu/g or Count (cfu/g or
Route of Administration cfu/mL) cfu/mL) Specified Microorganism(s)
Nonaqueous preparations for oral use 103 102 Absence of Escherichia coli (1 g or 1 mL)
Aqueous preparations for oral use 102 101 Absence of Escherichia coli (1 g or 1 mL)
Rectal use 103 102 —
Oromucosal use 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
Gingival use Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Cutaneous use
Nasal use
Auricular use
Vaginal use 102 101 Absence of Pseudomonas aeruginosa (1 g or 1 mL)
Absence of Staphylococcus aureus (1 g or 1 mL)
Absence of Candida albicans (1 g or 1 mL)
Transdermal patches (limits for one 102 101 Absence of Staphylococcus aureus (1 patch)
patch including adhesive layer Absence of Pseudomonas aeruginosa (1 patch)
and backing)
Inhalation use (special requirements 102 101 Absence of Staphylococcus aureus (1 g or 1 mL)
apply to liquid preparations for Absence of Pseudomonas aeruginosa (1 g or 1 mL)
nebulization) Absence of bile-tolerant Gram-negative bacteria
(1 g or 1 mL)
Pharmacopeial Forum
If it has been shown that none of the prescribed tests will allow In addition to the microorganisms listed in Table 1, the significance
valid enumeration of microorganisms at the level prescribed, a val- of other microorganisms recovered should be evaluated in terms of
idated method with a limit of detection as close as possible to the in- the following:
dicated acceptance criterion is used. The use of the product: hazard varies according to the route of
administration (eye, nose, respiratory tract).
Table 2. Acceptance Criteria for Microbiological Quality of The nature of the product: Does the product support growth?
Nonsterile Substances for Pharmaceutical Use Does it have adequate antimicrobial preservation?
The method of application.
Total Combined The intended recipient: risk may differ for neonates, infants, the
Total Aerobic Yeasts/Molds debilitated.
Microbial Count Count Use of immunosuppressive agents, corticosteroids.
(cfu/g or cfu/mL) (cfu/g or cfu/mL) The presence of disease, wounds, organ damage.
Where warranted, a risk-based assessment of the relevant factors is
Substances for phar- 103 102 conducted by personnel with specialized training in microbiology and
maceutical use in the interpretation of microbiological data. For raw materials, the
assessment takes account of the processing to which the product is
subjected, the current technology of testing, and the availability of
materials of the desired quality.
.
(Official May 1, 2009).2
IN-PROCESS REVISION

BRIEFING
(DSN: L. Evans) RTS—C-55678-1
.
new text.
~
new text~USP30
&
new text&
In-Process Revision
~
&
revision will appear if approved. For example, .2 indicates that the revision is proposed for the Second Interim Revision Announce-
ment, &2S (USP 29) indicates that the proposed revision is slated for the Second Supplement to USP 29, and ~USP30 and ~NF25 indicate that
the revisions are proposed for USP 30 and NF 25, respectively.
becomes official.
Pharmacopeial Forum
210 IN-PROCESS REVISION Vol. 33(2) [Mar.–Apr. 2007]

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Baclofen (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Bupropion Hydrochloride (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Bupropion Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Calcium Carbonate and Magnesia Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Calcium Carbonate and Magnesia Chewable Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . 212
Carbachol (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Carbachol Intraocular Solution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Carbachol Ophthalmic Solution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Citalopram Hydrobromide (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Diclofenac Sodium Extended-Release Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
Enalapril Maleate and Hydrochlorothiazide Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Estradiol and Norethindrone Acetate Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Estradiol Transdermal System [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Estradiol Benzoate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Fludarabine Phosphate Injection [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Flumazenil Injection (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Galantamine Hydrobomide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Heparin Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Ipratropium Bromide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Letrozole Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Meclizine Hydrochloride (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Meclizine Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Methylphenidate Hydrochloride Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Octinoxate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Oxandrolone (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Paclitaxel (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Paricalcitol (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Sucralfate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Sulfadimethoxine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
DIETARY SUPPLEMENT–MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Lutein (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Lutein Preparation (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Excipients, USP and NF Excipients, Listed by Category (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Propylene Glycol Monocaprylate [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Trehalose [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
h11i USP Reference Standards (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
h503i Acetic Acid in Peptides [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
h1087i Intrinsic Dissolution (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
In-Process Revision

a-Cyclodextrin [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Sodium Phosphate, Monobasic, Anhydrous [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Sodium Phosphate, Monobasic, Dihydrate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Tetrapropylammonium Chloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Chromatographic Reagents [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Container Specifications for Capsules and Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Description and Solubility (1st Supp to USP 31 and to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
PENDING PROPOSALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] IN-PROCESS REVISION 211
MONOGRAPHS (USP) BRIEFING
Bupropion Hydrochloride Tablets, USP 29 page 321. It is

proposed to replace the current colorimetric Identification test A with
BRIEFING the Fourier transform infrared spectroscopy (FTIR) method. It is also
proposed to delete Identification test C for chloride, because it does
not provide additional information.
Baclofen, USP 29 page 237. On the basis of supporting
information received, it is proposed to revise the Assay to specify (MD-PP: R. Ravichandran) RTS—C50652
the use of the reagent glacial acetic acid instead of glacial acetic acid
TS.
Change to read:
(MD-PP: R. Ravichandran) RTS—C51595
Identification—
A: .Tablets meet the requirements under Identification—Organ-
Change to read: ic Nitrogenous Bases h181i
Assay—Dissolve about 40 mg of Baclofen, accurately weighed, in &

Infrared Absorption h197Ki—
10 mL of glacial acetic acid TS, and
Test specimen—Crush 1 Tablet, using a mortar and pestle.
&
a suitable volume of glacial acetic acid, sufficient to im-
Prepare an approximate 1% (w/w) dispersion of the sample in
merse the electrodes.&1S (USP31)
Titrate with 0.1 N perchloric acid VS, determining the endpoint potassium bromide: the Test specimen shows strong bands at
potentiometrically, using a glass electrode and a calomel electrode
containing a saturated solution of lithium chloride in glacial acetic about 1690, 1560, and 1240 cm–1 and a weaker band at about
acid (see Titrimetry h541i). Perform a blank determination, and make
any necessary correction. Each mL of 0.1 N perchloric acid is 740 cm–1, similar to the reference preparation.&1S (USP31)
equivalent to 21.37 mg of C10H12ClNO2.
the Assay preparation corresponds to that in the chromatogram of
C: A solution of Tablets meets the requirements of the tests for
Chloride h191i.
BRIEFING
&
&1S (USP31)
Bupropion Hydrochloride, USP 29 page 320. It is proposed to

delete the test for Content of chloride, which is redundant. To ensure
the counter ion, it is proposed to add Identification test C, a visual
test for chloride ion.
BRIEFING
Calcium Carbonate and Magnesia Tablets, USP 29 page 348—

Change to read: See briefing under Calcium Carbonate and Magnesia Chewable
Tablets.
Identification—
A: Infrared Absorption h197Ki. (MD-GRE: E. Gonikberg; NOM: L. Paul) RTS—C51022
In-Process Revision
the Assay preparation corresponds to that in the chromatogram of
&
C: A solution of 1 mg per mL in water meets the
requirement of the silver nitrate precipitate test for Chloride Calcium Carbonate and Magnesia
h191i.&1S (USP31) Tablets
Delete the following: Any article currently titled Calcium Carbonate and Magnesia
Tablets that must be chewed before swallowing will be officially
& titled Calcium Carbonate and Magnesia Chewable Tablets as of
Content of chloride—Dissolve about 50.0 mg of Bupropion February 1, 2011.
Hydrochloride, accurately weighed, in 50 mL of water, and titrate
with 0.1 N silver nitrate VS, determining the endpoint potentiomet-
rically. Perform a blank determination, and make any necessary Change to read:
corrections. Each mL of 0.1 N silver nitrate is equivalent to 3.545 mg
of chloride (Cl): not less than 12.6% and not more than 13.1% of Labeling—Label the Tablets to indicate that they are to be chewed
chloride, calculated on the anhydrous basis, is found.&1S (USP31) before being swallowed.
Pharmacopeial Forum
&
After February 1, 2011, Calcium Carbonate and Magnesia delayed implementation is intended to allow time for product label
changes to be made and for health practitioners and consumers to
Tablets that must be chewed are to be titled Calcium become familiar with the revised terminology.
Carbonate and Magnesia Chewable Tablets provided they
(MD-GRE: E. Gonikberg; NOM: L. Paul) RTS—C51022
comply with the requirements of that monograph. Until that
time, the title Calcium Carbonate and Magnesia Tablets can
be used for tablets that can be administered without chewing
and for tablets that must be chewed. In the latter case, the
Add the following:
Tablets are to be labeled to indicate that they are to be chewed &Calcium Carbonate and Magnesia
before being swallowed.&1S (USP31) Chewable Tablets
(Title for this new monograph—to become official February 1,

BRIEFING 2011)
(Prior to February 1, 2011, the current practice of labeling the

article of commerce with the name Calcium Carbonate and
Calcium Carbonate and Magnesia Chewable Tablets; Calcium Magnesia Tablets may be continued)
Carbonate and Magnesia Tablets, USP 29 page 348. Calcium
Carbonate and Magnesia Tablets are marketed in two forms,
including the form that must be chewed before swallowing
(chewable tablets). During its May 23–24, 2006 meeting, the USP
Nomenclature Expert Committee (NOM EC) adopted the following
policy for nomenclature and labeling of chewable tablets: » Calcium Carbonate and Magnesia Chewable
1. The format ‘‘[DRUG] Tablets’’ will be used for tablets that are
swallowed whole or that MAY be chewed AND for which there Tablets contain not less than 90.0 percent and not
is no intended alternative method of administration. When
appropriate, there will also be a labeling statement indicating more than 110.0 percent of the labeled amount of
that the tablets MAY be chewed.
2. The format ‘‘[DRUG] Chewable Tablets’’ will be used for calcium carbonate (CaCO3) and not less than 90.0
tablets that MUST be chewed AND for which there is no other
alternative route of administration. There will also be a labeling
statement indicating that the tablets MUST be chewed. percent and not more than 115.0 percent of the
In the discussion of this topic, it was noted that the main issue is
when to include product characteristics in the title of the article, and labeled amount of magnesium hydroxide
when to include this information in a labeling statement. The NOM
EC agreed that ensuring the product is dispensed and used properly [Mg(OH)2].
is the key consideration. One nomenclature option considered was
that the word ‘‘chewable’’ should be part of the labeling statement
but not part of the title. Another option was to use different Packaging and storage—Preserve in well-closed containers.
nomenclature for a product that MAY be chewed vs. a product that
MUST be chewed. As shown in policy points (1) and (2) above, the
NOM EC agreed that the preferred nomenclature approach is to label Labeling—Label the Chewable Tablets to indicate that they
a product that MAY be chewed as ‘‘Tablets’’ with a labeling
statement indicating that the tablets MAY be chewed, while a product are to be chewed before being swallowed.
that MUST be chewed would be labeled ‘‘Chewable Tablets’’ with
a labeling statement indicating that the tablets MUST be chewed.
In-Process Revision
Therefore, based on the above chewable tablets nomenclature

Identification—
policy, a new monograph for Calcium Carbonate and Magnesia
Chewable Tablets is proposed herein to cover those dosage forms A: The addition of 3 N hydrochloric acid to the Chewable
that must be chewed. The existing Calcium Carbonate and Magnesia
Tablets monograph covers those dosage forms that cannot be chewed Tablets produces effervescence, and the resulting solution,
and must be swallowed.
The title for the new Calcium Carbonate and Magnesia Chewable after being boiled to expel carbon dioxide and neutralized
Tablets monograph will become official on February 1, 2011. Use of
this title would be permitted as of the August 1, 2008 official date of with 6 N ammonium hydroxide, meets the requirements of the
the First Supplement to USP 31–NF 26, but use of this title would
not become mandatory until February 1, 2011. The 30-months tests for Calcium h191i.
B: Heat 2 Chewable Tablets in 20 mL of 1 N sulfuric
acid. Cool, add 20 mL of alcohol, mix, and allow to stand for
30 minutes. Filter this solution, and add 2 mL of 1 N
hydrochloric acid to the filtrate: this solution meets the
requirements of the tests for Magnesium h191i.
Pharmacopeial Forum
Uniformity of dosage units h905i: meet the requirements the volume of 0.05 M edetate disodium corresponding to the
for Weight Variation with respect to calcium carbonate and to content of calcium carbonate in the volume, in mL, of the
magnesia. filtrate taken, represents the volume, in mL, of 0.05 M edetate
Acid-neutralizing capacity h301i—The acid consumed by disodium equivalent to the quantity of magnesium hydroxide
the minimum single dose recommended in the labeling is not present. Each mL of 0.05 M edetate disodium is equivalent to
less than 5 mEq and not less than the number of mEq 2.916 mg of Mg(OH)2.&1S (USP31)
calculated by the formula: (Official February 1, 2011)
0.8(0.0343M ) + 0.9(0.02C)
BRIEFING
in which 0.0343 and 0.02 are the theoretical acid-neutralizing

Carbachol, USP 29 page 368. It is proposed to replace the
capacities, in mEq, of Mg(OH)2 and CaCO3, respectively; and nonselective Identification tests A, B,and D with a selective Fourier
transform IR test.
M and C are the respective quantities, in mg, of Mg(OH)2 and
CaCO3 in the specimen tested, based on the labeled
quantities.
Change to read:
Assay for calcium carbonate—Weigh and finely powder not
Identification—
fewer than 20 Chewable Tablets. Transfer an accurately A: To a solution of about 5 mg in 5 mL of water add 5 mL of
ammonium reineckate solution (1 in 30), and shake vigorously for
weighed portion of the powder, equivalent to about 400 mg of 1 minute: a red precipitate is formed, and it is soluble in acetone.
calcium carbonate, to a beaker with 25 mL of water, and add &

Infrared Absorption h197Ki.&1S (USP31)
40 mL of 1 N hydrochloric acid. Heat on a steam bath for 30 B: To 500 mg add 10 mL of alcoholic potassium hydroxide TS,
and boil gently for 1 to 2 minutes: a white precipitate is formed, and
minutes, allow to cool, transfer to a 100-mL volumetric flask an amine odor is perceptible when the mixture cools. Decant the
supernatant, and add to the precipitate 3 mL of 3 N hydrochloric
with the aid of water, dilute with water to volume, mix, and acid: effervescence is produced.
C:
filter. Transfer 20.0 mL of the filtrate to a suitable container,
&
B: A solution (1 in 20) meets the requirements of the
dilute with water to 100 mL, add 30 mL of 1 N sodium
tests for Chloride h191i.&1S (USP31)
hydroxide, 5 mL of triethanolamine, and 100 mg of hydroxy
D: To a solution of 100 mg in 1 mL of water add 3 mL of gold
naphthol blue, and titrate with 0.05 M edetate disodium VS chloride solution (1 in 10): a precipitate of yellow crystals of the
aurichloride is formed. The precipitate, upon recrystallization from
until the solution is deep blue in color. Each mL of 0.05 M about 5 mL of hot water, separates in glistening scale-like crystals
which, after drying at 1058 for 1 hour, melt between 1838 and 1858.
edetate disodium is equivalent to 5.004 mg of calcium
In-Process Revision
&
&1S (USP31)
carbonate (CaCO3).
Assay for magnesium hydroxide—Transfer an accurately

measured portion of the filtrate remaining from the Assay for
BRIEFING
calcium carbonate, equivalent to about 120 mg of calcium
carbonate and magnesium hydroxide combined, to a suitable Carbachol Intraocular Solution, USP 29 page 369. Because of
container, dilute with water to 100 mL, add 10 mL of potential safety issues regarding hexanitrodiphenylamine, it is
proposed to revise the Identification test.
ammonia–ammonium chloride buffer TS, 5 mL of trietha-
nolamine, and 0.3 mL of eriochrome black TS, and titrate
with 0.05 M edetate disodium VS to a blue endpoint. The
volume, in mL, of 0.05 M edetate disodium consumed, less
Pharmacopeial Forum
Change to read:
Identification—Dilute, if necessary, an accurately measured volume

of Intraocular Solution quantitatively and stepwise with water to BRIEFING
obtain a solution containing about 100 mg of carbachol per mL.
Transfer 5 mL of this test solution to a 125-mL separator. To another
separator, add 5 mL of water to provide a blank. To each separator
add 1.0 mL of 1 N sodium hydroxide and 2.0 mL of a 2 in 1000 Citalopram Hydrobromide, page 3562 of the First Supplement
solution of hexanitrodiphenylamine in 0.1 N sodium hydroxide. Mix, and page 1060 of PF 32(4) [July–Aug. 2006]. The Identfication test
add 15 mL of methylene chloride to each separator, shake for C is revised to require only the silver nitrate test for Bromide in the
1 minute, and allow the layers to separate: a deep amber color is general chapter Identification Tests—General h191i.
produced in the methylene chloride layer obtained from the test
solution. (MD-PP: R. Ravichandran) RTS—C51467
&
To 5 mL of Intraocular Solution, add 4 or 5 drops of
Add the following:
saturated (filtered) ammonium reineckate solution: a pink
precipitate is formed that is soluble in acetone; the acetone
&
Labeling—If a test for Related compounds other than Test
solution is red.&1S (USP31) 1 is used, then the labeling states with which Related
compounds test the article complies.&2S (USP30)
Change to read:
BRIEFING
USP Reference standards h11i—USP Citalopram Hydrobromide
RS. USP Citalopram Hydrobromide Related Compound D RS.
Carbachol Ophthalmic Solution, USP 29 page 369. It is &
USP Citalopram Hydrobromide RS. USP Citalopram
proposed to remove the cross-reference to the monograph for
Carbachol from the Identification test. The proposed revsion will Related Compound A RS. USP Citalopram Related Com-
make the test consistent with the Identification test under Carbachol
Intraocular Solution. pound C RS. USP Citalopram Related Compound D RS. USP
(MD-PP: R. Ravichandran) RTS—C51698 Citalopram Related Compound G RS. USP Citalopram
Related Compound H RS.&2S (USP30)
Change to read:
Identification— Change to read:

A: When diluted to a concentration of about 1 mg of carbachol
per mL, it responds to Identification test A under Carbachol. Identification—
B: Evaporate a volume of Ophthalmic Solution, equivalent to
about 500 mg of carbachol, on a steam bath to dryness: the residue A: Infrared Absorption h197Ki.
responds to Identification test B under Carbachol. B: The retention time of the major peak in the chromatogram of
C: Evaporate a volume of Ophthalmic Solution, equivalent to the Assay preparation corresponds to that in the chromatogram of
about 100 mg of carbachol, on a steam bath to dryness: the residue the Standard preparation, as obtained in the Assay.
responds to Identification test D under Carbachol. C: A solution of 10 mg per mL meets the requirements of the
test
&
Dilute the test article to a concentration of about 1 mg of &
requirement of the silver nitrate precipitate test&1S (USP31)
carbachol per mL. Add 5 mL of ammonium reineckate for Bromide h191i.
In-Process Revision
solution (1 in 30), and shake vigorously for 1 minute: a red Add the following:
precipitate soluble in acetone is formed.&1S (USP31) &
NOTE—On the basis of the synthetic route used, perform
either Test 1 or Test 2. However, if the chloro and bromo
analogs are potential related compounds in the synthetic route
used, Test 2 is recommended.
Pharmacopeial Forum
between citalopram related compound D and citalopram is
TEST 1—
not less than 1.8; the tailing factor for the citalopram
Buffer, Mobile phase, Diluent, and Chromatographic
hydrobromide peak is not less than 0.8 and not more than 1.5;
system—Proceed as directed in the Assay. Make adjustments
and the relative standard deviation for replicate injections,
if necessary (see System Suitability under Chromatography
based on the citalopram peak, is not more than 5%.
h621i).
NOTE—For the purpose of identification, the approximate
Standard solution—Use the Standard preparation, pre-
relative retention times are 0.90 for citalopram related
pared as directed in the Assay.
compound D and 1.0 for citalopram hydrobromide.
Working standard solution—Dilute the Standard solution
with Mobile phase, quantitatively and stepwise if necessary,
of the Working standard solution and the Test solution into
to obtain a solution having a concentration of 0.625 mg per
the chromatograph, record the chromatograms for about 40
mL of citalopram hydrobromide.
minutes, and measure the responses for the major peaks.
System suitability solution—Dissolve an accurately
Calculate the percentage of related compounds in the portion
weighed quantity of USP Citalopram Hydrobromide RS and
of Citalopram Hydrobromide taken by the formula:
USP Citalopram Related Compound D RS in Diluent, and
dilute quantitatively, and stepwise if necessary, with Diluent
100(CS / CT)(ri / rS)(324.39/405.30)(1/F)
to obtain a solution having a known concentration of about
0.001 mg per mL. in which CS and CT are the concentrations, in mg per mL, of
Sensitivity solution—Dilute 5.0 mL of the Working Citalopram Hydrobromide in the Working standard solution
standard solution with Diluent to 50 mL to obtain a solution and the Test solution, respectively; ri is the peak response for
having 0.0625 mg of citalopram hydrobromide per mL. each impurity obtained from the Test solution; rS is the peak
Test solution—Use the Assay preparation. response for the citalopram peak, obtained from the Working
Chromatographic system (see Chromatography h621i)— standard solution; 324.39 and 405.30 are the molecular
Inject the Diluent as directed for Procedure to verify that weights for citalopram and citalopram hydrobromide, respec-
there are no interfering peaks. Chromatograph the Sensitivity
Procedure: the signal-to-noise ratio is at least 3. Chromato-
graph the System suitability solution, and record the peak
responses as directed for Procedure: the resolution, R,
In-Process Revision
Pharmacopeial Forum
tively; and F is the relative response factor for each impurity Standard solution—Dissolve accurately weighed quantities
relative to citalopram (free base), as presented in Table 1. of USP Citalopram Hydrobromide RS, USP Citalopram
TEST 2— Related Compound A RS, USP Citalopram Related Com-
Buffer—Dissolve about 2.7 g of monobasic potassium pound C RS, USP Citalopram Related Compound D RS, USP
phosphate in 1000 mL of water, add 1 mL of N,N- Citalopram Related Compound G RS, and USP Citalopram
dimethyloctylamine, stir, and adjust with phosphoric acid to Related Compound H RS in Diluent to obtain a final solution
a pH of 3.0. having a concentration of 1.5 mg per mL of each compound.
Diluent—Prepare a mixture of Buffer and acetonitrile Test solution—Dissolve an accurately weighed quantity of
(70 : 30). Citalopram Hydrobromide in a suitable volume of Diluent to
Solution A—Prepare a mixture of Buffer, methanol, and obtain a solution having a final concentration of 1.5 mg per
tetrahydrofuran (70 : 24 : 6). mL of citalopram hydrobromide.
Solution B—Prepare a mixture of acetonitrile and Buffer Chromatographic system (see Chromatography h621i)—
(80 : 20). The liquid chromatograph is equipped with a 224-nm detector
Mobile phase—Use variable mixtures of Solution A and and a 4.6-mm 6 25-cm column that contains 3-mm packing
Solution B as directed in Table 2 for Chromatographic L1. The flow rate is about 0.8 mL per minute. The column
system. Make adjustments if necessary (see System Suitability
under Chromatography h621i).
Table 1
Relative Response
Relative Reten- Factor Limit
Related Compound tion Time (F) (%)
1-(3-Dimethylaminopropyl)-1-(4’-fluorophenyl)-5-(4-dimethyl- 0.13 0.34 NMT* 0.1
aminobutyryl)-1,3-dihydrobenzofuran
Citalopram related compound A 0.18 0.77 NMT 0.1
4-[4-Dimethylamino-1-(4’-fluorophenyl)-1-hydroxy-1-butyl]-3- 0.26 0.99 NMT 0.1
In-Process Revision
hydroxymethyl benzonitrile
Citalopram related compound B 0.40 0.98 NMT 0.1
Citalopram related compound C 0.67 0.69 NMT 0.1
Citalopram related compound D 0.90 1.04 NMT 0.1
Citalopram hydrobromide 1.0 1.0 —
Citalopram related compound E 1.29 0.91 NMT 0.1
Unkown Individual unknown impurity — 1.0 NMT 0.1 each

Total known and unknown Total impurities — — NMT 0.2% NMT
0.5%
*
Pharmacopeial Forum
temperature is maintained at 408. The chromatograph is Table 3 (Continued)
programmed as shown in Table 2.

Relative
Table 2
Retention Limit
Time Solution A Solution B Related Compound Time (%)
(minutes) (%) (%) Elution Individual unspecified im-
0–18 100 0 isocratic purity
18–40 100?10 0?90 linear gradient Total specified and unspeci- — NMT 0.50
40–45 10 90 isocratic fied impurities
45–46 10?100 90?10 linear gradient *
46–55 100 0 re-equilibration
Chromatograph the Standard solution, and record the peak Procedure—Inject equal volumes (about 10 mL) of the
responses as directed for Procedure: the resolution, R, Standard solution and the Test solution into the chromato-
between citalopram and citalopram related compound D is graph, record the chromatograms, and measure all the peak
not less than 2.0, and that between citalopram related responses. Calculate the percentage of each citalopram related
compound G and citalopram related compound H is not compound in the portion of Citalopram Hydrobromide taken
less than 4.0; and the relative standard deviation for the by the formula:
citalopram peak in replicate injections is not more than 2.0%.
NOTE—For the purpose of identification, the approximate 100(CS / CT)(ri / rS)(324.39/405.30)
relative retention times of citalopram related compounds are
provided in Table 3. in which CS is the concentration, in mg per mL, of each
citalopram related compound in the Standard solution; CT is
Table 3
the concentration of citalopram hydrobromide in the Test
Relative
solution; ri is the peak area of each impurity obtained from
Retention Limit
the Test solution; rS is the peak area of each corresponding
Related Compound Time (%)
impurity obtained from the Standard solution; and 324.39
Citalopram related com- 0.40 NMT 0.10*
and 405.30 are the molecular weights of citalopram free base
pound A
In-Process Revision
and citalopram hydrobromide, respectively. &2S (USP30)
Citalopram related com- 0.88 NMT 0.10

pound C
Citalopram 1.0 —
pound D
pound G
pound H
— NMT 0.10
Pharmacopeial Forum
Test solution—Finely powder not fewer than 10 Tablets.

BRIEFING Accurately weigh a portion of the powder, equivalent to about
50 mg of diclofenac sodium, and transfer to a 25-mL
Diclofenac Sodium Extended-Release Tablets, page 476 of PF
30(2) [Mar.–Apr. 2004]. It is proposed to add Dissolution Test 2 and volumetric flask. Add about 15 mL of methanol, sonicate for
Dissolution Test 3 to this monograph. A Labeling section is also
being added. 10 minutes, shake by mechanical means for 10 minutes,
(BPC: M. Marques) RTS—C41598; C51160 dilute with methanol to volume, and mix. Centrifuge this
solution, and use the clear supernatant as the Test solution.
Standard solution—Accurately weigh about 50 mg of USP
Diclofenac Sodium RS into a 25-mL volumetric flask. Add 10
Add the following: mL of methanol, shake by mechanical means for 10 minutes,

&Diclofenac dilute with methanol to volume, and mix.
Sodium Extended-Release
Tablets Change to read:
TEST 1—
» Diclofenac Sodium Extended-Release Tablets
Medium: 0.05 M phosphate buffer, pH 7.5; 900 mL.
contain not less than 90.0 percent and not more
Apparatus 2: 50 rpm; use wire sinkers.
than 110.0 percent of the labeled amount of
Times: 1, 5, 10, 16, and 24 hours.
diclofenac sodium (C14H10Cl2NNaO2).
Procedure—Determine the amount of C14H10Cl2NNaO2
Packaging and storage—Preserve in well-closed containers. dissolved by employing UV absorption at the wavelength of
Store at controlled room temperature, and protect from light. maximum absorbance at about 276 nm on filtered portions of
the solution under test, suitably diluted with Medium, if
Add the following:
necessary, in comparison with a Standard solution having
&
Labeling—When more than one Dissolution Test is given, a known concentration of USP Diclofenac Sodium RS in the
the labeling states the Dissolution Test used only if Test 1 is same Medium.
not used.&1S (USP31) Tolerances—The percentages of the labeled amount of
USP Reference standards h11i—USP Diclofenac Sodium C14H10Cl2NNaO2 dissolved at the times specified conform to
In-Process Revision
RS. USP Diclofenac Related Compound A RS. Acceptance Table 2.
Identification— Time (hours) Amount dissolved

in the Assay.
B: Thin-Layer Chromatographic Identification Test
h201i—
Solvent system: methanol, toluene, glacial acetic acid
&
(40 : 60 : 0.5).
Pharmacopeial Forum
Medium, Apparatus, and Procedure—Proceed as directed Mobile phase—Prepare a filtered and degassed mixture of
for Test 1. acetonitrile, 0.05 M Monobasic potassium phosphate buffer,
Times: 1, 2, 4, 6, and 10 hours. and tetrahydrofuran (43 : 57 : 2). Make adjustments if neces-
Tolerances—The percentages of the labeled amount of sary (see System Suitability under Chromatography h621i).
C14H10Cl2NNaO2 dissolved at the times specified conform to Diclofenac related compound A solution—Dissolve an
Acceptance Table 2. accurately weighed quantity of USP Diclofenac Related
Compound A RS in Diluent, and quantitatively dilute with
1 not more than 28%
about 200 mg per mL.
quantity of USP Diclofenac Sodium RS in Diluent, and
quantitatively dilute with Diluent to obtain a solution having
a known concentration of about 200 mg per mL.
System suitability solution—Transfer 10 mL of the
TEST 3—If the product complies with this test, the labeling Standard preparation and 5 mL of Diclofenac related
indicates that it meets USP Dissolution Test 3. compound A solution to a 20-mL volumetric flask. Dilute
Medium and Procedure—Proceed as directed for Test 1. with Diluent to volume, and mix.
Apparatus 1: 100 rpm. Assay preparation—Powder not fewer than 20 Tablets, and
Times: 2, 4, 8, and 16 hours. transfer an accurately weighed portion of the powder,
Tolerances—The percentages of the labeled amount of equivalent to about 100 mg of diclofenac sodium, to a 100-
C14H10Cl2NNaO2 dissolved at the times specified conform to mL volumetric flask, add about 50 mL of Diluent, sonicate
Acceptance Table 2. for about 15 minutes, then shake by mechanical means for 15
minutes. Add a few drops of methanol to remove the foam,
dilute with Diluent to volume, and mix. Transfer 10.0 mL of
the supernatant to a 50-mL volumetric flask, dilute with
Diluent to volume, and mix.
In-Process Revision
&1S (USP31)
L1. The flow rate is about 1.5 mL per minute. Inject 40 mL of
Assay—[NOTE—Protect the Assay preparation, Standard the System suitability solution into the chromatograph, and
preparation, and System suitability solution from light.] record the peak responses as directed for Procedure: the
Diluent: a mixture of acetonitrile and water (43 : 57). relative retention times are about 0.9 for diclofenac related
0.05 M Monobasic potassium phosphate buffer—Dissolve compound A and 1.0 for diclofenac; and the resolution, R,
6.8 g of monobasic potassium phosphate in 950 mL of water, between the diclofenac peak and the diclofenac related
adjust with dilute phosphoric acid or dilute potassium compound A peak is not less than 2.0. Inject 20 mL of the
hydroxide solution to a pH of 4.0 + 0.05, dilute with water Standard preparation into the chromatograph, and record the
to 1 L, and mix. peak responses as directed for Procedure: the tailing factor of
Pharmacopeial Forum
220 IN-PROCESS REVISION Vol. 33(2) Mar.–Apr. 2007
the diclofenac peak is not more than 2.0; and the relative &
and at 360 nm&1S (USP31)
in 1-cm cells, on filtered portions of the solution under test, suitably
standard deviation of the diclofenac peak for replicate diluted with Medium, in comparison with a Standard solution having
a known concentration of USP Hydrochlorothiazide RS dissolved in
injections is not more than 2.0%. 20 mL of methanol and diluted with Medium.
Procedure—Separately inject equal volumes (about 20 mL) &

Calculate the quantity, in mg, of hydrochlorothiazide
of the Standard preparation and the Assay preparation into dissolved by the formula:
the area responses for the major peaks. Calculate the quantity, (TC/D)(A320 – A360)U /(A320 – A360)S
in mg, of diclofenac sodium (C14H10Cl2NNaO2) in the portion

in which T is the Tablet label claim, in mg, for hydrochlo-
of Tablets taken by the formula:
rothiazide; C is the concentration, in mg per mL, of
500C(rU / rS) hydrochlorothiazide in the Standard solution; D is the

concentration, in mg per mL, of hydrochlorothiazide in the
in which C is the concentration, in mg per mL, of USP test solution; and (A320 – A360)U and (A320 – A360)S are the
Diclofenac Sodium RS in the Standard preparation; and rU differences in the absorbances at 320 and 360 nm of the Test
and rS are the diclofenac peak responses obtained from the solution and the Standard solution, respectively.&1S (USP31)
Assay preparation and the Standard preparation, respec- enalapril maleate (C20H28N2O5 C4H4O4) and not less than 60% (Q) of
the labeled amount of hydrochlorothiazide (C7H8ClN3O4S2) are
tively.&2S (USP30) dissolved in 30 minutes.
BRIEFING BRIEFING
Enalapril Maleate and Hydrochlorothiazide Tablets, USP 29 Estradiol and Norethindrone Acetate Tablets, page 1364 of PF
page 799. It is proposed to revise the Dissolution test to add 31(5) [Sept.–Oct. 2005]. It is proposed to add a Dissolution test to
a requirement to monitor hydrochlorothiazide at 360 nm in addition this monograph. The brands of L1 packing suitable for the
to 320 nm, and to add a formula for the calculation of the amount of chromatographic procedure in the test are Luna C18(2), Symmetry
hydrochlorothiazide dissolved. C18, and Nova-Pak C18. Minor editorial changes have also been
made to the monograph.
Change to read:
In-Process Revision
Medium: water; 900 mL. Add the following:

Time: 30 minutes. &Estradiol and Norethindrone Acetate
Determine the amount of C20H28N2O5 C4H4O4 dissolved, using
filtered portions of the solution under test and following the Tablets
Procedure for content uniformity of enalapril maleate in the test for
Uniformity of dosage units, making any necessary volumetric
adjustments, in comparison with a Standard solution of USP
Enalapril Maleate RS having similar concentrations in the same
Medium.
Determine the amount of C7H8ClN3O4S2 dissolved by employing » Estradiol and Norethindrone Acetate Tablets
UV absorption at the wavelength of maximum absorbance at about
320 nm
contain not less than 90.0 percent and not more
than 110.0 percent of the labeled amount of
estradiol (C18H24O2) and not less than 90.0 percent
and not more than 110.0 percent of the labeled
amount of norethindrone acetate (C22H28O3).
Pharmacopeial Forum
Vol. 33(2) Mar.–Apr. 2007 IN-PROCESS REVISION 221
Packaging and storage—Preserve in well-closed containers, Microbial limits h61i—The total aerobic microbial count
and store at controlled room temperature. does not exceed 1000 cfu per g, and the total combined molds
USP Reference standards h11i—USP Estradiol RS. USP and yeasts count does not exceed 100 cfu per g. The Tablets
Estrone RS. USP Norethindrone Acetate RS. meet the requirements of the tests for the absence of
Salmonella species and Escherichia coli.
Identification—
A: Thin-Layer Chromatographic Identification Test Change to read:
h201i—
Dissolution—[To come.]
Test solution—Place 2 Tablets into a 10-mL vial, and add
&
Medium: 0.3% sodium lauryl sulfate in water; 500 mL.
0.2 mL of water. When the Tablets are partially disintegrated,
add a few glass beads, and shake vigorously to disintegration.
Time: 30 minutes.
Add 4.0 mL of dehydrated alcohol, and shake. Centrifuge
Determine the percentage of the labeled amounts of
until the supernatant is clear before application to the plate.
C18H24O2 and C22H28O3 dissolved by employing the following
Standard solution—Dissolve accurately weighed quantities
method.
of USP Estradiol RS and USP Norethindrone Acetate RS in
dehydrated alcohol to obtain a solution having known
acetonitrile and water (55 : 45). Make adjustments if neces-
concentrations of 0.5 mg per mL and 0.25 mg per mL,
sary (see System Suitability under Chromatography h621i).
respectively.
Standard solution—Prepare a solution of USP Estradiol RS
Application volume: 2 mL.
in alcohol having an accurately known concentration of about
Developing solvent solution: a mixture of chloroform and
0.02 mg per mL. Prepare a solution of USP Norethindrone
acetone (9 : 1).
Acetate RS in alcohol having an accurately known concen-
Procedure—Proceed as directed in the chapter, using the
tration of about 0.01 mg per mL. Dilute both solutions
Developing solvent solution. After removal of the plate, mark
quantitatively, and stepwise if necessary, with Medium to
the solvent front, and allow the solvent to evaporate. Place the
obtain a solution having a known concentration of both drugs
plate on a heating plate at 1008 for 15 minutes. Allow the
similar to the one expected in the Test solution, assuming
plate to cool, and then immerse it in a mixture of dehydrated
complete dissolution.
alcohol and concentrated sulfuric acid (95 : 5). Place the plate
Test solution—Use portions of the solution under test
on a piece of thick horizontal paper until it is almost dry. Heat
passed through a suitable 0.45-mm filter.
In-Process Revision
the plate at 1008 until it has fully developed. Examine under
UV light at 365 nm. The color and RF value of the principal
The liquid chromatograph is equipped with a 241/280 dual-
spots obtained from the Test solution correspond to those
band or wavelength-switchable UV detector and a 4.6-mm
obtained from the Standard solution.
6 15-cm column that contains packing L1. The flow rate is
B: The retention time and UV spectrum of the major
about 1.0 mL per minute. Make an investigative run to
peaks in the chromatogram of the Assay preparation
determine the retention times for estradiol and norethindrone
correspond to those in the chromatogram of the Standard
acetate so that the absorption of estradiol at 280 nm and
preparation, as obtained in the Assay.
norethindrone acetate at 241 nm can be included in a single
run with a switch of the wavelength. Chromatograph replicate
injections of the Standard solution, and record the peak area
Pharmacopeial Forum
responses as directed for Procedure: the tailing factor is not Diluent—Prepare a mixture of water and dehydrated
more than 2.0, and the relative standard deviation for replicate alcohol (1 : 1).
injections is not more than 2.0%. System suitability solution—Dissolve accurately weighed
Procedure—Separately inject equal volumes (about 150 quantities of USP Estradiol RS, USP Norethindrone Acetate
mL) of the Standard solution and the Test solution into the RS, and USP Estrone RS in Diluent to obtain a solution
chromatograph, record the chromatograms, and measure the having known concentrations of about 240 mg per mL, 60 mg
area responses for the major peaks. Calculate the percentage per mL, and 1 mg per mL, respectively.
of C18H24O2 and of C22H28O3 in the portion of Tablets taken by Test solution—Accurately weigh and finely powder 20
the formula: Tablets. Transfer the equivalent of 12 Tablets to an
appropriate flask, and dissolve in a known volume of Diluent
to obtain a solution having known concentrations of estradiol
and norethindrone acetate of about 240 mg per mL and 120 mg
per mL, respectively. Filter the solution, if necessary.
Estradiol standard stock solution—Dissolve an accurately
weighed quantity of USP Estradiol RS in alcohol to obtain
in which rU and rS are the peak responses for the Test solution
a solution having a known concentration of estradiol of about
and the Standard solution, respectively; CS is the concentra-
250 mg per mL.
tion, in mg per mL, of estradiol and norethindrone acetate in
Norethindrone acetate standard stock solution—Dissolve
the Standard solution; 500 is the volume, in mL, of Medium;
an accurately weighed quantity of USP Norethindrone
100 is the conversion factor to percentage; and LC is the
Acetate RS in alcohol to obtain a solution having a known
Tablet label claim, in mg, for estradiol and norethindrone
concentration of norethindrone acetate of about 150 mg per
acetate.
mL.
Tolerances—Not less than 75% (Q) of the labeled amounts
Standard solution—Combine 250 mL of Estradiol standard
of C18H24O2 and C22H28O3 are dissolved in 30 min-
stock solution and 100 mL of Norethindrone acetate standard
utes.&1S (USP31)
stock solution, and dilute with 50.0 mL of Diluent.
Loss on drying h731i—Dry about 1200 mg of finely
Chromatographic system—The liquid chromatograph is
powdered Tablets in a tared evaporating dish at a pressure
equipped with a dual-wavelength detector (235 nm and 254
not exceeding 25 mm of mercury at 608 for 3 hours: it loses
In-Process Revision
nm) and a 3.9-mm 6 30-cm column that contains 4-mm

not more than 7.5% of its weight.
packing L1. The flow rate is about 0.8 mL per minute. The
Chromatographic purity— chromatograph is programmed as follows.
Solution A—Prepare a mixture of water and tetrahydrofuran
(200 : 1).
Solution B—Prepare a degassed solution of acetonitrile,
water, and tetrahydrofuran (160 : 40 : 1). 0 80 20 equilibration
Mobile phase—Use variable mixtures of Solution A and 0–2 80?65 20?35 linear gradient
Solution B as directed for Chromatographic system. Make 2–35 65?20 35?80 linear gradient
adjustments, if necessary (see System Suitability under 35–49 20 80 isocratic
Chromatography h621i). 49–50 20?80 80?20 linear gradient

Pharmacopeial Forum
Chromatograph the System suitability solution, and record the Not more than 0.1% of any other impurity is found, and more
peak responses as directed for Procedure: the relative than 1.0% of total impurities is found. Calculate the
retention times are about 1.4 for estrone, about 3.0 for percentage of any norethindrone acetate related impurities
norethindrone acetate, and 1.0 for estradiol. The resolution, R, in the portion of Tablets taken by the formula:
between estrone and estradiol is not less than 1.3, measured at
254 nm. 100F(CS / CT) (ri / rS)

in which F is the relative response factor of any norethindrone
acetate related impurity relative to norethindrone acetate; CS
and CT are the concentrations of the Standard solution and the
peak responses. Calculate the percentage of any estradiol
Test solution, respectively; ri is the peak area at 254 nm for
impurity in the portion of Tablets taken by the formula:
each impurity obtained from the Test solution; and rS is the
100F(CS / CT)(ri / rS) peak area at 254 nm obtained from the Standard solution. The
Tablets meet the requirements given in Table 2. Not more
in which F is the relative response factor of any estradiol than 0.5% of any other impurity is found, and not more than
impurity relative to estradiol; CS and CT are the concentrations 1.0% of total impurities is found.
of the Standard solution and the Test solution, respectively; ri Assay—
is the peak area at 235 nm for each impurity obtained from Mobile phase—Prepare a filtered and degassed mixture of
the Test solution; and rS is the peak area at 235 nm obtained acetonitrile and water (55 : 45) (see Chromatography h621i).
Diluent—Prepare a mixture of water and dehydrated
from the Standard solution. The Tablets meet the require-
alcohol (1 : 1).
ments given in Table 1.
Table 1
Relative Relative Limit

Compound Retention Time Response Factor (%)
6-a Hydroxyl estradiol about 0.47 1.0 0.1 0.5
In-Process Revision
6-b Hydroxyl estradiol about 0.51 1.0 0.1 0.5
6-Keto estradiol about 0.62 1.0 0.1 0.5
16-Keto estradiol about 0.65 1.0 0.1 0.5
6-Keto estrone about 0.75 1.0 0.1 0.5
b-Equilenol about 0.88 0.04 0.1 0.5
6-Dehydro estradiol about 0.95 1.0 0.1 0.5
Estradiol 1.0 1.0 0.1 0.5
a-Estradiol about 1.06 1.0 0.1 0.5
Estrone about 1.17 1.0 0.1 0.5
4-Methyl estradiol about 1.24 1.0 0.1 0.5
Pharmacopeial Forum
Table 2
Relative Relative Limit

Compound Retention Time Response Factor (%)
6-b Hydroxy-norethindrone acetate about 0.58 1.0 0.05 0.5
Norethindrone about 0.66 1.0 0.05 0.5
6-Keto-norethindrone acetate about 0.79 1.8 0.05 0.5
19-Nor-17-alpha-preg-4-ene-3,20-dione about 0.90 1.0 0.05 0.5
6-Dehydro-norethindrone acetate about 0.97 2.2 0.05 0.5
Norethindrone acetate about 1.0 1.0 0.05 0.5
Perform an investigational run to determine the retention

Estrone standard stock solution—Transfer about 6.00 mg
times for estradiol and norethindrone acetate. Thus, the
of USP Estrone RS, accurately weighed, to a 50-mL
absorption of estradiol at 280 nm and norethindrone acetate at
volumetric flask, and dissolve in 10 mL of dehydrated
254 nm can be included in a single run by altering the
alcohol. Dilute with dehydrated alcohol to volume, and mix.
wavelength. Chromatograph the System suitability prepara-
Estradiol standard stock solution—Prepare a solution of
tion, and record the peak areas as directed for Procedure: the
USP Estradiol RS in dehydrated alcohol having a known
resolution, R, between estradiol and estrone acetate is not less
concentration of 0.25 mg per mL.
than 1.8. Chromatograph the Standard preparation, and
Norethindrone acetate standard stock solution—Prepare
record the peak area as directed for Procedure: the relative
a solution of USP Norethindrone Acetate RS in dehydrated
alcohol having a known concentration of 0.15 mg per mL.
3%.
System suitability preparation—Transfer 800 mL of Estra-
diol standard stock solution, 600 mL of Norethindrone acetate
standard stock solution, and 200 mL of Estrone standard
stock solution to a suitable flask containing 10.0 mL of
the areas for the estradiol and norethindrone acetate peaks.
Diluent.
Calculate the quantity, in mg, of estradiol (C18H24O2) in each
Standard preparation—Prepare a solution of Estradiol
of the Tablets taken by the formula:
standard stock solution and Norethindrone acetate standard
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stock solution in Diluent having a known concentration of

(VC/12)(rU / rS)
about 20 mL per mL and 10 mL per mL, respectively.
Assay preparation—Add 12 Tablets into a measured in which V is the volume, in mL, of Diluent taken to prepare
amount of Diluent to obtain a solution having an estradiol the Assay preparation; C is the concentration, in mg per mL,
concentration of about 20 mL per mL and a norethindrone of USP Estradiol RS in the Standard preparation; and rU and
acetate concentration of about 10 mL per mL. rS are the peak areas obtained from the Assay preparation and
Chromatographic system (see Chromatography h621i)— the Standard preparation, respectively. Calculate the quantity,
The liquid chromatograph is equipped with a diode array in mg, of norethindrone acetate (C22H28O3) in each of the
detector and a 4.6-mm 6 15-cm column that contains Tablets taken by the formula:
packing L1. The flow rate is about 1.0 mL per minute.
Pharmacopeial Forum
Drug release h724i—

(VC/12)(rU / rS)
TEST 1—

in which V is the volume, in mL, of Diluent used in the Assay
Medium: water; 900 mL, deaerated.
preparation; C is the concentration, in mg per mL, of USP
Norethindrone Acetate RS in the Standard preparation; and
rU and rS are the peak areas obtained from the Assay
Determine the amount of C18H24O2 released by employing
preparation and the Standard preparation, respec-
tively.&1S (USP30)
water and acetonitrile (3 : 2). Make adjustments if necessary
BRIEFING (see System Suitability under Chromatography h621i).

Standard solutions—Dissolve an accurately weighed quan-
Estradiol Transdermal System, page 1063 of PF 31(4) [July– tity of USP Estradiol RS in dehydrated alcohol, and dilute
Aug. 2005]. It is proposed to provide additional information and
make some editorial changes in Drug release Test 2. quantitatively, and stepwise if necessary, to obtain a solution
(BPC: M. Marques) RTS—C44111 having a known concentration of about 9 mg per mL. Dilute
this solution with water to obtain additional solutions having
known concentrations of about 0.9, 0.45, and 0.045 mg per
mL.
Add the following: Test solution—At each sampling time interval, withdraw
&Estradiol Transdermal System a 10-mL aliquot of the solution under test.
The liquid chromatograph is equipped with a fluorometric
detector, set at an excitation wavelength of 220 nm and an
» Estradiol Transdermal System contains not less
emission wavelength of 270 nm, and a 4.6-mm 6 3-cm
column that contains packing L1. The column temperature is
of the labeled amount of estradiol (C18H24O2).
maintained at 408. The flow rate is about 1.0 mL per minute.
Packaging and storage—Preserve in hermetic, light- Chromatograph the Standard solutions, and record the peak
In-Process Revision
resistant, unit-dose pouches. responses as directed for Procedure: the tailing factor is
between 0.9 and 2.5; and the relative standard deviation for
Labeling—When more than one Drug Release Test is given,
replicate injections of the 0.45 mg per mL Standard solution is
the labeling states the Drug Release Test used only if Test 1 is
not more than 3.0%.
not used.
USP Reference standards h11i—USP Estradiol RS.
of the Standard solutions and the Test solution into the
Identification—The retention time of the major peak in the chromatograph, record the chromatograms, and measure the
chromatogram of the Assay preparation corresponds to that in responses for the major peaks. Plot the peak responses of the
the chromatogram of the Standard preparation, as obtained in Standard solutions versus concentration, in mg per mL, of
the Assay.
Pharmacopeial Forum
estradiol. From the graph so obtained, determine the amount,

in mg per mL, of C18H24O2 released, using the formulas that
indicates that it meets USP Drug Release Test 2.
follow:
Medium: 0.005 M phosphate buffer, pH 5.5, containing
mg of estradiol released in the interval 0 to 24 hours:
0.3% sodium lauryl sulfate; 500 mL.
Apparatus 5: 100 rpm. Use a 76-mm stainless steel disk
assembly. Adhere the patch to the disk assembly using
double-faced adhesive transfer tape. [NOTE—A suitable tape is
available as 3M adhesive transfer tape 927, www.mmm.com.]
Determine the amount of estradiol (C18H24O2) released by
mg of estradiol released in the interval 24 to 48 hours: employing the following method.
acetonitrile and water (1 : 1). Make adjustments if necessary
Standard stock solution—Dissolve an accurately weighed
quantity of USP Estradiol RS in acetone, and dilute
quantitatively, and stepwise if necessary, with acetone to
cumulative mg of estradiol released: obtain a solution having a known concentration of about 800
mg per mL.
Standard working solution—Dilute the Standard stock
solution with Medium to obtain a solution having a known
concentration close to that expected in the solution under test,
assuming 100% drug release.
in which A1 is the peak area of estradiol in the sample solution Chromatographic system (see Chromatography h621i)—
at the first release interval; An is the peak area of estradiol in The liquid chromatograph is equipped with a 205-nm detector
the sample solution at the release interval n; m is the slope of and a 4.0-mm 3.9-mm 6 30-cm column that contains 4-mm
the calibration curve; and b is the y-intercept of the calibration packing L1. The flow rate is about 1.0 mL per minute.
In-Process Revision
curve. Chromatograph the Standard working solution, and record
Tolerances—The amounts of C18H24O2 released, as per- the peak responses as directed for Procedure: the tailing
centages of the labeled amount of the dose absorbed in vivo factor is not more than 2.0; and the relative standard deviation
released to the skin at the times specified, conform to for replicate injections is not more than 2.0%.3.0%.
Acceptance Table 4. Acceptance Table 1. Procedure—Separately inject equal volumes (about 100
mL) of the Standard working solution and the solution under
test into the chromatograph, record the chromatograms, and
24 between 2.4% and 26.4% measure the responses for the major peaks. Calculate the
48 between 4.8% and 52.0% amount of estradiol released at each time point by the
96 between 10.0% and 85.0% following formulas:
Pharmacopeial Forum
Tolerances—The amounts of estradiol (C18H24O2) released

, as percentages of the labeled amount of the dose released to
the skin, at the times specified conform to Acceptance Table
1.
Time (hours) Amount released

Uniformity of dosage units h905i: meets the requirements.
Alcohol content—
Diluent—Prepare a mixture of acetonitrile and water (1 : 1).
Internal standard solution—Pipet 4.0 mL of dehydrated
methanol into a 100-mL volumetric flask. Dilute with water
to volume, and mix.
Standard solution—Accurately weigh, by difference, about
1.6 mL of dehydrated alcohol into a tared 50-mL volumetric
flask containing about 15 mL of water. Dilute with Diluent to
volume, and mix. Pipet 10.0 mL of this solution into a 50-mL
volumetric flask, dilute with Diluent to volume, and mix.
Pipet 25.0 mL of this solution into a 50-mL volumetric flask,
add 5.0 mL of Internal standard solution, dilute with water to
volume, and mix.
in which Mi is the amount, in mg, of estradiol released into the Test solutions—Prepare as directed for Assay preparations,
Medium at a given time interval; rU is the peak response of with the following changes. Pipet 25.0 mL of each solution
In-Process Revision
estradiol in the sample solution; rS is the peak response of into individual 50-mL volumetric flasks. Add 5.0 mL of
estradiol in the Standard working solution; CS is the Internal standard solution, dilute with water to volume, and
concentration, in mg per mL, of estradiol in the Standard mix.
working solution; Vi is the corrected volume, in mL, of the Chromatographic system (see Chromatography h621i)—
Medium at a given time interval; m1, m2, m3, and m4 are the The gas chromatograph is equipped with a flame-ionization
total amounts of estradiol, in mg, released from the patch at detector and a 2-mm 6 2-m glass column that contains
given time intervals; M1, M2, M3, and M4 are the amounts of support S2. The carrier gas is helium, flowing at a rate of 30
estradiol, in mg, released into the Medium at given time mL per minute. The column temperature is 1008. The
intervals; Va is the volume, in mL, of the aliquot taken from injection port temperature and the detector temperature are
the dissolution vessel at each time point; and V1, V2, and V3 maintained at 2008. Chromatograph the Standard solution,
are the volumes of the Medium at given time intervals. and record the peak areas as directed for Procedure: the
Pharmacopeial Forum
relative retention times are about 0.4 for the internal standard having a concentration of about 0.1 mg of estradiol per mL.
and about 1.0 for alcohol; and the relative standard deviation Shake by mechanical means for about 3 hours, and sonicate
for replicate injections, determined from the ratios of the for 15 minutes.
alcohol peak areas to those of the internal standard, is not Chromatographic system (see Chromatography h621i)—
more than 1.5%. The liquid chromatograph is equipped with a 280-nm detector
Procedure—Separately inject equal volumes (about 2 mL) and a 4.6-mm 6 15-cm column that contains packing L1.
of the Standard solution and each of the Test solutions into The column temperature is maintained at 358. The flow rate is
the chromatograph, record the chromatograms, and measure about 1 mL per minute. Chromatograph the Standard
the areas for the major peaks. Calculate the amount of preparation, and record the peak responses as directed for
alcohol, in mg, in each Transdermal System taken by the Procedure: the tailing factor is between 0.9 and 1.6; and the
formula: relative standard deviation for replicate injections is not more
than 2.5%.
160C(RU / RS) Procedure—Separately inject equal volumes (about 25 mL)
of the Standard preparation and the Assay preparations into
in which C is the concentration, in mg per mL, of dehydrated the chromatograph, record the chromatograms, and measure
alcohol in the Standard solution; and RU and RS are the ratios the responses for the major peaks. Calculate the quantity, in
of the peak responses of alcohol to the internal standard mg, of estradiol (C18H24O2) in each Transdermal System taken
obtained from the Test solutions and the Standard solution,
by the formula:
respectively. Calculate the average amount of alcohol in the
Test solution taken: between 80% and 120% of the labeled VC(rU / rS)
amount of C2H5OH is found.
in which V is the volume, in mL, of Diluent used to prepare
Assay—
the Assay preparation; C is the concentration, in mg per mL,
Diluent—Prepare a mixture of acetonitrile and water (1 : 1).
Mobile phase—Prepare a filtered and degassed mixture of of USP Estradiol RS in the Standard preparation; and rU and
rS are the peak responses obtained from the Assay preparation
acetonitrile and water (55 : 45). Make adjustments if neces-
and the Standard preparation, respectively. Calculate the
sary (see System Suitability under Chromatography h621i).
Standard preparation—Dissolve an accurately weighed average quantity, in mg, of estradiol in each Transdermal
System. Use the individual assays to determine the Unifor-
In-Process Revision
quantity of USP Estradiol RS in Diluent. Dilute quantitative-

mity of dosage units.&1S (USP31)
ly, and stepwise if necessary, with Diluent to obtain a solution
Assay preparations—Cut 10 Transdermal Systems into
pieces, keeping the pieces from each system separate.
Remove the protective liners, if any, from the strips, and
discard. Transfer the pieces of each system into separate
stoppered flasks of suitable size, and add an accurately
measured volume of Diluent to each flask to obtain solutions
Pharmacopeial Forum
USP Reference standards h11i—USP Estradiol Benzoate

BRIEFING
RS.
Estradiol Benzoate. Because there is no USP monograph for this Identification—
drug substance, a new monograph is being proposed. The gas
chromatographic procedures in the test for Limit of methanol and A: Infrared Absorption h197Ki.
dichloromethane are based on analyses performed with a 3.2-mm
6 1.8-m stainless steel column packed with support S3, using ethyl B: The retention time of the major peak in the
acetate as an internal standard. The typical retention times for
methanol, dichloromethane, and ethyl acetate are about 1, 4, and 11 chromatogram of the Assay preparation corresponds to that
minutes, respectively. USP has received data indicating that an
Altech Porapak Q, 80/100 mesh brand of column is suitable. The in the chromatogram of the Standard preparation, as obtained
TLC procedures in the test for Chromatographic purity are based on
analyses using 0.25-mm silica gel plates. The HPLC procedures in in the Assay.
the Assay are based on analyses performed with a 4.6 mm 64.5-cm
guard column that contains packing L1 and a 4.6-mm 6 25-cm
analytical column that contains 5-mm packing L1, using estradiol 17- Specific rotation h781Si: between +57.08 and +63.08.
acetate as an internal standard. The typical retention times for
estradiol 17-acetate and estradiol benzoate are about 6 and 13 Test solution: 10 mg per mL, previously dried, in
minutes, respectively. USP has received data indicating that the
Beckman Ultrasphere brand of guard and analytical L1 columns are dioxane.
suitable. Interested parties are invited to submit comments.
Loss on drying—Dry it at 1008 to 1058 for 3 hours: it loses
(VET: I. DeVeau) RTS—C46941
Residue on ignition h281i: not more than 0.20%.
Particle size h786i—

Suspension fluid—To a mixture of glycerin and water
Add the following:
(60 : 40, w/w) add a sufficient quantity of polysorbate 20 to
&Estradiol Benzoate obtain a solution having a concentration of 125 mL of
polysorbate 20 per 100 g of solution.
Test suspension—Saturate the Suspension fluid by adding
about 100 mg of fine Estradiol Benzoate per 100 g of
Suspension fluid, and sonicate for about 10 minutes. Filter the
resulting suspension through a 0.45-um nylon filter. To the
C25H28O3 376.49 filtrate, add about 50 mg of Estradiol Benzoate per mL of the

filtered, saturated Suspension fluid, and mix on a vortex mixer
Estra-1,3,5(10)-triene-3,17-diol, (17b)-, 3-benzoate.
until dispersed (about 10 minutes).
In-Process Revision
Estradiol 3-benzoate [50-50-0]. Procedure—Using a suitable multi-wavelength particle size
analyzer,1 determine the particle size distribution within the
Test suspension, analyzing the results in the range from 5 mm
» Estradiol Benzoate contains not less than 97.0
to 600 mm. Not more than 50% of the particles are less than
percent and not more than 103.0 percent of 30 mm, and not less than 90% of the particles are less than
C25H28O3, calculated on the dried basis. 450 mm. The mean diameter of fine grade Estradiol Benzoate
is not more than 100 mm, and the mean diameter of course
Packaging and storage—Preserve in tight, light-resistance
grade Estradiol Benzoate is not less than 100 mm and not
containers.
more than 200 mm.
1
Labeling—Label it to indicate it is for veterinary use only. A suitable multi-wavelength particle size analyzer is model LS 13
320, obtained from Beckman Coulter, Inc., Fullerton, CA, or
Label it to indicate whether it is course grade or fine grade. equivalent.
Pharmacopeial Forum
Limit of methanol and dichloromethane— in which CI is the concentration, in mL per mL, of the solvent
Internal standard solution—Prepare a solution that contains of interest in the Standard solution; DI is the density, in g per
0.1% (v/v) ethyl acetate in pyridine. mL, of the solvent of interest; CU is the concentration, in mg
Standard solution—Transfer 50 mL of methylene chloride per mL, of Estradiol Benzoate in the Test solution; and RU and
and 50 mL of methanol into a 50-mL volumetric flask, and RS are the peak response ratios of the solvent of interest to the
dilute with Internal standard solution to volume. Mix well. internal standard obtained from the Test solution and the
Test solution—Accurately weigh about 100 mg of Estradiol Standard solution, respectively: the sum of the percentages of
Benzoate into a low-actinic glass vial. Dissolve in 1.0 mL of methanol and methylene chloride is not more than 0.20%.
Internal standard solution, and mix. Chromatographic purity—

Chromatographic system (see Chromatography h621i)— Adsorbent: a 0.25-mm layer of chromatographic silica gel
The gas chromatograph is equipped with a flame-ionization mixture.
detector and a 3.2-mm 6 1.8-m stainless steel column packed Developing solvent system—Use a mixture of toluene and
with support S3. The injection port is maintained at ethyl acetate (70 : 30).
a temperature of about 1658, the detector temperature is Ammonium molybdate solution—Dissolve 5 g of ammoni-
maintained at about 1658, and the column temperature is um molybdate in 100 mL of 10% (v/v) sulfuric acid.
maintained at 1408 for 20 minutes, programmed thereafter to Diluent—Prepare a solution containing a mixture of
rise to 2508 at a rate of 408 per minute, and then maintained at methylene chloride and alcohol (2 : 1).
2508 for 15 minutes. Helium is used as the carrier gas, Standard solution—Dissolve an accurately weighed quan-
flowing at a rate of about 40 mL per minute. Chromatograph tity of USP Estradiol Benzoate RS in Diluent to obtain
the Internal standard solution and the Standard solution, and a solution containing about 5 mg per mL.
record the peak responses as directed for Procedure: the order Test solution 1—Dissolve an accurately weighed quantity
of elution is methanol, methylene chloride, and ethyl acetate; of Estradiol Benzoate in Diluent to obtain a solution
no peaks are present within the Internal standard solution that containing about 5 mg per mL.
would interfere with the integration of either the methanol or Test solution 2—Transfer 200 mL of Test solution 1 to a
methylene chloride peak; baseline resolution is achieved 10-mL volumetric flask, and dilute with Diluent to volume.
among the internal standard peak and residual solvent peaks; Procedure (see Thin-Layer Chromatography under
and the standard deviation of replicate injections of the Chromatography h621i)—Apply to the thin-layer chromato-
In-Process Revision
Standard solution is not more than 5.0%. graphic plate 20-mL aliquots of the Standard solution and Test
Procedure—Separately inject equal volumes (about 2.0 mL) solution 1 and 20-mL, 15-mL, 10-mL, 5-mL, and 2 -mL aliquots
of the Standard solution and the Test solution into the of Test solution 2; the volumetric series of Test solution
chromatograph, record the chromatograms, and measure the 2 represents 2.0%, 1.5%, 1.0%, 0.5% and 0.2% of the
peak areas for methanol, methylene chloride, and ethyl concentration of Estradiol Benzoate within the Test solution
acetate. Calculate the w/w percentage of each residual solvent 1 spot. Allow the spots to dry, and develop the chromatogram
in the portion of Estradiol Benzoate taken by the formula: until the solvent front has moved about three-fourths of the
length of the plate. Remove the plate from the developing
100CI (DI / CU)(RU / RS) chamber, mark the solvent front, and allow the solvent to
evaporate from the plate. Spray the plate thoroughly with the
Ammonium molybdate solution, and dry. Heat the plate in
Pharmacopeial Forum
a drying oven for about 10 minutes at about 1158. Calculate Assay preparation—Transfer an accurately weighed quan-
the relative retardation factor, Rrel, (relative to estradiol tity of about 20.0 mg of Estradiol Benzoate into a 100-mL
benzoate), of all spots within the lanes for Test solution volumetric flask. Add 70 mL of acetonitrile, and sonicate
1 and Test solution 2. Possible estradiol benzoate impurities until dissolved. Add 25 mL of water, mix well, and allow to
include, but are not limited to, estradiol [estra-1,3,5(10)- equilibrate to ambient temperature. Dilute with water to
triene-3,17b-diol], 17a-estradiol benzoate [estra-1,3,5(10)- volume, and mix.
triene-3,17a-diol 3-benzoate], and estrone [estra-1,3,5(10)- Chromatographic system (see Chromatography h621i)—
triene-17-one, 3-hydroxy]; their relative retardation factors, The liquid chromatograph is equipped with a 230-nm
Rrel, are about 0.84, 1.15 and 1.21, respectively. Determine the detector, a 4.6-mm 6 4.5-cm guard column that contains
percentages of each impurity by comparing the intensity of packing L1, and a 4.6-mm 6 25-cm analytical column that
the impurity spots within Test solution 1 to those of the main contains 5-mm packing L1. The flow rate is about 1.5 mL per
spots obtained from the series of Test solution 2, ignoring any minute. Chromatograph the System suitability preparation
impurity peak less intense than the main spots found in the and the Standard preparation, and record the peak responses
Test solution 2 lane containing 0.2% of the amount of as directed for Procedure: the relative retention times are
estradiol benzoate of Test solution 1. Not more than 1.0% of about 0.5 for estradiol 17-acetate and 1.0 for estradiol
any individual impurity is found, and not more than 2.0% of benzoate; the resolution, R, between estradiol 17-acetate and
total impurities is found. estradiol benzoate is not less than 6.0; the column efficiency
Assay— is not less than 8000 theoretical plates for estradiol benzoate;
Mobile phase—Prepare a filtered and degassed mixture of the tailing factor for estradiol benzoate is not more than 2.0;
acetonitrile and water (7 : 3). Make adjustments if necessary and, using the Standard preparation, the relative standard
(see System Suitability under Chromatography h621i). deviation for replicate injections is not more than 1.5%.
System suitability preparation—Transfer an accurately Procedure—Separately inject equal volumes (about 20 mL)
weighed quantity of about 20.0 mg each of USP Estradiol of the Standard preparation and the Assay preparation into
Benzoate RS and estradiol 17-acetate into a 100-mL the chromatograph, record the chromatograms, and measure
volumetric flask. Add 70 mL of acetonitrile, and sonicate the responses for the major peaks. Calculate the quantity, in
until dissolved. Add 25 mL of water, mix well, and allow to mg, of C25H28O3 in the portion of Estradiol Benzoate taken by
equilibrate to ambient temperature. Dilute with water to the formula:
volume, and mix.
In-Process Revision
100C(rU / rS)
Standard preparation—Transfer an accurately weighed
quantity of about 20.0 mg of USP Estradiol Benzoate RS
in which C is the concentration, in mg per mL, of USP
into a 100-mL volumetric flask. Add 70 mL of acetonitrile,
Estradiol Benzoate RS in the Standard preparation; and rU
and sonicate until dissolved. Add 25 mL of water, mix well,
and rS are the peak responses obtained from the Assay
and allow to equilibrate to ambient temperature. Dilute with
water to volume, and mix.
tively.&1S (USP31)
Pharmacopeial Forum
Sterility h71i—It meets the requirements when tested as

BRIEFING
directed for Membrane Filtration under Test for Sterility of
Fludarabine Phosphate Injection. Because there is no existing the Product to be Examined.
USP monograph for this drug product, a new monograph is being
proposed. The liquid chromatographic procedure in the Assay is pH h791i: between 6.0 and 7.1.
based on analysis performed with the Discovery C18 brand of L1
column. The typical retention time is about 7.0 minutes for
fludarabine phosphate. Particulate matter h788i: meets the requirements.
(MD-OOD: C. Anthony; MSA: R. Tirumalai) RTS—C42588 Related compounds—

TEST 1—
Buffer solution and Mobile phase—Prepare as directed in

the Assay.
Add the following:
Standard solution—Quantitatively transfer 1.0 mL of the
&Fludarabine Phosphate Injection Standard preparation, prepared as directed in the Assay, into
a 100-mL volumetric flask. Dilute with Buffer solution to
volume, and mix to obtain a solution having a known
» Fludarabine Phosphate Injection is a sterile concentration of 0.001 mg of fludarabine phosphate per mL.
solution of Fludarabine Phosphate in Sterile Test solution—Use the Assay preparation.

Sensitivity solution—Quantitatively transfer 2.0 mL of the
Water for Injection. It contains not less than 95.0
Standard solution into a 25-mL volumetric flask. Dilute with
percent and not more than 105.0 percent of the
Buffer solution to volume, and mix to obtain a solution
labeled amount of C10H13FN5O7P.
having a known concentration of 0.08 mg of fludarabine
Caution: Fludarabine Phosphate is potentially phosphate per mL.
cytotoxic. Great care should be taken to prevent Resolution solution—Add 3 drops of 2 N hydrochloric acid
inhaling particles and exposing the skin to it. solution to 1.5 mL of the Standard solution. Mix well, and
heat at 808 for 30 minutes.
Packaging and storage—Preserve in well-closed containers,
preferably of Type I glass, protected from light. Store in
The liquid chromatograph is equipped with a 260-nm UV
a refrigerator.
detector and a 4.6-mm 6 25-cm column containing 5-mm
USP Reference standards h11i—USP Fludarabine Phos-
packing L1. The flow rate is 1.0 mL per minute.
In-Process Revision
phate RS.
Chromatograph the Sensitivity solution at 260 nm. The ratio
Identification— of the fludarabine phosphate peak height to the noise height is
A: Ultraviolet Absorption h197Ui— not less than 10, the noise height being determined by
Solution: 27 mg per mL. a suitable procedure. Chromatograph the Resolution solution,
Medium: 0.1 M hydrochloric acid. and record the peak responses as directed for Procedure: the
B: The retention time of the major peak in the resolution, R, between the fludarabine phosphate peak and the
chromatogram of the Assay preparation corresponds to that 2-fluoroadenine peak (relative retention time about 1.3) is not
in the chromatogram of the Standard preparation, as obtained less than 5. Chromatograph the Standard solution, and record
in the Assay. the peak responses as directed for Procedure: the tailing
Bacterial endotoxins h85i—It contains not more than 7.7
USP Endotoxin Units per mg of fludarabine phosphate.
Pharmacopeial Forum
factor is not more than 1.8 for the fludarabine phosphate peak, TEST 2—
and the relative standard deviation for replicate injections is Mobile phase, Standard solution, System suitability
not more than 1%. solution, Sensitivity check solution, Chromatographic
Procedure—Separately inject equal volumes (about 20 mL) system, Procedure, and Limits—Proceed as directed in
of the Standard solution and the Test solution into the Related compounds, Test A and Test B, under Fludarabine
chromatograph, and record the chromatograms at 260 nm. Phosphate for Injection.
Measure the response of the fludarabine phosphate peak for Test solution—Quantitatively transfer 1.0 mL of Injection
the Standard solution, and measure the responses of all the into a 25-mL volumetric flask. Dilute with Buffer solution to
major peaks, excluding the fludarabine phosphate peak, for volume, and mix to obtain a solution having a concentration
the Test solution. Calculate the percentage of each impurity of about 1 mg of fludarabine phosphate per mL.
present in the portion of Injection taken by the formula: Other requirements—It meets the requirements under
Injections h1i.
1000 C/F(rU / rS)
Assay—
Buffer solution—Dissolve 13.8 g of monobasic sodium
phosphate monohydrate in 2000 mL of water (50 mM).
Fludarabine Phosphate RS in the Standard solution; F is
Adjust with 1.0 N sodium hydroxide to a pH of 4.5 + 0.2.
a relative response factor (see Table 1 for values) and equal to
Mobile phase—Prepare a mixture of filtered and degassed
1.0 for any other impurities; rU is the peak response for each
Buffer solution and methanol (47 : 3).
individual impurity in the Test solution; and rS is the peak
response for fludarabine phosphate in the Standard solution.
quantity of USP Fludarabine Phosphate RS in Buffer solution.
The limits of impurities are specified in Table 1.
Dilute quantitatively with Buffer solution to volume, and mix
Table 1 to obtain a solution having a known concentration of about

0.1 mg of fludarabine phosphate per mL.
Relative Relative
Assay preparation—Quantitatively transfer 1.0 mL of
Response Retention Limit
Injection into a 250-mL volumetric flask. Dilute with Buffer
Impurity Factor (F) Time (w/w, %)
solution to volume, and mix to obtain a solution having
Iso-ara-guanine mono- 0.28 0.45 0.4
a concentration of about 0.1 mg of fludarabine phosphate per
phosphate
In-Process Revision
mL.
2-Amino analog 0.45 0.54 0.2
Compound A 1.0 0.62 0.3
The liquid chromatograph is equipped with a 260-nm UV
2-Fluoroadenine 1.0 1.3 0.2
detector and a 4.6-mm 6 25-cm column containing 5-mm
Individual unspecified 1.0 — 0.3
packing L1. The flow rate is 1.0 mL per minute.
impurity
Chromatograph the Standard preparation, and record the
peak responses as directed for Procedure: the tailing factor is
not more than 1.8 for the fludarabine phosphate peak, and the
than 1%.
Pharmacopeial Forum

BRIEFING
Galantamine Hydrobromide. Because there is no existing USP
the response for the fludarabine phosphate peak. Calculate the monograph for this active drug substance, a new monograph is being
proposed. The proposed liquid chromatographic procedures in the
quantity, in mg per mL, of C10H13FN5O7P in the portion of test for Related compounds and in the Assay are based on analyses
performed with the Waters XTerra MS brand of C18 column. The
Injection taken by the formula: typical retention time for the galantamine peak is about 16 minutes.

250 (C/V)(rU / rS)

Fludarabine Phosphate RS in the Standard preparation; V is
Add the following:
the volume, in mL, of Injection taken; and rU and rS are the
&Galantamine Hydrobromide
peak responses for fludarabine phosphate in the Assay
tively.&1S (USP31)
BRIEFING
C17H21NO3 HBr 368.27
Flumazenil Injection, USP 29 page 920. It is proposed to revise
the limit for the Bacterial endotoxins test to be consistent with the 6H-Benzofuro[3a,3,2-ef][2]benzazepin-6-ol, 4a,5,9,10,11,12-
limit approved for use in pediatric patients.
hexahydro-3-methoxy-11-methyl-, hydrobromide,
(MSA: R. Tirumalai) RTS—C51685
(4aS,6R,8aS)-.
Change to read:
(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-
Bacterial endotoxins h85i: not more than 25.0 methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hy-
&
100&1S (USP31) drobromide. [1953-04-4].
USP Endotoxin Units per mg of flumazenil.
» Galantamine Hydrobromide contains not less

In-Process Revision

of C17H21NO3 HBr, calculated on the dried basis.
Packaging and storage—Store at room temperature. Pre-

serve in well-closed containers.
USP Reference standards h11i—USP Galantamine Hydro-
bromide RS. USP Galantamine Hydrobromide Related
Compounds Mixture RS. USP Galantamine Hydrobromide
Racemic RS.
Pharmacopeial Forum
Identification— Test solution—Weigh accurately 1 g of Galantamine
A: Infrared Absorption h197Ki—Specimens are to be Hydrobromide. Transfer the sample into an appropriate
prepared using undried USP Galantamine Hydrobromide RS digestion system, and digest using appropriate acids (e.g.,
and the test article. nitric acid or mixtures of nitric acid and sulfuric acid and
B: The retention time of the major peak in the mixtures of nitric acid and hydrogen peroxide). After
chromatogram of the Test solution corresponds to that in digestion, heat to dryness. Add 0.5 mL of Aqua regia and
the chromatogram of the Resolution solution, as obtained in 2 mL of water. Warm gently to dissolve any residue. Allow to
the Assay. cool. Transfer quantitatively upon rinsing with several mL of
C: A solution of 7 mg per mL in water meets the water into a 10-mL volumetric flask, and dilute with water to
requirement of the silver nitrate precipitate test for Bromide volume.
h191i. Atomic absorption spectrophotometer system—Use a stan-

dard atomic absorption spectrophotometric system (see
Loss on drying h731i—Dry at 1058 for 4 hours: it loses not
Spectrophotometry and Light Scattering h851i) equipped
more than 0.5% of its weight.
with a palladium hollow-cathode lamp. Measure the absor-
bances in an air–acetylene flame at 247.6 nm (e.g., using
Heavy metals, Method II h231i: 0.002%. a 0.2-nm slit width) of the Blank solution and the 0.2, 1.0, and
Limit of palladium— 2.0 mg per L Standard solutions, and construct the calibration
Standard stock solution—Transfer an accurately measured curve: the correlation coefficient must be not less than 0.99.
quantity of palladium reference stock solution (NIST Measure the absorbance of the System suitability solution, and
traceable), and dilute quantitatively with water to obtain calculate the concentration of the System suitability solution:
a solution having a known concentration of about 20 mg per the recovery is between 87.5% and 112.5% of the actual
L. concentration.
Aqua regia—Carefully mix under a hood hydrochloric acid Procedure—Measure the absorbance of the Digestion blank
and nitric acid (3 : 1). solution and the Test solution. Calculate the concentration of
Standard solutions—Quantitatively dilute suitable volumes palladium in the Test solution using the calibration curve,
of Standard stock solution to obtain solutions having known after correcting appropriately for the absorbance of the
concentrations of 0.2, 1.0, and 2.0 mg per L of palladium. Digestion blank solution and sample weight. Calculate the
[NOTE—It is recommended that the required volume of amount of palladium in the Galantamine Hydrobromide taken
In-Process Revision
Standard stock solution be mixed with a volume of Aqua to prepare the Test solution: not more than 0.001% (w/w) of
regia equivalent to 5% of the final volume followed by water palladium is found.
to obtain each of the required Standard solutions.] Limit of 4R,8R stereoisomer—
System suitability solution—Prepare a solution having Background electrolyte solution—Dissolve 8.9 g of dibasic
a known concentration of 1.6 mg per L of palladium, as sodium phosphate dihydrate in 1 L of water. Adjust the pH of
directed for Standard solutions. the solution to 3.0 using ortho-phosphoric acid.
Blank solution—Dilute 5 mL of Aqua regia with water to Run buffer—Prepare a solution containing approximately
100 mL. 19.6 mg of a-cyclodextrin hydrate per mL of Background
Digestion blank solution—Prepare this solution following electrolyte solution. Pass the solution through a 0.22-mm
the procedure for Test solution, without the test article. filter.
Pharmacopeial Forum
Standard solution—Transfer an accurately weighed portion Procedure—Inject the Test solution twice into the electro-
of USP Galantamine Hydrobromide Racemic RS to an phoresis system (34.5 mbar for 4 seconds followed by Run
appropriately sized volumetric flask. Dissolve in and dilute buffer at 6.9 mbar for 5 seconds). Record the electrophero-
with purified water to volume to obtain a solution having grams for an approximate run time of 35 minutes. Measure
a known concentration of about 5 mg per mL. Pass the the migration times and peak responses: the migration times
solution through a 0.22-mm filter, discarding the first 8 mL. for 4R,8R stereoisomer in the electropherograms for the Test
Test solution—Transfer an accurately weighed portion of solution should not deviate by more than 5% of the migration
Galantamine Hydrobromide to an appropriately sized volu- time for the same component in the electropherogram of the
metric flask to obtain a final concentration of about 0.5 mg Standard solution. Calculate the limit of the 4R,8R isomer, in
per mL. Dissolve in and dilute with purified water to volume. percent, in the portion of Galantamine Hydrobromide taken,
Pass the solution through a 0.22-mm filter, discarding the first by the formula:
8 mL.
Blank solution: water, passed through a 0.22-mm filter. 100(CS / CU)P(rCU / rCS)
Capillary rinsing procedure—Use separate Run buffer vials
for the capillary rinse and sample analysis. Rinse the capillary in which CS is the concentration, in mg per mL, of USP
Galantamine Hydrobromide Racemic RS in the Standard
for 15 minutes with 0.1 N sodium hydroxide, followed by
solution; CU is the concentration of Galantamine Hydrobro-
water for 10 minutes, and dry it with a current of air or
a stream of nitrogen or other suitable gas for 5 minutes. If mide in the Test solution; P is the chiral purity of USP
Galantamine Hydrobromide Racemic RS; and rCU and rCS are
a new or dry capillary is being used, rinse with 1 N sodium
the average corrected peak responses for the 4R,8R isomer in
hydroxide for 30 minutes, followed by water for 15 minutes,
and dry it with air or nitrogen for 10 minutes. Rinse the the Test solution and the Standard solution, respectively. The
corrected peak responses are calculated using the formula:
capillary between injections as follows: water for 5 minutes,
followed by Run buffer for 5 minutes. Rinse times are based
(r/m)
on a rinse pressure of 1.4 bar.
System setup (see Capillary Electrophoresis h727i)—The
in which r is the peak response; and m is the migration time of
system is equipped with a 214-nm detector and a 75-mm
the peak, in minutes. Not more than 0.10% of the 4R,8R
6 60-cm uncoated fused-silica capillary column. The
stereoisomer is found.
In-Process Revision
temperature is maintained at 208. A voltage of 250 V/cm

with positive polarity is applied. Inject the five replicates of
Buffer solution, Solution A, Solution B, Mobile phase,
Standard solution, and record the peak responses as directed
Resolution solution, Chromatographic system, and Diluent—
for Procedure: the resolution, R, between the two enantio-
Prepare as directed in the Assay.
mers is not less than 2.5; the relative standard deviation for
Standard solution—Dilute the Standard preparation quan-
the 4R,8R stereoisomer peak is not more than 10%. [NOTE—
titatively, and stepwise if necessary, with Diluent to obtain
For the purpose of identification, the 4S,8S stereoisomer
a solution having a known concentration of about 5.0 mg per
elutes at an approximate relative migration time (RMT) of
mL of galantamine hydrobromide.
1.00, and the 4R,8R stereoisomer elutes at an RMT of about
1.05.]
Pharmacopeial Forum
Procedure—Inject equal volumes (about 20 mL) of the Assay—

Standard solution and the Test solution into the chromato- Buffer solution—Dissolve 0.79 g of dibasic sodium phos-
graph, and record the chromatogram. Identify the impurities, phate dihydrate and 2.46 g of monobasic sodium phosphate
based on the relative retention times given in Table 1, and anhydrous in 1 L of water.
measure the peak responses. [NOTE—Ignore the peak due to Solution A—To 950 mL of the Buffer solution, pipet exactly
bromide near the void volume and any peak below 0.05%. 50 mL of methanol, and mix.
The approximate relative retention times in Table 1 are for Solution B: acetonitrile.
peak identification purposes only.] Calculate the percentage Mobile phase—Use variable mixtures of Solution A and
of each of the galantamine hydrobromide related compounds Solution B as directed for Chromatographic system. Make
in the portion of Galantamine Hydrobromide, taken on the adjustments if necessary (see System Suitability under
dried basis, by the formula: Chromatography h621i).
Diluent—Prepare a mixture of water and methanol (95 : 5).
100(CS / CU)(rU / rS)(1/F)(100/100 – L) Resolution solution—Dissolve an accurately weighed
quantity of USP Galantamine Hydrobromide Related Com-
in which CS and CU are the concentrations, in mg per mL, of
pounds Mixture RS in Diluent, and dilute quantitatively, and
Galantamine Hydrobromide in the Standard solution and the
stepwise if necessary, to obtain a solution having a concen-
Test solution, respectively; rU is the peak response of each
tration of about 1 mg per mL.
impurity obtained from the Test solution; rS is the peak
response of galantamine hydrobromide obtained from the
quantity of USP Galantamine Hydrobromide RS in Diluent,
Standard solution; F is the relative response factor for each of
and dilute with Diluent quantitatively, and stepwise if
the impurities relative to galantamine hydrobromide; and L is
necessary, to obtain a solution having a known concentration
the loss on drying, in percent, as determined in the test for
Loss on drying. The limits are given in Table 1.
Table 1
Relative Retention Relative Response Limit

Related Compound Time Factor (F) (%, w/w)
1,6
6b-hexahydrogalantamine 0.65 0.96 —
6b-octahydrogalantamine2 0.82 0.81 NMT 0.35
In-Process Revision
Galantamine hydrobromide 1.00 1.0 —
6a-hexahydrogalantamine3,6 1.16 0.95 —
Tetrahydrogalantamine4 2.05 1.2 NMT 0.40
Individual unspecified impurity — 1.0 NMT 0.10
Total impurities5 — — NMT 1.0
1
[4aS-(4aa,6b,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, N-oxide.
2
[4aS-(4aa,6b,,8aR*)]-4a,5,7,8,9,10,11,12-octahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol.
3
[4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol.
4
[4aS-(4aR*,8aR*)]-9,10,11,12-tetrahydro-3-methoxy-11-methyl-4aH-benzofuro[3a,3,2-ef][2]benzazepine.
5
Do not include 4R,8R stereoisomer measure from the test for Limit of 4R,8R stereoisomer.
6
This is not a specified impurity and is included in the table for peak identification purposes only.
Pharmacopeial Forum
Assay preparation—Dissolve an accurately weighed quan-

tity of Galantamine Hydrobromide in Diluent, and dilute with
100(CS / CU)(rU / rS)
Diluent quantitatively, and stepwise if necessary, to obtain
a solution having a known concentration of about 1.0 mg per in which CS and CU are the concentrations of galantamine
mL. hydrobromide, in mg per mL, of the Standard preparation
Chromatographic system (see Chromatography h621i)— and the Assay preparation, respectively; and rU and rS are the
The liquid chromatograph is equipped with a 230-nm detector peak responses obtained from the Assay preparation and the
and a 4.6-mm 6 10-cm column that contains 3.5-mm packing Standard preparation, respectively.&1S (USP31)
L1. The flow rate is about 1.5 mL per minute. The column
temperature is maintained at 558. The chromatograph is
programmed as indicated in Table 2. BRIEFING
Table 2 Heparin Sodium, USP 29 page 1047. On the basis of supporting

data and comments received, it is proposed to revise the Assay to
replace the existing anticoagulation assay with a new anti-factor IIa
Time Solution A Solution B activity assay. In the Definition, it is proposed to delete the reference
to the potency stated on the label, which was inadvertently carried
(minutes) (%) (%) Elution over from the Heparin Sodium Injection monograph.
0–6.0 100 0 isocratic (BB BBP: A. Szajek) RTS—C51741
6.0–20.0 100?95 0?5 linear gradient

20.0–35.0 95?85 5?15 linear gradient Change to read:
35.0–50.0 85?80 15?20 linear gradient » Heparin Sodium is the sodium salt of sulfated
50.0–51.0 80?40 20?60 linear gradient glycosaminoglycans present as a mixture of heteroge-
neous molecules varying in molecular weights. It is
51.0–55.0 40 60 isocratic present in mammalian tissues and is usually obtained
from the intestinal mucosa or other suitable tissues of
55.0–56.0 40?100 60?0 linear gradient domestic mammals used for food by man. It is purified
56.0–60.0 100 0 re-equilibration to retain a combination of activities against different
fractions of the blood clotting sequence. It is composed
of polymers of alternating derivatives of D-glucosamine
Chromatograph the Resolution solution, and record the peak
(N-sulfated, O-sulfated, or N-acetylated) and uronic acid
responses as directed for Procedure. Identify the peaks using (L-iduronic acid or D-glucuronic acid) joined by
glycosidic linkages. The component activities of the
the relative retention times given in Table 1: the resolution, R, mixture are in ratios corresponding to those shown by
between galantamine and 6a-hexahydrogalantamine is not the USP Heparin Sodium Reference Standard. Some of
In-Process Revision
these components have the property of prolonging the

less than 4.5; the tailing factor for galantamine hydrobromide clotting time of blood. This occurs mainly through the
formation of a complex of each component with the
is not more than 2.0. Chromatograph the Standard prepara- plasma proteins antithrombin III and heparin cofactor II
tion, and record the peak responses as directed for Procedure: to potentiate the inactivation of thrombin. Other
coagulation proteases in the clotting sequence, such as
the relative standard deviation for replicate injections is not activated factor X, are also inhibited. The potency of
Heparin Sodium, calculated on the dried basis, is not
more than 1.0%. less than 140 USP Heparin Units in each mg. , and not
Procedure—Separately inject equal volumes (about 20 mL) less than 90.0 percent and not more than 110.0 percent
of the potency stated on the label.
&
&1S (USP31)
the chromatograph, and measure the responses for the
galantamine hydrobromide peak. Calculate the quantity, in NOTE—The USP Heparin Unit is defined by the USP
Heparin Sodium Reference Standard and can be
percent, of C17H21NO3 HBr in the portion of Galantamine independent of International Units. The respective
units are not equivalent (see General Notices). The
Hydrobromide taken, by the formula:
Pharmacopeial Forum
Unit for Anti-Factor Xa activity is defined by the USP

&
assay&1S (USP31)
activity by the formula:
Heparin Sodium Reference Standard and is equivalent
in potency to that Standard. 100(anti-factor Xa potency / anticoagulant potency).
Change to read:
Anti-factor Xa activity—
&
100(anti-factor Xa potency / assay potency).&1S (USP31)
pH 8.4 Buffer—Dissolve amounts of tris(hydroxymethyl)amino-
methane, edetic acid, and sodium chloride in water containing 0.1% Not less than 80% and not more than 120% is found.
of polyethylene glycol 6000 to obtain a solution having concentra-
tions of 0.050 M, 0.0075 M, and 0.175 M, respectively. Adjust, if
necessary, with hydrochloric acid or sodium hydroxide solution to Change to read:
a pH of 8.4.
Antithrombin III solution—Reconstitute an accurately weighed Assay—
quantity of antithrombin III (see Reagent Specifications under Standard preparation—Determine by preliminary trial, if neces-
Reagents, Indicators, and Solutions) in pH 8.4 Buffer to obtain sary, approximately the minimum quantity of USP Heparin Sodium
a solution having a concentration of 1.0 Antithrombin III Unit per RS which, when added in 0.8 mL of saline TS, maintains fluidity in
mL. 1 mL of prepared plasma for 1 hour after the addition of 0.2 mL of
Factor Xa solution—Reconstitute an accurately weighed quantity calcium chloride solution (1 in 100). This quantity is usually
of bovine factor Xa (see Factor Xa in Reagent Specifications under between 1 and 3 USP Heparin Units. On the day of the assay prepare
Reagents, Indicators, and Solutions) in pH 8.4 Buffer to obtain a Standard preparation such that it contains, in each 0.8 mL of saline
a solution that gives an absorbance value between 0.65 and 1.25 at TS, the above-determined quantity of the Reference Standard.
405 nm when assayed as described below but using 30 mL of pH 8.4 Assay preparation—Dissolve about 25 mg of Heparin Sodium,
Buffer instead of 30 mL of the Standard solutions or the Test accurately weighed, in sufficient saline TS to give a concentration of
solutions. 1 mg per mL, and dilute quantitatively to a concentration estimated
NOTE—Factor Xa solution contains about 3 nanokatalytic units per to correspond to that of the Standard preparation.
mL, but can vary depending upon the manufacturer of factor Xa or Preparation of plasma—Collect blood from sheep directly into
the substrate used. a vessel containing 8% sodium citrate solution in the proportion of
Chromogenic substrate solution—Prepare a solution of a suitable one volume to each 19 volumes of blood to be collected. Mix
chromogenic substrate for amidolytic test (see Reagent Specifica- immediately by gentle agitation and inversion of the vessel.
tions under Reagents, Indicators, and Solutions) specific for factor Promptly centrifuge the blood, and pool the separated plasma. To
Xa in water to obtain a concentration of about 1 mM. a 1-mL portion of the pooled plasma in a clean test tube add 0.2 mL
Stopping solution—Prepare a 20% (v/v) solution of acetic acid in of calcium chloride solution (1 in 100), and mix. Consider the
water. plasma suitable for use if a solid clot forms within 5 minutes. To
Standard solutions—Dilute an accurately measured volume of store plasma for future use, subdivide the pooled lot into portions not
USP Heparin Sodium RS with pH 8.4 Buffer to obtain at least 5 (out exceeding 100 mL in volume, and store in the frozen state,
of 7 below) solutions having known activities of about 0.375, preventing even partial thawing prior to use. For use in the assay,
0.3125, 0.25, 0.188, 0.125, 0.0625, and 0.0313 USP Heparin Unit thaw the frozen plasma in a water bath at a temperature not
per mL. exceeding 378. Remove particulate matter by straining the thawed
Test solutions—Dissolve or dilute an accurately measured quantity plasma through a coarse filter.
of Heparin Sodium in pH 8.4 Buffer, and dilute with the same buffer Procedure—To meticulously clean 13-mm 6 100-mm test tubes
to obtain solutions having activities approximately equal to those of add graded amounts of the Standard preparation, selecting the
the Standard solutions. amounts so that the largest does not exceed 0.8 mL and so that they
Procedure—[NOTE—Perform the test with each Standard solution correspond roughly to a geometric series in which each step is
and Test solution in duplicate.] To each of a series of suitable plastic approximately 5% greater than the next lower. To each tube so
tubes placed in a water bath set at 378, transfer 120 mL of pH 8.4 prepared add sufficient saline TS to make the total volume 0.8 mL.
Buffer. Then separately transfer 30 mL of the different dilutions of the Add 1.0 mL of prepared plasma to each tube. Then add 0.2 mL of
Standard solutions or the Test solutions to the tubes. Add 150 mL of calcium chloride solution (1 in 100), note the time, immediately
Antithrombin III solution, prewarmed at 378 for 15 minutes, to each insert a suitable stopper in each tube, and mix the contents by
tube, mix, and incubate for 2 minutes. Add 300 mL of Factor Xa inverting three times in such a way that the entire inner surface of the
solution, prewarmed at 378 for 15 minutes, to each tube, mix, and tube is wet.
incubate for 2 minutes. Add 300 mL of Chromogenic substrate In the same manner set up a series using the Assay preparation,
solution, prewarmed at 378 for 15 minutes, to each tube, mix, and completing the entire process of preparing and mixing the tubes of
In-Process Revision
incubate for exactly 2 minutes. Add 150 mL of Stopping solution to both the Standard preparation and the Assay preparation within 20
each tube, and mix. Prepare a blank for zeroing the spectrophotom- minutes after the addition of the prepared plasma. One hour,
eter by adding the reagents in reverse order, starting with the accurately timed, after the addition of the calcium chloride,
Stopping solution and ending with the addition of 150 mL of pH 8.4 determine the extent of clotting in each tube, recognizing three
Buffer, and excluding the Standard solutions or the Test solutions. grades (0.25, 0.50, and 0.75) between zero and full clotting (1.0). If
Record the absorbance at 405 nm against the blank. the series does not contain 2 tubes graded more than 0.5 and 2 tubes
Calculations—Plot the log of the absorbance values of the graded less than 0.5, repeat the assay, using appropriately modified
Standard solutions and the Test solutions versus heparin concentra- Standard preparation and Assay preparation.
tions in USP Units. Construct separate straight lines of best fit using Calculation—Convert to logarithms the volumes of Standard
least-squares linear regression analyses for the Standard solutions preparation used in the successive 5 or 6 tubes that bracket a grade
and the Test solutions, and determine the slope for each regression of clotting of 0.5, including at least 2 tubes with a larger and 2 tubes
line. Calculate the potency of Heparin Sodium by the formula: with a smaller grade than 0.5. Number and list the tubes serially, and
tabulate for each the grade of clotting observed in each tube. From
P(ST / SS) the log-volumes, x, and separately from their corresponding grades
in which P is the potency of USP Heparin Sodium RS; and ST and SS of clotting, y, compute the paired averages xi and yi of Tubes 1, 2, and
are the slopes of the lines from the Test solutions and the Standard 3, of Tubes 2, 3, and 4, of Tubes 3, 4, and 5, and, where the series
solutions, respectively. Express the Anti-factor Xa potency of the Test consists of 6 tubes, of Tubes 4, 5, and 6, respectively. If for one of
solution as a percentage of the heparin concentration determined in these paired averages the average grade, yi, is exactly 0.50, the
the Assay. Calculate the percentage of anti-factor Xa activity against
anticoagulant
Pharmacopeial Forum
corresponding xi is the median log-volume of the Standard Chromogenic substrate solution—Prepare a solution of
preparation, xS. Otherwise, interpolate xS from the paired values of
yi, xi and yi +1, xi +1 that fall immediately below and above grade 0.5 as a suitable chromogenic thrombin substrate for amidolytic test
xS = xi + (yi – 0.5)(xi +1 – xi) / (yi – yi +1). (see Reagents Specifications in the section Reagents,
From the paired data on the tubes of the Assay preparation, compute
similarly its median log-volume xU. Indicators, and Solutions) for thrombin in water to obtain
The log potency of the Assay preparation is
a concentration of 1.25 mM.
M = xS – xU + log R,
Standard preparations—Dilute USP Heparin Sodium RS
where R = vS /vU is the ratio of the USP Heparin Units (vS) per mL of
the Standard preparation to the mg (vU) of Heparin Sodium per mL with pH 8.4 Buffer to obtain four dilutions in the
of the Assay preparation.
Repeat the assay independently, and average the two or more concentration range between 0.005 and 0.05 USP Heparin
values of M to obtain M. If the second determination of M differs by
more than 0.05 from the first determination, continue the assay until Unit per mL.
the log confidence interval computed as directed under Confidence
Intervals for Individual Assays in Design and Analysis of Biological Assay preparations—Proceed as directed for Standard
Assays h111i does not exceed 0.20. The potency of Heparin Sodium
in USP Heparin Units per mg is P* = antilog M. preparations to obtain concentrations of Heparin Sodium
&
Acetic acid solution—Transfer 42 mL of glacial acetic similar to those obtained for the Standard preparations.
acid into a 100-mL volumetric flask, dilute with water to Procedure—[NOTE—The procedure can also be performed
volume, and mix. using microtiter plates. The subsequent absorbance measure-
pH 8.4 Buffer—Dissolve 6.10 g of tris(hydroxymethyl)a- ments are then conducted in a microtiter plate reader.] Label
minomethane, 10.20 g of sodium chloride, 2.80 g of edetate 18 suitable tubes: B1 and B2 for blanks; T1, T2, T3, and T4
sodium, and, if suitable 10.00 g of polyethylene glycol 6000 each in duplicate for the dilutions of the Assay preparations;
and/or 2.00 g of bovine serum albumin in 800 mL of water. and S1, S2, S3, and S4 each in duplicate for the dilutions of
[NOTE—2.00 g of human albumin may be substituted for the Standard preparations. [NOTE—Treat the tubes in the
2.00 g of bovine serum albumin.] Adjust with hydrochloric order B1, S1, S2, S3, S4, T1, T2, T3, T4, T1, T2, T3, T4, S1,
acid to a pH of 8.4, and dilute with water to 1000 mL. S2, S3, S4, B2.] To each tube add the same volume, 2V, (100
Antithrombin III solution—Reconstitute a vial of antithrom- to 200 mL) of Antithrombin III solution and an equal volume,
bin III (see Reagents Specifications in the section Reagents, V, (50 to 100 mL) of either the blank, pH 8.4 Buffer, or an
Indicators, and Solutions) in water to obtain a solution of appropriate dilution of the Assay preparations or the Standard
5 Antithrombin III IU per mL. Dilute this solution with pH preparations. Mix, but do not allow bubbles to form. Incubate
8.4 Buffer to obtain a solution having a concentration of 0.125 at 378 for 1.0 minute. Add to each tube volume 0.5V (25 to 50
Antithrombin III IU per mL. mL) of Thrombin human solution, and incubate for 1.0
In-Process Revision
Thrombin human solution—Reconstitute thrombin human minute. Add V (50 to 100 mL) volume of Chromogenic
(factor IIa) (see Reagents Specifications in the section substrate solution. Two different types of measurements can
Reagents, Indicators and Solutions) in water to give 20 be recorded:
thrombin IU per mL, and dilute with pH 8.4 Buffer to obtain 1. ENDPOINT MEASUREMENT: Stop the reaction after 3.0
a solution having a concentration of 5 thrombin IU per mL. minutes with 2V (100 to 200 mL) volume of Acetic acid
Please note that the thrombin should have a specific activity solution. Measure the absorbance of each solution at 405
of not less 750 IU per mg. nm using a suitable spectrophotometer (see Spectropho-
tometry and Light-Scattering h851i) against the Blank
B1. The reading of the Blank B2 is not more than +0.05
absorbance units.
Pharmacopeial Forum
2. KINETIC MEASUREMENT: Follow the change in absorbance 8-Azoniabicyclo[3.2.1]octane-3-(3-hydroxy-1-oxo-2-phenyl-

for each solution over 1.0 minute at 405 nm using propoxy)-8-methyl-8-(1-methylethyl)-, bromide, mono-
a suitable spectrophotometer (see Spectrophotometry and hydrate(endo,syn)-, (+)-.
Light-Scattering h851i) against the Blank B1. The (8r)-3a-Hydroxy-8-isopropyl-1aH,5aH-tropanium bromide
reading of the Blank B2 is not more than +0.05 (+)-tropate monohydrate [66985-17-9].
absorbance units. Calculate the change in absorbance per
minute.
» Ipratropium Bromide contains not less than 98.0
Calculations—For each series, calculate the regression of
percent and not more than 102.0 percent of
the absorbance or change in absorbance per minute against
log concentrations of the Assay preparations and the C20H30BrNO3 H2O, calculated on the anhydrous
Standard preparations, and calculate the potency of Heparin basis.
Sodium in USP Units per mL using statistical methods for
Packaging and storage—Preserve in tight containers, and
parallel-line assays. Express the activity of Heparin Sodium
store at room temperature.
per mg, calculated on the dried basis.&1S (USP31)
USP Reference standards h11i—USP Ipratropium Bromide
RS. USP Ipratropium Bromide Related Compound A RS. USP
Ipratropium Bromide Related Compound B RS. USP
BRIEFING Ipratropium Bromide Related Compound C RS.
Ipratropium Bromide. Because there is no existing USP Identification—

monograph, a new monograph is being proposed. The reverse
phase HPLC method used in the test for Related compounds and in A: Infrared Absorption h197Mi.
the Assay was validated using a Nova-pak C18 brand of L1 column.
Ipratropium elutes at approximately 4.9 minutes; ipratropium related B: A solution (1 in 100) responds to the test for Bromide
compound B [(8s)-ipratropium bromide] and ipratropium related
compound C (tropic acid) elute at approximately 6.2 minutes and 3.3 h191i.
minutes, respectively.
C: The retention time of the major peak in the
(MD-PS: D. Bempong; NOM: L. Paul) RTS—C39432 chromatogram of the Assay preparation corresponds to that
in the Assay.
pH h791i: between 5.0 and 7.0, in a solution (1 in 10).

Add the following:
Water, Method I h921i:
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between 3.9% and 4.4%.
&Ipratropium Bromide
Heavy metals, Method II h231i: 0.001%.
Limit of ipratropium related compound A—

Adsorbent—Use a suitable high-performance thin-layer
chromatographic silica gel mixture containing a fluorescent
indicator having an optimal intensity at 254 nm.
C20H30BrNO3 H2O 430.38 Test solution—Dissolve about 100 mg of Ipratropium
Bromide, accurately weighed, in 5 mL of methanol.
Pharmacopeial Forum
Stock standard solution—Dissolve an accurately weighed Standard solution—Dissolve an accurately weighed quan-
quantity of USP Ipratropium Bromide Related Compound A tity of USP Ipratropium Bromide RS in Mobile phase and
RS in methanol and dilute quantitatively, and stepwise if dilute quantitatively, and stepwise if necessary, with Mobile
necessary, with methanol to obtain a solution having a known phase to obtain a solution having a known concentration of
concentration of about 0.05 mg per mL. about 0.03 mg per mL.
Standard solutions—In separate flasks, dilute 0.5, 1.0, and Test solution—Transfer about 250 mg of Ipratropium
2.0 mL of the Stock standard solution with methanol to 5 mL Bromide, accurately weighed, to a 25-mL volumetric flask,
to obtain a set of standard solutions having known dissolve in and dilute with Mobile phase to volume, and mix.
concentrations of approximately 0.005, 0.01, and 0.02 mg Chromatographic system (see Chromatography h621i)—
of ipratropium bromide per mL. These solutions correspond Chromatograph the System suitability solution, and record the
to 0.025% (Standard solution C), 0.05% (Standard solution peak responses as directed for Procedure: the relative
B), and 0.1% (Standard solution A), respectively, relative to retention times are listed in the accompanying table; the
the Test solution. resolution, R, between ipratropium and ipratropium related
Application volume: 1 mL. compound B is not less than 4; the tailing factor of the
Developing solvent system—Prepare a mixture of methy- ipratropium peak is not more than 2.5; and the relative
lene chloride, dehydrated alcohol, water, and formic acid standard deviation for replicate injections is not more than
(18 : 18 : 3 : 1). 5%.
Procedure—Proceed as directed for Thin-Layer Chroma- Procedure—Separately inject equal volumes (about 5 mL)
tography under Chromatography h621i. Develop the plate for of the Standard solution and the Test solution into the
about 15 minutes, then remove from the tank and dry at 608 chromatograph, record the chromatograms, and measure the
for 15 minutes. Spray the plate with the Dragendorff’s TS, peak responses. Calculate the percentage of related com-
and allow to dry briefly. Spray the plate with sodium nitrite pounds in the portion of Ipratropium Bromide taken by the
solution (5 in 100), and immediately cover with a glass plate. formula:
The RF for ipratropium bromide related compound A and
ipratropium bromide are about 0.15 and 0.36, respectively. 100(1/F)(CS / CT)(ri / rS)
Any spot in the chromatogram obtained from the Test

in which F is the relative response factor of the related
solution, except for the principal spot, is not more intense
compound relative to ipratropium bromide; CS is the
In-Process Revision
than the spot in the chromatogram obtained from Standard

concentration, in mg per mL, of USP Ipratropium Bromide
solution A (0.1%).
RS in the Standard solution; CT is the concentration, in mg
per mL, of Ipratropium Bromide in the Test solution; ri is the
Phosphate solution, Buffer, Mobile phase, and
individual peak response of the individual related compound;
System suitability solution—Dissolve suitable quantities of
USP Ipratropium Bromide RS and USP Ipratropium Bromide
Related Compound B RS in Mobile phase to obtain a solution
containing about 0.03 mg per mL and 0.01 mg per mL,
respectively.
Pharmacopeial Forum
and rS is the peak response of ipratropium in the Standard Mobile phase—Prepare a filtered and degassed mixture of
solution. See the accompanying table for relative retention Buffer and methanol (87 : 13). Do not use the Mobile phase
times, relative response factors, and acceptance criteria. after 36 hours. Make adjustments if necessary (see System
Relative Relative
System suitability solution—Dissolve suitable quantities of
USP Ipratropium Bromide RS and USP Ipratropium Related
Related Compound Time Factor (%)
Compound C RS in Mobile phase and dilute quantitatively,
Ipratropium related com- 0.7 3.8 0.10
and stepwise if necessary, with Mobile phase to obtain
pound C1
a solution having a known concentration of about 0.5 mg per
Ipratropium bromide 1.0 1.0 —
mL and 0.1 mg per mL, respectively.
Ipratropium related com- 1.3 1.0 0.10
pound B [(8s)-
quantity of USP Ipratropium Bromide RS in Mobile phase,
ipratropium bromide]2
and dilute quantitatively, and stepwise if necessary, with
Atropic acid3 1.9 5.3 0.05
Mobile phase to obtain a solution having a known concen-
N-isopropylnoratropinium 2.3 1.0 0.10
tration of about 0.5 mg per mL.
bromide4
Assay preparation—Transfer about 50 mg of Ipratropium
Apo-ipratropium bromide5 5.1 2.0 0.10
Bromide, accurately weighed, to a 100-mL volumetric flask,
Any individual unknown — — 0.10
dissolve in and dilute with Mobile phase to volume, and mix.
impurity
1
(2RS)-3-hydroxy-2-phenylpropanoic acid.
2
(1R,3r,5S,8s)-3-[[(2RS)-3-hydroxy-2-phenylpropanoyl]oxy]-8- and 3.9-mm 6 15-cm column that contains 4-mm packing
methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane, bromide.
3
2-Phenylpropenoic acid.
4
(1R,3r,5S)-8-(1-methylethyl)-8-azabicyclo[3.2.1]oct-3-yl (2RS)-3- temperature is maintained at 308. Chromatograph the System
hydroxy-2-phenylpropanoate.
5
(1R,3r,5S,8r)-8-methyl-8-(1-methylethyl)-3-[(2-phenylpropeno- suitability solution and record the peak responses as directed
yl)oxy]-8-azoniabicyclo[3.2.1]octane.
for Procedure: the relative retention times are about 0.7 for
ipratropium related compound C and 1.0 for ipratropium
Assay—
bromide; the resolution, R, between ipratropium related
Phosphate solution—Transfer 8.9 g of sodium phosphate
compound C and ipratropium is not less than 4; the tailing
In-Process Revision
dibasic dihydrate to a 100-mL volumetric flask. Dissolve in
factor of the ipratropium peak is not more than 2.5; and the
and dilute with water to volume.
Buffer—Transfer 14.3 g of sodium phosphate monobasic
than 1%.
dihydrate and 2.0 g of tetrapropylammonium chloride to a 1-L
volumetric flask, and dissolve in and dilute with water to
volume. Adjust with Phosphate solution to a pH of 5.5 + 0.2.
Pass through a nylon membrane filter having a porosity of
the responses for the major peaks. Calculate the quantity, in
0.45 mm or finer.
Pharmacopeial Forum
percent, of C20H30BrNO3 H2O in the portion of Ipratropium

BRIEFING
Bromide taken by the formula:
Meclizine Hydrochloride, USP 29 page 1321. In the Procedure

100(CS / CT)(rU / rS) section of the test for Chromatographic purity, it is proposed to add
a formula for calculating the percentage of impurities.

in which CS is the concentration, in mg per mL, of USP
Ipratropium Bromide RS in the Standard preparation; CT is Change to read:
the concentration, in mg per mL, of Ipratropium Bromide in
Chromatographic purity—
the Assay preparation; and rU and rS are the peak responses Mobile phase—Dissolve 1.5 g of sodium 1-heptanesulfonate in
300 mL of water, and mix this solution with 700 mL of acetonitrile.
obtained from the Assay preparation and the Standard Adjust with 0.1 N sulfuric acid to a pH of 4, filter, and degas. Make
adjustments if necessary (see System Suitability under Chromatog-
preparation, respectively.&1S (USP31) raphy h621i).
USP Meclizine Hydrochloride RS in Mobile phase, and dilute
quantitatively, and stepwise if necessary, with Mobile phase to obtain
BRIEFING Test solution—Prepare a solution of Meclizine Hydrochloride in
Mobile phase having a known concentration of about 0.5 mg per
mL.
System suitability solution—Prepare a solution in Mobile phase
Letrozole Tablets, USP 29 page 1233. On the basis of comments containing about 0.01 mg of USP Meclizine Hydrochloride RS and
received, it is proposed to correct the preparation of the Test solution 0.01 mg of 4-chlorobenzophenone per mL.
in the test for Related compounds by deleting the second dilution Chromatographic system (see Chromatography h621i)—The
step. liquid chromatograph is equipped with a 230-nm detector and
a 4.6-mm 6 25-cm column that contains 10-mm packing L1. The
(MD-OOD: F. Mao) RTS—C51196 flow rate is about 1.3 mL per minute. Chromatograph the System
suitability solution, and record the peak responses as directed for
Procedure: the relative retention times are about 0.8 for meclizine
Change to read: hydrochloride and 1.0 for 4-chlorobenzophenone; and the resolution,
R, between 4-chlorobenzophenone and meclizine hydrochloride is
not less than 2.0. Chromatograph the Standard solution, and record
Related compounds— the peak responses as directed for Procedure: the tailing factor for
Solution A, Solution B, Mobile phase, and Diluent—Prepare as the analyte peak is not more than 1.5; the column efficiency, N,
directed in the Assay under Letrozole. determined from the analyte peak is not less than 1800 theoretical
System suitability solution, Reference solution, and plates; and the relative standard deviation for replicate injections is
Chromatographic system—Proceed as directed in the test for Related not more than 1.5%.
compounds under Letrozole, except to use an injection volume of 50 Procedure—Separately inject equal volumes (about 20 mL) of the
mL. Standard solution and the Test solution into the chromatograph.
Test solution—Place a number of Tablets, equivalent to about 25 Allow the Test solution to elute for not less than three times the
mg of letrozole, in a 250-mL volumetric flask. Add 150 mL of retention time of meclizine hydrochloride. Record the chromato-
Diluent, shake for 15 minutes, dilute with Diluent to volume, and grams and measure all of the peak areas. the sum of the peak
mix. Centrifuge a portion of this solution, and dilute an accurately responses, excluding that of meclizine hydrochloride, from the Test
measured volume of it with Diluent to obtain a solution containing solution is not more than two times the meclizine hydrochloride
about 10 mg of letrozole per mL. response from the Standard solution (1.0%), and no single peak
response is greater than that of the meclizine hydrochloride response
In-Process Revision
&
suspension, and use a portion of the clear supernatant for from the Standard solution (0.5%).
injection.&1S (USP31)
&
Calculate the percentage of each impurity in the portion of
Procedure—Proceed as directed in the test for Related compounds
under Letrozole, except to use an injection volume of 50 mL. Meclizine Hydrochloride taken by the formula:
Calculate the percentage of each letrozole related compound in the
Tablets, disregarding any values obtained that are less than 0.05%:
not more than 0.3% of letrozole related compound A is found; not
more than 0.2% of 4,4’,4’’-methylidenetrisbenzonitrile is found; not 100(0.001CS / CU)(rU / rS)
more than 0.1% of any other impurity is found; and not more than
0.3% of all other impurities is found.
in which CS is the concentration, in mg per mL, of meclizine
hydrochloride in the Standard solution, and the multiplier of
0.001 is for conversion of mg per mL to mg per mL; CU is the
concentration, in mg per mL, of meclizine hydrochloride in
the Test solution; rU is the peak response for each impurity
obtained from the Test solution; and rS is the response of the
Pharmacopeial Forum
meclizine peak obtained from the Standard solution: not Chromatographic system (see Chromatography h621i)—The
liquid chromatograph is equipped with a 230-nm detector, a
more than 0.5% of any single impurity is found, and not more 4.6-mm 6 25-cm precolumn positioned between the pump and
the injection valve that contains packing L27,
than 1.0% of total impurities is found.&1S (USP31)
&
&1S (USP31)
and a 4.6-mm 6 25-cm analytical column that contains packing L9.
The flow rate is about 2 mL per minute. Chromatograph replicate
injections of the Standard solution, and record the peak responses as
directed for Procedure: the relative standard deviation is not more
than 2.0%.
BRIEFING Procedure—Inject about 100 mL of a filtered portion of the
solution under test, suitably diluted with Mobile phase, if necessary,
into the chromatograph, record the chromatogram, and measure the
Meclizine Hydrochloride Tablets, USP 29 page 1322. It is response for the major peak. Determine the amount of
proposed to revise Identification test A to replace the test for C25H27ClN2 2HCl dissolved from the peak response obtained in
Identification—Organic Nitrogenous Bases h181i with the HPLC comparison with the peak response obtained from a Standard
retention time agreement of the major peak in the Assay preparation solution having a known concentration of USP Meclizine Hydro-
and the Standard preparation. The proposed revision is consistent chloride RS in a mixture of Medium and Mobile phase (1 : 1),
with current pharmaceutical industry practice and eliminates the use similarly chromatographed. An amount of alcohol not to exceed 1%
of toxic carbon disulfide. It is also proposed to delete the requirement of the total volume of the Standard solution may be used to dissolve
to use a precolumn in the test for Dissolution and in the Assay. USP Meclizine Hydrochloride RS prior to dilution.
According to the explanation provided by the HPLC column Tolerances—Not less than 75% (Q) of the labeled amount of
manufacturer, the precolumns were designed to saturate the mobile C25H27ClN2 2HCl is dissolved in 45 minutes.
phase in applications where the pH range is below 3 or above 7,
because the mobile phase at these pHs can cause the silica backbone
of the column to dissolve. The pH of the Mobile phase used under Change to read:
Dissolution and the Assay is 4.0, and the use of a precolumn is not
necessary. In addition, it is proposed to clarify the numeric Assay—
coefficient in the formula in the Procedure under the Assay. Mobile phase—Prepare a filtered and degassed mixture of
methanol and water (65 : 35) that contains 0.69 g of monobasic
(MD-GRE: E. Gonikberg) RTS—C51416 sodium phosphate in each 100 mL, and adjust with phosphoric acid,
if necessary, to a pH of 4.0. Make adjustments if necessary (see
Solvent mixture—Prepare a mixture of 0.1 N hydrochloric acid and
Change to read: Mobile phase (1 : 1).
Standard preparation—Dissolve an accurately weighed quantity
Identification— of USP Meclizine Hydrochloride RS in Solvent mixture to obtain
A: Tablets meet the requirements under Identification—Organic a solution having a known concentration of about 0.25 mg per mL.
Nitrogenous Bases h181i. Assay preparation—Weigh and finely powder not fewer than 20
Tablets. Transfer an accurately weighed portion of the powder,
&
The retention time of the major peak in the chromatogram of equivalent to about 25 mg of meclizine hydrochloride, to a 100-mL
volumetric flask. Add about 60 mL of Solvent mixture, sonicate for
the Assay preparation corresponds to that in the chromato- about 10 minutes, and shake by mechanical means for about 30
minutes. Dilute with Solvent mixture to volume, mix, and filter
gram of the Standard preparation, as obtained in the a portion of this solution, discarding the first 5 mL of the filtrate.
Assay.&1S (USP31) liquid chromatograph is equipped with a 230-nm detector, a
B: Thin-Layer Chromatographic Identification Test h201i— 4.6-mm 6 25-cm precolumn (positioned between the pump and
Adsorbent: 0.5-mm layer of chromatographic silica gel mixture. the injection valve) that contains packing L27,
Test solution—Extract a quantity of finely powdered Tablets, &
equivalent to about 125 mg of meclizine hydrochloride, by shaking &1S (USP31)
for 15 minutes with 50 mL of methanol. and a 4.6-mm 6 25-cm analytical column that contains packing L9.
Standard solution—Prepare a solution of USP Meclizine Hydro- The flow rate is about 1.6 mL per minute. Chromatograph the
chloride RS in methanol, containing 2.5 mg per mL. Standard preparation, and record the peak responses as directed for
In-Process Revision
Application volume: 50 mL. Procedure: the tailing factor for the analyte peak is not more than
Developing solvent system: a mixture of cyclohexane, toluene, 2.0, and the relative standard deviation for replicate injections is not
and diethylamine (15 : 3 : 2). more than 2.0%.
Procedure—Proceed as directed in the chapter, except to place the Procedure—Separately inject equal volumes (about 25 mL) of the
plate in a developing chamber that contains and has been Standard preparation and the Test preparation into the chromato-
equilibrated with Developing solvent system. graph, record the chromatograms, and measure the responses for the
major peaks. Calculate the quantity, in mg, of meclizine hydrochlo-
ride (C25H27ClN2 2HCl) in the portion of Tablets taken by the
Change to read: formula:
100C(rU / rS)
Dissolution, Procedure for a Pooled Sample h711i—
Time: 45 minutes.
Determine the amount of C25H27ClN2 2HCl dissolved by
&
CV(rU / rS)&1S (USP31)
employing the following method.
Mobile phase—Prepare a suitable degassed and filtered mixture of in which C is the concentration, in mg per mL, of USP Meclizine
water and methanol (55 : 45) that contains 0.69 g of monobasic Hydrochloride RS in the Standard preparation;
sodium phosphate in each 100 mL and is adjusted with phosphoric
acid, if necessary, to a pH of 4.0. &
V is the volume, in mL, of the Assay preparation;&1S (USP31)
Pharmacopeial Forum
and rU and rS are the peak responses obtained from the Assay Procedure—Separately inject equal volumes (about 50 mL) of the
preparation and the Standard preparation, respectively. Standard preparation and the Assay preparation into the chromat-
ograph, record the chromatograms, and measure the responses for
the major peaks. Calculate the quantity, in mg,
&
percentage of the labeled amount&1S (USP31)
of methylphenidate hydrochloride (C14H19NO2 HCl) in the portion
BRIEFING of Tablets taken by the formula:
100C(RU / RS)
Methylphenidate Hydrochloride Tablets, USP 29 page 1405. It
is proposed to require the use of USP Phenylephrine Hydrochloride
RS as the internal standard in the Assay. It is also proposed to revise
the calculation in the Assay to calculate the percentage of the labeled
amount of methylphenidate hydrochloride.
&
100(CS / CU)(RU / RS)&1S (USP31)

in which Cis the concentration, in mg per mL, of Methylphenidate
Hydrochloride RS in the standard stock solution used to prepare the
Standard preparation;and
Change to read: &
CS is the concentration of methylphenidate hydrochloride, in
USP Reference standards h11i—USP Methylphenidate Hydrochlo- mg per mL, in the Standard preparation; CU is the
ride RS.
concentration, in mg per mL, of methylphenidate hydrochlo-
&
USP Phenylephrine Hydrochloride RS.&1S (USP31)
ride in the Assay preparation, based on the label claim;
Change to read: and&1S (USP31)

RU and RS are the peak response ratios of the analyte to the internal
standard obtained from the Assay preparation and the Standard
Assay— preparation, respectively.
Acetate buffer—Dissolve 1.64 g of anhydrous sodium acetate in
900 mL of water, adjust with acetic acid to a pH of 4.0, dilute with
water to 1000 mL, and mix.
methanol, acetonitrile, and Acetate buffer (4 : 3 : 3). Make adjust-
ments if necessary (see System Suitability under Chromatography BRIEFING
h621i).
Internal standard solution—Dissolve phenylephrine hydrochlo-
ride Octinoxate, USP 29 page 1573. On the basis of comments
received, it is proposed to revise the test for Chromatographic purity
&
USP Phenylephrine Hydrochloride RS&1S (USP31) to eliminate the unnecessary preparation of the System suitability
in Mobile phase to obtain a solution having a concentration of about solution. It is also proposed to revise the Assay to add a split
0.4 mg per mL. injection system with a split ratio in accordance with the validation
Standard preparation—Dissolve an accurately weighed quantity report received. Also, for clarification, the measurement of peak
of USP Methylphenidate Hydrochloride RS in Mobile phase, and areas is specified in the test for Chromatographic purity and in the
quantitatively dilute with Mobile phase to obtain a standard stock Assay.
solution having a known concentration of about 0.2 mg per mL.
Transfer 10.0 mL of this standard stock solution to a glass-stoppered, (MD-OOD: F. Mao) RTS—C51165
25-mL conical flask, add 5.0 mL of Internal standard solution, and
mix.
Change to read:
In-Process Revision

equivalent to about 20 mg of methylphenidate hydrochloride, to
a 100-mL volumetric flask, add 70 mL of Mobile phase, and sonicate Chromatographic purity—
for 15 minutes. Cool to room temperature, dilute with Mobile phase System suitability solution—Prepare a solution of benzyl benzoate
to volume, and mix. Pass a portion of this solution through a suitable and USP Octinoxate RS in acetone containing about 50 mg of each
membrane filter, discarding the first portion of the filtrate. [NOTE— per mL.
Avoid the use of glass filters. Polypropylene filters are suitable for
use.] Transfer 10.0 mL of the clear filtrate to a glass-stoppered, &
&1S (USP31)
25-mL conical flask, add 5.0 mL of Internal standard solution, and Test solution—Transfer about 5 mL of Octinoxate to a 100-mL
mix. volumetric flask, dilute with acetone to volume, and mix.
Chromatographic system (see Chromatography h621i)—The Chromatographic system (see Chromatography h621i)—Proceed
liquid chromatograph is equipped with a 210-nm detector and as directed in the Assay. but chromatograph the System suitability
a 4.6-mm 6 25-cm column that contains packing L10. The flow rate solution.
is about 1.5 mL per minute. Chromatograph the Standard
preparation, and record the peak responses as directed for &
&1S (USP31)
Procedure: the relative retention times are about 0.8 for phenyleph- Procedure—Inject a volume (about 1 mL) of the Test solution into
rine hydrochloride and 1.0 for methylphenidate hydrochloride; the the chromatograph, record the chromatogram, and measure the
resolution, R, between the analyte and the internal standard peaks is responses
not less than 2.0; and the relative standard deviation determined from
the peak response ratios of the analyte to the internal standard for &
areas&1S (USP31)
replicate injections is not more than 2.0%.
Pharmacopeial Forum
for all the peaks. Calculate the percentage of each impurity in the 4. Provide relative response factors consistent with the USP
portion of Octinoxate taken by the formula: definition of this term.
5. Revise the formula to indicate that impurities eluting at relative
100(ri / rs) retention times not less than 2.2 are to be quantitated using
in which ri is the peak response for each impurity; and rs is the sum oxandrolone related compound C as the standard.
of the responses for all the peaks: not more than 0.5% of any 6. Add a Blank solution injection.
individual impurity is found; and not more than 2.0% of total It is also proposed to revise the Assay to delete the System
impurities is found. suitability solution because this is not needed for this test. The HPLC
procedures used in the test for Related compounds and Assay were
validated using Eclipse XDB C18 brand of L1 column. The retention
Change to read: time of oxandrolone is about 8 minutes in both the Assay and in the
test for Related compounds.
Assay—
Internal standard solution—Transfer about 25 mL of benzyl (MD-PS: D. Bempong) RTS—C42602
benzoate to a 500-mL volumetric flask, dilute with acetone to
volume, and mix.
Standard preparation—Dilute an accurately measured quantity of Delete the following:
USP Octinoxate RS quantitatively, and stepwise if necessary, with
Internal standard solution to obtain a solution having a known
concentration of about 50 mg per mL.
&
Ordinary impurities h466i—
Assay preparation—Transfer about 5 mL of Octinoxate, accurate- Test solution: methanol.
ly measured, to a 100-mL volumetric flask, dilute with Internal Standard solution: methanol.
standard solution to volume, and mix. Application volume: 10 mL.
Chromatographic system (see Chromatography h621i)—The gas Eluant: a mixture of toluene and isopropyl alcohol (90 : 10), in
chromatograph is equipped with a flame-ionization detector, a a nonequilibrated chamber.
0.32-mm 6 25-m column that contains coating G1, Visualization: 5.&1S (USP31)
&
and a split injection system with a split ratio of about Add the following:
85 : 1.&1S (USP31)
&
The carrier gas is helium, flowing at a rate of about 2 mL per minute. Related compounds—
The chromatograph is programmed as follows. Initially the
temperature of the column is equilibrated at 808, then the Solution A: acetonitrile.
temperature is increased to 3008 over a period of 10 minutes, and
maintained at 3008 for 10 minutes. The injection port temperature is Solution B: water.
maintained at 2508, and the detector temperature is maintained at
3008. Chromatograph the Standard preparation, and record the peak Mobile phase—Use variable mixtures of Solution A and
responses as directed for Procedure: the relative retention times are
about 0.68 for benzyl benzoate and 1.0 for octinoxate; the resolution, Solution B as directed for Chromatographic system. Make
R, between benzyl benzoate and octinoxate is not less than 20; the
column efficiency is not less than 65,000 theoretical plates; and the adjustments if necessary (see System Suitability under
relative standard deviation for replicate injections is not more than
2.0%. Chromatography h621i).
Standard preparation and the Assay preparation into the chromat- Blank solution—Prepare a mixture of Solution A and
ograph, record the chromatograms, and measure the responses
Solution B (50 : 50).
&
areas&1S (USP31)
for the major peaks. Calculate the quantity, in mg, of C18H26O3 in the Standard stock solution—Dissolve accurately weighed
portion of Octinoxate taken by the formula:
quantities of USP Oxandrolone Related Compound A RS,
100C(RU / RS)
in which C is the concentration, in mg per mL, of USP Octinoxate
USP Oxandrolone Related Compound B RS, USP Oxandro-
RS in the Standard preparation; and RU and RS are the peak response lone Related Compound C RS, and USP Oxandrolone RS in
In-Process Revision
ratios of octinoxate to benzyl benzoate obtained from the Assay
preparation and the Standard preparation, respectively. acetonitrile, and dilute quantitatively, and stepwise if
necessary, with acetonitrile to obtain a solution having
known concentrations of about 4 mg of USP Oxandrolone
BRIEFING
Related Compound A RS per mL, 120 mg of USP
Oxandrolone, USP 29 page 1591 and page 3737 of the Second Oxandrolone Related Compound B RS per mL, 4 mg of
Supplement. It is proposed to re-introduce the HPLC test for Related
compounds that was first proposed in PF 31(1) [Jan.–Feb. 2005], to USP Oxandrolone Related Compound C RS per mL, and 200
replace the current Ordinary impurities test. On the basis of
comments received, the following changes are proposed in the test mg of USP Oxandrolone RS per mL. [NOTE—Sonicate if
for Related compounds.
1. Simplify the preparation of the Standard solution. necessary to dissolve.]
2. Change the tailing factor requirement.
3. Provide limits for two additional impurities and also provide
corrected chemical names of oxandrolone related compounds A
and C.
Pharmacopeial Forum
Standard solution—Dilute 1.0 mL of the Standard stock in which C is the concentration, in mg per mL, of oxandrolone
solution with 4.0 mL of acetonitrile and 5.0 mL of water, and related compound A in the Standard solution; W is the
mix. weight, in mg, of Oxandrolone taken to prepare the Test
Test solution—Weigh accurately 40 mg of Oxandrolone solution; rU is the peak area of oxandrolone related compound
into a 10-mL volumetric flask, dissolve in 5.0 mL of A in the chromatogram of the Test solution; and rS is the peak
acetonitrile using an ultrasonic bath, dilute with water to area obtained for oxandrolone related compound A in the
volume, and mix. [NOTE—The Test solution, the Standard chromatogram of the Standard solution.
solution, and the Blank solution are made up fresh and Calculate the percentage of oxandrolone related compound
injected immediately.] C and each impurity eluting at a relative retention time greater
Chromatographic system—The liquid chromatograph is than or equal to 2.2 (relative to retention time of
equipped with a 210-nm detector and a 4.6-mm 6 25-cm oxandrolone), by the formula:
column that contains 5-mm packing L1. The column
temperature is maintained at 408. The flow rate is about 0.7 (C/W)(rU / rS)
mL per minute. The chromatograph is programmed as
follows. in which C is the concentration, in mg per mL, of oxandrolone
related compound C in the Standard solution; W is the
weight, in mg, of Oxandrolone taken to prepare the Test
solution; rU is the peak area of oxandrolone related compound
0 50 50 equilibration C or each impurity eluting at a relative retention time greater
0–30 50?100 50?0 linear gradient than or equal to 2.2 in the chromatogram of the Test solution;
30–32 100?50 0?50 linear gradient and rS is the peak area obtained for oxandrolone related
32–40 50 50 re-equilibration compound C in the chromatogram of the Standard solution.
Chromatograph the Standard solution, and record the peak Calculate the percentage of each impurity, except oxan-
responses as directed for Procedure: the resolution, R, drolone related compound A, oxandrolone related compound
between oxandrolone related compound A and oxandrolone C, and other impurities eluting at relative retention times
related compound B is not less than 1.5, and the resolution, R, greater than or equal to 2.2 by the formula:
between oxandrolone related compound B and oxandrolone is

not less than 2.0; the tailing factor is not more than 1.5; and (1/F)(C/W)(rU / rS)
In-Process Revision
the relative standard deviation for replicate injections is not

in which F is the relative response factor for each impurity
more than 5.0%.
(see accompanying table for values); C is the concentration,
in mg per mL, of USP Oxandrolone RS in the Standard
of the Blank solution, the Standard solution, and the Test
solution; W is the weight, in mg, of Oxandrolone taken to
solution into the chromatograph, record the chromatograms,
prepare the Test solution; rU is the peak area of each impurity,
and measure the peak responses. Calculate the percentage of
in the chromatogram of the Test solution, other than peak
oxandrolone related compound A in the portion of Oxandro-
areas of oxandrolone related compound A, oxandrolone
lone taken by the formula:
related compound C, and other impurities eluting at relative
retention times greater than or equal to 2.2; and rS is the peak
(C/W)(rU / rS)
area obtained for oxandrolone in Standard solution. Disregard
Pharmacopeial Forum
any peak observed in the chromatogram obtained from the Chromatographic system (see Chromatography h621i)—The
Blank solution. Disregard any impurity peak that is less than a 4.6-mm 6 25-cm column that contains packing L1. The flow rate
0.05%. The impurities meet the requirements specified in the preparation, and the System suitability solution,
&
accompanying table. &1S (USP31) &1S (USP31)
and record the peak responses as directed for Procedure: the column
efficiency is not less than 2000 theoretical plates; the tailing factor is
Change to read: not more than 2.0; and the relative standard deviation for replicate
Assay— Procedure—Separately inject equal volumes (about 20 mL) of the
&
Mobile phase—Prepare a filtered and degassed mixture of water Standard preparation and the Assay preparation into the chromat-
and acetonitrile (50 : 50). Make adjustments if necessary (see System ograph, record the chromatograms, and measure the responses for
Suitability under Chromatography h621i). the major peaks. Calculate the quantity, in mg, of C19H30O3 in the
System suitability solution—Weigh accurately 30 mg of USP portion of Oxandrolone taken by the formula:
Oxandrolone RS, and place into a 10-mL volumetric flask. Dissolve
in and dilute with acetonitrile to volume, and mix. VC(rU / rS)
&
in which V is the final volume, in mL, of the Assay preparation; C is
&1S (USP31) the concentration, in mg per mL, of USP Oxandrolone RS in the
Standard preparation—Dissolve an accurately weighed quantity Standard preparation; and rU and rS are the peak responses obtained
of USP Oxandrolone RS in acetonitrile, and dilute quantitatively, from the Assay preparation and the Standard preparation,
and stepwise if necessary, with acetonitrile to obtain a solution respectively.&2S (USP29)
having a known concentration of about 3 mg per mL. [NOTE—
Sonicate if necessary to dissolve.]
Assay preparation—Transfer to a suitable volumetric flask an
accurately weighed quantity of Oxandrolone, and dissolve in and
dilute with acetonitrile to volume to obtain a solution having
a concentration of about 3 mg per mL.
Relative Response
Compound Relative Retention Time Factor (F) Limit (%)
Secodicarboxylic acid1 0.46 4.1 0.1
7,8-Didehydro-oxandrolone2 (Oxandrolone 0.90 — 0.1
related compound A)
4-Oxa-isomer3 (Oxandrolone related 0.94 1.4 0.3
compound B)
Oxandrolone 1.00 — —
Oxandrolone open lactone methyl ester4 1.09 1.5 0.1
Secoacid anhydride5 1.12 2.5 0.1
17-epi-Oxandrolone6 1.33 1.0 0.3

1.52 1.4 0.3
In-Process Revision
4-Oxa-isomer (beta epimer)7
Oxandrolone-17-acetate8 2.14 1.9 0.1
Anhydro-oxandrolone9 (Oxandrolone related 3.29 — 0.5
compound C)
Individual unknown impurity — 1.0 0.1
1
2
17b-Hydroxy-17a-methyl-2-nor-5a-androstan-1,3-dioic acid.
3
17b-Hydroxy-17a-methyl-2-oxa-5a-androst-7-en-3-one.
4
17b-Hydroxy-17a-methyl-4-oxa-5a-androstan-3-one.
5
Methyl-(1,17b-dihydroxy-17a-methyl-1,3-seco-2-nor-5a-androstane-3-oate.
6
17b-Hydroxy-17a-methyl-2-oxa-5a-androstan-1,3-dione.
7
17a-Hydroxy-17b- methyl-2-oxa-5a-androstan-3-one.
8
17b-Hydroxy-17a-methyl-4-oxa-5b-androstan-3-one
9
(17b-Hydroxy-17a-methyl-2-oxa-5a-androstan-3-one 17-acetate).
17,17-Dimethyl-18-nor-2-oxa-5a-androst-13-en-3-one.
Pharmacopeial Forum
Procedure—Inject a volume (about 15 mL) of the Test solution

BRIEFING into the chromatograph, record the chromatogram, and measure the
areas for the major peaks. Calculate the percentage of each impurity
in the portion of Paclitaxel taken by the formula:
Paclitaxel, USP 29 page 1624 and page 361 of PF 32(2) [Mar.– 100(Fri / rU)
Apr. 2006]. On the basis of comments received, it is proposed to
revise several of the chemical names for paclitaxel related impurities in which F is the relative response factor for each impurity peak (see
in the footnotes to Table 3 in the test for Related compounds. Table 1 for values); ri is the peak area for each individual impurity;
and rU is the peak area for paclitaxel.
Table 1
Change to read: Relative Relative

USP Reference standards h11i—USP Endotoxin RS. USP Time Factor (F) Name (%)
Paclitaxel RS. USP Paclitaxel Related Compound A RS. USP 0.24 1.29 Baccatin III 0.2
Paclitaxel Related Compound B RS. 0.53 1.00 10-Deacetylpaclitaxel 0.5
0.57 1.00 7-Xylosylpaclitaxel 0.2
&
USP Paclitaxel Impurity Mixture RS.&1S (USP30) 0.78 1.26 Cephalomannine (paclitaxel a11
related compound A)
0.78 1.26 2’’,3’’-Dihydrocephaloman- a21
nine
Change to read: 0.86 1.00 10-Deacetyl-7-epipaclitaxel 0.5
(paclitaxel related
Related compounds— compound B)
TEST 1 (FOR MATERIAL LABELED AS ISOLATED FROM NATURAL
1.10 1.00 Benzyl analog3 b12
SOURCES)—If the material complies with this test, the labeling
1.10 1.00 3’’,4’’-Dehydropaclitaxel C b22
1.40 1.00 7-Epicephalomannine 0.3
indicates that it meets USP Related compounds Test 1. 1.85 1.00 7-Epipaclitaxel 0.5
Diluent—Prepare as directed in the Assay.
Solution A—Prepare filtered and degassed acetonitrile. 1
Solution B—Prepare filtered and degassed water. Resolution may be incomplete for these peaks, depending upon the relative
Mobile phase—Use variable mixtures of Solution A and Solution amounts present; the sum of a1 and a2 is not more than 0.5%.
2
Resolution may be incomplete for these peaks depending upon the relative
B as directed for Chromatographic system. Make adjustments if amounts present; the sum of b1 and b2 is not more than 0.5%.
necessary (see System Suitability under Chromatography h621i). 3
The following chemical name is assigned to the related compound, benzyl
System suitability solution—Dissolve accurately weighed quan- analog: Baccatin III 13-ester with (2R,3S)-2-hydroxy-3-phenyl-3-(2-phen-
tities of USP Paclitaxel Related Compound A RS and USP Paclitaxel ylacetylamino)propanoic acid.
Related Compound B RS in methanol to obtain a solution having In addition to not exceeding the limits for paclitaxel related
known concentrations of about 10 mg of each per mL. Transfer 5.0 impurities in Table 1, not more than 0.1% of any other single
mL of this solution to a 50-mL volumetric flask, dilute with Diluent impurity is found; and not more than 2.0% of total impurities is
to volume, and mix. found.
Standard solution—Dissolve, with the aid of sonication, an TEST 2 (FOR MATERIAL LABELED AS PRODUCED BY A SEMISYNTHETIC
accurately weighed quantity of USP Paclitaxel RS in Diluent, and PROCESS)—If the material complies with this test, the labeling
dilute quantitatively, and stepwise if necessary, with Diluent to indicates that it meets USP Related compounds Test 2.
obtain a solution having a known concentration of about 5 mg per Diluent—Use acetonitrile.
mL. Solution A—Use a filtered and degassed mixture of water and
Test solution—Use the Assay preparation. acetonitrile (3 : 2).
Chromatographic system (see Chromatography h621i)—The Solution B—Use filtered and degassed acetonitrile.
liquid chromatograph is equipped with a 227-nm detector and Mobile phase—Use variable mixtures of Solution A and Solution
a 4.6-mm 6 25-cm column that contains 5-mm packing L43. The B as directed for Chromatographic system. Make adjustments if
flow rate is about 2.6 mL per minute. The column temperature is necessary (see System Suitability under Chromatography h621i).
maintained at 308. The chromatograph is programmed as follows. System suitability solution—Dissolve accurately weighed quan-
In-Process Revision
Time Solution A Solution B tities of USP Paclitaxel RS and USP Paclitaxel Related Compound B
(minutes) (%) (%) Elution RS in Diluent, shaking and sonicating if necessary, to obtain
a solution having known concentrations of about 0.96 mg and 0.008
0–35 35 65 isocratic mg per mL, respectively.
35–60 35?80 65?20 linear gradient Test solution—Transfer about 10 mg of Paclitaxel, accurately
60–70 80?35 20?65 linear gradient weighed, to a 10-mL volumetric flask, dissolve in and dilute with
70–80 35 65 isocratic Diluent to volume, shaking and sonicating if necessary, and mix.
Chromatograph the System suitability solution, and record the peak Chromatographic system (see Chromatography h621i)—The
responses as directed for Procedure: the relative retention times are liquid chromatograph is equipped with a 227-nm detector and
about 0.78 for paclitaxel related compound A and 0.86 for paclitaxel a 4.6-mm 6 15-cm column that contains 3-mm packing L1. The
related compound B (relative to the retention time for paclitaxel flow rate is about 1.2 mL per minute. The column temperature is
obtained from the Test solution); and the resolution, R, between maintained at 358. The chromatograph is programmed as follows.
paclitaxel related compound A and paclitaxel related compound B is Time Solution A Solution B
not less than 1.0. Chromatograph the Standard solution, and record (minutes) (%) (%) Elution
the peak responses as directed for Procedure: the relative standard
deviation for replicate injections is not more than 2.0%. 0–20 100 0 isocratic
Chromatograph the System suitability solution, and record the peak
responses as directed for Procedure: the relative retention times are
about 0.94 for paclitaxel related compound B and 1.0 for paclitaxel;
Pharmacopeial Forum
the resolution, R, between paclitaxel related compound B and Mobile phase—Use variable mixtures of Solution A and
paclitaxel is not less than 1.2; and the relative standard deviation for
replicate injections is not more than 2.0%. Solution B as directed for Chromatographic system. Make
Diluent and the Test solution into the chromatograph, record the adjustments if necessary (see System Suitability under
chromatograms, and measure the areas for all the peaks. Disregard
any peaks due to the Diluent. Calculate the percentage of each Chromatography h621i).
impurity in the portion of Paclitaxel taken by the formula:
System suitability solution—Dissolve USP Paclitaxel Im-
100(Fri / rs)
in which F is the relative response factor for each impurity (see Table purity Mixture RS in acetonitrile, sonicating if necessary, to
2 for values); ri is the peak area for each impurity obtained from the
Test solution; and rs is the sum of the areas of all the peaks obtained obtain a solution having a known concentration of about 1 mg
from the Test solution.
per mL.
Table 2 Standard solution—Dissolve an accurately weighed quan-
Relative Relative tity of USP Paclitaxel RS in acetonitrile, sonicating if
Time Factor (F) Name (%) necessary, to obtain a solution having a known concentration
0.11 1.24 10-Deacetylbaccatin III 0.1
0.20 1.29 Baccatin III 0.2 of about 1 mg per mL.
0.42 1.39 Photodegradant2 0.1
0.47 1.00 10-Deacetylpaclitaxel 0.5 Test solution—Transfer about 10 mg of Paclitaxel,
0.80 1.00 2-Debenzoylpaclitaxel-2- 0.7
pentenoate accurately weighed, to a 10-mL volumetric flask. Dissolve
0.921 1.00 Oxetane ring opened, acetyl x1
and benzoyl2 in and dilute with acetonitrile to volume, sonicating if
0.921 1.00 10-Acetoacetylpaclitaxel x2
0.941 1.00 10-Deacetyl-7-epipaclitaxel x3 necessary, and mix.
(paclitaxel related com-
pound B) Chromatographic system (see Chromatography h621i)—
1.37 1.00 7-Epipaclitaxel 0.4
1.45 1.00 10,13-Bissidechainpacli- 0.5 The liquid chromatograph is equipped with a 227-nm detector
taxel2
1.54 1.00 7-Acetylpaclitaxel 0.6 and a 4.6-mm 6 15-cm column that contains 3-mm packing
1.80 1.75 13-Tes-baccatin III 0.1
2.14 1.00 7-Tes-paclitaxel 0.3 L1. The flow rate is about 1.2 mL per minute. The
1
Resolution may be incomplete for these peaks, depending upon the relative chromatograph is programmed as follows.
amounts present; the sum of x1, x2, and x3 is not more than 0.4%.
2
The following chemical names are assigned to the related compounds
Photodegradant; Oxetane ring opened, acetyl and benzoyl; and 10,13- Time Solution A Solution B
Bissidechainpaclitaxel:
Photodegradant (minutes) (%) (%) Elution
(1R,2R,4S,5S,7R,10S,11R,12S,13S,15S,16S)-2,10-diacetyloxy-5,13-dihy-
droxy-4,16,17,17-tetramethyl-8-oxa-3-oxo-12-phenylcarbonyloxypentacy-
clo[11.3.1.01,11.04,11.07,10]heptadec-15-yl 0–28 100 0 isocratic
(2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
Oxetane ring opened, acetyl and benzoyl migrated 28–33 100?98 0?2 linear gradient
(1S,2S,3R,4S,5S,7S,8S,10R,13S)-5,10-diacetyloxy-1,2,4,7-tetrahydroxy-
8,12,15,15-tetramethyl-9-oxo-4-(phenylcarbonyloxymethyl)tricy- 33–58 98?10 2?90 linear gradient
clo[9.3.1.03,8]pentadec-11-en-13-yl
(2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbonylamino)propanoate
10,13-Bissidechainpaclitaxel 58–60 10 90 isocratic
Baccatin III 13-ester with (2R,3S)-2-hydroxy-3-phenyl-3-(phenylcarbony-
In-Process Revision
lamino)propanoic acid, 10-ester with (2S,3S)-2-hydroxy-3-phenyl-3-(phenyl- 60–63 10?100 90?0 linear gradient
carbonylamino)propanoic acid
In addition to not exceeding the limits for paclitaxel related 63–70 100 0 isocratic
impurities in Table 2, not more than 0.1% of any other single
impurity is found; and not more than 2.0% of total impurities is Chromatograph the System suitability solution, and record the
found.
&
peak responses as directed for Procedure: the resolution, R,
TEST 3 (FOR MATERIAL LABELED AS PRODUCED BY A PLANT
between paclitaxel and benzyl analog is not less than 1.8.
CELL FERMENTATION PROCESS)—If the material complies with
this test, the labeling indicates that it meets USP Related
responses as directed for Procedure: the relative standard
compounds Test 3.
deviation for replicate injections is not more than 2.0%.
Solution A—Prepare a filtered and degassed mixture of
water and acetonitrile (3 : 2).
Solution B—Prepare filtered and degassed acetonitrile.
Pharmacopeial Forum
[NOTE—For the purpose of peak identification, the approxi- percentage of each impurity in the portion of Paclitaxel taken
mate relative retention times are given in Table 3. The relative by the formula:
retention times are measured versus Paclitaxel.]
Table 3 100(ri / rU)
Relative
in which ri is the response of each individual impurity; and rU
Retention Limit
is the sum of the areas of all the peaks obtained from the Test
Name Time (%)
solution. In addition to not exceeding the limits for paclitaxel
Propyl analog 1 0.54 0.2 related impurities in Table 3, not more than 0.1% of any other
Cephalomannine 0.76 0.5 single impurity is found; and not more than 2.0% of total
(Paclitaxel related impurities is found.&1S (USP30)
compound A)
sec-Butyl analog2 0.81 0.2
n-Butyl analog3 0.89 0.1
BRIEFING
Benzyl analog 1.10 0.4
Baccatin VI 1.23 0.2 Paricalcitol, USP 29 page 1640 and page 132 of PF 32(1) [Jan.–
Feb. 2006]. Comments have been received that mixing water and
Pentyl analog 4 1.31 0.2 acetonitrile in the course of gradient elution in the test for
Chromatographic purity might result in a noisy baseline. To address
7-Epipaclitaxel 1.51 0.4 these comments, it is proposed to revise the composition of Solution
A and to modify the gradient program accordingly. In addition, it is
1
The following chemical name is assigned to the related compound proposed to add the re-equilibration steps to the gradient table.
Propyl analog: Baccatin III 13-ester with (2R,3S)-2-hydroxy-3- Finally, it is proposed to add a small amount of phosphoric acid to
(propanoylamino)propanoic acid.&Baccatin III 13-ester with (2R,3S)- Solution A. On the basis of data received, this adjustment can
3-butanoylamino-2-hydroxy-3-phenylpropanoic acid.&1S (USP31) improve the butylparaben peak shape and, as a result, can help meet
2
The following chemical name is assigned to the related compound the resolution requirement. In addition to the previously reported
sec-Butyl analog: Baccatin III 13-ester with (2R,3S)-2-hydroxy-3- Supelcosil LC-18-DB brand of L1 column, the analyses can also be
(2-methylbutanoylamino)-3-phenylpropanoic
3
acid. performed with the Supelco Discovery HS C18 brand of L1 column.
The following chemical name is assigned to the related compound The typical retention time for paricalcitol is about 37 minutes.
n-Butyl analog: Baccatin III 13-ester with (2S,3S)-3-(butanoyl-
amino)-2-hydroxy-3-phenylpropanoic acid.&Baccatin III 13-ester
with (2S,3S)-2-hydroxy-3-(pentanoylamino)-3-phenylpropanoic (MD-GRE: E. Gonikberg) RTS—C51331
acid.
4 &1S (USP31)
The following chemical name is assigned to the related compound
Pentyl analog: Baccatin III 13-ester with (2R,3S)-2-hydroxy-3- Change to read:
(pentanoylamino)-3-phenylpropanoic acid.&Baccatin III 13-ester
with (2R,3S)-3-(hexanoylamino)-2-hydroxy-3-phenylpropanoic Identification—
acid.&1S (USP31)
B: Ultraviolet Absorption h197Ui
In-Process Revision
Solution: 5 mg per mL.

Procedure—Inject a volume (about 12 mL) of the Test Medium: dehydrated alcohol.
Ratios: A243 / A251, between 0.80 and 0.86; and A261 / A251, between
solution into the chromatograph, record the chromatogram, 0.63 and 0.69.
~
and measure the areas for all the peaks. Calculate the The retention time of the major peak in the chromatogram of
the Assay preparation corresponds to that in the chromato-
gram of the Standard preparation, as obtained in the
Assay.~USP30
Change to read:
~
[NOTE—Use low-actinic glassware to prepare solutions of
Paricalcitol.]~USP30
Pharmacopeial Forum
Diluent—Prepare a mixture of water and dehydrated alcohol responses, disregarding any peaks corresponding to those obtained
(1 : 1). from the Diluent. Calculate the percentage of each impurity in the
Butylparaben solution—Transfer about 25 mg of butylparaben to portion of Paricalcitol taken by the formula:
a 100-mL volumetric flask, dilute with Diluent to volume, and mix.
Solution A—Use filtered and degassed water 10(C/W)(ri / rS)
in which C is the concentration, in mg per mL, of USP Paricalcitol
&
a filtered and degassed mixture of water and acetonitrile RS in the Standard solution; W is the weight, in mg, of Paricalcitol
taken to prepare the Test stock solution;
(95 : 5), and add 1 drop of phosphoric acid per L of
solution.&1S (USP31)
Solution B—Use filtered and degassed acetonitrile.
Mobile phase—Use variable mixtures of Solution A and Solution
~
B as directed for Chromatographic system. Make adjustments if 100(CS / CU)(ri / rS)
necessary (see System Suitability under Chromatography h621i).
Standard solution—Dilute USP Paricalcitol Solution RS in
Diluent to a known concentration of about 0.1 mg of paricalcitol
per mL. in which CS and CU are the concentrations, in mg per mL, of
Control standard solution—Transfer 3.0 mL of the Standard
solution to a 10.0-mL volumetric flask, dilute with Diluent to paricalcitol in the Standard solution and the Test solution,
volume, and mix.
Test stock solution—Transfer about 10 mg of Paricalcitol, respectively;~USP30
accurately weighed, to a 50-mL volumetric flask, dissolve in and ri is the peak response for each impurity obtained from the Test
dilute with dehydrated alcohol to volume, and mix. solution; and rS is the paricalcitol peak response obtained from the
Standard solution: not more than 0.1% of any individual impurity is
~
Prepare a solution of Paricalcitol in dehydrated alcohol, found; and not more than 0.5% of total impurities is found.
having a known concentration of about 200 mg per mL.~USP30

Resolution solution—Transfer 1 mL of the Butylparaben solution Change to read:
and 1 mL of the Test stock solution to a 100-mL volumetric flask,
dilute with Diluent to volume, and mix. Transfer 1 mL of this Assay—
solution to a 10-mL volumetric flask, dilute with Diluent to volume, ~
and mix. [NOTE—Use low-actinic glassware to prepare solutions of
Test solution—Prepare a mixture of the Test stock solution and
water (1 : 1). paricalcitol.]~USP30
Chromatographic system (see Chromatography h621i)—The Mobile phase—Prepare a filtered and degassed mixture of
liquid chromatograph is equipped with a 252-nm detector and methanol and water (4 : 1). Make adjustments if necessary (see
a 4.6-mm 6 25-cm column that contains 5-mm packing L1. The System Suitability under Chromatography h621i).
flow rate is about 2 mL per minute. The chromatograph is Diluent—Prepare a mixture of methanol and water (1 : 1).
programmed as shown in the table below. Chromatograph the Standard preparation—Prepare a solution of USP Paricalcitol RS
Resolution solution, and record the peak responses as directed for in dehydrated alcohol having a known concentration of about 0.5 mg
Procedure: the resolution, R, between paricalcitol and butylparaben per mL.
is not less than 12.0. Chromatograph the Standard solution and the ~
Control standard solution, and record the peak responses as directed Transfer an accurately weighed amount of USP Paricalcitol
for Procedure: the area ratio for the paricalcitol peak from the
Standard solution to that from the Control standard solution is RS to a suitable volumetric flask, dissolve in a minimum
between 1.8 and 4.0; and the relative standard deviation for replicate
injections of the Standard solution is not more than 10.0%. amount of dehydrated alcohol, and dilute with Diluent to
Diluent, the Standard solution, and the Test solution into the volume. Further~USP30
chromatograph, record the chromatograms, and measure the peak

In-Process Revision
&
100&1S (USP31) &
0&1S (USP31)
&
100?47&1S (USP31) &
0?53&1S (USP31)
&
47&1S (USP31) &
53&1S (USP31)
&
47?0&1S (USP31) &
53?100&1S (USP31)
&
50–51&1S (USP31) &
0?100&1S (USP31) &
100?0&1S (USP31) &
linear gradient&1S (USP31)
&
51–60&1S (USP31) &
100&1S (USP31) &
0&1S (USP31) &
re-equilibration&1S (USP31)
Pharmacopeial Forum
dilute this solution quantitatively, and stepwise if necessary, with

Diluent to obtain a solution having a known concentration of about BRIEFING
5.0 mg per mL.
Assay preparation—Transfer about 25 mg of Paricalcitol,
accurately weighed, to a 50-mL low actinic volumetric flask, Sucralfate, USP 29 page 2013. To address frequent inquiries, it is
dissolve in and dilute with dehydrated alcohol to volume, and mix. proposed to provide additional details under Identification test B.
Transfer 2.0 mL of this solution to a 200-mL volumetric flask, dilute
with Diluent to volume, and mix.
~
Transfer an accurately weighed amount of Paricalcitol to
a suitable volumetric flask, dissolve in a minimum amount of Change to read:
dehydrated alcohol, and dilute with Diluent to volume. Identification—

A: The retention time of the sucrose octasulfate peak in the
Further dilute this solution quantitatively, and stepwise if chromatogram of the Assay preparation corresponds to that in the
chromatogram of the Standard preparation, as obtained in the Assay.
necessary, with Diluent to obtain a solution having a known B: Add 0.1 N hydrochloric acid to a few g of Sucralfate, boil,
and neutralize
concentration of about 5.0 mg per mL.~USP30
Chromatographic system (see Chromatography h621i)—The &
Add 100 mL of 0.1 N hydrochloric acid to about 500 mg of
a 4.6-mm 6 25-cm column that contains 5-mm packing L1. The Sucralfate, and boil the mixture gently, with stirring, for 20
flow rate is about 2 mL per minute. Chromatograph the Standard
preparation, and record the peak responses as directed for minutes until the sample is completely dissolved. Neutral-
Procedure: the tailing factor is not more than 2.0; and the relative
standard deviation for replicate injections is not more than 2.0%. ize&1S (USP31)
Procedure—Separately inject equal volumes (about 100 mL) of the with 0.1 N sodium hydroxide, Add
ograph, record the chromatograms, and measure the responses for &
and allow to cool. Add 4 mL of&1S (USP31)
the major peaks. Calculate the quantity, in mg, alkaline cupric tartrate TS. Boil a small amount of this solution: a red
~ precipitate of cuprous oxide is produced.
percentage~USP30 C: A solution in 3 N hydrochloric acid meets the requirements
of C27H44O3 in the portion of Paricalcitol taken by the formula: of the tests for Aluminum h191i.
5C(rU / rS)
BRIEFING
~
100(CS / CU)(rU / rS)~USP30
Sulfadimethoxine Sodium, USP 29 page 2029. On the basis of
in which C is the concentration, in mg per mL, of USP Paricalcitol comments and support data received, it is proposed to change the
RS in the Standard preparation; drying temperature specified in the monograph from 1058 for 3 hours
to 1258 for 3 hours. Interested parties are invited to submit
~
CU and CS are the concentrations, in mg per mL, of comments.
paricalcitol in the Assay preparation and the Standard (VET: I. DeVeau) RTS—C51112
preparation, respectively;~USP30
and rU and rS are the paricalcitol peak responses obtained from the Change to read:
Assay preparation and the Standard preparation, respectively.
In-Process Revision
Loss on drying h731i—Dry it at 1058

&
1258&1S (USP31)
for 3 hours: it loses not more than 5.0% of its weight.
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of hexane

and ethyl acetate (75 : 25). Make adjustments if necessary (see
DIETARY SUPPLEMENTS— System Suitability under Chromatography h621i).
Standard solution—Dissolve a suitable quantity of USP Lutein RS
MONOGRAPHS in Mobile phase to obtain a solution containing about 150 mg per
mL.
Test solution—Transfer about 1 mL of Test stock solution from the
test for Content of total carotenoids, and evaporate under a stream of
nitrogen to dryness. Add 1 mL of Mobile phase, and sonicate to
dissolve.
BRIEFING Chromatographic system (see Chromatography h621i)—The
a 4.6-mm 6 25-cm column that contains 3-mm
Lutein, USP 29 page 2353 and page 3751 of the Second
Supplement. On the basis of comments received, it is proposed to &
5-mm&1S (USP31)
revise the specifications in the tests for Residue on ignition and for packing L3. The flow rate is about 1.5 mL per minute.
Zeaxanthin and other related compounds. These proposals are based Chromatograph the Standard solution, and record the peak responses
on historical data and manufacturing capabilities. Finally, in the test as directed for Procedure: the relative retention times are about 1.05
for the Content of lutein, it is proposed to use a 5-mm column with for zeaxanthin and 1.0 for lutein; the resolution, R, between lutein
L3 packing, which has been found to provide better resolution and zeaxanthin is not less than 1.0; the tailing factor is not more than
between the lutein and zeaxanthin peaks. 2; and the relative standard deviation for replicate injections is not
more than 2.0%.
(DSN: L. Evans) RTS—C44100 Procedure—Inject a volume (about 10 mL) of the Test solution
peak &area&2S (USP29) responses. &The peak area of lutein is not less
than 85.0% of the total detected area of peaks in the chromato-
Change to read: gram.&2S (USP29) Calculate the percentage of Lutein taken by the
formula:
Residue on ignition h281i: not more than 1.0%
T(ri / rs)
&
2.0%.&1S (USP31) in which T is the content, in percentage, of total carotenoids as
determined in the test for Content of total carotenoids; ri is the
individual peak response of lutein in the Test solution; and rs is the
Change to read: sum of the responses of all the peaks: not less than &74.0%&2S (USP29)
of lutein is found.
Zeaxanthin and other related compounds—&[NOTE—Use low-
actinic glassware.]&2S (USP29)
Solvent, Mobile phase, Standard solution, Test solution, and
Chromatographic system—Proceed as directed under Content of
lutein. BRIEFING
peak responses. &The peak area of zeaxanthin is not more than 9.0%
of the total detected area of peaks in the chromatogram of the Test Lutein Preparation, USP 29 page 2354 and page 3752 of the
solution.&2S (USP29) Calculate the percentage of zeaxanthin in the Second Supplement. The following revisions are being proposed in
portion of Lutein taken by the formula: several sections of the monograph.
1. In the Definition, an upper limit of 130.0% of the labeled
T(ri / rs) amount of lutein, based on historical data, is being proposed.
However, where applicable legal requirements for dietary
in which T is the content, in percentage, of total carotenoids as supplements state that a minimum legal tolerance can be
determined in the test for Content of total carotenoids; ri is the higher than the minimum monograph tolerance, the maximum
individual peak response of zeaxanthin; and rs is the sum of the monograph tolerance shall be increased by a corresponding
responses of all the peaks: not more than &8.5%&2S (USP29) of amount. In this case, the legal requirement of 100.0% is higher
zeaxanthin is found. Calculate the percentage of other related than the monograph minimum tolerance of 95.0%. Therefore, in
compounds in the portion of Lutein taken by the formula: determining the legal requirement, the maximum tolerance
In-Process Revision
described in the monograph of 130.0% would be increased by
100(ri / rs) 5.0%, to 135.0%. Because of this legal requirement, dietary
in which ri is the individual peak response of any other peak in the supplements containing 135.0% of the labeled amount of lutein
chromatogram (excluding zeaxanthin and lutein); and rs is the sum of would therefore be in compliance with the monograph.
the responses of all the peaks: not more than 0.1% 2. In the test for Water, a specification of not more than 10.0% is
being proposed in order to allow for water found in beadlets.
&
1.0%&1S (USP31) 3. On the basis of historical data, it is proposed to revise the
of any &
other&2S (USP29) single &
related compound&2S (USP29) is specification in the test for Heavy metals to 10 mg per g.
found. 4. In the test for Zeaxanthin and other related compounds, it is
proposed to revise the specification for any other single related
compound to 1.0%. It is also proposed to replace the 3-mm
Change to read: packing in the L3 column with 5-mm packing.
5. On the basis of comments received, it is proposed to revise the
Content of lutein— specification in the test for Residue on ignition to 2.0%.
Solvent: a mixture of hexanes, acetone, toluene, and dehydrated
alcohol (10 : 7 : 7 : 6). (DSN: L. Evans) RTS—C44100
Pharmacopeial Forum
&
1.0%&1S (USP31)
Change to read: of any other &single related compound&2S (USP29) is found; &and the
total related compounds (including zeaxanthin) found are not more
» Lutein Preparation is a combination of Lutein with than 15.0%.&2S (USP29)
one or more inert substances. It may be in a solid or
a liquid form. It contains not less than 95.0 percent and Change to read:
not more than 120.0
Content of lutein—
&
130.0&1S (USP31) Solvent: a mixture of hexanes, acetone, toluene, and dehydrated
percent of the labeled amount of &lutein,&2S (USP29) alcohol (10 : 7 : 7 : 6).
Mobile phase—Prepare a filtered and degassed mixture of hexane
calculated as &&2S (USP29)C40H56O2 on the anhydrous and ethyl acetate (75 : 25). Make adjustments if necessary (see
basis. The lutein content of total carotenoids is not System Suitability under Chromatography h621i).
less than &85.0&2S (USP29) percent, and the zeaxanthin Standard solution—Dissolve a suitable quantity of USP Lutein RS
content is not more than &9.0&2S (USP29) percent. in Mobile phase to obtain a solution containing about 150 mg per
mL.
Test solution—Transfer 1.0 mL of Test stock solution 1, or 1.0 mL
of Test stock solution 2, or 2.0 mL of Test stock solution 3 from the
Change to read: test for Content of total carotenoids into a suitable vial. Evaporate
the solvent to dryness under a stream of nitrogen. Add about 1.0 mL
Water, Method I h921i: not more than 1.0% of Mobile phase, and sonicate to dissolve.
&
10.0%.&1S (USP31) liquid chromatograph is equipped with a 446-nm detector and
a 4.6-mm 6 25-cm column that contains 3-mm
Change to read: &
5-mm&1S (USP31)
Residue on ignition h281i: not more than 1.0% Chromatograph the Standard solution, and record the peak responses
as directed for Procedure: the relative retention times are about 1.05
&
2.0%.&1S (USP31) for zeaxanthin, and 1.0 for lutein; the resolution, R, between lutein
and zeaxanthin is not less than 1.0; the tailing factor is not more than
2; and the relative standard deviation for replicate injections is not
Change to read: more than 2.0%.
Heavy metals, Method II h231i: not more than 5 into the chromatograph, record the chromatogram, and measure the
peak responses. Calculate the percentage of lutein relative to total
&
10&1S (USP31) carotenoids in the Preparation taken by the formula:
mg per g.
100(ri / rs)
Change to read: in which ri is the individual peak response of lutein, and rs is the sum
of the responses of all the peaks: not less than &85.0%&2S (USP29) of
lutein is found. &Calculate the amount of lutein in the Preparation
Zeaxanthin and other related compounds— taken by the formula:
Solvent, Mobile phase, Standard solution, Test solution, and
Chromatographic system—Proceed as directed under Content of T(ri / rs)
lutein.
Procedure—Inject a volume (about 10 mL) of the Test solution in which T is the content, in percentage, of total carotenoids as
into the chromatograph, record the chromatogram, and measure the determined in the test for Content of total carotenoids; ri is the
peak responses. Calculate the percentage of zeaxanthin relative to individual peak response of lutein in the Test solution; and rs is the
total carotenoids in the Preparation taken by the formula: sum of the responses of all the peaks.&2S (USP29)
100(ri / rs)
in which ri is the individual peak response of zeaxanthin, and rs is the
In-Process Revision
sum of the responses of all the peaks: &not more than 9.0% of
zeaxanthin is found;&2S (USP29) not more than 0.1%
Pharmacopeial Forum
Hypromellose (formerly Hydroxypropyl Methylcellulose)

Hypromellose Acetate Succinate
Hypromellose Phthalate (formerly Hydroxypropyl
Methylcellulose Phthalate)
Maltodextrin
Methacrylic Acid Copolymer
BRIEFING Methacrylic Acid Copolymer Dispersion
Methylcellulose
Excipients, USP and NF Excipients, Listed by Category, NF 24 &
Palm Kernel Oil&2S (NF25)
page 3257, page 3816 of the Second Supplement, and page 1768 of Polyethylene Glycol
PF 32(6) [Nov.–Dec. 2006]. It is proposed to add Propylene Glycol
Monocaprylate to the Emulsifying and/or Solubilizing Agent, Tablet &
Polyvinyl Acetate&1S (NF25)
and/or Capsule Diluent, and Vehicle (Solid Carrier) categories and Polyvinyl Acetate Phthalate
Trehalose to the Bulking Agent for Freeze Drying, Sweetening Agent, ~
Tablet Binder, Tablet and/or Capsule Diluent, Tablet Disintegrant, Fully Hydrogenated Rapeseed Oil~NF26
and Vehicle (Flavored and/or Sweetened) categories to complement ~
the proposed new monographs for Propylene Glycol Monocaprylate Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26
and Trehalose, respectively, which appear elsewhere in this issue of Shellac
PF. Starch, Pregelatinized Modified
Sucrose
(EM1; EM2) RTS—C41589; C47678 Titanium Dioxide
Wax, Carnauba
Wax, Microcrystalline
Zein
Change to read: Change to read:
Bulking Agent for Freeze-Drying Desiccant

Creatinine Calcium Chloride
Mannitol Calcium Sulfate
&
Polydextrose&2S (NF25)
&
Silicon Dioxide
&
Trehalose&1S (NF26)
Change to read:
Change to read:
Emollient
Coating Agent Alkyl (C12-15) Benzoate
Hydrogenated Soybean Oil
&
Amino Methacrylate Copolymer&1S (NF25)
Ammonio Methacrylate Copolymer
&
Oleyl Oleate&2S (NF25)
Ammonio Methacrylate Copolymer Dispersion
Carboxymethylcellulose, Sodium
Cellaburate Change to read:
Cellacefate (formerly Cellulose Acetate Phthalate)
Cellulose Acetate Emulsifying and/or Solubilizing Agent
Cellulose Acetate Phthalate (see Cellacefate) Acacia
Carbomer Copolymer
&
Coconut Oil&1S (NF25) Carbomer Interpolymer
Copovidone Cholesterol
In-Process Revision
&
Corn Syrup Solids&2S (NF25) &
Coconut Oil&1S (NF25)
Diethanolamine (Adjunct)
&
Ethyl Acrylate and Methyl Methacrylate Copolymer Dis- Diethylene Glycol Stearates
Ethylene Glycol Stearates
persion&2S (NF25) Glyceryl Distearate
Ethylcellulose Glyceryl Monolinoleate
Ethylcellulose Aqueous Dispersion Glyceryl Monooleate
Gelatin Glyceryl Monostearate
Glaze, Pharmaceutical Lanolin Alcohols
Hydroxypropyl Cellulose Lecithin
Hydroxypropyl Methylcellulose (see Hypromellose) Mono- and Di-glycerides
Hydroxypropyl Methylcellulose Phthalate (see Hypromellose Monoethanolamine (Adjunct)
Phthalate)
Pharmacopeial Forum
Oleic Acid (Adjunct) Cellaburate

Oleyl Alcohol (Stabilizer) Cellulose Acetate
&
Oleyl Oleate&2S (NF25) &
Ethyl Acrylate and Methyl Methacrylate Copolymer Dis-
&
Palm Kernel Oil&2S (NF25) persion&1S (NF25)
Poloxamer
Polyoxyethylene 50 Stearate
Polyoxyl 10 Oleyl Ether
Polyoxyl 20 Cetostearyl Ether Change to read:
Polyoxyl 35 Castor Oil
Polyoxyl 40 Hydrogenated Castor Oil Sequestering Agent
Polyoxyl 40 Stearate Beta Cyclodextrin (see Betadex)
Polyoxyl Lauryl Ether Betadex (formerly Beta Cyclodextrin)
Polyoxyl Stearyl Ether
Polysorbate 20
&
Gamma Cyclodextrin&2S (NF25)
Polysorbate 40
Polysorbate 60
&
Hydroxypropyl Betadex&2S (NF25)
Polysorbate 80 Sodium Tartrate
&
Propylene Glycol Monocaprylate&1S (NF26)
Propylene Glycol Monostearate Change to read:
~
Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26 Solvent
Sodium Cetostearyl Sulfate Acetone
Sodium Lauryl Sulfate Alcohol
Sodium Stearate Alcohol, Diluted
Sorbitan Monolaurate Amylene Hydrate
Sorbitan Monooleate Benzyl Benzoate
Sorbitan Monopalmitate Butyl Alcohol
Sorbitan Monostearate
Sorbitan Sesquioleate ~
Canola Oil~NF25
Sorbitan Trioleate Caprylocaproyl Polyoxylglycerides
Stearic Acid Corn Oil
Trolamine Cottonseed Oil
Wax, Emulsifying Diethylene Glycol Monoethyl Ether
Ethyl Acetate
Glycerin
Change to read: Hexylene Glycol
Isopropyl
~
Alcohol
Humectant Lauroyl Polyoxylglycerides~NF24
Linoleoyl Polyoxylglycerides
&
Corn Syrup Solids&2S (NF25) Methyl Alcohol
Methylene Chloride
&
Erythritol&1S (NF25) Methyl Isobutyl Ketone
Glycerin Mineral Oil
Hexylene Glycol Oleoyl Polyoxylglycerides
&
Maltitol&2S (NF24) Peanut Oil
Polyethylene Glycol
&
Polydextrose&2S (NF25) Polyethylene Glycol Monomethyl Ether
Propylene Glycol Propylene Glycol
Sorbitol Sesame Oil
Sorbitol Sorbitan Solution Stearoyl Polyoxylglycerides
&
Tagatose&1S (NF24) Water for Injection
Water for Injection, Sterile
In-Process Revision
Water for Irrigation, Sterile

Water, Purified
Change to read:
Polymer Membrane
Change to read:
&
Ammonio Methacrylate Copolymer Stiffening Agent
Ammonio Methacrylate Copolymer Dispersion Castor Oil, Hydrogenated
Cetostearyl Alcohol
Pharmacopeial Forum
Cetyl Alcohol Change to read:

Cetyl Esters Wax
Cetyl Palmitate Sweetening Agent
Hard Fat Acesulfame Potassium
Paraffin Aspartame
Synthetic Paraffin Aspartame Acesulfame
~
Fully Hydrogenated Rapeseed Oil~NF26 &
Corn Syrup Solids&2S (NF25)
~
Dextrates
Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26 Dextrose
Stearyl Alcohol Dextrose Excipient
Wax, Emulsifying
Wax, White &
Erythritol&1S (NF25)
Wax, Yellow Fructose
Galactose
&
Maltitol&2S (NF24)
Maltose
Change to read: Mannitol
Saccharin
Suspending and/or Viscosity-Increasing Agent Saccharin Calcium
Acacia Saccharin Sodium
Agar Sorbitol
Alamic Acid Sorbitol Solution
Alginic Acid Sucralose
Aluminum Monostearate Sucrose
Attapulgite, Activated Sugar, Compressible
Attapulgite, Colloidal Activated Sugar, Confectioner’s
Bentonite Syrup
Bentonite, Purified &
Tagatose&1S (NF24)
Bentonite Magma
Carbomer 910 &
Trehalose&1S (NF26)
Carbomer 934
Carbomer 934P
Carbomer 940
Carbomer 941 Change to read:
Carbomer 1342
Carbomer
~
Copolymer Tablet Binder
Carbomer Homopolymer~NF24 Acacia
Carbomer Interpolymer Alginic Acid
Carboxymethylcellulose Calcium
Carboxymethylcellulose Sodium &
Carboxymethylcellulose Sodium 12 Ammonio Methacrylate Copolymer
Carrageenan Ammonio
~
Methacrylate Copolymer Dispersion
Cellulose, Microcrystalline, and Carboxymethylcellulose Carbomer Homopolymer~NF24
Sodium Carbomer Interpolymer
Carboxymethylcellulose Sodium
&
Corn Syrup Solids&2S (NF25) Cellulose, Microcrystalline
Dextrin Copovidone
Gelatin
Gellan Gum &
Guar Gum Dextrin
Hydroxyethyl Cellulose
Hydroxypropyl Cellulose &
Hydroxypropyl Methylcellulose (see Hypromellose)
Hypromellose (formerly Hydroxypropyl Methylcellulose) persion&1S (NF25)
In-Process Revision
Magnesium Aluminum Silicate Ethylcellulose
Maltodextrin Gelatin
Methylcellulose Glucose, Liquid
Pectin Guar Gum
Polyethylene Oxide Low-Substituted Hydroxypropyl Cellulose
Polyvinyl Alcohol Hydroxypropyl Methylcellulose (see Hypromellose)
Povidone Hypromellose (formerly Hydroxypropyl Methylcellulose)
Propylene Glycol Alginate Hypromellose Acetate Succinate
Silicon Dioxide Maltodextrin
Silicon Dioxide, Colloidal Maltose
Sodium Alginate Methylcellulose
Starch, Corn Polyethylene Oxide
Starch, Potato
Starch, Tapioca &
Starch, Wheat Povidone
Tragacanth Starch, Corn
Xanthan Gum Starch, Potato
Starch, Pregelatinized
Starch, Pregelatinized Modified
Starch, Tapioca
Starch, Wheat
Pharmacopeial Forum
Syrup Starch, Potato

&
Trehalose&1S (NF26) Starch, Pregelatinized Modified
Starch, Tapioca
Starch, Wheat
Change to read: &
Trehalose&1S (NF26)
Tablet and/or Capsule Diluent
Calcium Carbonate
Calcium Phosphate, Dibasic Change to read:
Calcium Phosphate, Tribasic
Calcium Sulfate Tonicity Agent
Cellulose, Microcrystalline
Cellulose, Powdered &
Dextrose
&
Corn Syrup Solids&2S (NF25) Glycerin
Dextrates Mannitol
Dextrin Potassium Chloride
Dextrose Excipient Sodium Chloride
Fructose
Kaolin
Lactitol
Lactose, Anhydrous Change to read:
Lactose, Monohydrate
&
Maltitol&2S (NF24) Vehicle
Maltodextrin FLAVORED AND/OR SWEETENED
Maltose Aromatic Elixir
Mannitol Benzaldehyde Elixir, Compound
&
Propylene Glycol Monocaprylate&1S (NF26) &
Sorbitol Dextrose
Starch Peppermint Water
Starch, Corn Sorbitol Solution
Starch, Potato Syrup
Starch, Pregelatinized Modified &
Trehalose&1S (NF26)
Starch, Tapioca OLEAGINOUS
Starch, Wheat Alkyl (C12-15) Benzoate
Sucrose Almond Oil
Sugar, Compressible
~
Sugar, Confectioner’s Canola Oil~NF25
Corn Oil
&
Trehalose&1S (NF26) Cottonseed Oil
Ethyl Oleate
Isopropyl Myristate
Isopropyl Palmitate
Change to read: Mineral Oil
Mineral Oil, Light
Tablet Disintegrant Octyldodecanol
Alginic Acid Olive Oil
Cellulose, Microcrystalline Peanut Oil
Croscarmellose Sodium Safflower Oil
Crospovidone Sesame Oil
Low-Substituted Hydroxypropyl Cellulose Soybean Oil
Maltose
In-Process Revision
Squalane
Polacrilin Potassium
Sodium Starch Glycolate SOLID CARRIER
Starch
Starch, Corn
&
Sugar Spheres
STERILE
Sodium Chloride Injection, Bacteriostatic
Water for Injection, Bacteriostatic
Pharmacopeial Forum
MONOGRAPHS (NF) Packaging and storage—Preserve in well-closed containers

and protect from moisture. No storage requirements specified.
Labeling—Label it to indicate the type (Type I or Type II).

BRIEFING
USP Reference standards h11i—USP Propylene Glycol RS.
USP Propylene Glycol Monocaprylate Type I RS. USP
Propylene Glycol Monocaprylate. Because there is no existing
NF monograph for this excipient, it is proposed to add a new Propylene Glycol Monocaprylate Type II RS.
monograph based on comments and data received. The liquid
chromatographic procedure in the Assay and Limit of propylene
glycol is based on analysis performed with the Phenomenex Identification—
(Polymer Labs) PLgel brand of L21 column. The typical retention
time ranges for propylene glycol dicaprylate, propylene glycol A: Infrared Absorption h197Ai.
monocaprylate, and propylene glycol are 13 to 14.5, 13.7 to 14.9,
and 15 to 16.5 minutes, respectively. B: Thin-Layer Chromatographic Identification Test
(EM2: H. Wang; NOM: W. Paul) RTS—C47678 h201i—

Test solution: 50 mg per mL, in methylene chloride.
Standard solution: 50 mg of USP Propylene Glycol
Monocaprylate Type I RS (or USP Propylene Glycol
Add the following:
Monocaprylate Type II RS) per mL, in methylene chloride.
&Propylene Glycol Monocaprylate
Developing solvent solution: a mixture of ether and
hexane (70 : 30).
Propylene glycol monooctanoate.
Spray reagent—Prepare a 0.1 mg per mL solution of
Octanoic acid, monoester with 1,2-propane diol. rhodamine 6G in alcohol.
Procedure—Develop the chromatogram over a path of 15
Caprylic acid, monoester with propane-1,2-diol.
cm, and dry the plate in a current of air. Spray the plate with
[31565-12-5].
Spray reagent, and locate the spots on the plate by
examination under UV light at a wavelength of 365 nm: the
» Propylene Glycol Monocaprylate is a mixture of RF values of the principal spots obtained from the Test
the propylene glycol monoesters and diesters of solution correspond to those obtained from the Standard
fatty acids composed predominately of caprylic solution.
acid. The requirements for monoester and diester C: It meets the requirements of the test for Fatty acid
In-Process Revision
composition.
content differ for the two types of Propylene Glycol
Monocaprylate, as set forth in the accompanying Acid value h401i: not more than 1.5.
table: Iodine value h401i: not more than 1.0.
Saponification value h401i: between 285 and 315 for

Content of mono- Content of diesters
Propylene Glycol Monocaprylate (Type I), and between 270
esters (% ) (%)
and 295 for Propylene Glycol Monocaprylate (Type II).
Min. Max. Min. Max.
Type I 55.0 80.0 20.0 45.0

Type II 90.0 — — 10.0
Pharmacopeial Forum
Peroxide value h401i: not more than 6.0. a standard curve of peak area versus concentration, in mg per
Fatty acid composition h401i—Propylene Glycol Mono- mL, of propylene glycol in the Propylene glycol standard
caprylate exhibits the composition profile of fatty acids solutions. Obtain the concentration, C, in mg per mL, of
shown in the accompanying table, as determined in the propylene glycol in the Test solution from the standard curve.
section Fatty Acid Composition under Fats and Fixed Oils Calculate the percentage of free propylene glycol in the
h401i: portion of Propylene Glycol Monocaprylate taken by the

formula:
Carbon-chain Number of double Percentage
length bonds (%) 100CV / W
8 0 90.0
10 0 53.0 in which V is the volume of the Test solution, and W is the
12 0 53.0 weight, in mg, of Propylene Glycol Monocaprylate used to
14 0 53.0 prepare the Test solution: not more than 1.5% is found for
16 0 51.0 Propylene Glycol Monocaprylate (Type I and Type II).
Assay—
Water, Method Ia h921i: not more than 1.0%, using Mobile phase: tetrahydrofuran.
a mixture of methanol and methylene chloride (1 : 1) in Assay preparation—Accurately weigh about 200 mg of
place of methanol in the titration vessel. Propylene Glycol Monocaprylate into a 5-mL volumetric
flask, dissolve in and dilute with tetrahydrofuran to volume,
Heavy metals, Method II h231i: not more than 10 mg per g.
and shake to mix thoroughly.
Total ash h561i: not more than 0.1%.
Limit of propylene glycol— The liquid chromatograph is equipped with a refractive index
Mobile phase—Proceed as directed in the Assay. detector and a 7-mm 6 60-cm column that contains 5-mm
Propylene glycol standard stock solution—Prepare a solu- packing L21 (100Å). The flow rate is about 1 mL per minute.
tion containing a known concentration of about 4 mg per mL The column and detector temperatures are maintained at 408.
of USP Propylene Glycol RS in tetrahydrofuran. [NOTE—Two 7-mm 6 30-cm L21 columns may be used in
Propylene glycol standard solutions—Into four 5-mL place of one 60-cm column, provided system suitability
volumetric flasks, introduce respectively 0.25 mL, 0.5 mL,
In-Process Revision
requirements are met.] Chromatograph the Assay preparation,

1.0 mL, and 2.5 mL of Propylene glycol standard stock and record the peak responses as directed for Procedure. The
solution, and dilute with tetrahydrofuran to volume. In a fifth order of elution is diester, monoester, and propylene glycol.
5-mL volumetric flask, introduce 5.0 mL of Propylene glycol The relative standard deviation for replicate injections
standard stock solution. determined from the monoester peak is not more than
Test solution—Use the Assay preparation. 2.0%. [NOTE—For information purposes only, relative reten-
Chromatographic system—Proceed as directed in the tions with reference to propylene glycol for diester are about
Assay. 0.85, for monoester about 0.90.]
Procedure—Separately inject equal volumes (about 40 mL) Procedure—Inject a volume (about 40 mL) of the Assay
of the Propylene glycol standard solutions and the Test preparation into the chromatograph, record the chromato-
solution into the chromatograph, record the chromatograms, gram, and measure the responses for the major peaks.
and measure the responses for the major peaks. Prepare
Pharmacopeial Forum
Calculate the percentage of monoester or diester in the » Trehalose is a stable, nonreducing disaccharide
portion of Propylene Glycol Monocaprylate taken by the with two glucose molecules linked in an a,a-1,1
formula:
configuration. It is obtained through enzymatic
conversion of food-grade starch. It contains not less
(100 – D)(rU / rS)
than 99.0 percent of C12H22O11, calculated on the
in which D is the sum of the percentage content of propylene anhydrous basis.
glycol and the percentage content of free fatty acids, rU is the
Packaging and storage—Preserve in tight containers. No
peak response for monoester or diester, and rS is the sum of
storage requirements specified.
the responses of the monoester and diester peaks. Calculate
the percentage content of free fatty acids using the formula: Labeling—Where Trehalose is intended for use in the
manufacture of injectable dosage forms, it is so labeled.
144(A/561.1) Where Trehalose must be subjected to further processing
during the preparation of injectable dosage forms to ensure
in which A is the acid value.&1S (NF26) acceptable levels of bacterial endotoxins, it is so labeled.
USP Reference standards h11i—USP Endotoxin RS. USP
Glycerin RS. USP Trehalose RS.
BRIEFING
Color and clarity of solution—
Trehalose. Because there is no existing NF monograph for this Test solution—Dissolve 33 g of Trehalose in 67 g of
excipient, the following new monograph is proposed, based on the
manufacturer’s tests and acceptance criteria and also on the recently boiled water. Confirm the concentration of the
Trehalose monograph in the Food Chemicals Codex, Fifth Edition,
page 486. The liquid chromatographic procedure in the Assay is solution with a suitable refractometer at 30 + 1%.
based on analysis performed with the Shodex SUGAR KS 801 brand
of L## column. Typical retention times for trehalose and glycerin are Procedure—Using a suitable spectrophotometer (see Spec-
16 minutes and 23 minutes, respectively.
trophotometry and Light-Scattering h851i), measure the
(EM1: C. Sheehan; NOM: W. Paul; MSA: R. Tirumalai) RTS—
C41589 absorbances of the Test solution at 420 nm and 720 nm in
a 10-cm cuvette. The absorbance of the Test solution at 720
nm is not more than 0.050. Determine the absorbance
difference by the following formula:
Add the following:
In-Process Revision
&Trehalose A420 – A720
in which A420 is the absorbance of the Test solution at 420 nm;

and A720 is the absorbance of the Test solution at 720 nm. The
absorbance difference is not more than 0.100.
Identification—
C12H22O11 2H2O 378.33 A: Infrared Absorption h197Ki.
B: Test solution—Dissolve Trehalose in water (2 in 5),
a-D-glucopyranosyl a-D-glucopyranoside.
and mix thoroughly.
Trehalose dihydrate [6138-23-4].
Pharmacopeial Forum
Add 5 to 6 drops of a solution containing 1-naphthol in Soluble starch—Prepare a 10% Trehalose solution (w/v), and
95% alcohol (1 in 20) to 1 mL of the Test solution. Gently add mix thoroughly. To this solution add several drops of iodine
2 mL of sulfuric acid to the solution. A violet color develops TS. No blue color develops.
at the interface between the two solutions. Chloride h221i: not more than 0.0125%. A 2.0-g sample
C: Test solution—Dissolve Trehalose in water (1 in 25), shows no more chloride than corresponds to 0.70 mL of 0.01
and mix thoroughly. mol per L hydrochloric acid.
Glycine solution—Dissolve glycine in water (1 in 25), and
Sulfate h221i: not more than 0.0200%. A 2.0-g sample
mix thoroughly.
shows no more sulfate than corresponds to 0.83 mL of 0.005
Add 1 mL of diluted hydrochloric acid to 2 mL of the Test
mol per L sulfuric acid.
solution. Allow to stand for 20 minutes at room temperature.
Heavy metals, Method I h231i: not more than 0.0005%.
Add 4 mL of sodium hydroxide TS and 2 mL of the Glycine
Test preparation—Use 5.0 g of Trehalose.
solution to the Test solution. When the solution is heated for
Monitor preparation—Prepare with 2.5 mL of Standard
10 minutes in boiling water, a brown color does not develop.
Lead Solution.
Specific rotation h781i: between +1978 and +2018 at 208,
Nitrogen content, Method I h461i: not more than 0.005%,
using a solution containing 100 mg per mL.
determined on a 5.0-g portion, accurately weighed. Proceed
Microbial limits h61i—The total aerobic microbial count as directed for Method I, increasing the sulfuric acid used for
does not exceed 100 cfu per g, and the total combined molds digestion to 30 mL and reducing the sodium hydroxide
and yeasts count does not exceed 100 cfu per g. It meets the solution (2 in 5) to 45 mL.
requirements of the tests for absence of Salmonella species
Assay—
and Escherichia coli. Mobile phase—Use degassed water.
Bacterial endotoxins h85i—If labeled for use in preparing Internal standard solution—Dissolve an accurately
parenteral dosage forms, it also meets the following weighed quantity of USP Glycerin RS in water to obtain
requirements. The level of bacterial endotoxins is such that a solution having a known concentration of about 100 mg per
the requirement in the relevant dosage form monograph(s) in mL.
which Trehalose is used can be met. Where the label states Standard preparation—Dissolve an accurately weighed
that Trehalose must be subjected to further processing during quantity of USP Trehalose RS in water and add Internal
the preparation of injectable dosage forms, the level of standard solution to obtain a solution having known
In-Process Revision
bacterial endotoxins is such that the requirement in the concentrations of about 10 mg per mL of Trehalose,
relevant dosage form monograph(s) in which Trehalose is calculated on the anhydrous basis, and about 10 mg per mL
used can be met. of glycerin.
pH h791i: between 4.5 and 6.5, using a solution containing Assay preparation—Transfer about 100 mg of Trehalose,
100 mg per mL. accurately weighed and calculated on the anhydrous basis, to
a 10-mL volumetric flask, add 1 mL of Internal standard
Water, Method I h921i: between 9.0% and 11.0%,
solution, and dilute with water to volume.
determined on 0.1 g of Trehalose.
Residue on ignition h281i: not more than 0.1%, deter-
The liquid chromatograph is equipped with a refractive index
mined on 2.0 g of Trehalose.
detector that is maintained at a constant temperature of about
408 and an 8-mm 6 30-cm column that contains packing L##
Pharmacopeial Forum
(see Chromatographic Reagents under Reagents, Indicators, the chromatograph, record the chromatograms, and measure
and Solutions) and is maintained at a constant temperature of the responses for the major peaks. Calculate the percentage of
808. The elution order is the trehalose peak followed by the C12H22O11 in the portion of Trehalose taken, by the formula:
glycerin peak. Adjust the flow rate so that the retention time
of trehalose is about 15 minutes. Chromatograph the 1000(C / W)(RU / RS)

directed for Procedure: the resolution, R, between trehalose
Trehalose RS in the Standard preparation; W is the weight, in
and glycerin is not less than 2, and the relative standard
mg, of Trehalose taken to prepare the Assay preparation; and
deviation for replicate injections determined from the peak
RU and RS are the ratios of the peak responses of trehalose and
response ratios is not more than 2.0%.
glycerin obtained from the Assay preparation and the
Standard preparation, respectively.&1S (NF26)
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Pharmacopeial Forum
Add the following:

GENERAL CHAPTERS &
USP Galantamine Hydrobromide Related Compounds
Mixture RS—Contains about 98% galantamine hydrobro-
General Tests and Assays
mide, 0.5% each of 6b-hexahydrogalantamine, 6b-octahydro-
galantamine, 6a-hexahydrogalantamine, and
General Requirements for tetrahydrogalantamine.&1S (USP31)
Tests and Assays
Add the following:
&
USP Galantamine Hydrobromide Racemic RS—A 50 : 50
mixture of 4S,8S and 4R,8R isomers.&1S (USP31)
Add the following:

&
USP Ipratropium Bromide RS [8-azoniabicyclo[3.2.1]oc-
BRIEFING
tane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-
h11i USP Reference Standards, USP 29 page 2458, page 3754 of methylethyl)-, bromide, monohydrate(endo,syn)-, (+)-]
the Second Supplement, page 1832 of PF 27(1) [Jan.–Feb. 2001],
page 1468 of PF 28(5) [Sept.–Oct. 2002], page 2022 of PF 29(6) (C20H30BrNO3 H2O 430.38).&1S (USP31)
[Nov.–Dec. 2003], page 1338 of PF 30(4) [July–Aug. 2004], page
2092 of PF 30(6) [Nov.–Dec. 2004], page 507 of PF 31(2) [Mar.– Add the following:
Apr. 2005], page 1154 of PF 31(4) [July–Aug. 2005], page 1433
of PF 31(5) [Sept.–Oct. 2005], page 1680 of PF 31(6) [Nov.–Dec.
2005], page 181 of PF 32(1) [Jan.–Feb. 2006], page 407 of PF
&
USP Ipratropium Bromide Related Compound A RS
32(2) [Mar.–Apr. 2006], page 829 of PF 32(3) [May–June 2006],
page 1161 of PF 32(4) [July–Aug. 2006], page 1491 of PF 32(5) [ ( 1R,3r,5S,8r ) -3-hydroxy-8-methyl-8- ( 1-methylethyl ) -8-
[Sept.–Oct. 2006], page 1779 of PF 32(6) [Nov.–Dec. 2006], and
page 95 of PF 33(1) [Jan.–Feb. 2007]. azoniabicyclo[3.2.1]octane, bromide] (C 11 H 2 2 BrNO
264.20).&1S (USP31)
(HDQ) RTS—C39432; C39916; C41589; C44337; C46941;
C47131; C47678; C49294
Add the following:
&
USP Ipratropium Bromide Related Compound B RS
[ [ (1R,3r,5S,8s)-3-[ [ (2RS)-3-hydroxy-2-phenylpropanoyl ]
Add the following:
oxy]-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]oc-
&
USP Glacial Acetic Acid RS.&1S (USP31)
tane, bromide] (C20H30BrNO3 412.36).&1S (USP31)
Add the following:
Add the following:
&
USP Acitretin RS.&1S
In-Process Revision
(USP31)
&
USP Ipratropium Bromide Related Compound C RS
Add the following:
[(2RS)-3-hydroxy-2-phenylpropanoic acid] (C 9 H 10 O 3
&
USP Estradiol Benzoate RS.&1S (USP31) 166.17).&1S (USP31)
Add the following: Add the following:

&
USP Galantamine Hydrobromide RS.&1S (USP31) &
USP Paclitaxel Impurity Mixture RS&2S (USP30)—
&
It is a
mixture of paclitaxel and the following related compounds:
Pharmacopeial Forum
propyl analog, cephalomannine, sec-butyl analog, n-butyl analog, Strong Sodium Hydroxide Solution—Dissolve 42 g of so-
benzyl analog, baccatin VI, pentyl analog, and 7-epi- dium hydroxide in water, and dilute with water to 100 mL.
paclitaxel.&1S (USP31) Solution A—Add 0.7 mL of phosphoric acid to 1000 mL of
water, and adjust with Strong Sodium Hydroxide Solution to a
Add the following:
pH of 3.0.
&
USP Propylene Glycol Monocaprylate Type I RS.&1S (USP31)
Add the following:
Diluent—Prepare a mixture of Solution A and Solution B
&
U SP P rop y l e ne G l y co l M o n o ca p ry l a t e Typ e II
(95 : 5).
RS.&1S (USP31)
Standard Solution—[NOTE—The concentration can be ad-
Add the following: justed depending on the amount of acetate or acetic acid ex-
&
USP Trehalose RS.&1S (USP31) pected to be present in the test material.] Dissolve an
accurately weighed quantity of USP Acetic Acid RS in Diluent
to obtain a solution having a known concentration of about 0.1
Chemical Tests and Assays mg per mL.
Test Solution—Prepare as directed in the individual mono-
OTHER TESTS AND ASSAYS graph. The amount of material used can be adapted depending
on the amount of acetic acid expected.
Chromatographic System (see Chromatography h621i)—

BRIEFING The liquid chromatograph is equipped with a 210-nm detector
and a 4.6-mm 6 25-cm column that contains not greater than
h503i Acetic Acid in Peptides. This proposed new general chapter
provides a single method for determining the amount of acetate or 5-mm packing L1. The flow rate is about 1.2 mL per minute.
acetic acid in peptides. Acetate is a common salt form of many ther-
apeutic peptides, and there are currently a variety of methods for its The chromatograph is programmed as follows.
determination in official and proposed monographs. The method pro-
posed here is similar to the method in the European Pharmacopoeia.
Eventually, it is intended that this method be used to determine the Time Solution A Solution B
amount of acetate for all peptides containing acetate.
(BB PP: L. Callahan) RTS—C49294
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Add the following: 5–10 95?50 5?50 linear gradient

&h503i ACETIC ACID IN PEPTIDES
Chromatograph the Standard solution, and record the peak re-
sponses as directed for Procedure: the retention time of acetic
The following procedure is to be used to determine the
acid is between 3 and 4 minutes; and the relative standard de-
amount of acetate or acetic acid in peptides. Acetate is a com-
viation for replicate injections is not more than 5%.
mon counterion in many peptide preparations.
USP Reference Standards h11i—USP Glacial Acetic Acid
RS.
Pharmacopeial Forum
of the Standard solution and the Test solution into the chro-
matograph, record the chromatograms, and measure the re-
h1087i INTRINSIC DISSOLUTION
sponses for the acetic acid peaks. Calculate the percentage
of acetic acid in the portion of test material taken by the for-
& APPARENT INTRINSIC DISSOLU-
mula:
TION—DISSOLUTION TESTING PRO-
100(CS / M)(rU / rS)
CEDURES FOR ROTATING DISK AND
STATIONARY DISK&1S (USP31)
in which CS is the concentration of acetic acid in the Standard
solution; M is the concentration, in mg per mL, of the Test so- This chapter discusses determination of the rate of intrinsic disso-
lution.
lution, based on the weight of test material taken and the extent The measurement of intrinsic dissolution rates is a tool in the func-
tionality and characterization of bulk drug substances and excipients.
of dilution; and rU and rS are the acetic acid peak responses The intrinsic dissolution rate is defined as the dissolution rate of pure
substances under the condition of constant surface area. The dissolu-
obtained from the Test solution and the Standard solution, re- tion rate and bioavailability of a drug substance are influenced by its
solid state properties: crystallinity, amorphism, polymorphism, hy-
spectively.&1S (USP31) dration, solvation, particle size, and particle surface area. The mea-
sured intrinsic dissolution rate is dependent on these solid state
properties. The dissolution rate is also influenced by extrinsic factors,
such as hydrodynamics (e.g., test apparatus, and disk rotation speed
or fluid flow) and test conditions (e.g., temperature, fluid viscosity,
pH, and buffer strength in the case of ionizable compounds). By ex-
GENERAL CHAPTERS posing the surface area of a material to an appropriate dissolution me-
dium while maintaining constant temperature, stirring rate, and pH,
the intrinsic dissolution rate can be determined. Typically the intrinsic
dissolution is expressed in terms of mg per minute per cm2.
General Information Apparatus—A typical apparatus consists of a punch and die fab-
ricated out of hardened steel. The base of the die has three threaded
holes for the attachment of a surface plate made of polished steel,
providing a mirror-smooth base for the compacted pellet. The die
has a 0.1-cm to 1.0-cm diameter cavity into which is placed a mea-
sured amount of the material whose intrinsic dissolution rate is to be
determined. The punch is then inserted in the die cavity and the test
material is compressed with a benchtop tablet press. [NOTE—A hole
through the head of the punch allows insertion of the metal rod to
BRIEFING facilitate removal from the die after the test.] A compacted pellet of
the material is formed in the cavity with a single face of defined area
exposed on the bottom of the die (see accompanying figure). The bot-
tom of the die cavity is threaded so that at least 50% to 75% of the
h1087i Intrinsic Dissolution, USP 29 page 2923. The revision compacted pellet can dissolve without its falling out of the die. The
proposed in PF 30(6) [Nov.–Dec. 2004] on page 2130 is hereby can- top of the die has a threaded shoulder that allows it to be attached to a
celed and reproposed in order to revise the current name and content holder. The holder is mounted on a laboratory stirring device, and the
of this General Information Chapter. The proposal accommodates the
In-Process Revision
entire die, with the compacted pellet still in place, is immersed in the
inclusion of a stationary disk dissolution procedure, includes changes dissolution medium and rotated by the stirring device (see Dissolu-
to the sections under Experimental Procedure, and adds a new section tion h711i).
on Data Analysis and Interpretation. Test Preparation—Weigh the material to be tested onto a piece of
tared weighing paper. Attach the surface plate to the underside of the
(BPC: W. Brown) RTS—C51036 die, and secure it with the three screws provided. Transfer the ac-
curately weighed portion of the material under test into the die cavity.
Place the punch into the chamber, and secure the metal plate on top of
the assembly. Compress the powder on a hydraulic press for 1 minute
at the minimum compression pressure necessary to form a nondisin-
tegrating compacted pellet. Detach the surface plate, and screw the
die with punch still in place into the holder. Tighten securely. Remove
all loose powder from the surface of the die by blowing compressed
air or nitrogen.
Procedure—Slide the die-holder assembly into the dissolution test
chuck, and tighten. Position the shaft in the spindle so that when the
tested head is lowered, the exposed surface of the compacted pellet
will be 3.8 cm from the bottom of the vessel. The disk assembly
should be aligned to minimize wobble, and air bubbles should not
be allowed to form on the compacted pellet or die surface as this
could alter fluid flow. [NOTE—Air bubbles may be avoided by using
Pharmacopeial Forum
an apparatus with a different configuration, such as a die holder that sion of the material under test using appropriate pressure con-
holds the compacted pellet in a fixed vertical position with agitation
provided by a paddle positioned 6 mm from the surface of the pellet.] ditions. A single surface having specified physical dimensions
Perform the analysis as directed in the individual monograph. If pos-
sible, sink conditions should be maintained throughout the test. The is presented for dissolution. Determination of the rate of dis-
data for the cumulative amount dissolved at each time point should be
corrected for sampling losses. To calculate the intrinsic dissolution solution can be important during the course of the develop-
rate, plot the cumulative amount of test specimen dissolved per unit
area of the compacted pellet against time until 10% is dissolved. The ment of new chemical entities because it sometimes permits
cumulative amount dissolved per unit area is given by the cumulative
amount dissolved at each time point divided by the surface area ex- prediction of potential bioavailability problems and may also
posed (0.5 cm2). Linear regression should then be performed on data
points up to and including the time point beyond which 10% is dis- be useful to characterize compendial articles such as excipi-
solved. The intrinsic dissolution rate of the test specimen, in mg per
minute per cm2, is determined from the slope of the regression line. ents or drug substances. Intrinsic dissolution studies are char-
acterization studies and are not referenced in individual
&
This General Information Chapter Apparent Intrinsic Dis-
monographs. Information provided in this General Informa-
solution—Dissolution Testing Procedures for Rotating Disk
tion Chapter is intended to be adapted via a specific protocol
and Stationary Disk h1087i discusses the determination of dis-
appropriate to a specified material.
solution rates from nondisintegrating compacts exposing a
fixed surface area to a given solvent medium. Compact, as
used here, is a nondisintegrating mass resulting from compres-
In-Process Revision
Apparatus for Intrinsic Dissolution
Pharmacopeial Forum
Dissolution rate generally is expressed as the mass of solute the die in a quiescent fluid, but fluid flow is generated by a
appearing in the dissolution medium per unit time (e.g., mass paddle or other stirring device for the stationary disk proce-
sec–1), but dissolution flux is expressed as the rate per unit area dure.
(e.g., mass cm–2 sec–1). Reporting dissolution flux is preferred
because it is normalized for surface area, and for a pure drug EXPERIMENTAL PROCEDURE
substance is commonly called intrinsic dissolution rate. Disso-
The procedure for carrying out dissolution studies with the
lution rate is influenced by intrinsic solid-state properties such
two types of apparatus consists of preparing a nondisintegrat-
as crystalline state, including polymorphs and solvates, as well
ing compact of material using a suitable compaction device,
as degree of noncrystallinity. Numerous procedures are avail-
placing the compact and surrounding die assembly in a suit-
able for modifying the physicochemical properties of chemical
able dissolution medium, subjecting the compact to the de-
entities so that their solubility and dissolution properties are
sired hydrodynamics near the compact surface, and
enhanced. Among these are co-precipitates and the use of ra-
measuring the amount of dissolved solute as a function of
cemates and enantiomeric mixtures. The effect of impurities
time.
associated with a material can also significantly alter its disso-
Compacts are typically prepared using an apparatus that
lution properties. Dissolution properties are also influenced by
consists of a die, an upper punch, and a lower surface plate
extrinsic factors such as surface area, hydrodynamics, and dis-
fabricated out of hardened steel or other material that allows
solution medium properties, including solvent (typically wa-
the compression of material into a nondisintegrating compact.
ter), presence of surfactants, temperature, fluid viscosity, pH,
An alternative compaction apparatus consists of a die and two
buffer type, and buffer strength.
punches. Other configurations that achieve a nondisintegrating
Rotating disk and stationary disk dissolution procedures are compact of constant surface area also may be used. The non-
sufficiently versatile to allow the study of characteristics of disintegrating compact typically has a diameter of 0.2 cm to
compounds of pharmaceutical interest under a variety of test 1.5 cm.
conditions. Characteristics common to both apparatuses in-
clude the following:
Compact Preparation
(1) They are adaptable to use with standard dissolution test-
ing stations, and both use a tablet die to hold the nondi- Attach the smooth lower surface plate to the underside of the
sintegrating compact during the dissolution test. die, or alternatively, insert the lower punch using an appropri-
In-Process Revision
ate clamping system. Accurately weigh a quantity of material
(2) They rely on compression of the test compound into a
necessary to achieve an acceptable compact and transfer to the
compact that does not flake or fall free during the disso-
die cavity. Place the upper punch into the die cavity, and com-
lution test.
press the powder on a hydraulic press at a compression pres-
(3) A single surface of known geometry and physical dimen- sure required to form a nondisintegrating compact that will
sion is presented for dissolution. remain in the die assembly for the length of the test. Compres-
(4) The die is located at a fixed position in the vessel, which sion for 1 minute at 15 MPa usually is sufficient for many or-
decreases the variation of hydrodynamic conditions. ganic crystalline compounds, but alternative compression
conditions that avoid the formation of capillaries should be
A difference between the two procedures is the source of
fluid flow over the dissolving surface. In the case of the rotat-
ing disk procedure, fluid flow is generated by the rotation of
Pharmacopeial Forum
evaluated. For a given substance, the compact preparation, pounds, this is relatively simple because no significant pH de-
once optimized is standardized to facilitate comparison of dif- pendence of dissolution rate is expected. For acids and bases,
ferent samples of the substance. the solute can alter the pH at and near the surface of the com-
Changes in crystalline form may occur during compression; pact as it dissolves. Under these conditions, the pH at the sur-
therefore, confirmation of solid state form should be per- face of the compact may be quite different from the bulk pH
formed by powder X-ray diffraction or other similar tech- due to the self-buffering capacity of the solute. To assess in-
nique. Remove the surface plate or lower punch. Remove trinsic solubility, experimental conditions should be chosen to
loose powder from the surface of the compact and die by eliminate the effect of solute buffering, alteration of solution
blowing compressed air or nitrogen over the surface. pH, and precipitation of other solid state forms at the surface
of the compact. For weak acids, the pH of the dissolution me-
dium should be one to two pH units below the pKa of the dis-
Dissolution Medium
solving species. For weak bases, the pH of the dissolution
The choice of dissolution medium is an important consider- medium should be one to two pH units above the pKa of the
ation. Whenever possible, testing should be performed under dissolving species.
sink conditions to avoid artificially retarding the dissolution
rate due to approach of solute saturation of the medium. Dis-
Apparatus
solution measurements are typically made in aqueous media.
To approximate in-vivo conditions, measurements may be run Rotating Disk—A typical apparatus (Figure 1) consists of a
in the physiological pH range at 378. The procedure when pos- punch and die fabricated out of hardened steel. The base of the
sible is carried out under the same conditions that are used to die has three threaded holes for the attachment of a surface
determine the intrinsic solubility of the solid state form being plate made of polished steel, providing a mirror-smooth base
tested. Dissolution media should be deaerated immediately for the compacted pellet. The die has a cavity into which is
prior to use to avoid air bubbles forming on the compact or placed a measured amount of the material whose intrinsic dis-
die surface.1 solution rate is to be determined. The punch is then inserted in
The medium temperature and pH must be controlled, espe- the die cavity and the test material is compressed with a hy-
cially when dealing with ionizable compounds and salts. In the draulic press. [NOTE—A hole through the head of the punch
latter cases, the dissolution rate may depend strongly on the allows insertion of a metal rod to facilitate removal from the
pH, buffer species, and buffer concentration. A simplifying as- die after the test.] A compacted pellet of the material is formed
In-Process Revision
sumption in constant surface area dissolution testing is that the in the cavity with a single face of defined area exposed on the
pH at the surface of the dissolving compact is the same as the bottom of the die.
pH of the bulk dissolution medium. For nonionizable com-
1
One method of deaeration is as follows: Heat the medium, while
stirring gently, to about 418, immediately filter under vacuum using
a filter having a porosity of 0.45 mm or less, with vigorous stirring,
and continue stirring under vacuum for about 5 minutes. Other
deaeration techniques for removal of dissolved gases may be used.
Pharmacopeial Forum
Figure 1
The die assembly is then attached to a shaft constructed of

an appropriate material (typically steel). The shaft holding the
die assembly is positioned so that when the die assembly is
lowered into the dissolution medium (Figure 2) the exposed
surface of the compact will be not less than 1.0 cm from the
bottom of the vessel and nominally in a horizontal position.
In-Process Revision
The die assembly should be aligned to minimize wobble,
and air bubbles should not be allowed to form on the compact
or die surface.
Figure 2
Pharmacopeial Forum
A rotating disk speed of 300 rpm is recommended. Typical

rotation speeds may range from 60 rpm to 500 rpm. The dis-
solution rate depends on the rotation speed used. This param-
eter should be selected in order to admit at least five sample
points during the test, but excessive stirring speeds may create
shear patterns on the surface of the dissolving material that
could cause aberrant results (i.e., nonlinearity). Typically,
the concentration of the test specimen is measured as a func-
tion of time, and the amount dissolved is then calculated. The
sampling interval will be determined by the speed of the dis-
solution process. If samples are removed from the dissolution
medium, the cumulative amount dissolved at each time point
should be corrected for losses due to sampling.
Stationary Disk—The apparatus (Figure 3) consists of a
Figure 3
steel punch, die, and a base plate. The die base has three holes
for the attachment of the base plate. The three fixed screws on
the base plate are inserted through the three holes on the die
and then fastened with three washers and nuts. The test mate-
rial is placed into the die cavity. The punch is then inserted into
the cavity and compressed, with the aid of a bench top press.
The base plate is then disconnected from the die to expose a
smooth compact pellet surface. A gasket is placed around the
threaded shoulder of the die and a polypropylene cap is then
screwed onto the threaded shoulder of the die.
The die assembly is then positioned at the bottom of a spe-
cially designed dissolution vessel with a flat bottom (Figure
4). The stirring unit (e.g., paddle) is positioned at an appropri-
ate distance (typically 2.54 cm) from the compact surface. The
In-Process Revision
die assembly and stirring unit should be aligned to ensure con-

sistent hydrodynamics, and air bubbles should not be present
on the compact surface during testing. Alternative configura-
tions may be utilized if adequate characterization and control Figure 4
of the hydrodynamics can be established.
The dissolution rate depends on the rotation speed and pre-
cise hydrodynamics that exist. Typically, the concentration of
the test specimen is measured as a function of time, and the
amount dissolved is then calculated. The sampling interval
will be determined by the speed of the dissolution process
Pharmacopeial Forum
(see Rotating Disk). If samples are removed from the dissolu- tive second derivative) curvature of the dissolution profile is
tion medium, the cumulative amount dissolved at each time often indicative of a transformation of the solid form of the
point should be corrected for losses due to sampling. compact at the surface or when saturation of the dissolution
medium is inadvertently being approached. This often occurs
DATA ANALYSIS AND INTERPRETATION when a less thermodynamically stable crystalline form con-
verts to a more stable form. Examples include conversion from
The dissolution rate is determined by plotting the cumula-
an amorphous form to a crystalline form or from an anhydrous
tive amount of solute dissolved against time. Linear regression
form to a hydrate form, or the formation of a salt or a salt con-
analysis is performed on data points in the initial linear region
verting to the corresponding free acid or free base. If such cur-
of the dissolution curve. The slope corresponds to the dissolu-
vature is observed, the crystalline form of the compact may be
tion rate (mass sec–1). (More precise estimates of slope can be
assessed by removing it from the medium and examining it by
obtained using a generalized linear model that takes into ac-
powder X-ray diffraction or another similar technique to deter-
count correlations among the measurements of the cumulative
mine if the exposed surface area is changing.
amounts dissolved at the various sampling times.)
The constant surface area dissolution rate is reported in units
The amount versus time profiles may show curvature. When
of mass sec–1, and the dissolution flux is reported in units of
this occurs, only the initial linear portion of the profile is used
mass cm–2 sec–1. The dissolution flux is calculated by dividing
to determine the dissolution rate. Upward curvature (positive
the dissolution rate by the surface area of the compact. Test
second derivative) of the concentration versus time data is typ-
conditions, typically a description of the apparatus, rotation
ically indicative of a systematic experimental problem. Possi-
speed, temperature, buffer species and strength, pH, and ionic
ble problems include physical degradation of the compact by
strength should also be reported with the analyses.&1S (USP31)
cracking, delaminating, or disintegration. Downward (nega-
In-Process Revision
Pharmacopeial Forum
REAGENTS, INDICATORS, BRIEFING

AND SOLUTIONS
Sodium Phosphate, Monobasic, Dihydrate. It is proposed to add
this new reagent used to prepare the Buffer in the Assay in the
monograph for Ipratropium Bromide, which appears elsewhere in
Reagent Specifications this issue of PF.
BRIEFING Add the following:

&
Sodium Phosphate, Monobasic, Dihydrate (Sodium
a-Cyclodextrin. It is proposed to add this new reagent used in the
test for Limit of 4R,8R-stereoisomer in the monograph for Dihydrogen Phosphate, Dihydrate), NaH2PO 4 2H2 O—
Galantamine Hydrobromide.
156.01 [13472-35-0]—Use a suitable grade with a content
(HDQ: M. Marques) RTS—C50644 of not less than 99.0%.&1S (USP31)
Add the following:

&
a-Cyclodextrin (Cyclomaltohexaose; Schardinger a-Dextrin), BRIEFING
C36H60O30—972.86 [10016-20-3]—Use a suitable grade with
a content of not less than 98.0%. Tetrapropylammonium Chloride. It is proposed to add this new
reagent used to prepare the Buffer in the Assay in the monograph for
[ NOTE— A suitable grade is available from Fluka, Ipratropium Bromide, which appears elsewhere in this issue of PF.
www.sigma-aldrich.com, catalog number 28705.]&1S (USP31) (HDQ:M. Marques) RTS—C51596
Add the following:
BRIEFING &
Tetrapropylammonium Chloride, C12H28ClN—221.82
[5810-42-4]—Use a suitable grade with a content of not less
Sodium Phosphate, Monobasic, Anhydrous. This new reagent
is used in the Buffer solution in the Assay under Galantamine than 98.0%.&1S (USP31)
Hydrobromide.
Add the following: BRIEFING
&
Sodium Phosphate, Monobasic, Anhydrous (Sodium
In-Process Revision
Chromatographic Reagents, page 104 of PF 33(1) [Jan.–Feb.

Biphosphate; Sodium Dihydrogen Phosphate; Acid Sodium 2007]. It is proposed to include the two types of columns used for
Enoxaparin Sodium. They are the same types as the columns used
Phosphate; Monosodium Orthophosphate), NaH2PO4— for Dalteparin Sodium and appear with those columns.
119.98 [7558-80-7]—Use a suitable grade with a content (HDQ: M. Marques) RTS—C51561
of not less than 99.0%.&1S (USP31)
Pharmacopeial Forum
Add the following: L8—An essentially monomolecular layer of aminopropyl-

silane chemically bonded to totally porous silica gel support,
&CHROMATOGRAPHIC 3 to 10 mm in diameter.
REAGENTS
L9—&&1S (USP29) Irregular or spherical, totally porous silica
gel having a chemically bonded, strongly acidic cation-
The following list of packings (L), phases (G), and supports exchange coating, &3 to 10 mm in diameter.&1S (USP29)
(S) is intended to be a convenient reference for the L10—Nitrile groups chemically bonded to porous silica
chromatographer. [NOTE—Particle sizes given in this listing particles, 5 to 10 mm in diameter.
are those generally provided. Where other, usually finer, sizes L11—Phenyl groups chemically bonded to porous silica
are required, the individual monograph specifies the desired particles, 5 &1.5&1S (USP30) to 10 mm in diameter.
particle size. Within any category of packings or phases listed L12—A strong anion-exchange packing made by chemi-
below, there may be a wide range of columns available. cally bonding a quaternary amine to a solid silica spherical
Where it is necessary to define more specifically the core, 30 to 50 mm in diameter.
chromatographic conditions, the individual monograph so L13—Trimethylsilane chemically bonded to porous silica
indicates.] particles, 3 to 10 mm in diameter.
Change to read: L14—Silica gel having a chemically bonded, strongly basic

quaternary ammonium anion-exchange coating, 5 to 10 mm in
diameter.
L15—Hexylsilane chemically bonded to totally porous
Packings silica particles, 3 to 10 mm in diameter.
L1—Octadecyl silane chemically bonded to porous silica L16—Dimethylsilane chemically bonded to porous silica
or ceramic micro-particles, 3 &

1.5&1S (USP30) to 10 mm in particles, 5 to 10 mm in diameter.
diameter, &or a monolithic silica rod.&1S (USP29) L17—Strong cation-exchange resin consisting of sulfonat-
L2—Octadecyl silane chemically bonded to silica gel of ed cross-linked styrene-divinylbenzene copolymer in the
a controlled surface porosity that has been bonded to a solid hydrogen form, 7 to 11 mm in diameter.
spherical core, 30 to 50 mm in diameter. L18—Amino and cyano groups chemically bonded to

~
L3—Porous silica particles, 5 3~USP31 to 10 mm in diameter, porous silica particles, 3 to 10 mm in diameter.
In-Process Revision
~
or a monolithic silica rod.~USP31 L19—Strong cation-exchange resin consisting of sulfonat-
L4—Silica gel of controlled surface porosity bonded to ed cross-linked styrene-divinylbenzene copolymer in the
a solid spherical core, 30 to 50 mm in diameter. calcium form, about 9 mm in diameter.
L5—Alumina of controlled surface porosity bonded to L20—Dihydroxypropane groups chemically bonded to
a solid spherical core, 30 to 50 mm in diameter. porous silica particles, 5 to 10 mm in diameter.
L6—Strong cation-exchange packing–sulfonated fluorocar- L21—A rigid, spherical styrene-divinylbenzene copolymer,
bon polymer coated on a solid spherical core, 30 to 50 mm in 5 to 10 mm in diameter.
diameter. L22—A cation-exchange resin made of porous polystyrene
L7—Octylsilane chemically bonded to totally porous silica gel with sulfonic acid groups, about 10 mm in size.
~
particles, 3 &1.5&1S (USP30) to 10 mm in diameter, or a mono-
lithic silica rod.~USP31
Pharmacopeial Forum
L23—An anion-exchange resin made of porous poly- L33—Packing having the capacity to separate dextrans by
methacrylate or polyacrylate gel with quaternary ammonium molecular size over a range of 4,000 to 500,000 Da. It is
groups, about 10 mm in size. spherical, silica-based, and processed to provide pH stability.
L24—A semi-rigid hydrophilic gel consisting of vinyl &
[NOTE—Available as TSKgel G4000 SWXL from Tosoh
polymers with numerous hydroxyl groups on the matrix Biosep (www.tosohbiosep.com).]&1S (USP29)
surface, 32 to 63 mm in diameter. L34—Strong cation-exchange resin consisting of sulfonat-
&
[NOTE—Available as YMC-Pack PVA-SIL manufactured ed cross-linked styrene-divinylbenzene copolymer in the lead
by YMC Co., Ltd. and distributed by Waters Corp. form, about 9 mm in diameter.
(www.waters.com).]&1S (USP29) L35—A zirconium-stabilized spherical silica packing with
L25—Packing having the capacity to separate compounds a hydrophilic (diol-type) molecular monolayer bonded phase
with a molecular weight range from 100 to 5000 (as having a pore size of 150 Å.
determined by polyethylene oxide), applied to neutral, L36—A 3,5-dinitrobenzoyl derivative of L-phenylglycine
anionic, and cationic water-soluble polymers. A polymetha- covalently bonded to 5-mm aminopropyl silica.
crylate resin base, cross-linked with polyhydroxylated ether L37—Packing having the capacity to separate proteins by
(surface containing some residual carboxyl functional groups) molecular size over a range of 2,000 to 40,000 Da. It is
was found suitable. a polymethacrylate gel.
L26—Butyl silane chemically bonded to totally porous L38—A methacrylate-based size-exclusion packing for
silica particles, &3&1S (USP29) to 10 mm in diameter. water-soluble samples.
L27—Porous silica particles, 30 to 50 mm in diameter. L39—A hydrophilic polyhydroxymethacrylate gel of
L28—A multifunctional support, which consists of a high totally porous spherical resin.
purity, 100-Å, spherical silica substrate that has been bonded L40—Cellulose tris-3,5-dimethylphenylcarbamate coated
with anionic exchanger, amine functionality in addition to porous silica particles, 5 to 20 mm in diameter.
a conventional reversed phase C8 functionality. L41—Immobilized a1-acid glycoprotein on spherical silica
L29—Gamma alumina, reverse-phase, low carbon percent- particles, 5 mm in diameter.
age by weight, alumina-based polybutadiene spherical L42—Octylsilane and octadecylsilane groups chemically
particles, 5 mm in diameter with a pore volume of 80 Å. bonded to porous silica particles, 5 mm in diameter.
L30—Ethyl silane chemically bonded to totally porous L43—Pentafluorophenyl groups chemically bonded to
In-Process Revision
silica particles, 3 to 10 mm in diameter. silica particles by a propyl spacer, 5 to 10 mm in diameter.

L31—A &
hydroxide-selective, &1S (USP29) strong anion- L44—A multifunctional support, which consists of a high
exchange resin-quaternary amine bonded on latex particles purity, 60 Å, spherical silica substrate that has been bonded
attached to a core of 8.5-mm macroporous particles having with a cationic exchanger, sulfonic acid functionality in
a pore size of 2000 Å and consisting of ethylvinylbenzene addition to a conventional reversed phase C8 functionality.
cross-linked with 55% divinylbenzene. L45—Beta cyclodextrin bonded to porous silica particles,
L32—A chiral ligand-exchange packing–L-proline copper 5 to 10 mm in diameter.
complex covalently bonded to irregularly shaped silica L46—Polystyrene/divinylbenzene substrate agglomerated
particles, 5 to 10 mm in diameter. with quaternary amine functionalized latex beads, about
10 mm in diameter.
Pharmacopeial Forum
L47—High-capacity anion-exchange microporous sub- L54—A size exclusion medium made of covalent bonding
strate, fully functionalized with trimethlyamine groups, of dextran to highly cross-linked porous agarose beads, about
8 mm in diameter. 13 mm in diameter.
&
[NOTE—Available as CarboPac MA1 and distributed by &
[ NOTE— Available as Superdex Peptide HR 10/30
Dionex Corp. (www.dionex.com).]&1S (USP29) from Amersham Pharmacia Biotech
L48—Sulfonated, cross-linked polystyrene with an outer (www.amershambiosciences.com).]&1S (USP29)
layer of submicron, porous, anion-exchange microbeads, 15 L55—A strong cation-exchange resin made of porous silica
mm in diameter. coated with polybutadiene–maleic acid copolymer, about
L49—A reversed-phase packing made by coating a thin 5 mm in diameter.
layer of polybutadiene onto spherical porous zirconia &
[NOTE—Available as IC-Pak C M/D from Waters Corp.
particles, 3 to 10 mm in diameter. (www.waters.com).]&1S (USP29)
&
[NOTE—Available as Zirchrom PBD, manufactured by L56—Propyl silane chemically bonded to totally porous
ZirChrom Separations, Inc., distributed by Alltech, silica particles, 3 to 10 mm in diameter.
www.Alltechweb.com.]&1S (USP29)
&
[NOTE—Available as Zorbax SB-C3 from Agilent Tech-
L50—Multifunction resin with reversed-phase retention nologies (www.agilent.com/chem).]&1S (USP29)
and strong anion-exchange functionalities. The resin consists L57—A chiral-recognition protein, ovomucoid, chemically
of ethylvinylbenzene, 55% cross-linked with divinylbenzene bonded to silica particles, about 5 mm in diameter, with a pore
copolymer, 3 to 15 mm in diameter, and a surface area not less size of 120 Å.
than 350 m2 per g. Substrate is coated with quaternary &
[NOTE—Available as Ultron ES-OVM from Agilent
ammonium functionalized latex particles consisting of styrene Technologies (www.agilent.com/chem).]&1S (USP29)
cross-linked with divinylbenzene. L58—Strong cation-exchange resin consisting of sulfonat-

&
[NOTE—Available as OmniPac PAX-500 and distributed ed cross-linked styrene-divinylbenzene copolymer in the
by Dionex Corp. (www.dionex.com).]&1S (USP29) sodium form, about 7 to 11 mm in diameter.
L51—Amylose tris-3,5-dimethylphenylcarbamate-coated, &
[NOTE—Available as Aminex HPX-87N from Bio-Rad
porous, spherical, silica particles, 5 to 10 mm in diameter. Laboratories, (2000/01 catalog, #125-0143) www.bio-
&
[NOTE—Available as Chiralpak AD from Chiral Technol- rad.com.]&1S (USP29)
ogies, Inc., (www.chiraltech.com).]&1S (USP29) L59—Packing having the capacity to separate proteins by
L52—A strong cation-exchange resin made of porous silica molecular weight over the range of 10 to 500 kDa. It is
In-Process Revision
with sulfopropyl groups, 5 to 10 mm in diameter. spherical (10 mm), silica-based, and processed to provide
&
[NOTE—Available as TSK IC SW Cation from Tosoh hydrophilic characteristics and pH stability.
Biosep (www.tosohbiosep.com).]&1S (USP29) &
[NOTE—Available as TSKgel G3000SW Column (analyt-
L53—Weak cation-exchange resin consisting of ethylvi- ical column) and TSKgel Guard (guard column) from Tosoh
nylbenzene, 55% cross-linked with divinylbenzene copoly- Biosep (part numbers 05789 and 05371, respectively)
mer, 3 to 15 mm diameter. Substrate is surface grafted with (www.tosohbiosep.com).]&1S (USP29)
carboxylic acid and/or phosphoric acid functionalized L60—Spherical, porous silica gel, 3 or 5 mm &10 mm or
monomers. Capacity not less than 500 mEq/column. less&1S (USP30) in diameter, the surface of which has been
&
[NOTE—Available as IonPac CS14 distributed by Dionex covalently modified with palmitamidopropyl &
alkyl
Corp. (www.dionex.com).]&1S (USP29) amide&1S (USP30) groups and endcapped.
Pharmacopeial Forum
&
[NOTE—Available as Supelcosil ABZ from Supelco L## (Levalbuterol, Chirobiotic T)—Glycopeptide teicopla-
(www.sigma-aldrich.com/supelco).]&1S (USP29) nin linked through multiple covalent bonds to a 100-Å units
L61—A hydroxide selective strong anion-exchange resin spherical silica.
consisting of a highly cross-linked core of 13-mm micro- [ NOT E— Available as Chirobiotic T from Astec
porous particles having a pore size less than 10 Å units and (www.astecusa.com).]
consisting of ethylvinylbenzene cross-linked with 55%
divinylbenzene with a latex coating composed of 85-nm
Phases
diameter microbeads bonded with alkanol quaternary ammo-
nium ions (6%). G1—Dimethylpolysiloxane oil.
&
[NOTE—Available as Ion Pac AS-11 and AG-11 from G2—Dimethylpolysiloxane gum.
Dionex (www.dionex.com).]&1S (USP29) G3—50% Phenyl-50% methylpolysiloxane.
L62—C30 silane bonded phase on a fully porous spherical G4—Diethylene glycol succinate polyester.
silica, 3 to 15 mm in diameter. G5—3-Cyanopropylpolysiloxane.
L## (Enoxaparin Sodium, Dowex 1X8)—[To come.] G6—Trifluoropropylmethylpolysiloxane.
L## (Enoxaparin Sodium, Dowex 50WX2)—[To G7—50% 3-Cyanopropyl-50% phenylmethylsilicone.
come.] G8—80% Bis(3-cyanopropyl)-20% 3-cyanopropylphenyl-
L## (Dalteparin Sodium, &Enoxaparin Sodium;&1S (USP31) polysiloxane (percentages refer to molar substitution).
anion-exchange Dowex 1X8)—[To come.] G9—Methylvinylpolysiloxane.
L## (Dalteparin Sodium, &
Enoxaparin Sodium;&1S (USP31) G10—Polyamide formed by reacting a C36 dicarboxylic
cation-exchange Dowex 50WX2)—[To come.] acid with 1,3-di-4-piperidylpropane and piperidine in the
L## (Glucosamine, Shodex NH2P-50)—Polyamine chem- respective mole ratios of 1.00 : 0.90 : 0.20.
ically bonded to cross-linked polyvinyl alcohol polymer, G11—Bis(2-ethylhexyl) sebacate polyester.
5 mm in diameter. G12—Phenyldiethanolamine succinate polyester.
[NOTE—Available as Shodex NH2P-50 from Shodex G13—Sorbitol.
(www.shodex.com).] G14—Polyethylene glycol (av. mol. wt. of 950 to 1050).
L## [Valganciclovir Hydrochloride, Crownpak CR(+)]—A G15—Polyethylene glycol (av. mol. wt. of 3000 to 3700).
crown ether coated on a 5-mm particle size silica gel substrate. G16—Polyethylene glycol compound (av. mol. wt. about
In-Process Revision
The active site is (S)-18-crown-6-ether. 15,000). A high molecular weight compound of polyethylene
[ NOTE— Available as Crownpak CR(+) from Daicel glycol with a diepoxide linker. Available commercially as
(www.daicel.com).] Polyethylene Glycol Compound 20M, or as Carbowax 20M,
L## (Trehalose, Sugar KS-801)—Strong cation-exchange from suppliers of chromatographic reagents.
resin consisting of sulfonated cross-linked styrene-divinyl- G17—75% Phenyl-25% methylpolysiloxane.
~
benzene copolymer in the sodium form, 6 to 17 30~USP31 mm G18—Polyalkylene glycol.
in diameter. G19—25% Phenyl-25% cyanopropyl-50% methylsilicone.
[ NOTE— Available as Sugar KS-801 from Shodex G20—Polyethylene glycol (av. mol. wt. of 380 to 420).
(www.shodex.com).] G21—Neopentyl glycol succinate.
G22—Bis(2-ethylhexyl) phthalate.
G23—Polyethylene glycol adipate.
Pharmacopeial Forum
G24—Diisodecyl phthalate. G46—14% Cyanopropylphenyl-86% methylpolysiloxane.

G25—Polyethylene glycol compound TPA. A high molec- G47—Polyethylene glycol (av. mol. wt. of about 8000).
ular weight compound of a polyethylene glycol and G48—Highly polar, partially cross-linked cyanopolysilox-
a diepoxide that is esterified with terephthalic acid. ane.&&1S (USP29)
&
[NOTE—Available commercially as Carbowax 20M-TPA G## (Docosahexaenoic acid, Famewax)—Polyethylene
from suppliers of chromatographic reagents.]&1S (USP29) glycol, cross-linked (average molecular weight of not more
G26—25% 2-Cyanoethyl-75% methylpolysiloxane. than 20,000).
G27—5% Phenyl-95% methylpolysiloxane. G## (Tetrafluoroethane, Bentone 34/SP-1200)—Alumino-
G28—25% Phenyl-75% methylpolysiloxane. silicate montmorrillonite that has been treated with dimethy-
G29—3,3’-Thiodipropionitrile. loctadecylammonium salts plus a low polarity ester phase.
G30—Tetraethylene glycol dimethyl ether. G## (Tetrafluoroethane, Krytox)—A perfluorinated poly-
G31—Nonylphenoxypoly(ethyleneoxy)ethanol (av. ethyle- ether fluid.
neoxy chain length is 30); Nonoxynol 30.
G32—20% Phenylmethyl-80% dimethylpolysiloxane.
Supports
G33—20% Carborane-80% methylsilicone.
G34—Diethylene glycol succinate polyester stabilized with NOTE—Unless otherwise specified, mesh sizes of 80 to 100
phosphoric acid. or, alternatively, 100 to 120 are intended.
G35—A high molecular weight compound of a polyethyl- S1A—Siliceous earth for gas chromatography has been
ene glycol and a diepoxide that is esterified with nitroter- flux-calcined by mixing diatomite with Na2CO3 flux and
ephthalic acid. calcining above 9008. The siliceous earth is acid-washed, then
G36—1% Vinyl-5% phenylmethylpolysiloxane. water-washed until neutral, but not base-washed. The
G37—Polyimide. siliceous earth may be silanized by treating with an agent
G38—Phase G1 containing a small percentage of a tailing such as dimethyldichlorosilane &
[NOTE—Unless otherwise
inhibitor. specified in the individual monograph, silanized support is
&
[NOTE—A suitable grade is available commercially as intended.]&1S (USP29) to mask surface silanol groups.
‘‘SP2100/0.1% Carbowax 1500’’ from Supelco, Inc. S1AB—The siliceous earth as described above is both
(www.sigma-aldrich.com/supelco).]&1S (USP29) acid- and base-washed. &[NOTE—Unless otherwise specified
G39—Polyethylene glycol (av. mol. wt. about 1500). in the individual monograph, silanized support is intend-
In-Process Revision
G40—Ethylene glycol adipate. ed.]&1S (USP29)
G41—Phenylmethyldimethylsilicone (10% phenyl- S1C—A support prepared from crushed firebrick and
substituted). calcined or burned with a clay binder above 9008 with
G42—35% phenyl-65% dimethylpolysiloxane (percent- subsequent acid-wash. It may be silanized.
ages refer to molar substitution). S1NS—The siliceous earth is untreated.
G43—6% cyanopropylphenyl-94% dimethylpolysiloxane S2—Styrene-divinylbenzene copolymer having a nominal
(percentages refer to molar substitution). surface area of less than 50 m2 per g and an average pore
G44—2% low molecular weight petrolatum hydrocarbon diameter of 0.3 to 0.4 mm.
grease and 1% solution of potassium hydroxide.
G45—Divinylbenzene-ethylene glycol-dimethylacrylate.
Pharmacopeial Forum
S3—Copolymer of ethylvinylbenzene and divinylbenzene

S9—A porous polymer based on 2,6-diphenyl-p-phenylene
having a nominal surface area of 500 to 600 m2 per g and an
oxide.
average pore diameter of 0.0075 mm.
S10—A highly polar cross-linked copolymer of acryloni-
S4—Styrene-divinylbenzene copolymer with aromatic –O
trite and divinylbenzene.
and –N groups, having a nominal surface area of 400 to 600
m2 per g and an average pore diameter of 0.0076 mm.
100 m2 per g modified with small amounts of petrolatum and
S5—40- to 60-mesh, high-molecular weight tetrafluorethy-
polyethylene glycol compound.
lene polymer.
&
[NOTE—Commercially available as SP1500 on Carbopack
B from Supelco (www.sigma-aldrich.com/supelco).]&1S (USP29)
surface area of 250 to 350 m2 per g and an average pore
diameter of 0.0091 mm.
100 m2 per g.
S## (Tetrafluoroethene, Porapak T)—Polymer based on
12 m2 per g.
highly polar ethylene glycol dimethacrylate monomer, with
S8—Copolymer of 4-vinyl-pyridine and styrene-divinyl-
a surface area of 225–350 m2 per g.&2S (USP30)
benzene.
In-Process Revision
Pharmacopeial Forum
REFERENCE TABLES Container Specifications for Capsules and Tablets (Continued)

Container
Monograph Title Specification
Add the following:

BRIEFING &
Dantrolene Sodium Capsules T, LR&2S (USP30)
Container Specifications for Capsules and Tablets, USP 29 page Add the following:
3184, page 3813 of the Second Supplement, and page 1809 of PF
32(6) [Nov.–Dec. 2006].
&
Desogestrel and Ethinyl Estradiol
Tablets W&1S (USP30)
(HDQ) RTS—C39916
Add the following:
~
The following table is provided as a reminder for the pharmacist Diclofenac Potassium Tablets T, LR~USP30
engaged in the typical dispensing situation who already is acquainted
with the Packaging and storage requirements set forth in the individ-
ual monographs. It lists the capsules and tablets that are official in the Add the following:
United States Pharmacopeia and indicates the relevant tight (T),
well-closed (W), and light-resistant (LR) specifications applicable
&
Didanosine Tablets T&2S (USP30)
to containers in which the drug that is repackaged should be dis-
pensed. Add the following:
This table is not intended to replace, nor should it be interpreted as
replacing, the definitive requirements stated in the individual mono- &
Estradiol Vaginal Tablets T&2S (USP30)
graphs.
Add the following:
Container Specifications for Capsules and Tablets &
Estradiol and Norethindrone Acetate
Container
Monograph Title Specification Tablets W&1S (USP30)
Add the following:

Add the following:
&
Acetaminophen, Chlorpheniramine, and
&
Fexofenadine Hydrochloride Tablets W&1S (USP30)
Dextromethorphan Tablets T&2S (USP30) Add the following:

&
Fosinopril Sodium Tablets T&1S (USP30)
Add the following:

Add the following:
&
Acitretin Capsules W, LR&1S (USP31)
&
Fosinopril Sodium and Hydrochloro-
Add the following: thiazide Tablets T&1S (USP30)
~
Benazepril Hydrochloride Tablets W~USP30
In-Process Revision
Add the following:
Add the following: ~
Gabapentin Tablets W~USP31
&
Capecitabine Tablets T&2S (USP30)
Add the following:
Ginkgo Capsules T, LR~USP30
~
Carprofen Tablets T~USP31
Add the following:
Ginkgo Tablets T, LR~USP30
&
Cat’s Claw Capsules T, LR&2S (USP30)
Change to read:
T, LR
Add the following: Asian Ginseng Capsules
&
&1S (USP30)
&
Cat’s Claw Tablets T, LR&2S (USP30)
Pharmacopeial Forum
Container Specifications for Capsules and Tablets (Continued) Container Specifications for Capsules and Tablets (Continued)
Container Container
Monograph Title Specification Monograph Title Specification
&
Glipizide and Metformin Hydrochloride &
Metformin Hydrochloride Tablets,
Tablets W&2S (USP30) Extended-Release W, LR&2S (USP30)

&
Glucosamine, Chondroitin Sulfate So- &
Methylsulfonylmethane Tablets T, LR&1S (USP30)
dium, and Methylsulfonylmethane

Add the following:
Tablets T, LR&2S (USP30) &
Modafinil Tablets T&2S (USP30)
Add the following:

Add the following:
&
Glucosamine and Methylsulfonyl- ~
Morphine Sulfate Capsules, Extended-
methane Tablets T, LR&2S (USP30)
Release T, LR~USP30
Add the following:

Add the following:
~
Hydrocodone Bitartrate and Homatro- &
Nefazodone Hydrochloride Tablets T&1S (USP30)
pine Methylbromide Tablets T, LR~USP31
Add the following:
Add the following: &
Nevirapine Tablets W&1S (USP30)
&
Irbesartan Tablets W&1S (USP30)
Add the following:
Norgestimate and Ethinyl Estradiol
&
Irbesartan and Hydrochlorothiazide
Add the following:
Ofloxacin Tablets W~USP31
&
Isosorbide Mononitrate Tablets T&1S (USP30)
Add the following:
Orlistat Capsules T~USP31
&
I s o s o r bi de M on on i t r a t e Ta bl e t s ,
Add the following:
Extended-Release T&2S
In-Process Revision
(USP30)
~
O x y b u t y n i n C h l o r i d e Ta b l e t s ,
Add the following:
Extended-Release T~USP30
&
Ketoprofen Capsules, Extended-
Add the following:
Release T&2S (USP30)
&
Oxycodone Hydrochloride Tablets,
Add the following:
Extended-Release T, LR&2S (USP30)
~
Loratadine and Pseudoephedrine
Add the following:
Sulfate Tablets, Extended-Release LR~USP31
&
Pravastatin Sodium Tablets T&1S (USP30)
Add the following:
Add the following:
&
Meloxicam Tablets W&2S (USP30)
&
Quinapril Tablets W&1S (USP30)
Pharmacopeial Forum
Container Specifications for Capsules and Tablets (Continued) Add the following:
Container
Monograph Title Specification &
Estradiol Benzoate: White to off-white, crystalline
Add the following: powder. Soluble in alcohol and in acetone; slightly soluble
&
Risperidone Tablets T, LR&2S (USP30)
in diethyl ether; insoluble in water.&1S (USP31)

~
Tizanidine Tablets T~USP30
&
Galantamine Hydrobromide: White to almost white
Add the following: powder. Soluble in 0.1 N sodium hydroxide; sparingly soluble
&
Valerian Capsules T, LR&2S (USP30) in water; very slightly soluble in alcohol; insoluble in n-
Add the following: propanol.&1S (USP31)
&
Valganciclovir Tablets T&2S (USP30) Add the following:
Add the following:

&
Ipratropium Bromide: White to off-white, crystalline
~
Valsartan and Hydrochlorothiazide
powder. Soluble in water; freely soluble in methanol; slightly
Tablets W T~USP30
soluble in alcohol.&1S (USP31)
Add the following:
BRIEFING
&
Propylene Glycol Monocaprylate: Clear, colorless, or
slightly yellow, oily liquid at 208. Very soluble in alcohol, in
Description and Relative Solubility of USP and NF Articles, chloroform, and in methylene chloride; practically insoluble in
USP 29 page 3191, page 3813 of the Second Supplement, page
8589 of PF 25(4) [July–Aug. 1999], page 1908 of PF 27(1) [Jan.– water. NF category: Emulsifying and/or solubilizing agent;
Feb. 2001], page 554 of PF 28(2) [Mar.–Apr. 2002], page 1953 of
PF 28(6) [Nov.–Dec. 2002], page 266 of PF 29(1) [Jan.–Feb. tablet and/or capsule diluent; vehicle.&1S (NF26)
2003], page 1405 of PF 30(4) [July–Aug. 2004], page 1822 of PF
page 122 of PF 31(1) [Jan.–Feb. 2005], page 591 of PF 31(2) [Mar.– Add the following:
Apr. 2005], page 861 of PF 31(3) [May–June 2005], page 1193 of PF
page 1703 of PF 31(6) [Nov.–Dec. 2005], page 188 of PF 32(1) &
Trehalose: White, odorless, nonhygroscopic, crystalline
[Jan.–Feb. 2006], page 662 of PF 32(2) [Mar.–Apr. 2006], page
942 of PF 32(3) [May–June 2006], page 1301 of PF 32(4) [July– powder. Soluble in water, solubility increases with tempera-
Aug. 2006], page 1541 of PF 32(5) [Sept.–Oct. 2006], page 1811
of PF 32(6) [Nov.–Dec. 2006], and page 110 of PF 33(1) [Jan.– ture; practically insoluble in dehydrated alcohol. Is typically
In-Process Revision
Feb. 2007].
used in the dihydrate form. NF category: Bulking agent for
(HDQ) RTS—C39432; C41589; C44337; C46941; C47678;
C51698 freeze-drying; sweetening agent; tablet binder; tablet and/or
capsule diluent; tablet disintegrant; vehicle.&1S (NF26)
Add the following:
&
Carbachol: White powder. Freely soluble in water;
sparingly soluble in alcohol; practically insoluble in chloro-
form and in ether.&1S (USP31)
Pharmacopeial Forum
Pending Proposals
published in the USP–NF, its Supplements, or an IRA. Those items that have not yet been adopted are marked as Pending Pro-
posals.
monographs; Dietary Supplements Monographs; General Chapters; Reference Tables; Excipients; and NF Monographs. Each
entry in the Pending Proposals list contains the monograph title and the citation of the most recent publication of the monograph.
When the appropriate USP Expert Committee is considering advancing to official status a pending proposal that is more than 2
years old, it is republished in PF for additional opportunity for public review and comment. Reprints of PF proposals may be
purchased from USP by sending a written request for information to custsvc@usp.org.
The briefing accompanying the monograph or general chapter lists the names of the Scientific Liaisons responsible for the proposed revi-
sions. The contact information (phone number and email) for the Scientific Liaison is available in the Staff Directory section of How to Use
PF. For USP–NF Online subscribers, the name and contact information for the assigned Scientific Liaison is available in the Auxiliary
Information portion of each monograph.
the email.

USP Monographs
Acetaminophen Extended-Release Tablets—Packaging and 32 6 1666
storage (add), Labeling, Dissolution
In-Process Revision

(add)
Alprazolam Tablets—Assay 33 1 41
Title (name change)
Tablets (new)
Title (name change)
(new)
Pharmacopeial Forum
Amitriptyline Hydrochloride—USP Reference standards, 31 6 1606
Identification, Chromatographic purity (delete),
and storage
compounds, Assay
Benazepril Hydrochloride Tablets (new) 32 1 52
Benzonatate Capsules—Dissolution (add) 32 1 55
Bisoprolol Fumarate Tablets—Labeling (add), Dissolution 32 6 1666
Bromocriptine Mesylate Capsules—Dissolution 32 1 58
Dissolution
Calcitriol (new) 33 1 44
Calcitriol Injection (new) 32 1 61
Calcium Carbonate and Magnesia Tablets (title change) 29 6 1852
In-Process Revision
Title (name change)
Tablets (new)
Calcium Lactate—USP Reference standards (add), Identification 31 6 1608
Calcium Lactate Tablets—Identification 31 6 1609
Calcium Pantothenate—USP Reference standards, Ordinary impurities 32 1 62
Carbamazepine—USP Reference standards, Chromatographic purity 32 1 65
(Related compounds), Assay
Pharmacopeial Forum
compounds
Cefonicid for Injection—Assay 32 1 67
Ceftazidime—USP Reference standards, Assay 32 1 67
Ceftazidime Injection—USP Reference standards 32 1 68
Ceftazidime for Injection—USP Reference standards 32 1 68
Chlorthalidone—USP Reference standards, Limit of 32 1 68
4’-chloro-3’-sulfamoyl-2-benzophenone carboxylic
acid (CCA) (Limit of chlorthalidone
related compound A), Assay
Cimetidine Tablets—Dissolution 32 1 72
USP Reference standards, Related compounds
Citalopram Tablets—Identification, Dissolution, 33 1 46
Clopidogrel Bisulfate—Related compounds, Assay 32 1 74
Clopidogrel Tablets—Dissolution, Related compounds 33 1 50
Clotrimazole Lozenges—Dissolution 32 1 78
Cytarabine for Injection—Assay 33 1 51
In-Process Revision

Desogestrel (new) (entire submission) 28 6 1785
Assay
Diclofenac Potassium (new) 31 5 1350
Diclofenac Potassium Tablets (new) 31 5 1352
Title (name change)
Pharmacopeial Forum
Tablets (new)
Diltiazem Hydrochloride Extended-Release Capsules—Dissolution 32 6 1673
Dimethyl Sulfoxide Gel—Deliverable volume (delete), 33 1 52
Minimum fill (add)
Assay (add)
Diphtheria Toxin for Schick Test (delete) 31 6 1616
Eprinomectin (new) 33 1 60
Etidronate Disodium—Limit of phosphite 31 6 1625
In-Process Revision
Flucytozine Oral Suspension (new) 32 1 92
Assay
content (delete)
Fluvastatin Sodium—Packaging and storage, Labeling (add), 33 1 64
USP Reference standards, Identification, Water,
Pharmacopeial Forum
Fluvastatin Capsules—USP Reference standards, 32 1 105
Gemcitabine for Injection—USP Reference standards, 31 6 1630
Gemcitabine Hydrochloride—USP Reference standards 32 1 114
compounds, Assay
Dissolution (add)
Hepatitis B Virus Vaccine Inactivated (delete) 31 6 1641
Tablets (new)
Hydrocortisone Tablets—USP Reference standards, Dissolution, 33 1 72
Hydroxyzine Hydrochloride—Definition, USP Reference standards, 32 5 1456
dosage units (add)
Sodium Iodide I 123 Capsules—Definition 31 6 1642
In-Process Revision
Sodium Iodide I 123 Solution—Definition, Radionuclidic purity, 31 6 1642

Bacterial endotoxins, pH
Sodium Iodide I 131 Solution—pH 31 6 1643
Iodoform—Molecular weight 32 1 115
Assay
Isosorbide Dinitrate Extended-Release Tablets—Labeling (add), 33 1 73
Dissolution
Ivermectin—Specific rotation, Limit of alcohol 31 6 1645
and formamide
Pharmacopeial Forum
Levalbuterol Hydrochloride (new) 33 1 75
Levalbuterol Inhalation Solution (new) 33 1 79
Lindane—Definition, Assay 31 6 1648
Lovastatin—Assay 32 1 118
to January 1, 2009)
to January 1, 2009)
Limit of lead (add)
Mangafodipir Trisodium—Limit of residual solvents 31 6 1650
Metformin Hydrochloride Tablets—Dissolution 32 6 1725
In-Process Revision
Related compounds
Miconazole Nitrate Cream—Identification 32 1 123
Morphine Sulfate Extended-Release Capsules— 32 1 124
Packaging and storage (add)
Naphazoline Hydrochloride—Definition, Assay 31 4 1093
Pharmacopeial Forum
Naproxen Delayed-Release Tablets—Packaging and 32 1 124
storage
Narasin Granular—Molecular weight, Assay 32 1 124
Narasin Premix—Assay 32 1 126
Naratriptan Hydrochloride—Assay 32 5 1462
Dissolution (add)
Norethindrone Acetate and Ethinyl Estradiol Tablets—Dissolution 33 1 81
compounds (add)
Ondansetron Oral Solution—Packaging and storage (add), 32 1 128
Limit of ondansetron related compound D, Related compounds
Orphenadrine Citrate Injection—Assay 31 6 1651
Oxandrolone—Related compounds (add), Ordinary 31 1 64
impurities (delete)
Oxaprozin—Packaging and storage (add) 32 1 130
Oxaprozin Tablets—Packaging and storage (add) 32 1 130
Oxybutynin Chloride Extended-Release Tablets (new) 32 6 1742
Pamidronate Disodium for Injection—Definition, 33 1 81
Packaging and storage, Bacterial endotoxins
Paricalcitol—Identification, Chromatographic purity, Assay 32 1 132
In-Process Revision

Phenylbutazone Boluses—Definition 33 1 82
Phenylbutazone Tablets—Definition, Labeling (add) 33 1 82
Pharmacopeial Forum
to January 1, 2009)
Assay
Identification
Progesterone Vaginal Suppositories—Definition 33 1 82
Related compounds
Pseudoephedrine Sulfate—Ordinary impurities 32 1 135
Related compounds
Rubella and Mumps Virus Vaccine Live (delete) 31 6 1662
Salicylic Acid—USP Reference standards (add), Sulfate, 33 1 83
Related compounds
In-Process Revision
Schick Test Control (delete) 31 6 1662
Senna—Title, Definition, Packaging and storage, Labeling (add), 32 1 137
USP Reference standards (add), Botanic characteristics,
Identification, Microbial enumeration (add)
Loss on drying (add), Total ash (add), Assay (add)
Senna Pods (new) 32 1 140
Sennosides—Definition, Packaging and storage, Residue on ignition 32 1 141
Simvastatin—Identification, Chromatographic purity, 32 1 141
Limit of lovastatin (delete), Assay
of ammonia
Sodium Chloride—Limit of phosphates 31 5 1401
Pharmacopeial Forum
Talc—Packaging and storage (add), Limit of iron, 31 6 1662
Limit of calcium, Limit of aluminum
Temazepam—Identification 32 1 145
standards, Assay
Thalidomide—Microbial limits, Chromatographic purity 32 5 1467
Thimerosal—Identification 32 1 147
Tizanidine Tablets (new) 32 1 147
Valsartan (new) 32 1 150
Valsartan and Hydrochlorothiazide Tablets (new) 31 4 1123
In-Process Revision

Pharmacopeial Forum
Zidovudine Tablets—USP Reference standards, 32 1 158
Limit of fluoride
Fish Oil Containing Omega-3 Acids (new) (entire submission) 31 2 474
Fish Oil Containing Omega-3 Acids Capsules (new) (entire submission) 31 2 481
Ginger—Packaging and storage, Labeling, USP Reference standards, 32 1 160
Identification, Microbial enumeration, Alcohol-soluble extractives,
Limit of shogaols, Content of gingerols and gingerdiones
Powdered Ginger—Packaging and storage, USP Reference standards 32 1 162
Ginger Capsules—USP Reference standards, Content of 32 1 163
gingerols, gingerdiones, and shogaols
Ginger Tincture—USP Reference standards, Thin-layer 32 1 163
chromatographic identification test, Microbial enumeration,
Content of gingerols
Ginkgo—Definition, Packaging and storage, USP Reference 32 1 164
standards, Thin-layer chromatographic identification test,
Microbial enumeration, Content of terpene lactones
Powdered Ginkgo Extract (new) 32 1 166
Ginkgo Capsules (new) 32 1 172
Ginkgo Tablets (new) 32 1 174
In-Process Revision
Identification
Pharmacopeial Forum
Ubidecarenone Capsules—Labeling (add), Disintegration and dissolution 33 1 93
Ubidecarenone Tablets—Labeling (add), Disintegration and dissolution 33 1 94
Valerian Capsules (new) (entire submission) 27 1 1825
Definition
Definition
Definition
Definition
Definition
Definition
28 2 433
28 3 839
28 5 1468
29 3 710
29 5 1601
29 6 2022
30 2 613
30 4 1338
30 5 1674
30 6 2092
31 1 99
31 2 507
31 3 822
31 5 1433
31 6 1680
32 1 181
32 2 407
32 3 829
32 4 1161
32 5 1491
32 6 1779
33 1 95
In-Process Revision

h381i Elastomeric Closures for Injections—Introduction, 30 1 220
Characteristics, Identification Tests, Test Procedures
Harmonization
Procedure
Pharmacopeial Forum
h467i Residual Solvents—Introduction, 32 5 1494
Classification of Residual Solvents by Risk Assessment,
Methods for Establishing Exposure Limits, Options for Describing
Limits of Class 2 Residual Solvents, Analytical Procedures (add),
Reporting Levels of Residual Solvents (add), Limits of
Residual Solvents, Identification, Control, and Quantification of
Residual Solvents, Glossary
h644i Conductivity (new) (entire submission) 31 3 841
Closure) (add), Multiple-Unit Containers and Unit-Dose Containers
Emulsions (new)
Introduction, Organization of This Chapter, Definitions (add),
Responsibility of Compounding Personnel, CSP Microbial
Contamination Risk Levels, Immediate Use CSPs (add),
Single-Dose and Multiple-Dose Containers (add),
Hazardous Drugs as CSPs (add), Radiopharmaceuticals
as CSPs (add), Verification of Compounding Accuracy and
Sterility, Personnel Training and Evaluation in Aseptic
Manipulation Skills, Environmental Quality and Control,
Suggested Standard Operating Procedures, Environmental
Monitoring (add), Processing, Finished Preparation
Release Checks and Tests, Storage and Beyond-Use
Dating, Maintaining Sterility, Purity, and Stability of
Dispensed and Distributed CSPs, Acronyms (add), Appendix
In-Process Revision
Pharmacopeial Forum
Other Locations, Special Handling, Shipment from Manufacturer
to Wholesaler, Shipment from Manufacturer or Wholesaler
to Pharmacy, Shipment from Pharmacy to Patient or
Customer, Storage of Physician Samples Handled by
Sales Representatives in Automobiles, Statements/Labeling
Analysis (new)
h1082i Genotoxicity Testing (new) (entire submission) 30 1 264
Contamination Control Effectiveness (add), Training of
In-Process Revision

Excipients (new)
Training and Safety
Introduction, Methods of Sterilization, Sterility Testing of Lots,
h1225i Validation of Compendial Procedures—Validation 33 1 96
Pharmacopeial Forum
Waters (new) (entire submission)
Acetone 32 2 608
Alum 32 2 611
Aluminon 32 2 611
Aluminum 32 2 611
Amaranth 32 2 612
2-Aminoheptane (new) 33 1 100
In-Process Revision
Aniline 32 2 619
Pharmacopeial Forum
Anisole 32 2 619
Anthracene 32 2 619
Anthrone 32 2 620
Benzene 32 2 623
Benzhydrol 32 2 623
Bibenzyl 32 2 625
Biphenyl 32 2 625
Boric Acid 32 2 628
In-Process Revision

Bromine 32 2 629
Pharmacopeial Forum
Calconcarboxylic Acid (new) 33 1 100
Calconcarboxylic Acid Triturate (new) 33 1 100
Carbazole 32 2 636
Casein 32 2 637
Catechol 32 2 637
Cedar Oil 32 2 637
Chlorine 32 2 638
Chloroform 32 2 640
Cholestane 32 2 641
In-Process Revision
Cinchonine 32 2 643
Congo Red 32 2 643
Copper 32 2 644
Cortisone 32 2 644
L-Cystine 32 2 646
Decanol 32 2 646
Pharmacopeial Forum
Dextrin 32 2 647
Digitonin 32 2 652
Dimethicone, viscosity 500 centistokes (new) 33 1 100
In-Process Revision

N,N-Dimethyldodecylamine-N-oxide (new) 27 4 2837
Pharmacopeial Forum
Dioxane 32 3 902
Dithizone 32 3 903
n-Eicosane 32 3 904
Eicosanol 32 3 904
Equilenin 32 3 904
Fluorene 32 3 909
Formamide 32 3 909
In-Process Revision
Geneticin (new) 31 6 1700
Gitoxin 32 3 910
Glucose 32 3 911
Glycerin 32 3 911
Guaiacol 32 3 912
Hematein 32 3 912
n-Hexane 32 3 913
Pharmacopeial Forum
Imidazole 32 3 918
Indene 32 3 918
Inosine 32 3 918
Inositol 32 3 918
Iodic Acid 32 3 919
Iodine 32 3 919
Isopropyl Iodide 31 6 1701
Kerosene 32 3 921
Lactose 33 1 100
In-Process Revision

Litmus 32 3 923
L-Lysine 32 3 923
Magnesium 32 3 923
Pharmacopeial Forum
Mercury 32 3 926
Methanol 32 3 927
Morpholine 32 3 933
In-Process Revision
1-Naphthol 32 3 934
2-Naphthol 32 3 934
Nickel 32 3 935
Ninhydrin 32 3 936
Pharmacopeial Forum
Nonadecane 32 3 939
Orange G 32 4 1240
Orcinol 32 4 1240
Pentane 32 4 1242
Pepsin 32 4 1242
Phenol 32 4 1243
In-Process Revision
Pharmacopeial Forum
Propylamine Hydrochloride (new) 33 1 101
Purine 32 4 1253
Pyrazole 32 4 1254
Pyrene 32 4 1254
Pyridine 32 4 1254
Pyrrole 32 4 1255
Selenium 32 4 1258
In-Process Revision
Sodium 32 4 1260
Sodium Carbonate, Monohydrate (new) 31 6 1701
Pharmacopeial Forum
Sodium Phosphate, Dibasic, Dihydrate 33 1 101
In-Process Revision

Sudan III 32 4 1273
Sudan IV 32 4 1273
Pharmacopeial Forum
Thiourea 32 4 1279
Thymol 32 4 1280
Tin 32 4 1280
Toluene 32 4 1281
p-Toluenesulfonyl-L-arginine Methyl Ester Hydrochloride 32 1 186
In-Process Revision
Uracil 32 4 1288
Urea 32 4 1288
Urethane 32 4 1288
Pharmacopeial Forum
Uridine 32 4 1288
Xanthine 32 4 1290
Xylene 32 4 1290
o-Xylene 32 4 1291
p-Xylene 32 4 1291
Xylose 32 4 1291
Zinc 32 4 1291
Test Solutions
Bismuth Nitrate, 0.01 mol/L (new) 32 4 1292
Ceric Sulfate, Tenth-Normal (0.1 N) 33 1 102
Mercuric Nitrate, Tenth Molar (0.1 M) 32 6 1805
Potassium Permanganate, Tenth-Normal (0.1 N) 33 1 103
Sodium Tetraphenylboron, Fiftieth Molar (0.02 M) 32 6 1807
Reference Tables
26 4 1135
27 1 1908
28 2 554
28 6 1953
29 1 266
29 3 812
In-Process Revision
29 5 1684
30 4 1405
30 5 1822
30 6 2183
31 1 122
31 2 591
31 3 861
31 4 1193
31 5 1491
31 6 1703
32 1 188
32 2 662
32 3 942
32 4 1301
32 5 1541
32 6 1811
33 1 110
Excipients 32 6 1768
Pharmacopeial Forum
NF Monographs
Acetyltributyl Citrate—Assay 32 1 177
Acetyltriethyl Citrate—Assay 32 1 178
Assay
Canola Oil (new) 31 6 1667
Cellacefate—USP Reference standards 32 1 179
Corn Syrup Solids (new) (entire submission) 28 6 1894
Dispersion (new)
Ethylcellulose Aqueous Dispersion—Labeling, Identification 31 6 1668
Gamma Cyclodextrin (new) (entire submission) 31 3 812
Glyceryl Monostearate—Labeling, USP Reference standards 31 6 1669
(delete), Assay for monoglycerides
Harmonization
Polacrilin Potassium—CAS number, Chemical name 31 6 1671
In-Process Revision
Polyoxyl 35 Castor Oil—Viscosity 31 6 1671
Pharmacopeial Forum
Tributyl Citrate—Assay 32 1 179
Triethyl Citrate—Assay 32 1 180
In-Process Revision
Pharmacopeial Forum
[PF 33(1)–PF 33(6)]
USP Monographs
USP General Information Chapters
{h1087i Intrinsic Dissolution (entire submission) 30 6 2130
{New cancellation in PF 33(2).
In-Process Revision
In-Process Revision
HARMONIZATION
staff.
Stage 5: Consensus
A. Provisional
B. Final
Harmonization
Pharmacopeial Forum
316 HARMONIZATION Vol. 33(2) [Mar.–Apr. 2007]
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Propylene Glycol [new] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
Harmonization
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] HARMONIZATION 317
MONOGRAPHS (USP) Readers are requested to review the proposal carefully and to
send comments to USP; the deadline for receipt is 31 May
2007.
(EM1: K. Moore) RTS—C44009

BRIEFING
Propylene Glycol. The European Pharmacopoeia is the coordi-

nating pharmacopoeia for the international harmonization of the
compendial standards for the Propylene Glycol monograph, as part Add the following:
of the process of international harmonization of monographs and
general analytical methods of the European, Japanese, and United Propylene Glycol
States pharmacopeias. The following monograph, which represents
the OFFICIAL INQUIRY STAGE 4 document, is based in part on
comments from the Japanese Pharmacopoeia and the United States
Pharmacopoeia in response to the Provisional Harmonized Text
Stage 4 draft prepared by the European Pharmacopoeia. Differences
between the OFFICIAL INQUIRY STAGE 4 document and the
current NF monograph include the following. Tests that are indicated
in the briefing below as ‘‘retained as a nonharmonized attribute’’ do
not appear as part of the harmonized draft proposal, but will be C3H8O2 76.09
retained with no changes based on its respective test in the current
NF monograph.
1. Definition—The current EP lower limit of 99.9% (anhydrous 1,2-Propanediol. [57-55-6].
based) is adopted.
2. Packaging and storage—No change. The USP text is retained
as a nonharmonized attribute.
3. USP Reference standards—No change. The USP text is
retained as a nonharmonized attribute. » Propylene Glycol contains not less than 99.9% of
4. Identification—No change.
5. Specific gravity—No change. The USP text is retained as C3H8O2, calculated on the anhydrous basis.
a nonharmonized attribute.
6. Acidity—The use of 0.01 N sodium hydroxide and 50.0 mL of
propylene glycol is proposed to align with the EP text. Identification, Infrared Absorption h197Fi: on undried
7. Water—Sample size is specified to align with the harmonized
proposal. specimen.
8. Residue on ignition—No change.
9. Chloride—No change. The USP text is retained as a non-
harmonized attribute. Appearance—It is clear and colorless.
10. Sulfate—No change. The USP text is retained as a nonharmo-
nized attribute. Acidity Phenolphthalein Solution—Dissolve 0.1 g of phe-
11. Heavy metals—No change. The USP text is retained as
a nonharmonized attribute. nolphthalein in 80 mL of alcohol and dilute to 100 mL with
12. Assay—The EP has proposed a GC method with a different
column, injection volume, and column temperature. This water. To 50 mL of water add 1 mL of Phenolphthalein
method results in a run time of 5 minutes, which is roughly
half that of the existing method. A minimum resolution of 4.0 Solution, then add 0.01 N sodium hydroxide VS until the
between propylene glycol and dipropylene glycol is proposed.
13. Appearance—This is a new test added by the EP. It is Ph. Eur. solution remains pink for 30 seconds. Add 50.0 mL of
policy to include this test in monographs for products that could
be administered parenterally. It is also seen as a general quality Propylene Glycol, and titrate with 0.01 N sodium hydroxide
criterion because it is liable to detect colored impurities that are
not controlled by other tests of the monograph. VS until the color turns back to pink and remains for more
14. Oxidizing substances—This is a new test, a titration method
with sodium thiosulfate, proposed by the EP. than 30 seconds. One mL of 0.01 N sodium hydroxide VS is
15. Aldehydes—This is a new test proposed by the EP. It is a visible
spectrophotometric test after reaction with methylbenzothiazo- equivalent to 0.6 mg of CH3COOH. Not more than 5.0 mg,
lone hydrazone hydrochloride and ferric chloride with detection
at 655 nm. A 20-ppm limit has been proposed by IPEC Europe. calculated as CH3COOH, is observed on a 50.0 mL sample.
Oxidizing substances—To 10 mL add 5 mL of water, 2 mL

of potassium iodide TS, and 2 mL of Sulfuric Acid, Diluted,
and allow to stand in a ground-glass-stoppered flask protected
from light for 15 minutes. Titrate with 0.05 N sodium
Harmonization
thiosulfate VS, using 1 mL of Starch TS as indicator. Not

more than 0.2 mL of 0.05 N sodium thiosulfate VS is required
(expressed as ppm of H2O2).
Pharmacopeial Forum
318 HARMONIZATION Vol. 33(2) [Mar.–Apr. 2007]
Aldehydes Formaldehyde Solution TS1—Complies with 5 minutes. Add methanol to each flask, and dilute to 50.0 mL
the requirements for Formaldehyde Solution TS, with the with the same solvent. Mix thoroughly, then allow to stand
following modification. The percentage of formaldehyde is for 1 minute.
determined in the following manner: To 2.0 g of Formalde- Blank solution—Prepare in the same manner as for the
hyde Solution TS, add 100 mL of a freshly prepared 100 g/L Reference solutions but omitting the Stock solution. Measure
solution of sodium sulfite in carbon-dioxide free water. Add the absorbance of the solutions at 655 nm. Calculate the
0.1 mL of Phenolphthalein Solution and titrate with 0.5 N content of aldehydes expressed as CHO in the substance to be
sulfuric acid until the color changes from pink to colorless. examined from the calibration curve obtained using the
Carry out a blank titration. Calculate the percentage content reference solutions. Not more than 20 ppm is observed,
of formaldehyde in Formaldehyde Solution TS1 using the calculated as CHO.
following expression: Water, Method I h921i: not more than 0.2%, determined on
5.0 g.
(V–B) 6 2M 6 3.0 / m
Assay—
in which V is the volume of 0.5 N sulfuric acid used in the
The gas chromatograph is equipped with a flame ionization
assay, in mL; B is the volume of 0.5 N sulfuric acid used in
detector, and contains a 30-m 6 0.32-mm column packed
the blank, in mL; M is the molarity of the titrant (0.25 M); and
with G27. The injection port temperature is 2508, the detector
m is the mass of sample, in g.
temperature is 2508, the column temperature is 1508, the flow
Stock solution—To 0.300 g of Formaldehyde Solution TSI,
rate is 1.4 mL per minute, the split ratio is 1 : 70, and helium
add carbon-dioxide free water and dilute to 100.0 mL with
is used as the carrier gas. Chromatograph the System
the same solvent. Dilute 1.0 mL of this solution to 100.0 mL
suitability solution, and record the peak responses as directed
with carbon-dioxide free water. Dilute 8.0 mL of this solution
for the Procedure: the resolution, R, between the peaks due to
to 200.0 mL with carbon-dioxide free water.
propylene glycol and dipropylene glycol is at least 4.0.
Test solution—Introduce 1.0 g, accurately weighed, of the
[NOTE—For information purposes only, the approximate
substance to be examined into a volumetric flask and add
retention time for propylene glycol is 2 minutes, and the
about 5 mL of carbon-dioxide free water. Then proceed as
relative retention time for the three isomers, when present, of
described below.
dipropylene glycol is about 1.4 relative to propylene glycol.]
Reference solutions—Introduce into volumetric flasks,
System suitability solution—Add 20.0 mg of dipropylene
respectively, 1.0 mL, 3.0 mL, 5.0 mL, 10.0 mL, 25.0 mL,
glycol to 1.0 g of Propylene Glycol, and mix.
40.0 mL, and 50.0 mL of Stock solution. Then proceed as
Procedure—Inject about 1 mL of Propylene Glycol into
described below. To each flask, add 2 mL of a freshly
a suitable gas chromatograph and record the chromatogram.
prepared 5 g/L solution of methylbenzothiazolone hydrazone
Calculate the percentage of C3H8O2 in the Propylene Glycol
hydrochloride adjusted to pH 4.0 using 0.02 N sodium
by dividing the area under the propylene glycol peak by the
hydroxide. Allow the solutions to stand for 30 minutes.
sum of the areas under all of the peaks, excluding those due to
Add 5 mL of a freshly prepared 7 g/L solution of ferric
Harmonization
air and water, and multiplying by 100.

chloride. Cap and swirl the flasks. Allow to stand for
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] HARMONIZATION 319
Description and solubility— liquid. Miscible with water and ethanol (96%). NF category:
Propylene Glycol: Viscous, clear, colorless, hygroscopic Humectant; plasticizer; solvent.
Harmonization
Harmonization

BRIEFING
(DSN: L. Evans) RTS—55678-1
STIMULI TO THE

REVISION PROCESS
commentaries
324 of the USPC or the USP Council of Experts Vol. 33(2) [Mar.–Apr. 2007]
A New Validated Differential Scanning Calorimetric Procedure for Monitoring the Less Active R,S Isomer of Ethambutol
Dihydrochloride in Bulk Drug Samples and Anti-tuberculosis Formulations, Bhagwat Prasad, Hemant Bhutani, Vijay Kumar, and
Saranjit Singh . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Vol. 33(2) [Mar.–Apr. 2007] of the USPC or the USP Council of Experts 325

be addressed to:
Pharmacopeial Forum
Rockville, MD 20852
A New Validated Differential Scanning Calorimetric Procedure for Monitoring

the Less Active R,S Isomer of Ethambutol Dihydrochloride in Bulk Drug
Samples and Anti-tuberculosis Formulations*
Bhagwat Prasad, Hemant Bhutani, Vijay Kumar, and Saranjit Singh, Department of Pharmaceutical Analysis, National Institute of
Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar 160 062, Punjab, India
ABSTRACT A new and simple validated differential scanning calorimetric (DSC) procedure was developed for quantitation of
the less active R,S diastereoisomer of ethambutol dihydrochloride in bulk drug samples and marketed anti-tuberculosis
formulations. The procedure involves determination of the enthalpy associated with polymorphic transitions, appearing at
42 8C and 77 8C for R,S and S,S isomers, respectively. Suitable equations were derived and could be successfully used to
determine the relative extents of the two isomers in commercial products. The unwanted R,S form was found to be present in
more than half of the tested drug substances and products and in some products constituted 100% of the active. This suggests that
an appropriate test procedure and relevant limits should be included in USP–NF and other international compendia to control the
inactive isomer in ethambutol dihydrochloride and also in anti-tuberculosis fixed-dose combination products that contain the
drug.
INTRODUCTION EB2HCl is removed by taking advantage of its low solubility

in a number of solvents, but it still can be present in the SS-
Ethambutol dihydrochloride (EB2HCl) can exist in three EB2HCl form of the drug. Incidentally, there is no procedure
different diastereoisomeric forms: S,S; R,S; and R,R; desig- given in any pharmacopeia to control or determine the extent
nated in this paper as SS-EB2HCl, RS-EB2HCl, and RR- of RS-EB2HCl in EB2HCl or its products. Only the range of
EB2HCl, respectively. SS-EB2HCl is therapeutically active, optical rotation values is prescribed to control quality or for
but RS-EB2HCl is 16 times less active, and RR-EB2HCl is assay of the active SS-EB2HCl. The compendial tests (2–5)
completely inactive (1). The synthesis of EB2HCl is carried are listed in Table 1, along with their anticipated limitations.
out using (+)-2-amino-1-butanol as the starting material;
hence the process primarily yields a mixture of SS-EB2HCl
and RS-EB2HCl without the presence of RR-EB2HCl. RS-
Table 1. Pharmacopoeial evaluations of the isomeric quality of EB2HCl (2–5)

Postulated drawback of
Pharmacopoeia Test the respective test
United States Pharmacopeia Specific rotation between +6.08 and 1. The wide range of the specific rotation may
(USP) 6.78 of 10% (w/v) solution at 25 8C allow up to 10% of (R,S) form as an impurity
and 100 mm 2. Not applicable in formulations
Indian Pharmacopoeia (IP) Same as above Same as above
Japanese Pharmacopoeia Specific rotation between +5.58 Same as above
(JP) and 6.18 of 10% (w/v) solution at
20 8C and 200 mm
British Pharmacopoeia (BP) Assay procedure based on 1. Not applicable in formulations
optical activity 2. Low sensitivity of the procedure
Fortunately, a few reports exist in the literature for the de- RS-EB2HCl and SS-EB2HCl. Although the procedure was
termination of RS-EB2HCl. These include a study done in novel, its use was severely restricted because quantitation of
early seventies by Ferrari and Graber (6), who used differential RS-EB2HCl was limited to the range of 0–5%. At higher con-
thermal analysis (DTA) for the detection and quantitation of centrations of RS-EB2HCl, the endotherm at 178 8C merged
the meso (or optically inactive) isomer. Several years later with the melting endotherm of EB2HCl at ~200 8C. Following
Varshney et al. (7) reported the use of more precise differential this report, another procedure appeared in the literature and in-
scanning calorimetry (DSC) for the purpose. The latter proce- volved chromatographic separation of diastereoisomers of
dure was based on quantitation of an endotherm at 178 8C at- EB2HCl using a chiral column (8). This procedure did not be-
tributed to solid–solid interaction (eutectic formation) between come popular, perhaps due to high costs and restricted com-
*
mercial availability of the chromatographic column.
Correspondence should be addressed to: Gary E. Ritchie, Scientific Fellow,
Department of Standards Development, USP, 12601 Twinbrook Parkway,
Rockville, MD 20852-1790; tel. 301.816.8353; e-mail ger@usp.org.
Lately, Rubin-Preminger et al. (9–10) explored the poly- Equipment
morphic behaviour of RS-EB2HCl and SS-EB2HCl (Figure
1) using a host of instrumental techniques, including vari- DSC analyses were performed using a Mettler Toledo
able-temperature solid-state carbon-13 nuclear magnetic reso- (Schwerzenbach, Switzerland) 821e instrument controlled by
nance (NMR), variable-temperature powder X-ray diffraction STAR software version 5.21. Thermogravimetric analysis
(XRD), differential scanning calorimetry (DSC), and optical (TGA) was performed using a model 851e instrument from
microscopy. That both RS-EB2HCl and SS-EB2HCl forms the same manufacturer. FTIR spectra of the samples were ob-
of the drug exist independently in two polymorphic states tained on an Impact 410 spectrophotometer (Nicolet, WI,

was confirmed through careful comparison of unit cell para- USA) equipped with OMNIC analyzing software. Optical ro-
meters of single-crystal XRD and packing diagrams, wherein tation and specific rotation were monitored using an analytical
large differences were observed between the bond angles and polarimeter (model 55, Rudolph Research, Hackettstown, NJ,
both lengths of the region surrounding C3. The same were also USA). Ultrapure water was obtained from a purification unit
proved through Rietveld fitting of powder XRD parameters (Elga Ltd., Bucks, England). Rotavapor from Buchi (Flawil,
and chemical shifts for C3 in the carbon-13 solid state– Switzerland) was used for solvent evaporation.
NMR spectra of more than 2 ppm. These techniques also in- The HPLC system consisted of a DGU-14A degasser mod-
dicated that phase transitions were enantiotropic and fully re- ule, FCV-10ALVP flow control valve, LC-10ATVP pump, SIL-
versible. The latter were also indicated by the appearance of 10AD VP auto injector, CTO-10AS VP column oven, SPD-
differences in torsion of additional endotherms in DSC for M10AVP photodiode array (PDA) detector, and an SCL-
RS-EB2HCl and SS-EB2HCl at 42 8C and 77 8C, respectively. 10AVP system controller; data were acquired and processed
The occurrence of characteristic endotherms in DSC below using CLASS-VP software version 6.13 (all from Shimadzu,
the melting point of EB2HCl at ~200 8C indicated the possi- Kyoto, Japan). A Zorbax XDB CN-SB (150 4.6 mm, parti-
bility of developing a simple and specific procedure for quan- cle size 5mm) column (Agilent Technologies, Wilmington,
tifying RS-EB2HCl in the presence of SS-EB2HCl. This was DE, USA) was used for the chromatographic study. Other de-
attempted, with development and validation of the procedure. vices employed were a pH meter (MA 235, Mettler Toledo
It was subsequently applied to the analysis of RS-EB2HCl in GmbH, Schwerzenbach, Switzerland), sonicator (Branson,
bulk drug samples and commercial products containing Ultra-Sonic Corporation, Danbury, CT, USA), analytical bal-
EB2HCl. The results suggested a need for a specific procedure ance (AG 135, Mettler Toledo, Greifensee, Switzerland), and
and limits for the unwanted isomer in compendial monographs autopipettes (Eppendorf, Hamburg, Germany).
on EB2HCl API and formulations containing the drug.
Initial DSC Studies
The first studies were carried out to determine if the charac-

teristic DSC endotherms for RS- and SS-EB2HCl at 42 8C and
77 8C appeared and resolved in all types of samples, whether
bulk drugs or the formulations. For this, the uncoated formu-
lations were powdered directly, but the coating of coated tab-
lets was removed manually, followed by powdering to a
uniform size suitable for DSC analysis. In some samples, in-
terference was linked to the presence of excipients, for which
solvent extraction was carried out. The extraction involved
dispersal of the powder in acetonitrile, filtration of the suspen-
sion, and collection of filtrate, followed by drying on a rotava-
por. The dried filtrate was further washed with acetone to
remove solvent-soluble impurities. After samples were re-
dried, thermograms were recorded between 25 and 250 8C
Figure 1. Chemical structure of SS-EB2HCl (a) and RS-EB2HCl (b)
at a rate of 10 8C/min.
Isolation and Characterization of RS-EB2HCl

MATERIALS AND PROCEDURES
During initial studies one of the single-drug tablet formula-
tions of EB2HCl showed a polymorphic endotherm at 42 8C
Materials without any transition at 77 8C. Studies showed that it con-
tained only RS-EB2HCl. The tablet was powdered and ex-
The APIs were procured directly from the manufacturers, tracted with water, followed by filtration and drying in order
and formulations were procured from local market. SS-
to obtain the pure drug sample. The isolated material was char-
EB2HCl was received as a gift sample from Themis Medicare,
acterized using DSC, polarimetry, FTIR, and TGA. The FTIR
Vapi, Gujarat, India. RS-EB2HCl was extracted from a mar- spectrum was taken using the conventional KBr pellet proce-
keted formulation that was determined during an initial study
dure. The specific rotation was determined taking a 10% solu-
to contain only this form. Calibration standards for DSC (in-
tion of the isolated substance in a 10-cm sample holder. DSC
dium and zinc) were procured from Mettler Toledo (Schwer- studies were performed in aluminium crucibles at a heating
zenbach, Switzerland). All solvents used for extraction were
of HPLC grade.
rate of 10 8C/min from 25 to 250 8C under nitrogen purging Determination of the Extent of RS-EB2HCl in Bulk Drug
(20 mL/min). TGA studies were conducted under conditions Samples and anti-TB Formulations
similar to those for DSC.
For these studies the samples were treated in a manner sim-
Study of Stability of Polymorphic Transitions ilar to that reported in ‘‘Initial DSC Studies,’’ and thermo-
grams were recorded again, focusing on enthalpy values.
A heating–cooling–heating cycle study was carried out to
determine the stability and reproducibility of the two enantio- Applicability of USP HPLC Procedure to Separate
tropic transitions at 42 8C and 77 8C. The isolated RS-EB2HCl RS-EB2HCl and SS-EB2HCl
and available pure SS-EB2HCl were independently subjected
to thermal cycles of 25–100–25–100 8C at a heating/cooling The HPLC procedure described in United States Pharmaco-
rate of 10 8C/min. poeia (USP) for the assay of EB2HCl in single-drug and four-
drug fixed-dose combination tablets was evaluated in terms of
Optimization of Sample Weight and Heating Rate its ability to separate RS-EB2HCl and SS-EB2HCl. The test
conditions, including column, were the same as prescribed
The two isomer samples were subjected to DSC studies. by USP (11). RS-EB2HCl alone was injected, followed by
The samples were weighed in the range of 2–7 mg and were RS-EB2HCl spiked with SS-EB2HCl. The chromatographic
heated between 25 to 250 8C at a rate of 10 8C/min. Subse- resolution between the two injections was compared, and the
quently, a 50:50 mixture of the two forms was subjected to peak purity was checked in both cases.
heating from 25 to 250 8C at the rates of 5, 10, and 20 8C/min.
RESULTS AND DISCUSSION
Quantitative Procedure Development and Validation
The selectivity and dependence on concentration of the en- Preliminary DSC Investigations
dothermic transitions at 42 8C and 77 8C were determined by
taking mixtures of SS-EB2HCl and RS-EB2HCl in various ra- The preliminary DSC studies on bulk drug samples and for-
tios from 0 to 100%. Precision was determined by carrying out mulations (Table 2) showed polymorphic endotherms at 42 8C
multiple studies on the same day (n=6), followed by studies on and 77 8C for RS-EB2HCl and SS-EB2HCl, respectively. This
two subsequent days to establish intra- and interday variabil- was in line with the values reported by Rubin-Preminger et al.
ity. This investigation was done also on marketed formulations (10). Some of the investigated samples had single poly-
to evaluate the applicability of the procedure in real situations. morphic transition, and others contained both of them. The ex-
traction step was able to remove interfering substances and
yielded well-resolved endotherms of interest at 42 8C and 77
8C. The nature of the thermograms obtained for the tested sam-
ples are shown in Figure 2.
Table 2. Bulk drugs and formulations selected for preliminary DSC studies
Bulk drug/formulation Code Manufacturing Date Expiry Date
Bulk drug BD-1 January 2003 December 2008
Bulk drug BD-2 September 2004 August 2009
Single drug tablets SD-1 October 2003 August 2007
Single drug tablets SD-2 April 2005 March 2008
Two-drug FDC* tablets FDC-2/1 April 2004 March 2008
Two-drug FDC tablets FDC-2/2 February 2005 January 2008
Three-drug FDC tablets FDC-3/1 March 2004 February 2006
Three-drug FDC tablets FDC-3/2 July 2004 June 2007
Four-drug FDC tablets FDC-4/1 January 2004 May 2006
Four-drug FDC tablets FDC-4/2 May 2005 April 2007
*
FDC = fixed-dose combination

Figure 2. DSC thermograms of selected bulk drug samples and formulations. Key: Sample codes are described in Table 2
Characterization of RS-EB2HCl
The DSC thermogram of isolated SS-EB2HCl showed a

single transition at 77 8C and a melting endotherm at 201 8C
(Figure 3a) in comparison to the characteristic polymorphic
transition at 42 8C and the melting endotherm at 202.9 8C
shown by pure RS-EB2HCl (Figure 3b). The small right shift
of melting endotherm of RS-EB2HCl with respect to SS-
EB2HCl was in line with the known behaviour for diastereoi- Figure 3. DSC thermogram of SS-EB2HCl (a), RS-EB2HCl (b), and
somers of EB2HCl (9–10). This is an unusual outcome and is a 50:50 (w/w) combination of the two isomers (c)
opposite to usual findings with chirally mixed diastereoi-
somers (12). The specific rotation values obtained for SS-EB2HCl and
RS-EB2HCl were 6.79 0.24 and 0.29 0.02, respectively.
The little specific rotation value for the isolated RS-EB2HCl
compared to that for SS-EB2HCl showed that the former was
virtually devoid of optical activity. The FTIR spectra of RS-
EB2HCl was superimposible on that of SS-EB2HCl (Figure
4), meaning that the isolated product was free from contami-
nants and excipients. The TGA profiles of both the isomers
showed no thermogravimetric steps between 0 and 200 8C
(Figure 5), thereby demonstrating the absence of hydrate or
solvate forms.
Figure 4. IR spectra of SS-EB2HCl (a) and RS-EB2HCl (b)
Figure 6. Enantiotropic behaviour of SS-EB2HCl (a) and RS-

EB2HCl (b) during heating–cooling–heating cycle in DSC
Sample Weight and Heating Rate Optimization
No difference in enthalpy was found when the DSC thermo-

grams were recorded by taking sample weights between 2 and
Figure 5. TGA thermograms of SS-EB2HCl (a) and RS-EB2HCl (b) 7 mg. Similarly, little difference was observed when the heat-
ing rate varied between 5 and 20 8C/min. In final studies, the
samples were weighed between 4 and 6 mg, and the heating
Stability of Polymorphic Transitions rate was fixed at 10 8C/min.
The profiles in Figure 6a and b show that the endotherms at DSC Behaviour of the Combinations of SS-EB2HCl and
77 8C and 42 8C were reversible after the heating–cooling– RS-EB2HCl
heating cycle. Both isomers displayed enantiotropic behaviour
that resulted in the transformation of one single polymorphic Figure 3c shows that the transition endotherms appearing at
form to another for each isomer. Also, there was no change in 42 8C and 77 8C for RS-EB2HCl and SS-EB2HCl, respective-
enthalpy values during the heating–cooling cycle. ly, did not change when the two isomers were mixed together
at a 50:50 ratio. This contrasted with the melting endotherm at
~200 8C, which showed a downward shift due to solid–solid
interaction (eutectic formation) between the two isomeric
forms (6–7). Figure 7 shows that the heights of the transition
endotherms at 42 8C and 77 8C varied proportionally to the
change in relative concentration of the two isomers between
0 and 100%. This finding suggests that the transition en-
dotherms could be employed for quantitative analysis of the
two isomers in the presence of each other. Accordingly, the
enthalpy values (which are independent of the weight of sam-
ple taken in the DSC crucible) were noted for the two en-
dotherms for each combination.
Method Validation
The data and regression parameters in Table 3 showed good

linearity between enthalpy and the relative percentage of RS-
EB2HCl and SS-EB2HCl in the range of 0 to 100%. The cor-
relation coefficients were >0.99. Also, good intra- and inter-
day precision was established (RSD <1.5%) even though the
investigation involved a complex formulation containing four

anti-TB drugs (Table 4).
Figure 7. Changes in DSC thermograms at 42 8C and 77 8C for

various relative concentrations of RS-EB2HCl and SS-EB2HCl
Table 3. Enthalpy data for RS-EB2HCl and SS-EB2HCl and regression parameters for the linearity curves
Enthalpy, J/g
Ratio of Endotherm at 42 8C for RS-EB2HCl Endotherm at 77 8C for SS-EB2HCl
RS-EB2HCl:SS-EB2HCl
0:100 0 25.85
2:98 0.52 25.09
10:90 2.21 22.40
20:80 4.67 19.88
30:70 7.16 17.49
40:60 9.10 15.44
50:50 11.53 11.35
60:40 13.78 9.24
70:30 16.58 6.90
80:20 18.48 3.96
90:10 21.51 2.22
100:0 23.10 0
Regression parameters for the y = 0.2338 x – 0.0366, y = 0.2605 x – 0.7506,
linearity curve r2 = 0.9992 r2 = 0.9968
Correction factor 1.114 1
Quantitation of Relative Percentages of RS and %RS-EB2HCl = [CF M/(CF M + D)] 100 [1]
SS-EB2HCl
As shown from the data in Table 3, the slopes for the line- %SS-EB2HCl = [D/(CF M + D)] 100 [2]
arity curves were different for RS-EB2HCl and SS-EB2HCl.
Accordingly, a correction factor (CF) was derived, given by where M and D are the phase transition enthalpies for RS-
Slope[SS-EB2HCl]/Slope[RS-EB2HCl]. The same was applied to the EB2HCl and SS-EB2HCl at 42 8C at 77 8C, respectively.
following equations for the calculation of the relative percen-
tages of RS and SS-EB2HCl in a mixture:
Table 4. Precision studies*
Validation
parameter Formulation %RS-EB2HCl SD, %RSD %SS-EB2HCl SD, %RSD
Intraday SD2 32.50 0.44, 1.36 67.39 0.44, 0.66
precision FDC-4/1 34.80 0.15, 0.43 65.20 0.15, 0.23
Interday SD2 33.14 0.25, 0.77 66.86 0.25, 0.38
precision FDC-4/1 35.20 0.53, 1.50 64.80 0.53, 0.82
*
Key: Codes for SD2 and FDC-4/1 are according to Table 2; SD = standard deviation; RSD = relative standard deviation
332 of the USPC or the USP Council of Experts Vol. 33(2) Mar.–Apr. 2007
Table 5 lists the relative percent values of RS-EB2HCl and Extent of the Presence of RS-EB2HCl in Bulk Samples and
SS-EB2HCl in two bulk drug samples and eight marketed for- Marketed Formulations
mulations.
As evident from Table 5, six of the ten bulk drugs and
Table 5. Respective content of isomers in tested bulk drugs products evaluated in this study contained from ~20% to
and formulations 100% of the less active RS-EB2HCl isomer, indicating a need
to limit this inactive related substance in compendial
Sample Code %SS-EB2HCl %RS-EB2HCl monographs.
BD-1 100.00 0.00

BD-2 80.84 19.16 Evaluation of the Procedure in USP 29
SD-1 0.00 100.00
SD-2 66.80 33.20 The chromatographic profiles obtained for RS-EB2HCl
FDC-2/1 52.05 47.95 alone and in combination with SS-EB2HCl, are shown in Fig-
FDC-2/2 100.00 0.00 ure 8. Evidently, a single peak appeared in both the cases at
FDC-3/1 0.00 100.00 almost the same retention time, and both were pure by photo-
FDC-3/2 100.00 0.00 diode array purity analysis. The current USP procedure for as-
FDC-4/1 64.80 35.20 say of EB2HCl was unable to distinguish between RS-
FDC-4/2 100.00 0.00 EB2HCl and SS-EB2HCl isomeric forms. This inability to dif-
ferentiate between the two isomers, with resulting conse-
quences for the efficacy of drug products to treat life-
threatening disease, justifies the need for inclusion of an alter-
native procedure in USP monographs on EB2HCl drug sub-
stance and products.
Figure 8. HPLC chromatograms of RS-EB2HCl (a) and combination of SS-EB2HCl and RS-EB2HCl (b)
Status in Other Pharmacopoeias keeping in view that tuberculosis is a global emergency and
good-quality drugs are necessary to control the dreaded dis-
As indicated in Table 1, the procedures in the Indian Phar- ease.
macopoeia (IP) and the Japanese Pharmacopoeia (JP) are al-
most similar to that in USP. Therefore, these pharmacopoeias REFERENCES
would also be unable to differentiate between the diastereo-
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the British Pharmacopoeia (BP) features the additional disad-
Chem Soc. 1961;83:2212–2213.

vantage that it cannot be applied to coloured formulations that
2. USP. USP 29–NF 24. Rockville, MD: United States Pharmaco-
contain rifampicin along with EB2HCl. This drawback should
peial Convention, Inc; 2006:859.
be considered along with the procedure’s low sensitivity.
3. IP 1996. New Delhi, India: Ministry of Health and Family Wel-
Therefore, the proposed DSC method is recommended for
fare; 1996:297.
adoption by all compendia for the detection and control of
4. JP 14. Tokyo, Japan, Ministry of Health, Labour, and Welfare;
RS-EB2HCl.
2001:460.
5. BP 2005. London, UK, British Pharmacopoeial Commission;
CONCLUSION
2005:764.
6. Ferrari H, Graber DG. Thermal properties of ethambutol
A procedure was developed for monitoring the relative
(myambutol): the detection of the (R,S) isomer in the presence
presence of the isomers of EB2HCl (RS-EB2HCl and SS-
of ethambutol by differential thermal analysis. Microchem J.
EB2HCl) in commercial bulk drug samples and formulations
1971;16:5–13.
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7. Varshney L, Sharma G, Gopal NGS. Determination of the meso
morphic transitions in DSC thermograms at 42 8C and 77
isomer in dextro ethambutol hydrochloride by differential scan-
8C for RS-EB2HCl and SS-EB2HCl, respectively. The proce-
ning calorimetry. Ind Drugs. 1988;26:117–119.
dure was validated and proven to be precise and simple and
8. Blessington B, Beiraghi A. A method for the quantitative enan-
required no sample preparation in most cases. It was also ap-
tioselective HPLC analysis of ethambutol and its stereoisomer.
plied successfully to complex two-, three-, and four-drug
Chirality. 1992;3:139–144.
fixed-dosage combinations containing EB2HCl along with ri-
9. Rubin-Preminger JM, Bernstein J, Haris RK, Evans IR, Ghi PY.
fampicin, isoniazid, and/or pyrazinamide. The applicability of
(R,S)-ethambutol dihydrochloride: variable-temperature studies
the procedure to coloured anti-TB formulations containing ri-
of a dimorphic system with very similar packing. J Pharm Sci.
fampicin is of particular benefit because optical rotation pro-
2004;93:2810–2819.
cedures, which are usually employed for monitoring isomers,
10. Rubin-Preminger JM, Bernstein J, Haris RK, Evans IR, Ghi PY.
fail when the test samples are coloured.
Variable temperature studies of a polymorphic system compris-
The study strongly suggests the need to control the un-
ing two pairs of enantiotropically related forms: (S,S)-ethambu-
wanted isomeric related substance in compendial monographs
tol dihydrochloride. Cryst Growth Des. 2004;4:431–439.
of EB2HCl, as well as in single-drug and fixed-dosage combi-
11. USP. USP 29–NF 24. Rockville, MD: United States Pharmaco-
nation formulations containing the drug. Because USP is the
peial Convention, Inc.; 2006:860,1922,1923.
first compendium to include monographs for anti-TB FDCs, it
12. Jacques J, Collet A, Wilen SH. Enantiomers, racemates, and res-
may take the lead to add a suitable test to monitor and control
olutions. New York: John Wiley & Sons; 1981:94,253–
the presence of RS-EB2HCl in monographs of EB2HCl and
259,238–339.
products. The same should be done even by other compendia,
NOMENCLATURE
Nomenclature
Nomenclature
INDEX
Index
Pharmacopeial Forum
338 INDEX Vol. 33(2) [Mar.–Apr. 2007]
[Note—This index covers Vol. 33 No. 1, pp. 1–150; Vol. 33 No. EXCIPIENTS
2 pp. 151–339] Excipients, USP and NF Excipients, Listed by Category (NF) .. 257
MONOGRAPHS GENERAL CHAPTERS

Acetaminophen Extended-Release Tablets (USP) . . . . . . . .. 183 Acetic Acid in Peptides h503i (USP) . . . . . . . . . . . . . . . . 268
Alprazolam Tablets (USP) . . . . . . . . . . . . . . . . . . . . .. 41 Injections h1i (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Baclofen (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 211 Intrinsic Dissolution h1087i (USP) . . . . . . . . . . . . . . . . . 269
Bismuth Subsalicylate Oral Suspension (USP) . . . . . . . . . .. 41 Microbiological Examination of Nonsterile Products: Acceptance
Bisoprolol Fumarate Tablets (USP) . . . . . . . . . . . . . . . .. 183 Criteria for Pharmaceutical Preparations and Substances for
Bupropion Hydrochloride (USP) . . . . . . . . . . . . . . . . . .. 211 Pharmaceutical Use h1111i (USP) . . . . . . . . . . . . . . . . . 207
Bupropion Hydrochloride Tablets (USP) . . . . . . . . . . . . .. 211 Microbiological Examination of Nonsterile Products: Microbial
Bupropion Hydrochloride Extended-Release Tablets (USP) . . . 42, 184 Enumeration Tests h61i (USP) . . . . . . . . . . . . . . . . . . . 189
Calcitriol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 44 Microbiological Examination of Nonsterile Products: Tests for
Calcium Carbonate and Magnesia Tablets (USP) . . . . . . . .. 211 Specified Microorganisms h62i (USP) . . . . . . . . . . . . . . 193
Calcium Carbonate and Magnesia Chewable Tablets (USP) . .. 212 Particulate Matter in Injections h788i (USP) . . . . . . . . . . . . 198
Carbachol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 213 USP Reference Standards h11i (USP) . . . . . . . . . . . . . . . . 95, 267
Carbachol Intraocular Solution (USP) . . . . . . . . . . . . . . .. 213 Validation of Compendial Methods h1225i (USP) . . . . . . . . . 96
Carbachol Ophthalmic Solution (USP) . . . . . . . . . . . . . .. 214
Citalopram Hydrobromide (USP) . . . . . . . . . . . . . . . . .. 214 REAGENTS, INDICATORS, AND SOLUTIONS
Citalopram Tablets (USP) . . . . . . . . . . . . . . . . . . . . . .. 46 Reagent Specifications
Cladribine (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49 2-Aminoheptane (USP) . . . . . . . . . . . . . . . . . . .. . . 100
Clopidogrel Tablets (USP) . . . . . . . . . . . . . . . . . . . . .. 50 Calconcarboxylic Acid (USP) . . . . . . . . . . . . . . . .. . . 100
Cytarabine for Injection (USP) . . . . . . . . . . . . . . . . . . .. 51 Calconcarboxylic Acid Triturate (USP) . . . . . . . . . .. . . 100
Diclofenac Sodium Extended-Release Tablets (USP) . . . . . .. 218 a-Cyclodextrin (USP) . . . . . . . . . . . . . . . . . . . .. . . 276
Diltiazem Hydrochloride Extended-Release Capsules (USP) . .. 184 Dimethicone, Viscosity 500 Centistokes (USP) . . . . . .. . . 100
Dimethyl Sulfoxide Gel (USP) . . . . . . . . . . . . . . . . . . .. 52 Lactose (USP) . . . . . . . . . . . . . . . . . . . . . . . .. . . 100
Enalapril Maleate and Hydrochlorothiazide Tablets (USP) . . .. 220 Propylamine Hydrochloride (USP) . . . . . . . . . . . . .. . . 101
Enoxaparin Sodium (USP) . . . . . . . . . . . . . . . . . . . . .. 52 Sodium Phosphate, Monobasic, Anhydrous (USP) . . . .. . . 276
Enoxaparin Sodium Injection (USP) . . . . . . . . . . . . . . . .. 58 Sodium Phosphate, Monobasic, Dihydrate (USP) . . . .. . . 276
Eprinomectin (USP) . . . . . . . . . . . . . . . . . . . . . . . . .. 60 Sodium Phosphate, Dibasic, Dihydrate (USP) . . . . . .. . . 101
Estradiol and Norethindrone Acetate Tablets (USP) . . . . . . .. 220 Tetrapropylammonium Chloride (USP) . . . . . . . . . .. . . 276
Estradiol Transdermal System (USP) . . . . . . . . . . . . . . .. 225 Triethylamine (USP) . . . . . . . . . . . . . . . . . . . . .. . . 101
Estradiol Benzoate (USP) . . . . . . . . . . . . . . . . . . . . . .. 229 Chromatographic Reagents (USP) . . . . . . . . . . . . . . .. . . 104, 276
Conjugated Estrogens Tablets (USP) . . . . . . . . . . . . . . .. 35 Volumetric Solutions
Fludarabine Phosphate Injection (USP) . . . . . . . . . . . . . .. 232 Ceric Sulfate, Tenth-Normal (0.1 N) (USP) . . . . . . . .... 101
Flumazenil Injection (USP) . . . . . . . . . . . . . . . . . . . . .. 234 Potassium Permanganate, Tenth-Normal (0.1 N) (USP) .... 102
Fluvastatin Sodium (USP) . . . . . . . . . . . . . . . . . . . . .. 64
Fosinopril Sodium and Hydrochlorothiazide Tablets (USP) . .. 66 REFERENCE TABLES
Galantamine Hydrobomide (USP) . . . . . . . . . . . . . . . . .. 234 Container Specifications (USP) ................... 283
Ginkgo (USP erratum) . . . . . . . . . . . . . . . . . . . . . . .. 37 Description and Solubility (USP) . . . . . . . . . . . . . . . . . . 110, 285
Heparin Sodium (USP) . . . . . . . . . . . . . . . . . . . . . . .. 238
Hydrocortisone Tablets (USP) . . . . . . . . . . . . . . . . . . .. 72 GENERAL SUBJECTS
Ipratropium Bromide (USP) . . . . . . . . . . . . . . . . . . . .. 241 Canceled Proposals . . . . . . . . . . . . . . . . . . . . . . . . . . 137, 313
Index
Isosorbide Dinitrate Extended-Release Tablets (USP) . . . . . .. 73 Catalog to Be Removed from Pharmacopeial Forum Print
Letrozole Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . .. 244 Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Levalbuterol Hydrochloride (USP) . . . . . . . . . . . . . . . .. 75 Dietary Supplements—Monographs . . . . . . . . . . . . . . . . . 93, 255
Levalbuterol Inhalation Solution (USP) . . . . . . . . . . . . . .. 79 Errata List for USP30–NF25
Lutein (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 255 Ginkgo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Lutein Preparation (USP) . . . . . . . . . . . . . . . . . . . . . .. 255 Magnesium Chloride . . . . . . . . . . . . . . . . . . . . . . . . 37
Magnesium Chloride (USP erratum) . . . . . . . . . . . . . . .. 37 Methdilazine Hydrochloride Oral Solution . . . . . . . . . . . 37
Meclizine Hydrochloride (USP) . . . . . . . . . . . . . . . . . .. 244 Pygeum Extract . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Meclizine Hydrochloride Tablets (USP) . . . . . . . . . . . . .. 245 Ramipril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Metformin Hydrochloride Tablets (USP) . . . . . . . . . . . . .. 187 Expert Committee Designations . . . . . . . . . . . . . . . . . . . 12, 162
Methdilazine Hydrochloride Oral Solution (USP erratum) . . .. 37 Extractable Volume, USP–NF General Chapter h1i, Injections:
Methylphenidate Hydrochloride Tablets (USP) . . . . . . . . .. 246 Notice of Harmonized Text . . . . . . . . . . . . . . . . . . . . 168
Norethindrone Acetate and Ethinyl Estradiol Tablets (USP) . .. 81 First Interim Revision . . . . . . . . . . . . . . . . . . . . . . . . . 31
Octinoxate (USP) . . . . . . . . . . . . . . . . . . . . . . . . . .. 246 Harmonization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139, 315
Oxandrolone (USP) . . . . . . . . . . . . . . . . . . . . . . . . .. 247 Harmonized Microbiology General Chapters: Notice of
Paclitaxel (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 250 Postponement . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Pamidronate Disodium for Injection (USP) . . . . . . . . . . . .. 81 How to Submit Comments . . . . . . . . . . . . . . . . . . . . . . 20, 170
Paricalcitol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . .. 252 How to Use PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9, 159
Phenylbutazone Boluses (USP) . . . . . . . . . . . . . . . . . .. 82 Implemenation Period for Upcoming Official Revisions to the USP–
Phenylbutazone Tablets (USP) . . . . . . . . . . . . . . . . . . .. 82 NF Extended . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Progesterone Vaginal Suppositories (USP) . . . . . . . . . . . .. 82 In Memoriam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Propylene Glycol (USP) . . . . . . . . . . . . . . . . . . . . . .. 317 Interim Revision Announcements . . . . . . . . . . . . . . . . . . 179
Propylene Glycol Monocaprylate (NF) . . . . . . . . . . . . . .. 261 First Interim Revision . . . . . . . . . . . . . . . . . . . . . . . 31
Pygeum Extract (USP erratum) . . . . . . . . . . . . . . . . . .. 37 International Correspondence . . . . . . . . . . . . . . . . . . . . . 20, 170
Ramipril (USP erratum) . . . . . . . . . . . . . . . . . . . . . . .. 37 Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147, 335
Salicylic Acid (USP) . . . . . . . . . . . . . . . . . . . . . . . .. 83 Pending Proposals . . . . . . . . . . . . . . . . . . . . . . . . . . . 111, 286
Sucralfate (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . .. 254 Pharmacopeial Education Courses . . . . . . . . . . . . . . . . . . 19, 169
Sulfadimethoxine Sodium (USP) . . . . . . . . . . . . . . . . .. 254 Pharmacopeial Forum Public Review and Comment Period
Trehalose (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 263 Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21, 170
Ubidecarenone Capsules (USP) . . . . . . . . . . . . . . . . . .. 93 Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . . . 18
Ubidecarenone Tablets (USP) . . . . . . . . . . . . . . . . . . .. 94
Valganciclovir Hydrochloride (USP) . . . . . . . . . . . . . . .. 84
Valganciclovir Tablets (USP) . . . . . . . . . . . . . . . . . . . .. 89
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] INDEX 339
Policies and Announcements Vice President of Pharmacopeial Education Named . . . . . . 18

Catalog to Be Removed from Pharmacopeial Forum Print Visit the USP Website at hhttp://www.usp.orgi . . . . . . . . . 20, 170
Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Pharmacopeial Previews . . . . . . . . . . . . . . . . . . . . . . . 141, 321
Extractable Volume, USP–NF General Chapter h1i, Injections: Priority New Monograph Items . . . . . . . . . . . . . . . . . . . 22, 171
Notice of Harmonized Text . . . . . . . . . . . . . . . . . . 168 Revision Bulletins .......................... 168
Food Chemicals Codex Public Notice and Comment . . . . . 171 Section Descriptions . . . . . . . . . . . . . . . . . . . . . . . . . . 10, 160
Harmonized Microbiology General Chapters: Notice of Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14, 164
Postponement . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Standards Development . . . . . . . . . . . . . . . . . . . . . . . . 5, 155
How to Submit Comments . . . . . . . . . . . . . . . . . . . . 20, 170 Stimuli to the Revision Process
Implemenation Period for Upcoming Official Revisions to the A New Validated Differential Calorimetric Procedure for
USP–NF Extended . . . . . . . . . . . . . . . . . . . . . . . 19 Monitoring the Less Active R,S Isomer of Ethambutol
In Memoriam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Dihydrochloride in Bulk Drug Samples and Anti-tuberculosis
International Correspondence . . . . . . . . . . . . . . . . . . . 20, 170 Formulations, Bhagwat Prasad, Hemant Bhutani, Vijay
Pharmacopeial Education Courses . . . . . . . . . . . . . . . . 19, 169 Kumar, and Saranjit Singh . . . . . . . . . . . . . . . . . . . 326
Pharmacopeial Forum Public Review and Comment Period Instructions to Authors . . . . . . . . . . . . . . . . . . . . . . . 145, 325
Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21, 170 Stimuli Articles Posted on USP’s Website . . . . . . . . . . . . . 169
Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . 18 Stimuli Articles to be Posted on USP’s Website . . . . . . . . . . 19
Priority New Monograph Items . . . . . . . . . . . . . . . . . . 22, 171 USP Annual Scientific Meeting 2007 . . . . . . . . . . . . . . . . 168
Revision Bulletins . . . . . . . . . . . . . . . . . . . . . . . . . 168 USP Catalog Available . . . . . . . . . . . . . . . . . . . . . . . . 169
Stimuli Articles Posted on USP’s Website . . . . . . . . . . . 169 2007 USP Dictionary . . . . . . . . . . . . . . . . . . . . . . . . . 170
Stimuli Articles to be Posted on USP’s Website . . . . . . . . 19 USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . . . 19
USP Annual Scientific Meeting 2007 . . . . . . . . . . . . . . 168 USP to Establish Office and Laboratory Facility in China . . . . 168
USP Catalog Available . . . . . . . . . . . . . . . . . . . . . . 169 USP Forms Stakeholder Forum to Address the food chemicals
2007 USP Dictionary . . . . . . . . . . . . . . . . . . . . . . . 170 Codex; First Meeting Set for February 2007 . . . . . . . . . . . 18
USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . 19 USP Seeks Chair Candidate for Four Expert Comittees; Expert
USP to Establish Office and Laboratory Facility in China . . 168 Committee Members also Sought . . . . . . . . . . . . . . . . . 18
USP Forms Stakeholder Forum to Address the food chemicals USP to Verify the Quality of Pharmaceutical Ingredients
Codex; First Meeting Set for February 2007 . . . . . . . . . 18 Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
USP Seeks Chair Candidate for Four Expert Comittees; Expert Vice President of Pharmacopeial Education Named . . . . . . . . 18
Committee Members also Sought . . . . . . . . . . . . . . . 18 Visit the USP Website at hhttp://www.usp.orgi . . . . . . . . . . . 20, 170
USP to Verify the Quality of Pharmaceutical Ingredients
Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Index
CHROMATOGRAPHIC REAGENTS
USED IN USP–NF AND
PHARMACOPEIAL FORUM
This is an update based on the proposals published in this issue of PF.
Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] CHROMATOGRAPHIC REAGENTS 1
Chromatographic Reagents Used in USP–NF and

Pharmacopeial Forum
Mar.–Apr. 2007
ABACAVIR SULFATE SOLUTION (DSD Mgh #77)

PF LGS# Reagent Brand Type of Test Comments
33(2) L1 Inertsil ODS-3 Related compounds 4.6 mm 6 25 cm, 5 mm, manufacturer GL Sciences.
33(2) L1 Inertsil ODS-3 Assay 4.6 mm 6 15 cm, 5 mm, manufacturer GL Sciences.
ACITRETIN (DSD Mgh #850)

33(2) L1 LiChrospher PAH Assay and Related com- 4.0 mm 6 25 cm, 5 mm, manufacturer Merck KGaA.
pounds
ACITRETIN CAPSULES (DSD Mgh #854)

33(2) L1 YMC-Pack ODS-A Assay and Limit of . . . . Limit of degradation products. 4.6 mm 6 15 cm, 5 mm,
manufacturer YMC Inc.
CEFDINIR (DSD Mgh #13982)

33(2) L1 YMC-Pack ODS- Assay, Identification, and 4.6 mm 6 15 cm, 5 mm, manufacturer YMC Inc.
AM Related compounds
CILOSTAZOL TABLETS (DSD Mgh #17665)

33(3) L1 TSKgel ODS-80Tm Assay 4.6 mm 6 15 cm, 5 mm, manufacturer Tosoh Corp.
CLIMBAZOLE (DSD Mgh #1371)

32(5) G16 DB Wax Limit of . . . . . . . . . Limit of chlorethylacetate, 2-ethylhexanol and octane.
0.25 mm 6 30 m, 0.25 mm, manufacturer J&W Scientific.
33(3) G3 DB-17 Limit of . . . . . . . . . Limit of chlorethylacetate, 2-ethylhexanol, and octane.
0.25 mm 6 30 m, 0.25 mm, manufacturer J&W Scientific.
CLOZAPINE (DSD Mgh #19045)

DORZOLAMIDE HYDROCHLORIDE (DSD Mgh #28035)

26(1) L3 Zorbax SIL Limit of . . . . . . . . . Limit of dorzolamide hydrochloride related compound A.
4.6 mm 6 25 cm, 5 mm, manufacturer Agilent Technolo-
gies.
26(1) L1 Inertsil ODS-2 Assay and Chrom. purity 4.6 mm 6 25 cm, 5 mm, manufacturer GL Sciences.
FOSCARNET SODIUM (DSD Mgh #34308)

0(0) L23 IC-Pak Anion Limit of . . . . . . . . . Limit of phosphate and phosphite. 4.6 mm 6 5 cm, manu-
facturer Waters Associates.
GALANTAMINE TABLETS (DSD Mgh #34619)

33(3) L1 YMC-Pack Pro C18 Assay, Identification, and 4.6 mm 6 10 cm, 3 mm, manufacturer YMC Inc.
Related compounds
Pharmacopeial Forum
2 CHROMATOGRAPHIC REAGENTS Vol. 33(2) [Mar.–Apr. 2007]
GLIMEPIRIDE TABLETS (DSD Mgh #35024)

33(2) L1 LiChrosphere 100 Related compounds 4 mm 6 25 cm, 3 mm, manufacturer EM Sciences.
RP-18
33(2) L1 LiChrosphere 100 Assay and Dissolution 4 mm 6 12.5 cm, 5 mm, manufacturer EM Sciences.
RP-18
HYDROGENATED POLYDECENE (DSD Mgh #66230)

33(2) G1 Petrocol B Limit of . . . . . . . . . Limit of short-chain hydrocarbons and Content of decene
oligomer. 0.52 mm 6 16 m, 0.1 mm, on silanized S1A,
manufacturer Supelco.
HYDROGENATED STARCH HYDROLYSATE (DSD Mgh #581)

33(3) L58 PL Hi-Plex Na Assay 7.7 mm 6 30 cm, 10 mm, manufacturer Polymer Labs.
INOSITOL (DSD Mgh #2307)

33(3) L19 CarboSep CHO-820 Assay, Identification, and 7.8 mm 6 30 cm, 9 mm, manufacturer Transgenomic, Inc.
Related compounds
LAMOTRIGINE (DSD Mgh #44250)

0(0) L1 Hypersil BDS C-18 Assay, Related com- Limit of related compound B. 4.6 mm 6 15 cm, 5 mm,
pounds, and Limit of... manufacturer Thermo Electron.
MIDAZOLAM (DSD Mgh #54040)

0(0) L60 Supelcosil LC-ABZ Assay and Chrom. purity 4.6 mm 6 25 cm, 5 mm, manufacturer Supelco.
OXANDROLONE (DSD Mgh #59110)

33(2) L1 Eclipse XDB C18 Assay and Related com- 4.6 mm 6 25 cm, 5 mm, manufacturer Agilent.
pounds
RALOXIFENE HYDROCHLORIDE (DSD Mgh #73024)

0(0) L7 Inertsil C8 Related compounds 4.6 mm 6 25 cm, 5 mm, manufacturer GL Sciences.
0(0) L7 Zorbax SB C8 Assay 4.6 mm 6 15 cm, 3.5 mm. Alternative column Zorbax RX
C8, same dimensions, manufacturer Agilent.
RALOXIFENE HYDROCHLORIDE TABLETS (DSD Mgh #73026)

33(3) L7 Inertsil C8 Related compounds 4.6 mm 6 25 cm, 5 mm, manufacturer GL Sciences.
33(3) L7 Zorbax RX-C8 Assay 4.6 mm 6 15 cm, 3.5 mm, manufacturer Agilent.
SUMATRIPTAN SUCCINATE (DSD Mgh #80104)

32(2) L3 Spherisorb Silica Limit of . . . . . . . . . Limit of sumatriptan related compound A. 4.6 mm 6 25 cm,
5 mm, manufacturer Waters Corp.

33(2) L1 Spherisorb ODS1 Assay and Related com- 4.6 mm 6 25 cm, 5 mm, manufacturer Waters Corp.
pounds
TERBINAFINE HYDROCHLORIDE (DSD Mgh #80845)

Pharmacopeial Forum
Vol. 33(2) [Mar.–Apr. 2007] CHROMATOGRAPHIC REAGENTS 3
TREHALOSE (DSD Mgh #84495)

33(2) L## Sugar KS-801 Assay 8 mm 6 30 cm, manufacturer Shodex.
Table of Contents*
PHARMACOPEIAL FORUM VOL. 33 NO. 3 MAY–JUNE 2007

HOW TO USE PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Immediate IRA Commentary USP Issues Immediate Interim Revision Announcement for General Chapter h467i
Residual Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Immediate Interim Revision Announcements for Ubidecarenone Capsules and Ubidecarenone Tablets . . . . . . . . . . . 358
Eric B. Sheinin, Ph.D. Retires from USP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
2007 USP Dictionary Now Available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Visit the USP Web Site at http://www.usp.org . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Isosorbide Dinitrate Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Pamidronate Disodium for Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
DIETARY SUPPLEMENTS—MONOGRAPHS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Ubidecarenone Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Ubidecarenone Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
GENERAL CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
h467i Organic Volatile Impurities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
h467i Residual Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
ERRATA LIST FOR USP 30–NF 25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Acarbose [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Acitretin [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Acitretin Capsules [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
Benzonatate Capsules (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Cilostazol Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Colchicine (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Dihydrocodeine Bitartate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Esomeprazole Magenesium [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Fluconazole (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Formoterol Fumarate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
Fosinopril Sodium Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Galantamine Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Glimepiride Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Isosorbide Mononitrate Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Levalbuterol Hydrochloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Levalbuterol Inhalation Solution [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
Levothyroxine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Liothyronine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
Lorazepam (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Pharmacopeial Forum
342 Contents* Vol. 33(3) [May–June 2007]
Lorazepam Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429

Mirtazapine (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Norethindrone Acetate and Ethinyl Estradiol Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Norethindrone Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Ofloxacin Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Omeprazole Magnesium [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Ondansetron Orally Disintegrating Tablets (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Oxandrolone Tablets (Proposal for 4th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Protein A [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
rProtein A, C-Cys [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
rProtein A [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
rProtein A, B4, C-Cys [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
Reserpine Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Sodium Fluoride and Acidulated Phosphate Topical Solution (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . 454
Sodium Fluoride and Phosphoric Acid Gel (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Sulfamethoxazole (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Sulisobenzone (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Sumatriptan Succinate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Terbinafine Hydrochloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Topiramate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Valsartan (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Warfarin Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Warfarin Sodium for Injection (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Warfarin Sodium Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Fish Oil Containing Omega-3 Acids [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Fish Oil Containing Omega-3 Acids Capsules [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Ginger (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Powdered Ginger (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Excipients, USP and NF Excipients, Listed by Category (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
Calcium Silicate (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
Hydrogenated Polydecene [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Hydrogenated Starch Hydrolysate [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Sodium Caprylate (1st to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
h1i Injections (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
h11i USP Reference Standards (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
h525i Sulfur Dioxide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Reagent Specifications Introduction (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Docusate Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
Tetrabutylammonium Iodide (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
Container Specifications for Capsules and Tablets (1st Supp to USP31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Description and Solubility (1st Supp to USP 31 and to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Carmellose [new] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
h85i Bacterial Endotoxins Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
h601i Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . 550
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] Contents* 343
STIMULI TO THE REVISION PROCESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

Instructions to Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing, Walter W. Hauck, Ronald
G. Manning, Todd L. Cecil, William Brown, and Roger L. Williams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Summary of Planned Revisions to Design and Analysis of Biological Assays h111i, Walter W. Hauck, Robert Singer,
and Larry N. Callahan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
NOMENCLATURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Pharmacopeial Forum
344 Contents* Vol. 33(3) [May–June 2007]
Nancy Blum, M.P.H.
Director, Information Programs and pharmacy. It publishes the U.S. Pharmacopeia and National
Deborah G. Perfetto, Pharm.D. Formulary, the legally recognized compendia of standards for drugs
Director, Publications and products of other health care technologies. The USP and NF in-
Linda M. Guard clude assays and tests for the determination of strength, quality, and
Director, Scientific Reports purity and requirements for packaging and labeling.
Kate Meringolo
Shona Bramble
Electronic and Desktop Publishing
Derrick Boone; Irena Smith Moving?
Senior Editors Our subscribers’ records and publication labels are computer-
Jesusa D. Cordova; Anthony Owens; Lorraine M. Scheinman; generated. Please send your new address, and your latest label, or
Melissa M. Smith an exact copy of it, to: USPC, PF Customer Service Dept., 12601
Editors Twinbrook Parkway, Rockville, MD 20852.
Elizabeth Gould-Leger; Patricia von Brook Fax: (301) 816-8148.
Rebecca Cambronero
Alejandra Franks
Vivian Lazo
Pharmacopeial Forum
346 STANDARDS DEVELOPMENT Vol. 33(3) [May–June 2007]
Previews)
USP welcomes comments and data on potential, proposed, or official standards.* Comments, along with USP’s responses, will be
*
If you are not immediately able to submit comments but you intend to do so,
please notify USP by using the Intent to Comment form provided before the
section Chromatographic Reagents Used in USP–NF and PF.
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] STANDARDS DEVELOPMENT 347
HOW TO USE PF
How to Use PF
Pharmacopeial Forum
350 HOW TO USE PF Vol. 33(3) [May–June 2007]
the beginning of that section. A general description of the types and amount of information expected in a Request for
Revision is available in the Guideline for Submitting Requests for Revision to the USP–NF on the USP website
(www.usp.org/USPNF/submitMonograph/subGuide.html).

How to Use PF
issues such as:
study; and
~
adopted.
pending.
the USP–NF.
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] HOW TO USE PF 351
Other Sections
Staff Directory

How to Use PF

Nomenclature
Index

Pharmacopeial Forum

2005–2010
AER Aerosols
How to Use PF

FO Food Additives
GC General Chapters
NOM Nomenclature
STAT Statistics
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2005–2010
*
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Pharmacopeial Forum
STAFF DIRECTORY
number is (301) 816-8373.

How to Use PF

(MD-CCA)
Affairs
Forms (PDF)
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Pharmacopeial Forum
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Statistics (STAT)
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POLICIES AND
ANNOUNCEMENTS
processes and announcements about issues being considered by USP. This section also includes publication and comment
schedules.

Pharmacopeial Forum
358 POLICIES AND ANNOUNCEMENTS Vol. 33(3) [May–June 2007]
IMMEDIATE IRA COMMENTARY Prior to coming to USP, Dr. Sheinin spent 30 years with the
USP ISSUES IMMEDIATE INTERIM REVISION Food and Drug Administration (FDA), most recently serving
ANNOUNCEMENT FOR GENERAL CHAPTER h467i as deputy director, Office of Pharmaceutical Science in FDA’s
RESIDUAL SOLVENTS. The General Chapter h467i Center for Drug Evaluation and Research. While at FDA, Dr.
method for Water-Insoluble Articles under Identification, Sheinin worked extensively as a USP volunteer in the Com-
Control, and Quantification of Residual Solvents is being mittee of Revision (now Council of Experts).
revised to replace the existing procedure for these products
Throughout his scientific, regulatory, and compendial careers,
with a new procedure. Changes proposed in PF 32(5)
Dr. Sheinin has lectured and taught widely. He is a member of
related to the analytical procedures are also included in this
the American Chemical Society, a charter member of the
Immediate Interim Revision, while the remaining changes
American Association of Pharmaceutical Scientists, and a Fel-
will be considered for the Second Supplement to USP 30–
low, AOAC-I. Dr. Sheinin is looking forward to a well-
NF 25. In addition, the chapter now indicates that users may
deserved retirement with his wife, five children, and three
skip Procedures A and B and test articles according to
grandchildren. He will continue as a consultant and lec-
Procedure C, based on information available from the
turer—perhaps at times for USP. We wish Dr. Sheinin a long
manufacturing process. Additional information regarding
and successful retirement, after many years of distinguished
General Chapter h467i can be found on USP’s website
work in public health.
under Notices–Explanatory note regarding USP–NF General
C h a p t e r h4 6 7 i O r g a n i c Vo l a t i l e I m p u r i t i e s a t
2 0 0 7 U S P D I C T I O N A R Y N O W AVA I L A B L E .
http://www.usp.org/USPNF/notices/generalChapter467.html.
The new USP Dictionary of USAN and International Drug

Please direct any comments or questions to Horacio Pappa, Names was published on April 1, 2007. It is available in
Ph.D., Senior Scientist (301-816-8319 or hp@usp.org). both print and online formats-$299 each.
The 2007 edition features more than 9,000 updates,
IMMEDIATE INTERIM REVISION including over 3,700 new and revised graphic formulas and
ANNOUNCEMENTS FOR UBIDECARENONE over 1,000 additional pronunciations! Order now at
CAPSULES AND UBIDECARENONE TABLETS. In the www.usp.org/products/dictionary/.
current dietary supplement market, it is possible to find
Ubidecarenone Capsules and Tablets containing a water- USP ANNUAL SCIENTIFIC MEETING 2007. Hold the
soluble form of the dietary ingredient. These dosage forms date! The USP Annual Scientific Meeting will be held in
usually claim improved bioavailability over the traditional Tampa, Florida, at the Hyatt Regency Tampa on September
dosage forms containing fat-soluble ubidecarenone. A 25–28, 2007. Information is available on USP’s website at
Dissolution test that differentiates between these two distinct www.usp.org.
products and is linked to a Labeling requirement to indicate
Contact Ms. Kelly Coates (ktc@usp.org or 301-816-8510) for
th at the pro duct c ontains a wa te r-solu ble form of
further information.
ubidecarenone is being added to these monographs.
Please direct any comments or questions to Ping Jin, Ph.D., USP CATALOG AVAILABLE. While no longer included in
Senior Scientific Associate (301-998-6827 or pj@usp.org). the back of this publication, the USP Catalog is still available
in online and stand-alone print versions. The online bi-
ERIC B. SHEININ, PH.D. RETIRES FROM USP. Eric B. monthly and daily catalogs can be accessed at www.usp.org/
Sheinin, Ph.D., departed USP on February 28, 2007. Dr. referenceStandards/catalog.html. You can also sign up to
Sheinin joined USP as Vice President, Division of Standards receive the USP Catalog in print (via postal mail) along with
Development, moved on to fill the Chief Science Officer monthly email alerts—which will keep you informed about
position in an acting capacity, and concluded his career as new Reference Standards, availability, and current lots—by
Vice President of USP’s Pharmaceutical Ingredient sending an email to marketing@usp.org or calling 301-816-
Verification Program. In his initial positions, he worked 8237.
closely with the USP Council of Experts to create and
advance content of the United States Pharmacopeia and the STIMULI ARTICLES POSTED ON USP’S WEBSITE.
National Formulary. In his final year, he implemented the The Stimuli articles that are published in Pharmacopeial
USP’s Board of Trustees’ decision to create a verification Forum will be simultaneously published on USP’s website.
program for pharmaceutical ingredients (drug substances and L o o k f o r t h e m a t h t t p : / / w w w. u s p . o r g / U S P N F / p f /
excipients). whatsInside.html. For more information about Stimuli
articles, please contact Stefan Schuber, Ph.D., Director,
Scientific Reports (301-816-8551 or sps@usp.org).
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] POLICIES AND ANNOUNCEMENTS 359
PHARMACOPEIAL EDUCATION COURSES. The USP www.usp.org/goto/pe. To discuss how USP can bring
Pharmacopeial Education (PE) courses offer specialized courses to a location of your choice or design a custom
instruction for chemists, other scientists, and professionals in course package for you, call 301-816-8589, or e-mail
the pharmaceutical and allied industries. USP scientists and PharmacopeialEducation@usp.org.
USP science experts, who play a key role in establishing
Beginning in the 2007 calendar year, USP’s PE program will
official USP standards, teach these courses and provide
expert insights into the practical applications of official test be initiating a significant expansion. Both the depth and
procedures and best practices in using the USP–NF and breadth of course offerings will grow as the Pharmacopeial
other USP resources. The courses also give participants an Education staff works to make the science behind the stan-
opportunity to learn how to get involved in USP’s dards more accessible. As this process begins, the PE program
standards-setting processes and the benefits of participating invites you to participate by suggesting titles, developing
in standards development. Courses offered in 2007 are listed course objectives, or even joining the teaching staff.
below. For more information and to register, visit

The Americas

6-Mar-07 Navigating Chapter h467i Residual Solvents East Brunswick, NJ (half-day seminar - $245
Morning)
Afternoon)
Morning only)
15-Mar-07 Essentials of USP Microbiological Testing Raleigh, NC (full day class) $595
20-Mar-07 Navigating Chapter h467i Residual Solvents San Francisco, CA (half-day seminar - $245
Morning)
20-Mar-07 Navigating Chapter h467i Residual Solvents San Francisco, CA (half-day seminar - $245
Afternoon)
22-Mar-07 Navigating Chapter h467i Residual Solvents Irvine, CA (half-day seminar - Morn- $245
ing)
22-Mar-07 Navigating Chapter h467i Residual Solvents Irvine, CA (half-day seminar - After- $245
noon)
1
27-Mar-07 Navigating Chapter h467i Residual Solvents (new) Montreal, Canada (half-day seminar -
Morning)
1
27-Mar-07 Navigating Chapter h467i Residual Solvents (new) Montreal, Canada (half-day seminar -
Afternoon)
3
10-Apr-07 Navigating Chapter h467i Residual Solvents (new) Toronto, Canada (half-day seminar)
17-Apr-07 Navigating Chapter h467i Residual Solvents (new) East Brunswick, NJ (half-day seminar - $245
Morning)
17-Apr-07 Navigating Chapter h467i Residual Solvents (new) East Brunswick, NJ (half-day seminar - $245
Afternoon)
19-Apr-07 Navigating Chapter h467i Residual Solvents (new) Rockville, MD (USP Headquarters - $245
Morning)
8–9 May-07 Fundamentals of Dissolution - Lecture and Lab North Brunswick, NJ (with Distek, 2 $1500
days)
8-May-07 Fundamentals of Dissolution - Lecture Only East Brunswick, NJ -One Day only $595
2
17-May-07 Analytical Method Validation (in Spanish) Mexico City, Mexico
22-May-07 Analytical Method Validation Raleigh, NC $595
19-Jun-07 Effectively Using the USP–NF—Sessions I & II Raleigh, NC $595
Europe/Middle East/Africa/India
23-Apr-07 Navigating Chapter h467i Residual Solvents (new) Munich, Germany (one seminar) $295
24-Apr-07 Navigating Chapter h467i Residual Solvents (new) Berlin, Germany (one seminar) $295
26-Apr-07 Navigating Chapter h467i Residual Solvents (new) Liverpool, United Kingdom (one semi- $295
nar)
27-Apr-07 Navigating Chapter h467i Residual Solvents (new) Brussels, Belgium (one seminar) $295
7-8 May 07 Fundamentals of Dissolution (2 days) Milan, Italy (2-day course, Lecture and
(In English with assistance for Italian) Lab)
10-11 May 07 Fundamentals of Dissolution (2 days) Rome, Italy (2-day course, Lecture and
(In English with assistance for Italian) Lab)
30-May-07 Analytical Method Validation Johannesburg, South Africa
31-May-07 Fundamentals of Dissolution (Lectures) Johannesburg, South Africa
Pharmacopeial Forum
Calendar of Forthcoming Pharmacopeial Education Courses (Continued)

11-Jun-07 Effectively Using the USP–NF—Sessions I & II Milan, Italy $595
(In English with assistance for Italian)
12-Jun-07 Analytical Method Validation Rome, Italy $595
(In English with assistance for Italian)
Registration Information
For registration and information, please contact USP Customer Service at custsvc@usp.org, or +1-301-881-0666 (Except where in-
dicated by footnote number—see below).
1
For registration information, contact custserv@acamchem.com
2
For registration information, contact ventas@proquifa.com.mx
3
For registration information go to www.psg.ca or phone 905-513-7743
VISIT THE USP WEBSITE AT http://www.usp.org. appeared in an issue of PF should be submitted to the
Various resources related to Pharmacopeial standards are appropriate USP scientific staff liaison identified at the end
presented, including highlights from PF. of the Briefing accompanying each item. To submit
comments and data to a liaison, use the e-mail address and
INTERNATIONAL CORRESPONDENCE. Individuals telephone number listed in the Staff Directory included in
who wish to correspond with the European and Japanese every PF.
Pharmacopoeias concerning monographs in the Official

Inquiry and Consensus stages of international harmonization Please note that USP–NF is being published in an annual edi-
should address their comments to the coordinating tion, with one three-volume primary publication and two Sup-
pharmacopeia, with a copy to USP, for a given article. The plements a year. In addition, the schedule provided below will
addresses for the European and Japanese Pharmacopoeias repeat every year so that users will know what to expect and
are as follows: will become familiar with the deadlines.
Technical Secretariat of the European For general inquiries or in cases where a particular liaison is
Pharmacopoeia Commission not identified, use the general USP telephone number 301-
B.P. 907 881-0666 or fax number 301-816-8373.
France
PHARMACOPEIAL FORUM PUBLIC REVIEW AND
NAKASHIMA Nobumasa COMMENT PERIOD DEADLINES. The full year’s
Evaluation and Licensing Division listing of comment period deadlines and the targeted official
Pharmaceutical and Medical Safety Bureau publications appears below. In accordance with the Rules
Ministry of Health, Labour and Welfare, Japan
and Procedures of the 2005–2010 Council of Experts, USP
Tel. +81-3-3595-2431, Fax +81-3-3597-9535
E-mail: nakashima-nobumasa@mhlw.go.jp has implemented a 90-day comment period by providing a
deadline for each issue of PF unless otherwise stated in the
individual Briefing. As previously stated, as a result of the
HOW TO SUBMIT COMMENTS. The USP welcomes and comment deadline extension, the ‘‘Intent to Comment’’ form
encourages interested parties to submit comments and data will no longer be used and will be removed from PF. The
regarding potential, proposed, or adopted (official) listing of comment period deadlines and the targeted official
standards. Submissions concerning a particular item that has publications appears below.
Targeted Official
PF 33(1) April 16, 2007
PF 34(1) April 15, 2008
Pharmacopeial Forum
in the upcoming Supplement. The official publication in which and official dates, and the book or Supplement that supersedes
USP 30–NF 25 Nov. 1, 2006 May 1, 2007 1st Supplement
IRA [PF 33(1)] Jan. 1, 2007 Feb. 1, 2007 2nd Supplement

USP 31–NF 26
USP 31–NF 26
USP 31–NF 26
* Tentative.
PRIORITY NEW MONOGRAPH ITEMS. USP is seeking Forum. (This list has been updated as of February 22, 2007.)
monographs for the following drug substances and drug prod- For additional information, contact Karen A. Russo, Ph.D.,
ucts that are or soon will be off patent and thus are of the high- kar@usp.org. Monograph sponsors should consult USP’s
est priority. USP also is seeking monographs for the excipients Guideline for Submitting Requests for Revision to the USP–
listed below. Monographs are marked received upon receipt of NF (http://www.usp.org/USPNF/submitMonograph/
the monograph proposal. Received monographs are removed subGuide.html).
f r o m t h i s l i s t u p o n p u b l i c a t i o n i n Ph a r m a co p ei a l

Acarbose Alfuzosin Hydrochloride Allopurinol Sodium
Aminopropazine Fumarate Aminopterin Sodium Anagrelide Hydrochloride
Arsenic Trioxide Auranfoin Azelaic Acid
Balsalazide Disodium Bentoquatam Benzphetamine Hydrochloride
Bivalirudin Cabergoline Calcipotriene
(Received)
Calcium Trisodium Pentetate Calfactant Candesartan Cilexetil
Carmustine Cefdinir Cefditoren Pivoxil
Ceftibuten Ceftiofur Hydrochloride Cysteamine Bitartrate
Cetrorelix Cevimeline Chloroxine
Choline Salicylate Cytarabine Liposome Cytarabine Liposome
Dalfopristin Dapirazole Hydrochloride Desirudin
Desonide Dexrazoxane Dextromethorphan Polistirex
(Received)
Difenoxin Hydrochloride Difloxacin Hydrochloride Entacapone
Pharmacopeial Forum
Epoprostenol Sodium Erythromycin Phosphate Erythromycin Thiocyanate

(Received)
Esmolol Hydrochloride Esomeprazole Magnesium Estazolam
(Received)
Estradiol Benzoate Estramustine Phosphate Sodium Ethanolamine Oleate
(Received)
Etomidate Etoposide Phosphate Exemestane
(Received)
Felbamate Flavoxate Hydrochloride Fluoromethane F 18
Foscarnet Sodium Fosfomycin Tromethamine Gadobenate Dimeglumine
Gadopentetic Acid Galantamine Hydrobromide Gallium Nitrate
(Received)
Ganirelix Glyceryl Aminobenzoate Granisetron Hydrochloride
(Received)
Guanidine Hydrochloride Halobetasol Propionate Haloperidol Decanoate
Hydrocodone Polistirex Ibandronate Sodium Imipramine Pamoate
Imiquimod Irinotecan Isosulfan Blue

Itraconazole Lamotrigine Latanoprost
Levetiracetam Lomustine Lopinavir
(Received)
Moexipril Hydrochloride Nalbuphine Hydrochloride Nalmefene Hydrochloride
Nateglinide Nedocromil Sodium Nicardipine Hydrochloride
(Received)
Nilutamide Nisoldipine Olopatadine
(Received)
Olsalazine Sodium Orbifloxacin Orlistat
Oxcarbazepine Oxiconazole Nitrate Pantoprazole Sodium
Pemirolast Potassium Pentamidine Isethionate Piperonyl Butoxide
(Received)
Pirbuterol Acetate Poractant Alpha Porfimer Sodium
Pramiprexole Dihydrochloride Proguanil Hydrochloride Quetiapine Fumarate
Ranitidine Rivastigmine Tartrate Rocuronium Bromide
(Received)
Rose Bengal Disodium Rosiglitazone Maleate Salmeterol Xinafoate
Sertraline Hydrochloride Sibutramine Hydrochloride Sodium Phenylbutyrate
Tacrolimus Tenofovir Disoproxil Fumarate
(Received)
Terconazole Terbinafine Hydrochloride
Tiludronate Disodium Tiopronin Trandolapril
Tranexamic Acid Tranylcypromine Sulfate Trimetrexate Glucuronate
(Received)
Venlafaxine Hydrochloride Voriconazole Zinc Tridosium Pentetate
Zoledronic Acid
Pharmacopeial Forum

Albuterol for Inhalation Albuterol Inhalation Aerosol Albuterol Sulfate Inhalation Solution
Albuterol Sulfate Oral Solution Alendronate Sodium Oral Solution Alfuzosin Tablets
Allopurinol for Injection Alprazolam Extended-Release Tablets Alprostadil Urethral Suppository
Aminopropazine Fumarate and Neomycin Aminopropazine Fumarate Injection Aminopropazine Fumarate Tablets
Sulfate Tablets
Aminopterin Sodium Tablets Amlodipine and Benazepril Hydrochloride Amphotericin B Injection
Capsules
Anagrelide Hydrochloride Capsules Arsenic Trioxide Injection Atovaquone and Proguanil Hydrochloride
Tablets
Atovaquone Tablets Auranofin Capsules Azatadine Maleate and Pseudoephedrine Sul-
fate Extended-Release Tablets
Azelaic Acid Cream Azithromycin for Injection Azithromycin Tablets
(Received)
Baclofen Injection Balsalazide Disodium Capsules Beclomethasone Dipropionate Inhalation
Aerosol
Beclomethasone Dipropionate Nasal Bentoquatam Topical Suspension Benzocaine and Cetylpyridinium Chloride

Suspension Lozenges
Benzocaine and Menthol Lotion Benzphetamine Hydrochloride Tablets Bicalutamide Tablets
(Received)
Bivalirudin Injection Brompheniramine Maleate, Dextromethor- Budesonide Inhalation Aerosol
phan Hydrobromide, and Pseudoephedrine
Bupivacaine and Lidocaine Hydrochlorides Buprenorphine Hydrochloride Injection Butalbital and Acetaminophen Capsules
Injection
Butalbital and Acetaminophen Tablets Calcipotriene Cream Calcipotriene Ointment
Calcipotriene Topical Solution Cabergoline Tablets Calcitriol Capsules
Calcitriol Oral Solution Calcium Acetate Capsules Calcium Trisodium Pentetate Injection
Calfactant Intratracheal Suspension Carbidopa and Levodopa Extended-Release Carbidopa and Levodopa Tablets for Oral
Tablets Suspension
Carbidopa, Levodopa, and Entacapone Carmustine for Injection Carmustine Implant
Tablets (Received)
Carvedilol Tablets Cefdinir Tablets Cefditoren Pivoxil Tablets
(Received)
Ceftibuten Capsules Ceftibuten for Oral Suspension Ceftiofur Hydrochloride Oral Suspension
Cetirizine Hydrochloride Oral Solution Cetirizine Hydrochloride Tablets Cetrorelix Injection
Cevimeline Hydrochloride Capsules Chloroxine Cream Chlorpromazine Hydrochloride Extended-
Release Capsules
Choline and Magnesium Salicylates Oral Choline and Magnesium Salicylates Tablets Choline Salicylate Oral Solution
Solution (Received)
Ciclopirox Shampoo Ciclopirox Topical Gel Ciclopirox Topical Solution
(Received)
Cilostazol Tablets Cimetidine Oral Solution Ciprofloxacin Hydrochloride and Hydrocorti-
(Received) sone Otic Suspension
Ciprofloxacin Otic Solution Citalopram Hydrobromide Oral Solution Citric Acid, Gluconolactone, and Magnesium
Carbonate Irrigation
Cladribine Injection Clemastine Fumarate Syrup Clobetasol Propionate Gel
Clonazepam Orally-Disintegrating Tablets Clorazepate Dipotassium Capsules Clorazepate Dipotassium Extended-Release
Tablets
Clotrimazole and Betamethasone Dipropio- Colestipol Hydrochloride Tablets Compound Undecylenic Acid Cream
nate Lotion
Compound Undecylenic Acid Topical Conjugated Estrogens and Medroxyproges- Cromolyn Sodium Nasal Solution
Powder terone Acetate Tablets
Pharmacopeial Forum

Release Tablets
Difloxacin Hydrochloride Tablets Dihydroergotamine Mesylate Metered Dinoprostone Vaginal Suppositories
Spray
Diphenhydramine Hydrochloride and Acet- Divalproex Sodium Delayed-Release Dorzolamide and Timolol Ophthalmic Solu-
aminophen Tablets Capsules tion
Dorzolamide Ophthalmic Solution Doxepin Hydrochloride Cream Doxycycline Oral Gel
Econazole Nitrate Cream Edrophonium Chloride and Atropine Sul- Enalapril Maleate and Diltiazem Malate
fate Injection Extended-Release Tablets
Enalapril Maleate and Felodipine Enalaprilat Injection Entacapone Tablets
Extended-Release Tablets (Received)
Ephedrine Sulfate and Guaifenesin Tablets Epoprostenol for Injection Epoprostenol Injection
Esmolol Hydrochloride Injection Esomeprazole Magnesium Capsules Estazolam Tablets
Estramustine Phosphate Sodium Capsules Ethanolamine Oleate Injection Etidronate Disodium Injection Concentrate
Etomidate Injection Exemestane Tablets Famotidine Orally Disintegrating Tablets
Felbamate Oral Suspension Felbamate Tablets Fentanyl Lozenges
Fentanyl Transdermal System Ferrous Fumarate and Docusate Sodium Flavoxate Hydrochloride Tablets
(Received) Extended-Release Capsules
Fluconazole Injection Fluconazole Tablets Flunisolide Inhalation Aerosol

Flunisolide Nasal Spray Fluocinolone Acetonide Shampoo Fluorescein Sodium Ophthalmic Solution
Fluorometholone Ointment Fluticasone Propionate Cream Fluticasone Propionate Inhalation Powder
(Received)
Fluticasone Propionate Ointment Fluticasone Propionate Pressurized Inhaler Foscarnet Sodium Injection
(Received)
Fosfomycin for Oral Solution Gabapentin Oral Solution Gadobenate Dimeglumine Injection
(Received)
(Received)
Guaifenesin and Salts of Dextromethorphan Guaifenesin and Pseudoephedrine Hydro- Guanidine Hydrochloride Tablets
and Pseudoephedrine Oral Solution chloride Extended-Release Tablets
othiazide Capsules
trate Oral Solution
tion (Received)
(Received)
(Received)
Levetriacepam Tablets Levocabastine Ophthalmic Suspension Levofloxacin Solution
Lincomycin Hydrochloride and Spectino- Liothyronine Injection Lisinopril and Hydrochlorothiazide Tablets
mycin Sulfate Soluble Powder (Received)
Lomustine Capsules Lopinavir and Ritonavir Solution Lopinavir Capsules
Lopinavir Solution Loratadine Orally-Disintegrating Tablets Losartan Potassium Tablets
Pharmacopeial Forum

tion
trate
Methyclothiazide and Deserpidine Tablets Methylphenidate Hydochloride Chewable Metipranolol Ophthalmic Solution
Tablets
(Received)
Milrinone Injection Misoprostol Tablets Moexipril Hydrochloride and Hydrochlor-
(Received) othiazide Tablets

Nitroglycerin Extended-Release Transder- Nitroglycerin Transdermal System Nitroglycerin Solution in Acrylic Adhesive
mal Film
(Received)
Orbifloxacin Tablets Orphenadrine Citrate Extended Release Orphenadrine Citrate, Aspirin, and Caffeine
(Received)
Tablets
Paroxetine Oral Suspension Pemirolast Potassium Ophthalmic Solution Penicillin G Potassium Tablets for Oral Solu-
tion
Pentamidine Isethionate for Inhalation Pentamidine Isethionate Injection Pentazocine Hydrochloride and Acetamino-
(Received) phen Tablets
Phendimetrazine Tartrate Extended-Release Phenobarbital Capsules Phentermine Resin Complex Capsules
Capsules
Phenylephrine Hydrochloride and Chlor- Phenylephrine Hydrochloride, Chlorphenir- Pilocarpine Hydrochloride Ophthalmic Gel
pheniramine Maleate Extended-Release amine Maleate, and Acetaminophen
Capsules Extended-Release Tablets
Pilocarpine Hydrochloride Ophthalmic Pilocarpine Hydrochloride Tablets Piperonyl Butoxide and Pyrethrins Aerosol
Ointment Foam
Pirbuterol Acetate Inhalation Aerosol Poractant Alpha Supension Porfimer Sodium for Injection
Povacrylate Solution Povacrylate-Iodine Topical Solution Povidone-Iodine Gauze
Povidone-Iodine Swabsticks Povidone-Iodine Topical Aerosol Foam Povidone-Iodine Vaginal Suppositories
Pramipexole Dihydrochloride Tablets Prednisolone Sodium Phosphate Oral Solu- Prochlorperazine Maleate Extended-Release
tion Capsules
Progesterone Capsules Promethazine and Phenylephrine Hydro- Promethazine and Phenylephrine Hydro-
chlorides and Codeine Phosphate Syrup chlorides Syrup
Promethazine Hydrochloride and Codeine Promethazine Hydrochloride and Dextro- Propafenone Hydrochloride Tablets
Phosphate Oral Solution methorphan Hydrobromide Syrup
Pseudoephedrine Hydrochloride and Brom- Pseudoephedrine Hydrochloride and Na- Pseudoephedrine Hydrochloride, Chlorphen-
pheniramine Maleate Extended-Release proxen Sodium Extended-Release Tablets iramine Maleate, and Codeine Phosphate Oral
Tablets Solution
Pseudoephedrine Hydrochloride, Guaifene- Pseudoephedrine Sulfate and Pseudoephedrine Sulfate and Dexbromphen-
sin, and Codeine Phosphate Oral Solution Dexbrompheniramine Maleate Extended- iramine Maleate Oral Solution
Release Tablets
Pseudoephedrine Sulfate, Dexbromphenira- Pyrilamine Maleate Injection Quinidine Sulfate Injection
mine Maleate, and Acetaminophen Ex-
tended-Release Tablets
zide Tablets
Pharmacopeial Forum

(Received)
Risperidone Orally-Disintegrating Tablets Rivastigmine Tartrate Capsules Rivastigmine Tartrate Oral Solution
(Received)
Rocuronium Bromide Injection Ropinirole Hydrochloride Tablets Rosiglitazone Maleate Tablets
Salicylic Acid and Sulfur Cleansing Lotion Salicylic Acid and Sulfur Lotion Salicylic Acid and Sulfur Shampoo
Salicylic Acid Cream Salicylic Acid Ointment Salmeterol Inhalation Aerosol
Salmeterol Xinafoate Inhalation Powder Scopolamine Transdermal System Selegiline Hydrochloride Capsules
Sertraline Hydrochloride Oral Solution Sibutramine Hydrochloride Capsules Sodium Bicarbonate and Sodium Citrate for
Oral Solution
Sodium Bicarbonate, Sodium Citrate, and Sodium Iodide Injection Sodium Phenylbutyrate Oral Powder
Sodium Tartrate for Oral Suspension
Sodium Phenylbutyrate Tablets Sodium Phosphates for Oral Suspension Sodium Phosphates Tablets
Sodium Salicylate and Sulfur Shampoo Sterile Talc Aerosol Streptozocin for Injection
Sucralfate Oral Suspension Sulconazole Nitrate Cream Sulfacetamide Sodium and Fluorometholone
Ophthalmic Suspension
Sulfacetamide Sodium and Prednisolone Sulfasalazine Oral Suspension Sulisobenzone Lotion
Sodium Phosphate Ophthalmic Solution

(Received)
(Received)
Technetium Tc 99m Teboroxime Injection Tenofovir Disoproxil Fumarate Tablets Terbinafine Hydrochloride Cream
(Received)
Trolamine Salicylate Topical Emulsion Undecylenic Acid Topical Foam Aerosol Urea Cream
(Received)
Verapamil Hydrochloride Capsules Verapamil Hydrochloride Extended-Release Voriconazole Injection
Capsules
(Received)
Excipients
Butadiene- Styrene Rubber Butylated Hydromethylphenol Butylene Glycol
Calcium Phosphate Monobasic Calcium Propionate Calcium Pyrophosphate
Pharmacopeial Forum
Calcium Sorbate Calcium Stearoyl Lactylate Caldiamide Sodium
Calteridol Calcium Capric Acid Caprylic/Capric Diglyceryl Succinate
Carbon Carboxymethyl Starch Carboxymethylamylopectin Sodium
Carboxymethylcellulose Potassium Cetostearyl Isononanoate Chlorodifluoroethane
Cholic Acid Cinnamaldehyde Cocamide Diethanolamine
Cocamide Oxide Cocoyl Caprylocaprate Crystal Gum
Cutina Cystine Dammar Gum
Decanoic Acid Decyl Oleate Dehydroacetic Acid
(Received)
Desoxycholic Acid Dextrin Palmitate Dextrins Modified
Diacetyl Tartaric Acid Esters of Mono- and Dicetyl Phosphate Dichlorofluoromethane
Diglycerides
Diethyl Sebacate Difluoroethane Diglycol Stearate
Diisobutyl Adipate Diisopropyl Adipate Diisopropylbenzothiazyl-2-Sulfenamide
Dilauryl Thiodipropionate Dimethyl Dicarbonate Dimyristoyl Lecithin
Dimyristoyl Phosphatidylglycerol Dipropylene Glycol Disodium Edisylate
Disodium Guanylate Disodium Inosinate Disodium Monooleamide Sulfasuccinate
D-Mannose Docusate Sodium/Sodium Benzoate Erythorbic Acid

(Received)
Erythrosine Ethoxylated Mono- and Diglycerides Ethoxyquin
Ethyl Hexanediol Ethyl Linoleate Ethyl Maltol
Ethylene Dichloride Ethylurea Ferric Ammonium Citrate
Ferric Citrate Ferric Oxide, Brown Ferric Phosphate
Ferric Pyrophosphate Ferrous Citrate Ferrous Glycinate
Ferrous Lactate Fluorochlorohydrocarbons Formic Acid
Furcelleran Gentistic Acid Geraniol
(Received)
Hydroxylated Lecithin Indigotine Inositol
(Received)
Iron Carbonyl Iron Subcarbonate Isobutylated- Isoprene Copolymer
Isooctylacrylate Isopropyl Isostearate Isopropyl Stearate
Isostearic Acid Isostearyl Alcohol Lactobionic Acid
Lactose Ferrin, Bovine Lactylated Fatty Acid Esters of Glycerol and Lactylic Esters of Fatty Acids
Propylene Glycol
Lanolin (Wool Fat), Hydrogenated Lanolin Alcohols, Acetylated Lanolin Hydrous
L-Ascorbyl Stearate Lauramine Oxide Lauric Myristic Diethanolamide
Lauric Acid Lauric Diethanolamide Lavender Oil
L-Cysteine Monohydrochloride Lecithin, Hydroxylated L-Glutamic Acid
Linoleic Acid L-Leucine Macrogol Sorbitan Tristearate
(Received)
Macrogolglycerol Cocoates Macrogolglycerol Triisostearate Magnesium Aluminum Silicate Hydrate
Magnesium Aspartame Dihydrate Magnesium Aspartate Magnesium Phosphate Tribasic
Magnesium Phosphate, Diabasic, Trihy- Magnesium Tartrate Malt Syrup
drate
Maltitol Syrup Maltol Isobutyrate Manganese Chloride
Manganese Citrate Manganese Glycerophosphate Manganese Hypophosphite
Medical Antifoam Emulsion C Medronate Disodium Medronic Acid
Methyl Chloride Methylchloroisothiazolinone Methylisothiazolinone
Microcrystalline Cellulose, Silicified Mineral Spirits Monoisostearyl Glyceryl Ester
(Received)
Monopotassium Glutamate Monohydrate Monosodium Citrate Mullein Leaf
Myristyl Gamma-Picolinium Chloride Myristyl Lactate N,N-Bis(2-Hydroxyethyl)Stearamide
N-Acetyl-L-Methionine Naphtha N-Methylpyrrolidone
(Received)
Pharmacopeial Forum
Non-Pareil Seeds Nutmeg Oil Octanoic Acid
Oxystearin Palm Kernel Oil Pentasodium Triphosphate
(Received)
Pentetate Calcium Trisodium Pentetate Pentasodium Phenprobamate
Phenylmercuric Acetate Phenylmercuric Nitrate Pine Oil
Polacrilin Polyglycerol Esters of Fatty Acids Polyglycerol Polyricinoleic Acid
Polyoxyethylene Castor Oil Polyoxyl Stearate Polypropylene Oleate
(USP has 35) (USP has 40)
Polypropylene Stearyl Ether Polysorbate 65 Polyvinylacetal Diethylanoacetate
Rice Bran Wax Rosin Silicone
Sodium Acid Pyrophosphate Sodium Aluminosilicate Sodium Aluminum Phosphate Acidic
(Received)
Sodium Aluminum Phosphate Basic Sodium Aspartate Sodium Bisulfate
Sodium Bisulfite Sodium Carbonate Hydrate Sodium Carboxymethyl Betaglucan
Sodium Caseinate Sodium Chlorate Sodium Citrate, Dibasic
Sodium Citrate, Monobasic Sodium Dehydroacetate Sodium Diacetate
Sodium Erythorbate Sodium Ferric Pyrophosphate Sodium Ferrocyanide
Sodium Hypophosphite Sodium Laureth Sulfate Sodium Lauroyl Sarcosinate
Sodium Lauryl Sulfoacetate Sodium Magnesium Aluminosilicate Sodium Magnesium Silicate
Sodium Malate Sodium Metaphosphate, Insoluble Sodium Metasilicate
Sodium Methylate Sodium Polyphosphates Glassy Sodium Potassium Tripolyphosphate
Sodium Pyrophosphate Sodium Pyrrolidone Carboxylate Sodium Sesquicarbonate
Sodium Sesquinoleate Sodium Stearoyl Lactylate Sodium Thiomalate
Sodium Trimetaphosphate Sodium Trioleate Sodium Tripolyphosphate
Soy Polysaccharides Stannous Chloride Stannous Tartrate
(Received)
Starch, Pregelatinized Corn Starch, Pregelatinized Tapioca Stearalkonium Chloride
Stearyl Citrate Stearyl Monoglyceridyl Citrate Succinylated Monoglycerides
Sucrose Acetate Isobutyrate Sucrose Fatty Acid Esters Sucrose Stearate
Sugar Fruit Fine Sulfobutyl Ether Beta Cyclodextran Tallow
Tallow Glycerides Tallow Oil Tetrafluoroethane
Thioglycerol Thyme Oil Tribehenin
Triceteareth-4 Phosphate Trichloroethylene Trimyristin
Trisodium Citrate Trolamine Lauryl Sulfate Vegetable Oil
Wheat Flour Wheat Germ Oil Wheat Gluten
(Received)
Whey
INTERIM REVISION
ANNOUNCEMENT
next page.)

Pharmacopeial Forum
370 INTERIM REVISION ANNOUNCEMENT Vol. 33(3) [May–June 2007]

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Isosorbide Dinitrate Extended-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 373
Pamidronate Disodium for Injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Ubidecarenone Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
Ubidecarenone Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374
h467i Organic Volatile Impurities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
h467i Residual Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] INTERIM REVISION ANNOUNCEMENT 371
INTERIM REVISION
ANNOUNCEMENT


Official June 1, 2007 Released May 1, 2007

Pharmacopeial Forum
New USP Reference Standards USP Albumin Human RS

The following USP Reference Standards, which were not USP Alteplase RS
USP Amifostine RS
available when the associated monograph was made official, USP Amifostine Thiol RS
have since become available. The respective official date of USP Antithrombin III Human RS
each USP 30 or NF 25 standard, test, or assay requiring the USP Aprotinin RS
USP Aprotinin System Suitability RS
use of the following USP Reference Standards is indicated USP Copolymer Polypropylene RS
in parentheses after the name of the Reference Standard. USP Cryopreserved Human Fibroblast-Derived Dermal
Substitute Reference Photomicrographs RS
USP Cetrimonium Bromide RS (November 1, 2007) USP Diethylstilbestrol Diphosphate RS
USP Cladribine RS (August 1, 2007) USP Powdered Echinacea pallida Extract RS
USP Cladribine Related Compound A RS (November 1, 2007) USP Eucatropine Hydrochloride RS
USP Citalopram Hydrobromide RS (May 1, 2007) USP Ginkgo Terpene Lactones RS
USP Decoquinate RS (November 1, 2007) USP Glyceryl Monolinoleate RS
USP Docosyl Ferulate RS (November 1, 2007) USP Glyceryl Monooleate RS
USP Fluvastatin Sodium RS (March 1, 2007) USP Gonadorelin Hydrochloride RS
USP Gabapentin Related Compound B RS (June 1, 2007) USP Hemoglobin RS
USP Powdered American Ginseng Extract RS USP Isosorbide Mononitrate RS
(November 1, 2007) USP Isosorbide Mononitrate Related Compound A RS
USP Irbesartan RS (August 1, 2007) USP Alpha Lipoic Acid RS
USP Irbesartan Related Compound A RS (November 1, 2007) USP Maritime Pine Extract RS
USP Naratriptan Resolution Mixture RS (May 1, 2007) USP Menotropins RS
USP Nimodipine RS (June 1, 2007) USP Methyldopa–Glucose Reaction Product RS
USP Nimodipine Related Compound A RS (June 1, 2007) USP Mibolerone RS
USP Cultured Rat Pheochromocytoma Reference USP Narasin RS
Photomicrographs RS (May 1, 2007) USP Near Infrared Calibrator
USP Polyoxyl 10 Oleyl Ether RS (August 1, 2007) USP Potassium Perchlorate RS
USP Quinapril Hydrochloride RS (November 1, 2007) USP Pyrethrum Extract RS
USP Ramipril Related Compound B RS (May 1, 2007) USP Powdered St John’s Wort Extract RS
USP Tizanidine Hydrochloride RS (August 1, 2007) USP Sargramostim RS
USP Tizanidine Related Compound A RS (June 1, 2007) USP Sincalide RS
USP Tizanidine Related Compound B RS (June 1, 2007) USP Human Fibroblast-Derived Temporary Skin Substitute
USP Tizanidine Related Compound C RS (June 1, 2007) Reference Photomicrographs RS
USP Valrubicin RS
Unavailable First-Time Official USP USP Valrubicin Related Compound A RS
USP Vasopressin RS
Reference Standards
The official dates of any USP 30 or NF 25 standards, tests,
or assays requiring the use of the following new USP Refer-
ence Standards are postponed until further notice pending
availability of the respective Reference Standards. This listing
was updated as of February 20, 2007.
Pharmacopeial Forum
MONOGRAPHS (USP) .TEST 2—If the product complies with this test, the labeling
Medium: pH 1.2 simulated gastric fluid (without pepsin) for the
first hour, 900 mL; pH 7.5 simulated intestinal fluid (without
Isosorbide Dinitrate Extended-Release enzymes) for the subsequent hours, 900 mL.
Apparatus 2: 50 rpm, with helix sinkers.
Tablets Times: 1, 3, 6, and 12 hours.
Determine the amount of isosorbide dinitrate (C6H8N2O8)
dissolved by employing the following method.
Buffer solution and Mobile phase—Prepare as directed in the
Add the following: Assay under Diluted Isosorbide Dinitrate.
Standard solution—Prepare two solutions, one in each Medium.
.Labeling—When more than one Dissolution test is given, the Dissolve an accurately weighed quantity of USP Diluted Isosorbide
Dinitrate RS in Medium, and dilute quantitatively, and stepwise if
labeling states the Dissolution test used only if Test 1 is not used..3 necessary, with Medium to obtain a solution having a known
concentration of about 40 mg per mL.
Test solution—Pass 5 mL of the solution under test through
Change to read: a suitable 10-mm filter. Replace the Medium withdrawn at the 3- and
6-hour timepoints.
Dissolution h711i— Chromatographic system (see Chromatography h621i)—Proceed
.TEST 1— as directed in the Assay under Diluted Isosorbide Dinitrate.
.3
Medium: water; 500 mL. Chromatograph the Standard solution, and record the chromatogram
Apparatus 2: 50 rpm. as directed for Procedure: the tailing factor is not more than 2.0; and
Times: 1, 2, 4, and 6 hours. the relative standard deviation for replicate injections is not more
Determine the amount of C6H8N2O8 dissolved, using the following than 2.0%.
method. Procedure—Separately inject equal volumes (about 20 mL) of the
pH 3.0 Buffer solution—Add 6.6 g of ammonium sulfate, Standard solution and the Test solution into the chromatograph,
accurately weighed, to 500 mL of water. Adjust with 1 N sulfuric record the chromatograms, and measure the peak responses.
acid to a pH of 3.0. Calculate the cumulative percentage of isosorbide dinitrate dissolved
Mobile phase—Prepare a filtered and degassed mixture of at each collection point, corrected for the quantities removed at
methanol and pH 3.0 Buffer solution (50 : 50). Make adjustments previous collection points (not applicable for the first hour), as
if necessary (see System Suitability under Chromatography h621i). follows:
liquid chromatograph is equipped with a UV wavelength detector
and a 5-mm 6 25-cm column that contains packing L1. The flow
rate is about 1 mL per minute. Chromatograph a Standard solution of
USP Diluted Isosorbide Dinitrate RS in the same Medium, and

record the chromatograms as directed for Procedure: the tailing
factor is not more than 2.5; and the relative standard deviation is not
more than 2.0%.
Procedure—Separately inject equal volumes (about 20 mL) of Percentage released at first hour (see Formula 1).
a filtered portion of the solution under test, and record the Percentage released at third hour (see Formula 2).
chromatograms. Determine the amount of C6H8N2O8 dissolved in Percentage released at sixth hour (see Formula 3).
comparison with a Standard solution of USP Diluted Isosorbide Percentage released at twelfth hour (see Formula 4).
Dinitrate RS in the same Medium, similarly chromatographed.
Tolerances—The percentages of the labeled amount of C6H8N2O8
6 not less than 75%
Formula 1
Formula 2
Pharmacopeial Forum
Formula 3
Formula 4
in which rU and rS are the peak responses for the Test solution and the Change to read:
Standard solution, respectively; CU is the sample concentration, in
mg per mL, at the indicated collection time point; CS is the Disintegration and dissolution h2040i: meet the requirements of
concentration, in mg per mL, of the Standard solution; 900 is the the test for Disintegration only, .except where the product is labeled
volume, in mL, of Medium; 1000 is the conversion factor from mg to to contain the water-soluble form of ubidecarenone. Ubidecarenone
mg; 100 is the conversion factor to percentage; LC is the tablet label Capsules labeled to contain the water-soluble form of ubidecarenone
claim, in mg; and 5 is the volume, in mL, of sample withdrawn and meet the requirements for the test for Dissolution, as follows.
of the Medium replaced. Medium: water; 500 mL.
Tolerances—The percentages of the labeled amount of C6H8N2O8 Apparatus 2: 75 rpm.
dissolved at the times specified conform to Acceptance Table 2. Time: 60 minutes.
Time (hours) Amount dissolved Determine the amount of C59H90O4 dissolved by employing the
following method.
1 between 5% and 25% Mobile phase and Chromatographic system—Proceed as directed
3 between 30% and 50% in the Assay.
6 between 50% and 80% Standard solution—Dissolve an accurately weighed quantity of
12 not less than 75% about 25 mg of USP Ubidecarenone RS in 1 mL of ethyl ether, and
dilute quantitatively and stepwise with alcohol to obtain a solution
.3 having a known concentration of about 2.5 mg per mL. Use a freshly
prepared solution only.
Test solution—Dilute quantitatively and stepwise with alcohol an
accurately measured volume of the solution under test, previously
passed through a suitable 0.45-mm filter, to obtain a solution having
a concentration of about 2.5 mg of ubidecarenone per mL.

Pamidronate Disodium for Injection Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the responses for the major
peaks. Calculate the percentage of C59H90O4 dissolved by the
formula:
Change to read: 500CD(rU / rS)100/LC
in which 500 is the volume, in mL, of Medium; C is the
» Pamidronate Disodium for Injection is a sterile, concentration, in mg per mL, of USP Ubidecarenone RS in the
freeze-dried mixture of Pamidronate Disodium and Standard solution; D is the dilution factor used to prepare the Test
suitable excipients. It contains not less than .93.0 solution; rU and rS are the peak areas of ubidecarenone obtained from
the Test solution and the Standard solution, respectively; 100 is the
percent.3 and not more than 108.0 percent of the labeled conversion factor to percentage; and LC is the label claim, in mg per
amount of pamidronate disodium (C3H9NNa2O7P2). Capsule.
Tolerances—Not less than 75% of the labeled amount of C59H90O4
is dissolved in 60 minutes..3
MONOGRAPHS Ubidecarenone Tablets
Add the following:

.Labeling—Where
Ubidecarenone Capsules the product contains the water-soluble form of
ubidecarenone, this is so stated in the label..3
Change to read:
Add the following:
.Labeling—Where the product contains the water-soluble form of the test for Disintegration only, .except where the product is labeled
ubidecarenone, this is so stated in the label..3 to contain the water-soluble form of ubidecarenone. Ubidecarenone
Tablets labeled to contain the water-soluble form of ubidecarenone
meet the requirements for Dissolution as directed in the test for
Disintegration and dissolution under Ubidecarenone Capsules..3
Pharmacopeial Forum
Class 2 Standard Stock Solutions—Transfer 1.0 mL of USP Resid-

ual Solvents Class 2—Mixture A RS to a 100-mL volumetric flask,
GENERAL CHAPTERS dilute with water to volume, and mix. This is Class 2 Standard Stock
Solution A. Transfer 1.0 mL of USP Residual Solvents Class 2—Mix-
ture B RS to a 100-mL volumetric flask, dilute with water to volume,
and mix. This is Class 2 Standard Stock Solution B.
General Tests and Assays Class 2 Mixture A Standard Solution—Transfer 1.0 mL of Class 2
Standard Stock Solution A to an appropriate headspace vial, add 5.0
mL of water, apply the stopper, cap, and mix.
Class 2 Mixture B Standard Solution—Transfer 5.0 mL of Class 2
Chemical Tests and Assays Standard Stock Solution B to an appropriate headspace vial, add 1.0
mL of water, apply the stopper, cap, and mix.
Test Stock Solution—Transfer about 250 mg of the article under
test, accurately weighed, to a 25-mL volumetric flask, dissolve in
and dilute with water to volume, and mix.
OTHER TESTS AND Test Solution—Transfer 5.0 mL of Test Stock Solution to an appro-
priate headspace vial, add 1.0 mL of water, apply the stopper, cap,
ASSAYS and mix.
Class 1 System Suitability Solution—Transfer 1.0 mL of Class 1
Standard Stock Solution to an appropriate headspace vial, add 5.0 mL
of Test Stock Solution, apply the stopper, cap, and mix.
Chromatographic System (see Chromatography h621i)—The gas
h467i ORGANIC VOLATILE chromatograph is equipped with a flame-ionization detector, a
0.32-mm 6 30-m fused-silica column coated with a 1.8-mm layer
IMPURITIES of phase G43 or a 0.53-mm 6 30-m wide-bore column coated with
a 3.0-mm layer of phase G43. The carrier gas is nitrogen or helium
with a linear velocity of about 35 cm per second, and a split ratio
(Current title—not to change until July 1, 2007) of 1 : 5. .[NOTE—Split ratio can be modified in order to optimize sen-
Chapter title change—to become official July 1, 2007 sitivity.].3 The column temperature is maintained at 408 for 20 min-
See h467i Residual Solvents utes, then raised at a rate of 108 per minute to 2408, and maintained at
2408 for 20 minutes. The injection port and detector temperatures are
maintained at 1408 and 2508, respectively. Chromatograph the Class
Change to read: 1 Standard Solution, Class 1 System Suitability Solution, and Class 2
Mixture A Standard Solution, and record the peak responses as direct-
IDENTIFICATION, CONTROL, AND ed for Procedure: the signal-to-noise ratio of 1,1,1-trichloroethane in
the Class 1 Standard Solution is not less than 5; the signal-to-noise
QUANTIFICATION OF RESIDUAL SOLVENTS ratio of each peak in the Class 1 System Suitability Solution is not less

.Whenever possible, the substance under test needs to be dissolved than 3; and the resolution, R, between acetonitrile and methylene
to release the residual solvent. Because the USP deals with drug prod- chloride in the Class 2 Mixture A Standard Solution is not less than
ucts, as well as active ingredients and excipients, it may be acceptable 1.0.
that in cases some of the components of the formulation will not dis- Procedure—Separately inject (following one of the headspace op-
solve completely. In those cases, the drug product may first need to be erating parameter sets described in the table below) equal volumes of
pulverized into a fine powder so that any residual solvent that may be headspace (about 1.0 mL) of the Class 1 Standard Solution, Class
present can be released. This operation should be as fast as possible to 2 Mixture A Standard Solution, Class 2 Mixture B Standard Solution,
prevent the loss of volatile solvents during the procedure..3 and the Test Solution into the chromatograph, record the chromato-
NOTE—The organic-free water specified in the following proce- grams, and measure the responses for the major peaks. .If a peak re-
dures produces no significantly interfering peaks when chromato- sponse of any peak, other than a peak for 1,1,1-trichloroethane, in the
graphed. Test Solution is greater than or equal to a corresponding peak in either
the Class 1 Standard Solution or either of the two Class 2 Mixture
Standard Solutions, or a peak response of 1,1,1-trichloroethane is
Class 1 and Class 2 Residual Solvents greater than or equal to 150 times the peak response corresponding
to 1,1,1-trichloroethane in the Class 1 Standard Solution, proceed to
.The following procedures are useful to identify and quantify re- Procedure B to verify the identity of the peak; otherwise the article
sidual solvents when the information regarding which solvents are meets the requirements of this test..3
likely to be present in the material is not available. When the infor-
mation about the presence of specific residual solvents is available, Table 5. Headspace Operating Parameters
only Procedure C is needed to quantify the amount of residual sol-
vents present..3 Headspace Operating
Parameter Sets
1 2 3
WATER-SOLUBLE ARTICLES Equilibration temperature (8) 80 105 80
Equilibration time (min.) 60 45 45
Procedure A— Transfer-line temperature (8) 85 110 105
Class 1 Standard Stock Solution—Transfer 1.0 mL of USP Class 1 Carrier gas: nitrogen or helium at an appropriate pressure
Residual Solvents Mixture RS to a 100-mL volumetric flask, add 9 Pressurization time (s) 30 30 30
mL of dimethyl sulfoxide, dilute with water to volume, and mix. Injection volume (mL) 1 1 1
Transfer 1.0 mL of this solution to a 100-mL volumetric flask, dilute
with water to volume, and mix. Transfer 1.0 mL of this solution to a
10-mL volumetric flask, dilute with water to volume, and mix.
Class 1 Standard Solution—Transfer 1.0 mL of Class 1 Standard
Stock Solution to an appropriate headspace vial, add 5.0 mL of water,
apply the stopper, cap, and mix.
Pharmacopeial Forum
lution, and record the peak responses as directed for Procedure: the
Procedure B— signal-to-noise ratio of 1,1,1-trichloroethane in the Class 1 Standard
Class 1 Standard Stock Solution, Class 1 Standard Solution, Class Solution is not less than 5; the signal-to-noise ratio of each peak in the
2 Standard Stock Solutions, Class 2 Mixture A Standard Solution, Class 1 System Suitability Solution is not less than 3; and the resolu-
Class 2 Mixture B Standard Solution, Test Stock Solution, Test Solu- tion, R, between acetonitrile and methylene chloride in the Class 2
tion, and Class 1 System Suitability Solution—Prepare as directed for Mixture A Standard Solution is not less than 1.0.
Procedure A. Procedure—Separately inject (following one of the headspace op-
. erating parameters described in Table 5) equal volumes of headspace
.3
Chromatographic System (see Chromatography h621i)—The gas (about 1.0 mL) of the Standard Solution, the Test Solution, and the
chromatograph is equipped with a flame-ionization detector, a Spiked Test Solution into the chromatograph, record the chromato-
0.32-mm 6 30-m fused-silica column coated with a 0.25-mm layer grams, and measure the responses for the major peaks. Calculate
of phase G16, or a 0.53-mm 6 30-m wide-bore column coated with a the amount, in ppm, of each residual solvent found in the article under
0.25-mm layer of phase G16. The carrier gas is nitrogen or helium test by the formula:
with a linear velocity of about 35 cm per second and a split ratio of 5(C/W)[rU /(rST – rU)]
1 : 5. .[NOTE—Split ratio can be modified in order to optimize sensi-
tivity.].3 The column temperature is maintained at 508 for 20 minutes, in which C is the concentration, in .mg per mL,.3 of the appropriate
then raised at a rate of 68 per minute to 1658, and maintained at 1658 USP Reference Standard in the Standard Solution; W is the weight, in
for 20 minutes. The injection port and detector temperatures are main- g, of the article under test taken to prepare the Test Stock Solution; and
tained at 1408 and 2508, respectively. Chromatograph the Class 1 rU and rST are the peak responses of each residual solvent obtained
Standard Solution and the Class 1 System Suitability Solution, ..3 from the Test Solution and the Spiked Test Solution, respectively.
and record the peak responses as directed for Procedure: the sig-
nal-to-noise ratio of benzene in the Class 1 Standard Solution is
not less than 5; the signal-to-noise ratio of each peak in the Class 1 WATER-INSOLUBLE ARTICLES
System Suitability Solution is not less than 3; and the resolution, R,
between acetonitrile and .cis-dichloroethene in the Class 2 Mixture A .Procedure A—[NOTE—Dimethy sulfoxide may be substituted as
Standard Solution.3 is not less than 1.0. an alternative solvent to dimethylformamide.]
Procedure—Separately inject (following one of the headspace op- Class 1 Standard Stock Solution—Transfer 1.0 mL of USP Class 1
erating parameter sets described in Table 5) equal volumes of head- Residual Solvents Mixture RS to a 100-mL volumetric flask previ-
space (about 1.0 mL) of the Class 1 Standard Solution, the Class 2 ously filled with about 80 mL of dimethylformamide, dilute with di-
Mixture A Standard Solution, the Class 2 Mixture B Standard Solu- methylformamide to volume, and mix. Transfer 1.0 mL of this
tion, and the Test Solution into the chromatograph, record the chro- solution to a 100-mL volumetric flask, previously filled with about
matograms, and measure the responses for the major peaks. If the 80 mL of dimethylformamide, dilute with dimethylformamide to vol-
peak response(s) in the Test Solution of the peak(s) identified in Pro- ume, and mix. [NOTE—Reserve a portion of this solution for the Class
cedure A is/are greater than or equal to a corresponding peak(s) in 1 System Suitability Solution.] Transfer 1.0 mL of this solution to a
either the Class 1 Standard Solution or either of the two Class 2 Mix- 10-mL volumetric flask, dilute with dimethylformamide to volume,
ture Standard Solutions, proceed to Procedure C to quantify the and mix.
peak(s); otherwise the article meets the requirements of this test. Class 1 Standard Solution—Transfer 1.0 mL of Class 1 Standard
Procedure C— Stock Solution to an appropriate headspace vial, containing 5.0 mL of

Class 1 Standard Stock Solution, Class 1 Standard Solution, Class water, apply the stopper, cap, and mix.
2 Standard Stock Solution A, Class 2 Mixture A Standard Solution, Class 2 Standard Stock Solutions—Transfer 1.0 mL of USP Resid-
Test Stock Solution, Test Solution, and Class 1 System Suitability So- ual Solvents Class 2—Mixture A RS to a 100-mL volumetric flask,
lution—Prepare as directed for Procedure A. previously filled with about 80 mL of dimethylformamide, dilute with
Standard Solution—[NOTE—.Prepare a separate Standard Solution dimethylformamide to volume, and mix. This is Class 2 Standard
for each peak identified and verified by Procedures A and B. For the Stock Solution A. Transfer 0.5 mL of USP Residual Solvents Class
Class 1 solvents other than 1,1,1-trichloroethane, prepare the first di- 2—Mixture B RS to a 10-mL volumetric flask, dilute with dimethyl-
lution as directed for the first dilution under Class 1 Standard Stock formamide to volume, and mix. This is Class 2 Standard Stock Solu-
Solution in Procedure A..3] Transfer an accurately measured volume tion B.
of each individual USP Reference Standard corresponding to each Class 2 Mixture A Standard Solution—Transfer 1.0 mL of Class 2
residual solvent peak identified and verified by Procedures A and B Standard Stock Solution A to an appropriate headspace vial, contain-
to a suitable container, and dilute quantitatively, and stepwise if nec- ing 5.0 mL of water, apply the stopper, cap, and mix.
essary, with water to obtain a solution having a final concentration of Class 2 Mixture B Standard Solution—Transfer 1.0 mL of Class 2
1/20 of the value stated in Table 1 or 2 (under Concentration Limit). Standard Stock Solution B to an appropriate headspace vial, contain-
Transfer 1.0 mL of this solution to an appropriate headspace vial, add ing 5.0 mL of water, apply the stopper, cap, and mix.
5.0 mL of water, apply the stopper, cap, and mix.
Test Stock Solution—Transfer about 500 mg of the article under
Spiked Test Solution—[NOTE—Prepare a separate Spiked Test Solu- test, accurately weighed, to a 10-mL volumetric flask, dissolve in
tion for each peak identified and verified by Procedures A and B.] and dilute with dimethylformamide to volume, and mix.
Transfer 5.0 mL of Test Stock Solution to an appropriate headspace
vial, add 1.0 mL of the Standard Solution, apply the stopper, cap, and Test Solution—Transfer 1.0 mL of Test Stock Solution to an appro-
mix. priate headspace vial, containing 5.0 mL of water, apply the stopper,
cap, and mix.
Chromatographic System (see Chromatography h621i)—[NOTE—
If the results of the chromatography from Procedure A are found to be Class 1 System Suitability Solution—Mix 5 mL of the Test Stock
inferior to those found with Procedure B, the Chromatographic Sys- Solution with 0.5 mL of the intermediate dilution reserved from Class
tem from Procedure B may be substituted.] The gas chromatograph is 1 Standard Stock Solution. Transfer 1.0 mL of this solution to an ap-
equipped with a flame-ionization detector, a 0.32-mm 6 30-m fused- propriate headspace vial, containing 5.0 mL of water, apply the stop-
silica column coated with a 1.8-mm layer of phase G43 or a 0.53-mm per, cap, and mix.
6 30-m wide-bore column coated with a 3.0-mm layer of phase G43. Chromatographic System (see Chromatography h621i—The gas
The carrier gas is nitrogen or helium with a linear velocity of about 35 chromatograph is equipped with a flame-ionization detector, a
cm per second, and a split ratio of 1 : 5. .[NOTE—Split ratio can be 0.53-mm 6 30-m wide-bore column coated with a 3.0-mm layer of
modified in order to optimize sensitivity.].3 The column temperature phase G43. The carrier gas is helium with a linear velocity of about
is maintained at 408 for 20 minutes, then raised at a rate of 108 per 35 cm per second, and a split ratio of 1 : 3. [NOTE—Split ratio can be
minute to 2408, and maintained at 2408 for 20 minutes. The injection modified in order to optimize sensitivity.] The column temperature is
port and detector temperatures are maintained at 1408 and 2508, maintained at 408 for 20 minutes, then raised at a rate of 108 per mi-
respectively. Chromatograph the Class 1 Standard Solution, the Class nute to 2408, and maintained at 2408 for 20 minutes. The injection
1 System Suitability Solution, and the Class 2 Mixture A Standard So- port and detector temperatures are maintained at 1408 and 2508,
Pharmacopeial Forum
respectively. Chromatograph the Class 1 Standard Solution, Class 1 dilute quantitatively, and stepwise if necessary, with water to obtain a
System Suitability Solution, and Class 2 Mixture A Standard Solution, solution having a final concentration of 1/20 of the value stated in
and record the peak responses as directed for Procedure: the signal- Table 1 or Table 2 (under Concentration Limit).
to-noise ratio of 1,1,1-trichloroethane in the Class 1 Standard Solu- Standard Solution—Transfer 1.0 mL of the Standard Stock Solu-
tion is not less than 5; the signal-to-noise ratio of each peak in the tion to an appropriate headspace vial, containing 5.0 mL of water,
Class 1 System Suitability Solution is not less than 3; and the resolu- apply the stopper, cap, and mix.
tion, R, between acetonitrile and methylene chloride in the Class Test Stock Solution—Proceed as directed for Procedure A.
2 Mixture A Standard Solution is not less than 1.0.
Test Solution—Transfer 1.0 mL of the Test Stock Solution to an ap-
Procedure—Separately inject (use headspace operating parameters propriate headspace vial, containing 5.0 mL of water, apply the stop-
3 in Table 5 with a vial pressure of 10 psi) equal volumes of head- per, cap, and mix.
space (about 1.0 mL) of the Class 1 Standard Solution, Class 2 Mix-
ture A Standard Solution, Class 2 Mixture B Standard Solution, and Spiked Test Solution—[NOTE—Prepare a separate Spiked Test Solu-
the Test Solution into the chromatograph, record the chromatograms, tion for each peak identified and verified by Procedures A and B.]
and measure the responses for the major peaks. If a peak response of Transfer 1.0 mL of the Test Stock Solution to an appropriate head-
any peak, other than a peak for 1,1,1-trichloroethane, in the Test So- space vial, add 1 mL of the Standard Stock Solution and 4.0 mL of
lution is greater than or equal to a corresponding peak in either the water, apply the stopper, cap, and mix.
Class 1 Standard Solution or either of the two Class 2 Mixture Stan- Chromatographic System—Proceed as directed for Procedure C
dard Solutions, or a peak response of 1,1,1-trichloroethane is greater under Water-Soluble Articles.
than or equal to 150 times the peak response corresponding to 1,1,1- Procedure—Separately inject (use headspace operating parameters
trichloroethane in the Class 1 Standard Solution, proceed to Proce- 3 in Table 5 with a vial pressure of 10 psi) equal volumes of head-
dure B to verify the identity of the peak; otherwise the article meets space (about 1.0 mL) of the Standard Solution, the Test Solution, and
the requirements of this test. the Spiked Test Solution into the chromatograph, record the chromat-
Procedure B— ograms, and measure the responses for the major peaks. Calculate the
Class 1 Standard Stock Solution, Class 1 Standard Solution, Class amount, in ppm, of each residual solvent found in the article under
1 System Suitability Solution, Class 2 Standard Stock Solutions, Class test by the formula:
2 Mixture A Standard Solution, and Class 2 Mixture B Standard So- 10 (C / W)[rU / (rST – rU)]
lution, Test Stock Solution, and Test Solution—Proceed as directed for
Procedure A. in which C is the concentration, in mg per mL, of the appropriate USP
Chromatographic System—Proceed as directed for Procedure B Reference Standard in the Standard Solution; W is the weight, in g, of
under Water-Soluble Articles with a split ratio of 1 : 3. [NOTE—Split the article under test taken to prepare the Test Stock Solution; and rU
ratio can be modified in order to optimize sensitivity.] and rST are the peak responses of each residual solvent obtained from
Procedure—Separately inject (use headspsce operating parameters the Test Solution and the Spiked Test Solution, respectively..3
3 in Table 5 with a vial pressure of 10 psi) equal volumes of head-
space (about 1.0 mL) of the Class 1 Standard Solution, Class 2 Mix-
ture A Standard Solution, Class 2 Mixture B Standard Solution, and Class 3 Residual Solvents
the Test Solution, into the chromatograph, record the chromatograms, .
and measure the responses for the major peaks. If the peak respon- If Class 3 solvents are present, the level of residual solvents may

se(s) in the Test Solution of the peak(s) identified in Procedure A be determined as directed under Loss on Drying h731i when the
is/are greater than or equal to a corresponding peak(s) in either the monograph for the article under test contains a loss on drying proce-
Class 1 Standard Solution or any of the two Class 2 Mixture Standard dure, or a specific determination of the solvent may be made. If there
Solutions, proceed to Procedure C to quantify the peak(s); otherwise is no loss on drying procedure in the monograph for the article under
the article meets the requirements of this test. test or if.3 a Class 3 solvent limit in an individual monograph is great-
er than 50 mg per day (corresponding to 5000 ppm or 0.5% under
Procedure C— Option 1), .the individual Class 3 residual solvent or solvents present
Class 1 Standard Stock Solution, Class 1 Standard Solution, Class in the article under test.3 should be identified and quantified, and the
1 System Suitability Solution, Class 2 Standard Stock Solution A, and procedures as described above, with appropriate modifications to the
Class 2 Mixture A Standard Solution—Proceed as directed for Proce- standard solutions, are to be applied wherever possible. Otherwise an
dure A. appropriate validated procedure is to be employed. ..3 USP Refer-
Standard Stock Solution—[NOTE—Prepare a separate Standard So- ence Standards, where available, should be used in these procedures.
lution for each peak identified and verified by Procedures A and B.] A flow diagram for the application of residual solvent limit tests is
Transfer an accurately measured volume of each individual USP Ref- shown in Figure 1.
erence Standard corresponding to each residual solvent peak identi-
fied and verified by Procedures A and B to a suitable container, and
Pharmacopeial Forum
Figure 1. Diagram relating to the identification of residual solvents and the application of limit tests.
Class 1 and Class 2 Residual Solvents

h467i RESIDUAL SOLVENTS .The following procedures are useful to identify and quantify re-
sidual solvents when the information regarding which solvents are
(Chapter under this new title—to become official July 1, 2007)
likely to be present in the material is not available. When the infor-
(Current chapter title is h467i Organic Volatile Impurities)
mation about the presence of specific residual solvents is available,
only Procedure C is needed to quantify the amount of residual sol-
vents present..3
Change to read:
WATER-SOLUBLE ARTICLES
IDENTIFICATION, CONTROL, AND
QUANTIFICATION OF RESIDUAL SOLVENTS Procedure A—
.Whenever possible, the substance under test needs to be dissolved Class 1 Standard Stock Solution—Transfer 1.0 mL of USP Class 1
Residual Solvents Mixture RS to a 100-mL volumetric flask, add 9
to release the residual solvent. Because the USP deals with drug prod- mL of dimethyl sulfoxide, dilute with water to volume, and mix.
ucts, as well as active ingredients and excipients, it may be acceptable Transfer 1.0 mL of this solution to a 100-mL volumetric flask, dilute
that in cases some of the components of the formulation will not dis- with water to volume, and mix. Transfer 1.0 mL of this solution to a
solve completely. In those cases, the drug product may first need to be 10-mL volumetric flask, dilute with water to volume, and mix.
pulverized into a fine powder so that any residual solvent that may be
present can be released. This operation should be as fast as possible to Class 1 Standard Solution—Transfer 1.0 mL of Class 1 Standard
prevent the loss of volatile solvents during the procedure..3 Stock Solution to an appropriate headspace vial, add 5.0 mL of water,
apply the stopper, cap, and mix.
NOTE—The organic-free water specified in the following proce- Class 2 Standard Stock Solutions—Transfer 1.0 mL of USP Resid-
dures produces no significantly interfering peaks when chromato- ual Solvents Class 2—Mixture A RS to a 100-mL volumetric flask,
graphed. dilute with water to volume, and mix. This is Class 2 Standard Stock
Pharmacopeial Forum
Solution A. Transfer 1.0 mL of USP Residual Solvents Class 2—Mix- Procedure B—

ture B RS to a 100-mL volumetric flask, dilute with water to volume, Class 1 Standard Stock Solution, Class 1 Standard Solution, Class
and mix. This is Class 2 Standard Stock Solution B. 2 Standard Stock Solutions, Class 2 Mixture A Standard Solution,
Class 2 Mixture A Standard Solution—Transfer 1.0 mL of Class 2 Class 2 Mixture B Standard Solution, Test Stock Solution, Test Solu-
Standard Stock Solution A to an appropriate headspace vial, add 5.0 tion, and Class 1 System Suitability Solution—Prepare as directed for
mL of water, apply the stopper, cap, and mix. Procedure A.
Class 2 Mixture B Standard Solution—Transfer 5.0 mL of Class 2 .
.3
Standard Stock Solution B to an appropriate headspace vial, add 1.0 Chromatographic System (see Chromatography h621i)—The gas
mL of water, apply the stopper, cap, and mix. chromatograph is equipped with a flame-ionization detector, a
Test Stock Solution—Transfer about 250 mg of the article under 0.32-mm 6 30-m fused-silica column coated with a 0.25-mm layer
test, accurately weighed, to a 25-mL volumetric flask, dissolve in of phase G16, or a 0.53-mm 6 30-m wide-bore column coated with a
and dilute with water to volume, and mix. 0.25-mm layer of phase G16. The carrier gas is nitrogen or helium
Test Solution—Transfer 5.0 mL of Test Stock Solution to an appro- with a linear velocity of about 35 cm per second and a split ratio of
priate headspace vial, add 1.0 mL of water, apply the stopper, cap, 1 : 5. .[NOTE—Split ratio can be modified in order to optimize sensi-
and mix. tivity.].3 The column temperature is maintained at 508 for 20 minutes,
Class 1 System Suitability Solution—Transfer 1.0 mL of Class 1 then raised at a rate of 68 per minute to 1658, and maintained at 1658
Standard Stock Solution to an appropriate headspace vial, add 5.0 mL for 20 minutes. The injection port and detector temperatures are main-
of Test Stock Solution, apply the stopper, cap, and mix. tained at 1408 and 2508, respectively. Chromatograph the Class 1
Standard Solution and the Class 1 System Suitability Solution, ..3
Chromatographic System (see Chromatography h621i)—The gas and record the peak responses as directed for Procedure: the sig-
chromatograph is equipped with a flame-ionization detector, a nal-to-noise ratio of benzene in the Class 1 Standard Solution is
0.32-mm 6 30-m fused-silica column coated with a 1.8-mm layer not less than 5; the signal-to-noise ratio of each peak in the Class 1
of phase G43 or a 0.53-mm 6 30-m wide-bore column coated with System Suitability Solution is not less than 3; and the resolution, R,
a 3.0-mm layer of phase G43. The carrier gas is nitrogen or helium between acetonitrile and .cis-dichloroethene in the Class 2 Mixture A
with a linear velocity of about 35 cm per second, and a split ratio Standard Solution.3 is not less than 1.0.
of 1 : 5. .[NOTE—Split ratio can be modified in order to optimize sen-
sitivity.].3 The column temperature is maintained at 408 for 20 min- Procedure—Separately inject (following one of the headspace op-
utes, then raised at a rate of 108 per minute to 2408, and maintained at erating parameter sets described in Table 5) equal volumes of head-
2408 for 20 minutes. The injection port and detector temperatures are space (about 1.0 mL) of the Class 1 Standard Solution, the Class
maintained at 1408 and 2508, respectively. Chromatograph the Class 2 Mixture A Standard Solution, the Class 2 Mixture B Standard Solu-
1 Standard Solution, Class 1 System Suitability Solution, and Class tion, and the Test Solution into the chromatograph, record the chro-
2 Mixture A Standard Solution, and record the peak responses as di- matograms, and measure the responses for the major peaks. If the
rected for Procedure: the signal-to-noise ratio of 1,1,1-trichloroeth- peak response(s) in the Test Solution of the peak(s) identified in Pro-
ane in the Class 1 Standard Solution is not less than 5; the signal- cedure A is/are greater than or equal to a corresponding peak(s) in
to-noise ratio of each peak in the Class 1 System Suitability Solution either the Class 1 Standard Solution or either of the two Class 2 Mix-
is not less than 3; and the resolution, R, between acetonitrile and ture Standard Solutions, proceed to Procedure C to quantify the
methylene chloride in the Class 2 Mixture A Standard Solution is peak(s); otherwise the article meets the requirements of this test.
not less than 1.0. Procedure C—

Procedure—Separately inject (following one of the headspace op- Class 1 Standard Stock Solution, Class 1 Standard Solution, Class
erating parameter sets described in the table below) equal volumes of 2 Standard Stock Solution A, Class 2 Mixture A Standard Solution,
headspace (about 1.0 mL) of the Class 1 Standard Solution, Class Test Stock Solution, Test Solution, and Class 1 System Suitability So-
2 Mixture A Standard Solution, Class 2 Mixture B Standard Solution, lution—Prepare as directed for Procedure A.
and the Test Solution into the chromatograph, record the chromato- Standard Solution—[NOTE—.Prepare a separate Standard Solution
grams, and measure the responses for the major peaks. .If a peak re- for each peak identified and verified by Procedures A and B. For the
sponse of any peak, other than a peak for 1,1,1-trichloroethane, in the Class 1 solvents other than 1,1,1-trichloroethane, prepare the first di-
Test Solution is greater than or equal to a corresponding peak in either lution as directed for the first dilution under Class 1 Standard Stock
the Class 1 Standard Solution or either of the two Class 2 Mixture Solution in Procedure A..3] Transfer an accurately measured volume
Standard Solutions, or a peak response of 1,1,1-trichloroethane is of each individual USP Reference Standard corresponding to each
greater than or equal to 150 times the peak response corresponding residual solvent peak identified and verified by Procedures A and B
to 1,1,1-trichloroethane in the Class 1 Standard Solution, proceed to to a suitable container, and dilute quantitatively, and stepwise if nec-
Procedure B to verify the identity of the peak; otherwise the article essary, with water to obtain a solution having a final concentration of
meets the requirements of this test..3 1/20 of the value stated in Table 1 or 2 (under Concentration Limit).
Transfer 1.0 mL of this solution to an appropriate headspace vial, add
Table 5. Headspace Operating Parameters 5.0 mL of water, apply the stopper, cap, and mix.
Spiked Test Solution—[NOTE—Prepare a separate Spiked Test Solu-
Headspace Operating tion for each peak identified and verified by Procedures A and B.]
Parameter Sets Transfer 5.0 mL of Test Stock Solution to an appropriate headspace
1 2 3 vial, add 1.0 mL of the Standard Solution, apply the stopper, cap, and
mix.
Equilibration temperature (8) 80 105 80
Equilibration time (min.) 60 45 45 Chromatographic System (see Chromatography h621i)—[NOTE—
Transfer-line temperature (8) 85 110 105 If the results of the chromatography from Procedure A are found to be
Carrier gas: nitrogen or helium at an appropriate pressure inferior to those found with Procedure B, the Chromatographic Sys-
Pressurization time (s) 30 30 30 tem from Procedure B may be substituted.] The gas chromatograph is
Injection volume (mL) 1 1 1 equipped with a flame-ionization detector, a 0.32-mm 6 30-m fused-
silica column coated with a 1.8-mm layer of phase G43 or a 0.53-mm
6 30-m wide-bore column coated with a 3.0-mm layer of phase G43.
The carrier gas is nitrogen or helium with a linear velocity of about 35
cm per second, and a split ratio of 1 : 5. .[NOTE—Split ratio can be
modified in order to optimize sensitivity.].3 The column temperature
is maintained at 408 for 20 minutes, then raised at a rate of 108 per
minute to 2408, and maintained at 2408 for 20 minutes. The injection
port and detector temperatures are maintained at 1408 and 2508,
respectively. Chromatograph the Class 1 Standard Solution, the Class
1 System Suitability Solution, and the Class 2 Mixture A Standard So-
lution, and record the peak responses as directed for Procedure: the
Pharmacopeial Forum
signal-to-noise ratio of 1,1,1-trichloroethane in the Class 1 Standard 1 System Suitability Solution, and Class 2 Mixture A Standard Solu-
Solution is not less than 5; the signal-to-noise ratio of each peak in the tion, and record the peak responses as directed for Procedure: the sig-
Class 1 System Suitability Solution is not less than 3; and the resolu- nal-to-noise ratio of 1,1,1-trichloroethane in the Class 1 Standard
tion, R, between acetonitrile and methylene chloride in the Class Solution is not less than 5; the signal-to-noise ratio of each peak in
2 Mixture A Standard Solution is not less than 1.0. the Class 1 System Suitability Solution is not less than 3; and the re-
Procedure—Separately inject (following one of the headspace op- solution, R, between acetonitrile and methylene chloride in the Class
erating parameters described in Table 5) equal volumes of headspace 2 Mixture A Standard Solution is not less than 1.0.
(about 1.0 mL) of the Standard Solution, the Test Solution, and the Procedure—Separately inject (use headspace operating parameters
Spiked Test Solution into the chromatograph, record the chromato- 3 in Table 5 with a vial pressure of 10 psi) equal volumes of head-
grams, and measure the responses for the major peaks. Calculate space (about 1.0 mL) of the Class 1 Standard Solution, Class 2 Mix-
the amount, in ppm, of each residual solvent found in the article under ture A Standard Solution, Class 2 Mixture B Standard Solution, and
test by the formula: the Test Solution into the chromatograph, record the chromatograms,
and measure the responses for the major peaks. If a peak response of
5(C/W)[rU /(rST – rU)] any peak, other than a peak for 1,1,1-trichloroethane, in the Test So-
in which C is the concentration, in .mg per mL,.3 of the appropriate lution is greater than or equal to a corresponding peak in either the
USP Reference Standard in the Standard Solution; W is the weight, in Class 1 Standard Solution or either of the two Class 2 Mixture Stan-
g, of the article under test taken to prepare the Test Stock Solution; and dard Solutions, or a peak response of 1,1,1-trichloroethane is greater
rU and rST are the peak responses of each residual solvent obtained than or equal to 150 times the peak response corresponding to 1,1,1-
from the Test Solution and the Spiked Test Solution, respectively. trichloroethane in the Class 1 Standard Solution, proceed to Proce-
dure B to verify the identity of the peak; otherwise the article meets
the requirements of this test.
WATER-INSOLUBLE ARTICLES Procedure B—
Class 1 Standard Stock Solution, Class 1 Standard Solution, Class
.Procedure A—[NOTE—Dimethy sulfoxide may be substituted as 1 System Suitability Solution, Class 2 Standard Stock Solutions, Class
an alternative solvent to dimethylformamide.] 2 Mixture A Standard Solution, and Class 2 Mixture B Standard So-
Class 1 Standard Stock Solution—Transfer 1.0 mL of USP Class 1 lution, Test Stock Solution, and Test Solution—Proceed as directed for
Residual Solvents Mixture RS to a 100-mL volumetric flask previ- Procedure A.
ously filled with about 80 mL of dimethylformamide, dilute with di- Chromatographic System—Proceed as directed for Procedure B
methylformamide to volume, and mix. Transfer 1.0 mL of this under Water-Soluble Articles with a split ratio of 1 : 3. [NOTE—Split
solution to a 100-mL volumetric flask, previously filled with about ratio can be modified in order to optimize sensitivity.]
80 mL of dimethylformamide, dilute with dimethylformamide to vol- Procedure—Separately inject (use headspsce operating parameters
ume, and mix. [NOTE—Reserve a portion of this solution for the Class 3 in Table 5 with a vial pressure of 10 psi) equal volumes of head-
1 System Suitability Solution.] Transfer 1.0 mL of this solution to a space (about 1.0 mL) of the Class 1 Standard Solution, Class 2 Mix-
10-mL volumetric flask, dilute with dimethylformamide to volume, ture A Standard Solution, Class 2 Mixture B Standard Solution, and
and mix. the Test Solution, into the chromatograph, record the chromatograms,
Class 1 Standard Solution—Transfer 1.0 mL of Class 1 Standard and measure the responses for the major peaks. If the peak respon-
Stock Solution to an appropriate headspace vial, containing 5.0 mL of se(s) in the Test Solution of the peak(s) identified in Procedure A
water, apply the stopper, cap, and mix. is/are greater than or equal to a corresponding peak(s) in either the
Class 2 Standard Stock Solutions—Transfer 1.0 mL of USP Resid- Class 1 Standard Solution or any of the two Class 2 Mixture Standard
ual Solvents Class 2—Mixture A RS to a 100-mL volumetric flask, Solutions, proceed to Procedure C to quantify the peak(s); otherwise
previously filled with about 80 mL of dimethylformamide, dilute with the article meets the requirements of this test.
dimethylformamide to volume, and mix. This is Class 2 Standard Procedure C—
Stock Solution A. Transfer 0.5 mL of USP Residual Solvents Class Class 1 Standard Stock Solution, Class 1 Standard Solution, Class
2—Mixture B RS to a 10-mL volumetric flask, dilute with dimethyl- 1 System Suitability Solution, Class 2 Standard Stock Solution A, and
formamide to volume, and mix. This is Class 2 Standard Stock Solu- Class 2 Mixture A Standard Solution—Proceed as directed for Proce-
tion B. dure A.
Class 2 Mixture A Standard Solution—Transfer 1.0 mL of Class 2 Standard Stock Solution—[NOTE—Prepare a separate Standard So-
Standard Stock Solution A to an appropriate headspace vial, contain- lution for each peak identified and verified by Procedures A and B.]
ing 5.0 mL of water, apply the stopper, cap, and mix. Transfer an accurately measured volume of each individual USP Ref-
Class 2 Mixture B Standard Solution—Transfer 1.0 mL of Class 2 erence Standard corresponding to each residual solvent peak identi-
Standard Stock Solution B to an appropriate headspace vial, contain- fied and verified by Procedures A and B to a suitable container, and
ing 5.0 mL of water, apply the stopper, cap, and mix. dilute quantitatively, and stepwise if necessary, with water to obtain a
Test Stock Solution—Transfer about 500 mg of the article under solution having a final concentration of 1/20 of the value stated in
test, accurately weighed, to a 10-mL volumetric flask, dissolve in Table 1 or Table 2 (under Concentration Limit).
and dilute with dimethylformamide to volume, and mix. Standard Solution—Transfer 1.0 mL of the Standard Stock Solu-
Test Solution—Transfer 1.0 mL of the Test Stock Solution to an ap- tion to an appropriate headspace vial, containing 5.0 mL of water,
propriate headspace vial, containing 5.0 mL of water, apply the stop- apply the stopper, cap, and mix.
per, cap, and mix. Test Stock Solution—Proceed as directed for Procedure A.
Class 1 System Suitability Solution—Mix 5 mL of the Test Stock Test Solution—Transfer 1.0 mL of the Test Stock Solution to an ap-
Solution with 0.5 mL of the intermediate dilution reserved from Class propriate headspace vial, containing 5.0 mL of water, apply the stop-
1 Standard Stock Solution. Transfer 1.0 mL of this solution to an ap- per, cap, and mix.
propriate headspace vial, containing 5.0 mL of water, apply the stop- Spiked Test Solution—[NOTE—Prepare a separate Spiked Test Solu-
per, cap, and mix. tion for each peak identified and verified by Procedures A and B.]
Chromatographic System (see Chromatography h621i—The gas Transfer 1.0 mL of the Test Stock Solution to an appropriate head-
chromatograph is equipped with a flame-ionization detector, a space vial, add 1 mL of the Standard Stock Solution and 4.0 mL of
0.53-mm 6 30-m wide-bore column coated with a 3.0-mm layer of water, apply the stopper, cap, and mix.
phase G43. The carrier gas is helium with a linear velocity of about Chromatographic System—Proceed as directed for Procedure C
35 cm per second, and a split ratio of 1 : 3. [NOTE—Split ratio can be under Water-Soluble Articles.
modified in order to optimize sensitivity.] The column temperature is Procedure—Separately inject (use headspace operating parameters
maintained at 408 for 20 minutes, then raised at a rate of 108 per mi- 3 in Table 5 with a vial pressure of 10 psi) equal volumes of head-
nute to 2408, and maintained at 2408 for 20 minutes. The injection space (about 1.0 mL) of the Standard Solution, the Test Solution, and
port and detector temperatures are maintained at 1408 and 2508, the Spiked Test Solution into the chromatograph, record the chromat-
respectively. Chromatograph the Class 1 Standard Solution, Class
Pharmacopeial Forum
ograms, and measure the responses for the major peaks. Calculate the dure, or a specific determination of the solvent may be made. If there
amount, in ppm, of each residual solvent found in the article under is no loss on drying procedure in the monograph for the article under
test by the formula: test or if.3 a Class 3 solvent limit in an individual monograph is great-
er than 50 mg per day (corresponding to 5000 ppm or 0.5% under
10 (C / W)[rU / (rST – rU)] Option 1), .the individual Class 3 residual solvent or solvents present
in which C is the concentration, in mg per mL, of the appropriate USP in the article under test.3 should be identified and quantified, and the
Reference Standard in the Standard Solution; W is the weight, in g, of procedures as described above, with appropriate modifications to the
the article under test taken to prepare the Test Stock Solution; and rU standard solutions, are to be applied wherever possible. Otherwise an
and rST are the peak responses of each residual solvent obtained from appropriate validated procedure is to be employed. ..3 USP Refer-
the Test Solution and the Spiked Test Solution, respectively..3 ence Standards, where available, should be used in these procedures.
A flow diagram for the application of residual solvent limit tests is
shown in Figure 1.
Class 3 Residual Solvents
.
If Class 3 solvents are present, the level of residual solvents may
be determined as directed under Loss on Drying h731i when the
monograph for the article under test contains a loss on drying proce-
Figure 1. Diagram relating to the identification of residual solvents and the application of limit tests.
Pharmacopeial Forum
ERRATA
official publication of USP–NF. If necessary, this list will be updated with every issue of PF. This information will also be available as a cu-
mulative table in future Supplements and will appear in its corrected form in a future annual edition of USP–NF. Errata are considered to be items
erroneously published that have not received the approval of the Council of Experts and that do not reflect the official requirement. USP staff is
USP30–NF25
Page Title Section Description
183 h467i Residual Solvents Limits of Residual Solvents Line 4 of NOTE under Class 2: Change ‘‘section of this
General Chapter: formamide, 2-ethoxyethanol, N-
methylpyrrolidone, and sulfolane.’’ to: section of this
General Chapter: formamide, 2-ethoxyethanol, 2-
methoxyethanol, ethylene glycol, N-methylpyrroli-
done, and sulfolane.
1806 Clorazepate Dipotassium Tab- Related Compounds Change ‘‘USP 7-Chloro-1,3-dihydro-5-phenyl-2H-
lets 1,4-benzodiazepin-2-one RS’’ and ‘‘7-chloro-1,3-dihy-
dro-5-phenyl-2H-1,4-benzodiazepin-2-one’’ to: USP
Nordazepam RS and nordazepam, respectively,
throughout.
2320 Hyoscyamine Sulfate Definition Line 3 under Definition: Change ‘‘calculated on the
dried basis.’’ to: calculated on the anhydrous basis.
First Supplement to USP30–NF25
3672 h1080i Bulk Pharmaceutical Testing Frequency Line 6 under Documentation: Delete ‘‘For further in-
Excipients—Certificate of Ana- formation on excipient changes, see Significant
lysis Change Guide for Bulk Pharmaceutical Excipients
h1195i.’’
Online First Supplement to USP30–NF25
Ranitidine Injection Assay Replace four subsections as follows:
Replace Mobile phase with:
Mobile phase—Prepare a filtered and degassed mixture
of methanol and 0.1 M aqueous ammonium acetate
(85:15). Make adjustments if necessary (see System

Replace Standard preparation with:
Standard preparation—Dissolve an accurately
weighed quantity of USP Ranitidine Hydrochloride
RS in Mobile phase to obtain a solution having a
known concentration of about 0.112 mg (equivalent
to 0.100 mg of ranitidine base) per mL.
Replace Resolution solution with:
System suitability solution—Dissolve accurately
weighed quantities of USP Ranitidine Hydrochloride
RS and USP Ranitidine Related Compound C RS in
Mobile phase to obtain a solution having known con-
centrations of about 0.112 mg per mL and 0.01 mg per
mL, respectively.
Replace Chromatographic system with:
Chromatographic system (see Chromatography
h621i)—The liquid chromatograph is equipped with
a 322-nm detector and a 4.6-mm 6 20- to 30-cm col-
umn that contains packing L1. The flow rate is about 2
mL per minute. Chromatograph the System suitability
Procedure: the resolution, R, between ranitidine hydro-
chloride and N-[2-[[[5-[(dimethylamino)methyl]-2-fur-
anyl]methyl]sulfinyl]ethyl]-N’-methyl-2-nitro-1,1-
ethenediamine (ranitidine related compound C) is not
less than 1.5. Chromatograph the Standard prepara-
tion, and record the peak responses as directed for
Procedure: the tailing factor for the ranitidine hydro-
chloride peak is not more than 2.0; the column effi-
ciency determined from the ranitidine hydrochloride
peak is not less than 700 theoretical plates; and the re-
lative standard deviation for replicate injections is not
more than 2%.
Ranitidine Oral Solution Assay Change ‘‘Mobile phase, Standard preparation, Reso-
lution solution, and Chromatographic system—’’ to:
Mobile phase, Standard preparation, System suitabili-
ty solution, and Chromatographic system—
Pharmacopeial Forum
USP30–NF25
Ranitidine Tablets Assay Change ‘‘Mobile phase, Standard preparation, Reso-
lution solution, and Chromatographic system—’’ to:
Ranitidine in Sodium Chloride Assay for ranitidine Change ‘‘Mobile phase, Standard preparation, Reso-
Injection lution solution, and Chromatographic system—’’ to:
IN-PROCESS REVISION

BRIEFING
(DSN: L. Evans) RTS—C55678
.
new text.
~
new text~USP31
&
new text&
In-Process Revision
~
&
revision will appear if approved. For example, .2 indicates that the revision is proposed for the Interim Revision Announcement that
will appear in issue 2 of a given PF volume, &2S (USP 30) indicates that the proposed revision is slated for the Second Supplement to
USP 30, and ~USP31 and ~NF26 indicate that the revisions are proposed for USP 31 and NF 26, respectively.
becomes official.
Pharmacopeial Forum
386 IN-PROCESS REVISION Vol. 33(3) [May–June 2007]

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Acarbose [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Acitretin [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Acitretin Capsules [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
Benzonatate Capsules (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Cilostazol Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Colchicine (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Dihydrocodeine Bitartate (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Esomeprazole Magenesium [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Fluconazole (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Formoterol Fumarate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
Fosinopril Sodium Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Galantamine Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407
Glimepiride Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
Isosorbide Mononitrate Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Levalbuterol Hydrochloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
Levalbuterol Inhalation Solution [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420
Levothyroxine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422
Liothyronine Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426
Lorazepam (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Lorazepam Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Mirtazapine (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Norethindrone Acetate and Ethinyl Estradiol Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Norethindrone Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Ofloxacin Tablets [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Omeprazole Magnesium [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Ondansetron Orally Disintegrating Tablets (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Oxandrolone Tablets (Proposal for 4th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Protein A [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
rProtein A, C-Cys [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
rProtein A [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
rProtein A, B4, C-Cys [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
Reserpine Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Sodium Fluoride and Acidulated Phosphate Topical Solution (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . 454
Sodium Fluoride and Phosphoric Acid Gel (Proposal for 5th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Sulfamethoxazole (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Sulisobenzone (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Sumatriptan Succinate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Terbinafine Hydrochloride [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Topiramate [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Valsartan (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Warfarin Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Warfarin Sodium for Injection (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Warfarin Sodium Tablets (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
In-Process Revision

Fish Oil Containing Omega-3 Acids [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Fish Oil Containing Omega-3 Acids Capsules [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Ginger (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Powdered Ginger (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Excipients, USP and NF Excipients, Listed by Category (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
Calcium Silicate (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
Hydrogenated Polydecene [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Hydrogenated Starch Hydrolysate [new] (1st Supp to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Sodium Caprylate (1st to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
h1i Injections (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
h11i USP Reference Standards (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
h525i Sulfur Dioxide [new] (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] IN-PROCESS REVISION 387
Reagent Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503

Reagent Specifications Introduction (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Docusate Sodium (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
Tetrabutylammonium Iodide (1st Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
REFERENCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Container Specifications for Capsules and Tablets (1st Supp to USP31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505
Description and Solubility (1st Supp to USP 31 and to NF 26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507
PREVIOUS PF PROPOSALS STILL PENDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509
CANCELED PROPOSALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
In-Process Revision
Pharmacopeial Forum
MONOGRAPHS (USP) B: The retention time of the acarbose peak in the

BRIEFING in the Assay.
Specific rotation h781Si: between +1688 and +1838.

Acarbose. Because there is no existing USP monograph for this
article, a new monograph is being proposed. The liquid chromat- Test solution: 10 mg per mL, in water.
ographic procedures in the test for Related compounds and in the
Assay are based on analyses performed with the Hypersil APS 2 pH h791i: between 5.5 and 7.5, in a solution containing 50
brand of L8 column. The typical retention time for acarbose is 16.5
minutes. mg per mL.
(BB PP: L. Callahan) RTS—C50968 Water, Method Ic h921i: not more than 4.0%.
Residue on ignition h281i: not more than 0.2% determined

on 1.0 g.
Add the following: Heavy metals, Method II h231i: 0.002%.
&Acarbose Related compounds—

Mobile phase, System suitablity solution, and
Diluted test solution—Transfer 1.0 mL of the Test solution
to a 100-mL volumetric flask, dilute with water to volume,
C25H43NO18 645.60
and mix.
D-Glucose, O-4,6-dideoxy-4-[[[1S-(1a,4a,5b,6a)]-4,5,6-trihy-
droxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]amino]-a-
of the Test solution and Diluted test solution into the
D-glucopyranosyl-(1?4)-O-a-D-glucopyranosyl-(1?4)-.
O -4,6-Dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hy-
peak responses. Calculate the percentage of each impurity in
droxymethyl)-2-cyclohexen-1-yl]amino]-a-D-glucopy-
the portion of Acarbose taken by the formula:
ranosyl-(1?4)-O-a- D -glucopyranosyl-(1?4)- D -glu-
cose [56180-94-0]. (1/F)(ri / rA)
In-Process Revision
in which F is the relative response factor for each impurity, as

» Acarbose is produced by certain strains of
listed in Table 1; ri is the individual peak response for each
Actinoplanes utahensis. It contains not less than
impurity; and rA is the response of the main acarbose peak in
95.0 percent and not more than 102.0 percent of
the chromatogram obtained from the Diluted test solution. In
C25H43NO18, calculated on the anhydrous basis. addition to not exceeding the limits for each impurity in Table
Packaging and storage—Preserve in tight containers. 1, not more than 3.0% of total impurites is found.
USP Reference standards h11i—USP Acarbose RS. USP

Acarbose System Suitability Mixture RS. Assay—
Phosphate buffer—Dissolve 0.6 g of monobasic potassium
Identification—
phosphate and 0.35 g of dibasic sodium phosphate in 900 mL
of water, dilute with water to 1 L, and mix.
Pharmacopeial Forum
Table 1
Approximate
Relative Relative
Retention Response
Time Factor (F) Name Limit (%)
0.9 1 Impurity A 1 0.6%
0.8 1.6 Impurity B2 0.5%
1.2 1 Impurity C3 1.5%
0.5 1.33 Impurity D4 1.0%
1.7 0.8 Impurity E5 0.2%
1.9 0.8 Impurity F6 0.3%
2.2 0.8 Impurity G7 0.3%
0.6 1 Impurity H8 0.2%
Any individual unknown 0.2%
impurity
1
O-4,6-Dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl-(1?4)-O-a-D-glucopy-
ranosyl-(1?4)-D-arabino-hex-2-ulopyranose
2
(1R,4R,5S,6R)-4,5,6-Trihydroxy-2-(hydroxymethyl)cyclohex-2-enyl 4-O-[4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxy-
methyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl]-a-D-glucopyranoside
3
a-D-Glucopyranosyl 4-O-[4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl]-
a-D-glucopyranoside
4
4-O-[4,6-Dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl]-D-glucopyranose
5
ranosyl-(1?4)-O-a-D-glucopyranosyl-(1?4)-D-arabino-hex-2-ulopyranose (4-O-a-acarbosyl-D-fructopyranose)
6
ranosyl-(1?4)-O-a-D-glucopyranosyl-(1?4)-D-glucopyranose (4-O-a-acarbosyl-D-glucopyranose)
7
a-D-Glucopyranosyl O-4,6-dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl-
(1?4)-O-a-D-glucopyranosyl-(1?4)-O-a-D-glucopyranoside (a-D-glucopyranosyl a-acarboside)
8
O-4,6-Dideoxy-4-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-enyl]amino]-a-D-glucopyranosyl-(1?4)-O-6-deoxy-a-D-
glucopyranosyl-(1?4)-D-glucopyranose
Mobile phase—Prepare a mixture of acetonitrile and flow rate is about 2 mL per minute. The column temperature
Phosphate buffer (750 : 250). Make adjustments if necessary is maintained at 358. Chromatograph the System suitablity
(see System Suitability under Chromatography h621i). solution, and identify the acarbose peak and the peaks due to
In-Process Revision
Standard preparation—Reconstitute a vial of USP Acar- the impurities listed in Table 1. Record the peak responses as
bose RS in 5.0 mL of water. directed for Procedure: the ratio of the height of the impurity
System suitablity solution—Reconstitute a vial of USP A peak to the height of the valley between the impurity A
Acarbose System Suitability Mixture RS in 1 mL of water. peak and acarbose peak is not less than 1.2. The
Assay preparation—Transfer about 200 mg of Acarbose, chromatogram obtained is similar to the chromatogram
accurately weighed, to a 10-mL volumetric flask, dissolve in supplied with USP Acarbose System Suitability Mixture RS.
and dilute with water to volume, and mix. Procedure—Separately inject equal volumes (about 10 mL)
Chromatographic system (see Chromatography h621i)— of the Standard preparation and the Assay preparation into
The liquid chromatograph is equipped with a 210-nm detector the chromatograph, record the chromatograms, and measure
and a 4-mm 6 25-cm column that contains packing L8. The
Pharmacopeial Forum
the responses for all of the peaks. Calculate the quantity, in » Acitretin contains not less than 98.0 percent and
mg, of C25H43NO18 in the portion of Acarbose taken by the not more than 102.0 percent of C21H26O3, calcu-
formula:
lated on the dried basis.
Caution—Acitretin is a teratogen. Great care
10C(rU / rS)
should be taken when handling to avoid inhalation
in which C is the concentration, in mg per mL, of USP of dust or contact with skin.
Acarbose RS in the Standard preparation; and rU and rS are NOTE—Use low actinic glassware and perform
the acarbose peak responses obtained from the Assay
all tests under yellow and subdued light.
tively.&1S (USP31)
Packaging and storage—Preserve in tight containers,
protected from light. Store at controlled room temperature.
USP Reference standards h11i—USP Acitretin RS. USP

BRIEFING Acitretin Related Compound A RS. USP Acitretin Related
Compound B RS. USP Tretinoin RS.
Acitretin. Because there is no existing USP monograph for this
drug substance, a new monograph, based on validated methods of
analysis, is being proposed. The liquid chromatographic procedures Identification—
in the test for Related compounds and in the Assay are based on
analyses performed with the LiChroCART 250-4 LiChrospher PAH A: Infrared Absorption h197Ki.
brand of L1 column. The typical retention time for the acitretin peak
is about 5.8 minutes. B: The retention time of the major peak in the
(MD-OOD: L. Evans) RTS—C39916
in the Assay.
Loss on drying—Dry it in vacuum at a pressure not

Add the following: exceeding 19 mm of mercury at 1008 for 4 hours: it loses
&Acitretin
Heavy metals, Method I h231i: not more than 0.002%.

In-Process Revision
Mobile phase—Proceed as directed in the Assay.
Standard solution—Dissolve 2.0 mg each of USP Acitretin
C21H26O3 326.43
RS, USP Acitretin Related Compound A RS, and USP
2,4,6,8-Nonatetraenoic acid, 9-(4-methoxy-2,3,6-trimethyl- Acitretin Related Compound B RS, accurately weighed, in
phenyl)-3,7-dimethyl-, (all-E)-. 2.5 mL of tetrahydrofuran, and dilute quantitatively with

alcohol to obtain a solution having known concentrations of
(all-E)-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-
0.8 mg per mL of each. [NOTE—Store the solution at 48 prior
2,4,6,8-nonatetraenoic acid [55079-83-9].
to injection.]
Pharmacopeial Forum
Test solution—Transfer about 25 mg of Acitretin, accurate- in which C is the concentration, in mg per mL, of USP
ly weighed, to a 100-mL volumetric flask, dissolve in 5 mL of Acitretin RS in the Standard solution; W is the quantity, in
tetrahydrofuran, dilute with alcohol to volume, and mix. mg, of Acitretin taken; rU is the peak response of each
[NOTE—Store the solution at 48 prior to injection.] individual unspecified impurity in the Test solution; and rS is
Chromatographic system (see Chromatography h621i)— the peak response of USP Acitretin RS in the Standard
Proceed as directed in the Assay. Chromatograph the solution: not more than 0.1% of any individual unspecified
Standard solution, and record the peak responses as directed impurity is found; not more than 0.4% of total unspecified
for Procedure: the resolution, R, between USP Acitretin impurities is found; and not more than 1.0% of total
Related Compound A RS (relative retention time of about impurities is found.
0.78) and USP Acitretin RS is not less than 1.5; the Assay—
resolution, R, between USP Acitretin Related Compound B Mobile phase—Prepare a filtered and degassed mixture of
RS (relative retention time of about 1.61) and USP Acitretin alcohol, water, and glacial acetic acid (92 : 8 : 0.3). Make
RS is not less than 1.5; and the relative standard deviation for adjustments if necessary (see System Suitability under
replicate injections is not more than 10.0% for acitretin Chromatography h621i).
related compound A and not more than 10.0% for acitretin System suitability preparation—In a 200-mL volumetric
related compound B. flask, dissolve 2.0 mg each of USP Acitretin RS and USP
Procedure—Separately inject equal volumes (about 10 mL) Tretinoin RS in tetrahydrofuran, dilute with alcohol to
of the Standard solution and the Test solution into the volume, and mix. Pipet 5.0 mL of this solution into a
chromatograph, record the chromatograms, and measure the 200-mL volumetric flask, dilute quantitatively with alcohol,
peak responses. Calculate the percentage of acitretin related and mix. [NOTE—Store the solution at 48 prior to injection.]
compound A and acitretin related compound B in the portion Standard preparation—Dissolve an accurately weighed
of Acitretin taken by the formula: quantity of USP Acitretin RS in tetrahydrofuran, and dilute
quantitatively with alcohol to obtain a solution having
10(C/W)(rU / rS)
a known concentration of about 0.1 mg per mL. [NOTE—
The final concentration of tetrahydrofuran in the preparation
will be 2% (v/v). Store the solution at 48 prior to injection.]
Acitretin Related Compound A RS or USP Acitretin Related
Assay preparation—Transfer about 50 mg of Acitretin,
Compound B RS in the Standard solution; W is the quantity,
In-Process Revision
in mg, of Acitretin taken; and rU and rS are the peak responses
10 mL of tetrahydrofuran, dilute with alcohol to volume, and
of the relevant impurity in the chromatograms of the Test
mix. Pipet 20 mL of the solution into a 50-mL volumetric
solution and the Standard solution, respectively: not more
flask, dilute with alcohol to volume, and mix. [NOTE—Store
than 0.3% of acitretin related compound A is found; and not
the solution at 48 prior to injection.]
more than 0.3% of acitretin related compound B is found.
Calculate the percentage of impurities other than acitretin
related compounds A and B in the portion of Acitretin taken
and a 4-mm 6 25-cm column that contains packing L1. The
by the formula:
flow rate is about 0.6 mL per minute. Chromatograph the
System suitability solution, and record the peak responses as
10(C/W)(rU / rS)
directed for Procedure: the resolution, R, between USP
Pharmacopeial Forum
Tretinoin RS (relative retention time of about 0.84) and USP NOTE—Use low-actinic glassware and perform
Acitretin RS is not less than 2.0; and the relative standard all tests under yellow and subdued light. Make all
deviation for replicate injections of acitretin is not more than
injections within 1 hour of sample preparation.
1.0%.
Procedure—Separately inject equal volumes (about 10 mL) Packaging and storage—Preserve in well-closed, light-
of the Standard preparation and the Assay preparation into resistant containers.
the chromatograph, record the chromatograms, and measure USP Reference standards h11i—USP Acitretin RS.
the responses for the acitretin peaks. Calculate the quantity, in Thin-layer chromatographic identification test h201i—
mg, of C21H26O3 in the portion of Acitretin taken by the
Test solution—Weigh a portion of Capsules, equivalent to
formula:
20 mg of acitretin. Grind to a fine powder, then triturate for 30
seconds with 2 mL of tetrahydrofuran. Transfer the
500C(rU / rS)
suspension to a 12-mL conical centrifuge tube, and centrifuge
to obtain a clear supernatant.
Acitretin RS in the Standard preparation; and rU and rS are
tity of USP Acitretin RS in tetrahydrofuran to obtain a solution
the peak responses obtained from the Assay preparation and
containing about 10 mg per mL.
the Standard preparation, respectively.&1S (USP31)
Developing solvent system: a mixture of chloroform and
BRIEFING methanol (80 : 20).

Procedure—Proceed as directed in the chapter, and then
Acitretin Capsules. Because there is no existing USP monograph air-dry. Spray the plate with a saturated solution of antimony
for this drug product, a new monograph, based on validated
procedures, is being proposed. The liquid chromatographic proce- trichloride chloroform (25 g in 100 mL) followed by
dures in the test for Limit of degradation products and in the Assay
are based on analyses performed with the YMC ODS-A brand of L1 concentrated sulfuric acid, and then locate the spots.
column. The typical retention time for the acitretin peak is about
24.8 minutes.
(MD-OOD: L. Evans; BPC: M. Marques) RTS—C39916 Medium: 3% sodium lauryl sulfate in deaerated water, pH
9.6 to 10.0; 900 mL.
In-Process Revision
Add the following: Time: 30 minutes.

&Acitretin Capsules Determine the amount of acitretin (C21H26O3) dissolved
Standard solution—Transfer about 14 mg of USP Acitretin
RS, accurately weighed, to a 500-mL volumetric flask.
» Acitretin Capsules contain not less than 90.0
Dissolve in 50 mL of alcohol, and dilute with Medium to
volume. For Capsules labeled to contain 10 mg, transfer 20.0
labeled amount of acitretin (C21H26O3). mL of this solution to a 50-mL volumetric flask, and dilute
Caution—Acitretin is a teratogen. Great care with Medium to volume.
should be taken when handling to avoid inhalation Capsule shell preparation—Dissolve 6 clean empty-shell
of dust or contact with skin. Capsules in 900 mL of Medium.
Pharmacopeial Forum
Test solution—Use portions of the solution under test Procedure—Inject a volume (about 25 mL) of the Test
passed through a suitable 0.45-mm filter. solution into the chromatograph, record the chromatogram,
Procedure—Determine the amount of C21H26O3 dissolved and measure the peak responses. Calculate the percentage of
by employing UV absorption at the wavelength of maximum each degradation product in the portion of Capsules taken by
absorbance at about 347 nm, using 2-mm cells, in comparison the formula:
with the appropriate Standard solution. Use the Medium as
a blank. Determine the absorbance of the Capsule shell 100(ri / rs)
preparation under the same conditions. Calculate the amount
in which ri is the peak response for each individual impurity;
of acitretin (C21H26O3) dissolved by the following formula:
and rs is sum of the responses of all of the peaks: not more
than 0.5% of acitretin related compound A, not more than
0.4% of any individual unspecified impurity, and not more
than 0.8% of total unspecified impurities is found.
Assay—
in which AU is the absorbance of the Test solution; ACS is the Diluent—Prepare a suitable mixture of methanol and
capsule shell correction, calculated as shown below; CS is the tetrahydrofuran (13 : 10).
concentration, in mg per mL, of the appropriate Standard Mobile phase—Prepare a filtered and degassed mixture of
solution; 900 is the volume, in mL, of Medium; 100 is the methanol, water, alcohol, and glacial acetic acid
conversion factor to percentage; AS is the absorbance of the (74 : 21 : 5 : 0.5). Make adjustments if necessary (see System
appropriate Standard solution; and LC is the Capsule label Suitability under Chromatography h621i).
claim, in mg. The capsule shell correction, ACS, is calculated Standard preparation—In a 100-mL volumetric flask,
using the following formula: dissolve about 10 mg of USP Acitretin RS, accurately
weighed, in 80 mL of Diluent, and sonicate for 5 minutes.
Add 8 mL of water, and quantitatively dilute with Diluent to
obtain a solution having a concentration of about 0.1 mg per
mL.
System suitability solution—Transfer 2 mL of the Standard
in which ACSS is the absorbance of the Capsule shell
preparation to a clear 4-mL glass vial. After sealing the vial
In-Process Revision
preparation; and N is the number of Capsule shells used to with a teflon-lined silicone septum and cap, place the vial on
prepare the Capsule shell preparation.
its side in a light chamber, expose it to 400 foot-candles of
fluorescent light for 5 minutes, and then completely wrap the
of acitretin (C21H26O3) is dissolved in 30 minutes.
vial with aluminum foil. [NOTE—Exposure to the fluorescent
Uniformity of dosage units h905i: meet the requirements. light allows for the formation of two degradation products:
Limit of degradation products— acitretin related compound A and the 9-cis isomer [(E,E,Z,E)-
Diluent, Mobile phase, System suitability solution, and 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-
Chromatographic system—Proceed as directed in the Assay. nonatetraenoic acid].
Pharmacopeial Forum
Assay preparation—Carefully separate and place both

BRIEFING
halves of 10 Capsules into a 100-mL volumetric flask.
Stopper and shake the flask to remove the fill. Add 8 mL of Benzonatate Capsules, USP 30 page 1503. In the Dissolution
test, it is proposed to correct the composition of the Mobile phase
water while rinsing any fill from the neck of the flask. Place and to revise the internal diameter of the column in the
Chromatographic system section.
the flask in a water bath set at 458 for 10 minutes, shaking
initially and at 5-minute intervals up to 10 minutes. Place the (BPC: M. Marques) RTS—C53336
resulting suspension in an ultrasonic bath for 15 minutes.

Change to read:
Dilute with Diluent to volume, and sonicate for 5 additional
~
minutes. Cool to room temperature and, if necessary, add
additional Diluent to dilute to volume. Filter the suspension, Apparatus 2: 50 rpm.
Time: 30 minutes.
and use the clear filtrate. Determine the amount of benzonatate dissolved by employing the
following method.
Chromatographic system (see Chromatography h621i)— Mobile phase—Prepare a filtered and degassed mixture of 0.04 M
monobasic potassium phosphate solution and acetonitrile
The liquid chromatograph is equipped with a 365-nm detector &
acetonitrile and 0.04 M monobasic potassium phos-
and a 4.6-mm 6 15-cm column that contains 5-mm L1
phate&1S (USP31)
packing. The flow rate is about 1.0 mL per minute. (3 : 1). Make adjustments if necessary (see System Suitability under
Chromatograph the System suitability solution, and record Standard solution—Transfer 50 mg, accurately weighed, of USP
Benzonatate RS to a 100-mL volumetric flask, and add about 50 mL
the peak responses as directed for Procedure: the resolution, of water. Sonicate for 10 minutes, cool, dilute with water to volume,
and mix. Transfer 10.0 mL of this solution to a 50-mL volumetric
R, between acitretin related compound A (relative retention flask, and dilute with water to volume.
Test solution—Pass a portion of the solution under test through
time of about 0.84) and acitretin is not less than 3.0; the a 0.45-mm filter.
resolution, R, between the 9-cis isomer (relative retention liquid chromatograph is equipped with a 310-nm detector and
a 4.0-mm
time of about 1.09) and acitretin is not less than 1.8. &
3.9-mm&1S (USP31)
Chromatograph the Standard preparation, and record the 6 30-cm column that contains packing L1. The flow rate is about
1.5 mL per minute. Chromatograph the Standard solution, and
peak responses as directed for Procedure: the relative record the peak responses as directed for Procedure: the relative
standard deviation for replicate injections is not more than 2.0%.
standard deviation for replicate injections of acitretin is not Procedure—Separately inject equal volumes (about 15 mL) of the
more than 2.0%. record the chromatograms, and measure the responses for the major
peaks. Calculate the amount of benzonatate dissolved by the
Procedure—Separately inject equal volumes (about 25 mL) formula:

In-Process Revision

in which rU and rS are the peak responses obtained from the Test
mg, of acitretin (C21H26O3) in the portion of Capsules taken by solution and the Standard solution, respectively; CS is the
concentration, in mg per mL, of USP Benzonatate RS in the
the formula: Standard solution; 900 is the volume, in mL, of Medium; 100 is the
conversion factor to percentage; and LC is the Tablet label claim, in
mg.
100C(rU / rS) benzonatate is dissolved in 30 minutes.~USP30

Acitretin RS in the Standard preparation; and rU and rS are
the Standard preparation, respectively.&1S (USP31)
Pharmacopeial Forum
Determine the amount of C20H27N5O2 dissolved using the

BRIEFING
following method.
Cilostazol Tablets. Because there is no existing USP monograph

Standard solution—Transfer about 28 mg, accurately
for this drug product, a new monograph, based on validated methods weighed, of USP Cilostazol RS to a 100-mL volumetric
of analysis, is being proposed. The liquid chromatographic
procedure in the test for the Assay is based on analyses performed flask, dissolve in and dilute with methanol to volume, and
with the TSK-80TM 5-mm column of packing L1 (an equivalent
column is the YMC-pack ODS-A302). The typical retention time for mix well. Transfer 4.0 mL of this solution to a 200-mL
cilostazol is about 8.5 minutes.
volumetric flask, dilute with Medium to volume, and mix
(MD-CV: S. Ramakrishna; BPC: M. Marques) RTS—C43944
well.
Test solution—Pass not less than 20 mL of the solution
under test through a suitable 0.45-mm filter, discarding the
Add the following:
first 10 mL of filtrate. Dilute with Medium in such a way as to
&Cilostazol Tablets obtain a final theoretical concentration of about 5.6 mg of
cilostazol per mL, considering complete dissolution of the
label claim.
» Cilostazol Tablets contain not less than 90.0 Procedure—Determine the amount of C20H27N5O2 dis-
percent and not more than 110.0 percent of the solved by employing UV absorption at the wavelength of
labeled amount of cilostazol (C20H27N5O2). about 257 nm on the Test solution in comparison with the
Standard solution, using a 1-cm cell and Medium as the
Packaging and storage—Preserve in tight and light-resistant blank. Calculate the amount of C20H27N5O3 dissolved, in
containers. Store at controlled room temperature. percentage, by the formula:
USP Reference standards h11i—USP Cilostazol RS.
Identification— CS 6 AU 6 9006100 / (AS 6 LC)
A: Infrared Absorption h197Si—

Standard solution—Prepare a solution of USP Cilostazol
Cilostazol RS in the Standard solution; AU and AS are the
RS in chloroform having a known concentration of 100 mg
absorbances obtained from the Test solution and the Standard
per mL.
solution, respectively; 900 is the volume, in mL, of Medium;
Test solution—Accurately transfer a quantity of finely
100 is the conversion factor to percentage; and LC is the
powdered Tablets, equivalent to about 100 mg of cilostazol,
In-Process Revision
Tablet label claim, in mg.
into a glass container. Add 1 mL of chloroform, shake for
1 minute, and filter through a 0.5-mm or finer filter.
of C20H27N5O2 is dissolved in 60 minutes.
B: The retention time of the cilostazol peak in the
chromatogram of the Assay preparation corresponds to that in Uniformity of dosage units h905i: meet the requirements.
the chromatogram of the Standard preparation, as obtained in Assay—

the Assay. Mobile phase—Prepare a filtered and degassed mixture of
Dissolution h711i— water, acetonitrile, and methanol (10 : 7 : 3). Make adjust-
Medium: 0.30% sodium lauryl sulfate in water; 900 mL. ments if necessary (see System Suitability under Chromatog-
Apparatus 2: 75 rpm. raphy h621i).
Time: 60 minutes.
Pharmacopeial Forum
Internal standard solution—Prepare a solution of benzo- in which CS is the concentration, in mg per mL, of USP
phenone in methanol having a known concentration of 4 mg Cilostazol RS in the Standard preparation; CU is the
per mL. concentration of cilostazol in the Assay preparation, based
Standard preparation—Dissolve an accurately weighed on the labeled quantity per Tablet and the extent of dilution;
quantity of USP Cilostazol RS and an appropriate amount of and rU and rS are the peak responses of cilostazol obtained
Internal standard solution and dilute quantitatively, and from the Assay preparation and the Standard preparation,
stepwise if necessary, with methanol to obtain a solution respectively.&1S (USP31)
having a known concentration of about 0.1 mg of USP
Cilostazol RS and 0.04 mg of the Internal standard solution.
Assay preparation—Weigh and finely powder not fewer BRIEFING
than 20 Tablets. Transfer an accurately weighed portion of the

Colchicine, USP 30 page 1826. It is proposed to revise the
powder, equivalent to about 50 mg of cilostazol, to a suitable Definition to include, as sources of colchicine, genera other than
Colchicum.
volumetric flask and add an appropriate quantity of Internal
(DSB: M. Sharaf) RTS—C53207
standard solution. Dilute quantitatively, and stepwise if
necessary, with methanol to obtain a solution having
Change to read:
a known concentration of about 0.1 mg of USP Cilostazol
RS and 0.04 mg of the Internal standard solution. Pass » Colchicine is an alkaloid contained in various species
of Colchicum
a portion of this solution through a membrane filter having
&
and in other genera.&1S (USP31)
a 0.5-mm or finer porosity, and use the filtrate. It contains not less than 94.0 percent and not more than
Chromatographic system (see Chromatography h621i)— 101.0 percent of C22H25NO6, calculated on the anhy-
drous, solvent-free basis.
The liquid chromatograph is equipped with a 254-nm detector Caution—Colchicine is extremely poisonous.
The flow rate is about 1 mL per minute. The column
temperature is maintained at ambient temperature. Chromat- BRIEFING
ograph the Standard preparation, and record the peak
responses as directed for Procedure: the resolution, R, Dihydrocodeine Bitartrate, USP 30 page 1944. In the Definition,
it is proposed to change the limit of C18H23NO3 C4H6O6 from 98.5 to
between the cilostazol and benzophenone peaks eluted in 100.5 percent to 98.0 to 102.0 percent to reflect the 2% injection
precision allowed by the HPLC procedure.
In-Process Revision
this order is not less than 9.0; and the relative standard
(MD-CCA: C. Anthony) RTS—C41848
deviation for replicate injections is not more than 1.5%.
» Dihydrocodeine Bitartrate contains not less than 98.5
the areas for the major peaks. Calculate the percentage of the
&
98.0&1S (USP31)
percent and not more than 100.5
labeled amount of C20H27N5O2 in the portion of Tablets taken &
102.0&1S (USP31)
by the formula: percent of C18H23NO3 C4H6O6, calculated on the dried
basis.
100(CS / CU)(rU / rS)
Pharmacopeial Forum
USP Reference standards h11i—USP Esomeprazole Mag-

BRIEFING
nesium RS. USP Omeprazole RS. USP Omeprazole Related
Esomeprazole Magnesium. Because there is no existing USP Compound A RS.
monograph for this drug substance, a new monograph, based on
validated methods of analysis, is being proposed. The liquid Identification—
chromatographic procedures in the test for Chromatographic
purity and in the Assay, although different, are both based on A: Infrared Absorption h197Ki.
analyses performed with the LiChrosorb brand of L7 column or with
the Nova-Pak C18 brand of L1 column. The typical retention time B: The Test solution, prepared and tested as directed in
for the omeprazole peak is about 8 to 10 minutes for the
Chromatographic purity test and about 4 to 5 minutes for the the test for Content of magnesium, exhibits the emission
Assay. The liquid chromatographic procedures in the test for
Enantiomeric purity are based on analyses performed with the maximum at about 285 nm.
Chiral AGP brand of L41 column. The typical retention time for the
esomeprazole peak is about 4 minutes. Color of solution—Prepare a solution of Esomeprazole
(MD-GRE: E. Gonikberg) RTS—C44030 Magnesium in methanol having a concentration of 20 mg per
mL, and filter. Determine the absorbance of this solution at
440 nm, in 1-cm cells, using methanol as the blank: the
absorbance is no greater than 0.2.
Add the following: Specific rotation h781Si: between –1378 and –1428,
&Esomeprazole Magnesium determined at 208.
Test solution: 10 mg per mL, in methanol.
Water, Method I h921i: between 6.0% and 8.0%.
Phosphate buffer pH 7.6—Dissolve 0.725 g of monobasic
sodium phosphate and 4.472 g of anhydrous dibasic sodium
C34H36MgN6O6S2 3H2O Anhydrous: 713.12 Trihy- phosphate in 300 mL of water, dilute with water to 1000 mL,
drate: 767.17 and mix. Dilute 250 mL of this solution with water to 1000
1H-Benzimidazole,5-methoxy-2-[(S)-[(4-methoxy-3,5-di- mL. If necessary, adjust with phosphoric acid to a pH of 7.6.
methyl-2-pyridinyl)methyl]sulfinyl], magnesium salt Mobile phase—Prepare a filtered and degassed mixture of
(2 : 1), trihydrate. Phosphate buffer pH 7.6 and acetonitrile (72.5 : 27.5). Make
5-Methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)- Chromatography h621i). [NOTE—To improve the resolution,
In-Process Revision
methyl]sulfinyl]benzimidazole, magnesium salt (2 : 1), the composition may be changed to 75 : 25, if necessary.]
trihydrate [217087-09-7]. Test solution—Dissolve about 4 mg of Esomeprazole
Magnesium in 25 mL of Mobile phase. [NOTE—Prepare this
» Esomeprazole Magnesium contains not less than solution fresh.]

System suitability solution—Dissolve about 1 mg of USP
Omeprazole RS and 1 mg of USP Omeprazole Related
C34H36MgN6O6S2, calculated on the anhydrous
Compound A RS in about 25 mL of Mobile phase. [NOTE—
basis.
Omeprazole Related Compound A is omeprazole sulfone.]
Packaging and storage—Preserve in tight containers, Chromatographic system (see Chromatography h621i)—
protected from light. Store at room temperature. The liquid chromatograph is equipped with a 280-nm detector
and a 4.0-mm 6 12.5-cm or a 4.6-mm 6 15-cm column that
Pharmacopeial Forum
contains 5-mm packing L7. (Alternatively, a 3.9-mm 6 Diluent pH 11—Mix 11 mL of 0.25 M tribasic sodium
15-cm column that contains 4-mm packing L1 may be used.) phosphate with 22 mL of 0.5 M dibasic sodium phosphate,
The flow rate is about 0.8 to 1.0 mL per minute. and dilute with water to 1000 mL.
Chromatograph the System suitability solution, and record Mobile phase—Prepare a mixture of Phosphate buffer pH
the peak responses as directed for Procedure: the relative 6 and acetonitrile (425 : 75).
retention times for omeprazole related compound A and System suitability solution—Dissolve about 2 mg of USP
omeprazole are about 0.8 and 1.0, respectively; the resolution, Omeprazole RS in 10 mL of Diluent pH 11. Dilute 1.0 mL of
R, between omeprazole related compound A and omeprazole this solution with Diluent pH 11 to 50 mL.
is not less than 3; and the capacity factor, k ’, for the Test solution—Dissolve about 40 mg of Esomeprazole
omeprazole peak is not less than 5.0. Magnesium in 5 mL of methanol, and dilute with Diluent pH
Procedure—Inject a volume of about 50 mL of the Test 11 to 25 mL. Dilute 1 mL of this solution with Diluent pH 11
solution into the chromatograph, record the chromatogram for to 50 mL.
at least 4.5 times the retention time of the omeprazole peak, Chromatographic system (see Chromatography h621i)—
and measure the peak responses. Identify the impurities based The liquid chromatograph is equipped with a 302-nm detector
on the retention times shown in Table 1. Calculate the and a 4.0-mm 6 10-cm column that contains packing L41.
percentage of any individual impurity in the portion of The flow rate is about 0.6 mL per minute. Chromatograph the
Esomeprazole Magnesium taken by the formula: System suitability solution, and record the peak responses as
directed for Procedure. The elution order is the R-enantiomer,
100(ri / rs) followed by the esomeprazole peak, which is the
S-enantiomer. The resolution, R, between the enantiomer
in which ri is the peak response of any individual impurity, peaks is not less than 3; and the capacity factor, k ’, for the
and rs is the sum of the responses of all the peaks: in addition esomeprazole peak is not less than 2.
to not exceeding the limits in Table 1, not more than 0.1% of Procedure—Inject a volume of about 20 mL of the Test
any other individual impurity is found; and not more than solution into the chromatograph, record the chromatogram,
0.5% of total impurities is found. and measure the peak responses. Calculate the percentage of
Enantiomeric purity— the R-enantiomer in esomeprazole by the formula:
Phosphate buffer pH 6—Mix 70 mL of 1 M monobasic
In-Process Revision
sodium phosphate with 20 mL of 0.5 M dibasic sodium 100(rU / rs)

phosphate, and dilute with water to 1000 mL. Dilute 250 mL
of this solution with water to 1000 mL.
Table 1.
Limit
Name Relative Retention Time (%)
OmeprazoleN-oxide1 0.45 0.1

Omeprazole Sulfone2 (Related Compound A) 0.8 0.2
Omeprazole 1.0 n/a
1
4-methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulfinyl]methyl]-3,5-dimethylpyridine 1-oxide
2
5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfonyl]-1H-benzimidazole
Pharmacopeial Forum
in which rU is the peak response for the R-enantiomer, and rs dissolved, and dilute with water to volume. Allow to stand for
is the sum of the responses of both the esomeprazole and 30 minutes. Transfer 10.0 mL of this solution to a 200-mL
R-enantiomer peaks. Not more than 0.2% of the volumetric flask, and dilute with water to volume. Transfer
R-enantiomer is found. 10.0 mL of the solution so obtained to another 100-mL
Content of magnesium— volumetric flask, add 4.0 mL of Lanthanum solution, and
Lanthanum solution—Transfer 58.7 g of lanthanum oxide dilute with water to volume.
into a 1000-mL volumetric flask, wet the substance with some Procedure—Concomitantly determine the absorbances of
water, and dissolve by cautious addition of 250 mL of the Standard solution, the Blank solutions, and the Test
hydrochloric acid in 20- to 30-mL portions, cooling between solution at the magnesium emission line at 285.2 nm with
the additions. Add water while stirring, cool to room a suitable atomic absorption spectrophotometer (see Spectro-
temperature, and dilute with water to volume. [NOTE—Store photometry and Light-Scattering h851i) using an air–
the solution in a plastic bottle.] acetylene flame. Determine the concentration, C, in mg per
Magnesium standard stock solution—Quantitatively dilute mL, of magnesium in the Test solution using the calibration
a suitable amount of a commercially prepared atomic graph. Calculate the content of magnesium, in percent, in the
absorption standard solution for magnesium with water to portion of Esomeprazole Magnesium taken by the formula:
obtain a solution containing 1000 mg of magnesium per mL.

100(0.001CD / W)[100 / (100 – L)]
[NOTE—Store the solution in a plastic bottle.]
Magnesium intermediate standard solution—Transfer 10.0
in which C is as defined above; the multiplier 0.001 is for
mL of Magnesium standard stock solution to a 500-mL
conversion of mg per mL to mg per mL; D is the dilution
volumetric flask, add 50 mL of 1 N hydrochloric acid, and
factor for the Test solution; W is the amount of Esomeprazole
dilute with water to volume. Transfer 20.0 mL of this solution
Magnesium, in mg, taken to prepare the Test solution; and L
to a 200-mL volumetric flask, and dilute with water to
is the content of water, in percent, as determined in the test for
volume. This solution contains 2 mg of magnesium per mL.
Water. The magnesium content, calculated on the anhydrous
Standard solutions—Transfer 5.0, 10.0, 15.0, 20.0, and
basis, is between 3.30% and 3.55%.
25.0 mL of Magnesium intermediate standard solution to
Assay—
separate 100-mL volumetric flasks. To each flask, add 4.0 mL
of Lanthanum solution, and dilute with water to volume.
These Standard solutions contain 0.1, 0.2, 0.3, 0.4, and 0.5
In-Process Revision
phosphate in 300 mL of water, dilute with water to 1000 mL,
mg of magnesium per mL, respectively. [NOTE—Concentra-
and mix. Dilute 250 mL of this solution with water to 1000
tions of the Standard solutions and the Test solution may be
mL. If necessary, adjust with phosphoric acid to a pH of 7.6.
modified to fit the linear or working range of the instrument.
Mobile phase—Prepare a mixture of Phosphate buffer pH
When using instruments with a linear calibration graph, the
7.6 and acetonitrile (650 : 350).
number of Standard solutions can be reduced.]
Blank solution—Transfer 4.0 mL of Lanthanum solution to Phosphate buffer pH 11—Mix 11 mL of 0.25 M tribasic
sodium phosphate with 22 mL of 0.5 M dibasic sodium
a 100-mL volumetric flask, and dilute with water to volume.
phosphate, and dilute with water to 100 mL.
Test solution—Transfer about 250 mg of Esomeprazole
Magnesium, accurately weighed, to a 100-mL volumetric
flask, add 20 mL of 1 N hydrochloric acid, swirl until
Pharmacopeial Forum
Standard preparation—Transfer about 10 mg of USP

BRIEFING
Omeprazole RS, accurately weighed, to a 200-mL volumetric
flask, and dissolve in about 10 mL of methanol. Add 10 mL Fluconazole, USP 30 page 2137 and page 335 of PF 32(2) [Mar.–
Apr. 2006]. In Test 2 under Related compounds, it is proposed to
of Phosphate buffer pH 11 and dilute with water to volume. revise the concentration of the Acetate buffer to correspond to the
original concentration. In addition, editorial changes have been
This solution contains about 0.05 mg of omeprazole per mL. made.
Assay preparation—Transfer about 10 mg of Esomeprazole
Magnesium, accurately weighed, to a 200-mL volumetric
flask, dissolve in about 10 mL of methanol, add 10 mL of Change to read:
Phosphate buffer pH 11, and dilute with water to volume. Related compounds—[NOTE—On the basis of information regard-
ing the manufacturing process, perform either Test 1 or Test 2 and
This solution contains about 0.05 mg of esomeprazole Test 3.]
magnesium per mL. TEST 1—
Mobile phase—Prepare a mixture of water and acetonitrile
Chromatographic system (see Chromatography h621i)— (80 : 20).
System suitability solution—Use the Standard solution.
The liquid chromatograph is equipped with a 280-nm detector Standard solution—Transfer accurately weighed quantities of USP
Fluconazole RS, USP Fluconazole Related Compound A RS, USP
and a 4.0-mm 6 12.5-cm or a 4.6-mm 6 15-cm column that Fluconazole Related Compound B RS, and USP Fluconazole
Related Compound C RS to a suitable volumetric flask, dissolve
contains 5-mm packing L7. (Alternatively, a 3.9-mm 6 in acetonitrile, dilute quantitatively, and stepwise if necessary, with
Mobile phase to volume, and mix to obtain a solution having known
15-cm column that contains 4-mm packing L1 may be used.) concentrations of 10 mg of each per mL.
Test solution—Transfer about 30 mg of Fluconazole, accurately
The flow rate is about 1 mL per minute. Chromatograph the weighed, to a 10-mL volumetric flask, dissolve in and dilute with
Mobile phase to volume, and mix.
Standard preparation, and record the peak responses as Chromatographic system (see Chromatography h621i)—The
directed for Procedure: the capacity factor, k ’, for omeprazole a 4.6-mm 6 15-cm column that contains 3.5-mm packing L1. The
flow rate is about 0.5 mL per minute. The column temperature is
peak is not less than 2; the column efficiency is not less than maintained at 408. Chromatograph the Standard solution, and record
the peak responses as directed for Procedure: typical retention times
2000 theoretical plates; and the relative standard deviation for are about 4.9 minutes for fluconazole related compound A, 8.0
minutes for fluconazole related compound B, 8.5 minutes for
replicate injections is not more than 2.0%. fluconazole related compound C, and 9.9 minutes for fluconazole;
the resolution, R, between fluconazole related compound B and
Procedure—Separately inject equal volumes (about 20 mL) fluconazole related compound C is not less than 1.5; and the relative
standard deviation of each peak for replicate injections is not more
of the Standard preparation and the Assay preparation into than 5.0%.
the chromatograph, record the chromatograms, and measure Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the responses for the major
the responses for the major peaks. Calculate the percentage of peaks. Calculate the percentage of fluconazole related compound A,
fluconazole related compound B, fluconazole related compound C,
C34H36Mg N6O6S2 in the portion of Esomeprazole Magnesium and any other impurities in the portion of Fluconazole taken by the
formula:
In-Process Revision
taken by the formula: 1000(C/W)(rU / rS)

in which C is the concentration, in mg per mL, of USP Fluconazole
Related Compound A RS, USP Fluconazole Related Compound B
100[(713.12 / (2 6 345.42)](CS / CU)(rU / rS) RS, USP Fluconazole Related Compound C RS, or USP Fluconazole
RS, respectively, in the Standard solution; W is the weight, in mg, of
Fluconazole taken to prepare the Test solution; rU is the peak
in which 713.12 and 345.42 are the molecular weights of response obtained from the Test solution; and rS is the average peak
response of fluconazole related compound A, fluconazole related
esomeprazole magnesium and omeprazole, respectively; CS is compound B, fluconazole related compound C, or fluconazole
obtained from replicate injections of the Standard solution: not more
the concentration, in mg per mL, of omeprazole in the than 1.0% of any impurity with a relative retention time (RRT) of
about 0.6 is found; not more than 0.2% of fluconazole related
Standard preparation; CU is the concentration, in mg per mL, compound A or fluconazole related compound C is found; not more
than 0.1% of fluconazole related compound B is found; not more
of esomeprazole magnesium in the Assay preparation; and rU than 0.1% of any other individual impurity is found; not more than
0.2%
and rS are the peak responses obtained from the Assay &
0.3%&1S (USP30)
preparation and the Standard preparation, respec- of total other
tively.&1S (USP31)
&
unknown&1S (USP30)
Pharmacopeial Forum
impurities is found; and not more than 1.2% Fluconazole RS in the Standard solution; W is the weight, in mg, of
Fluconazole taken to prepare the Test solution; and F is the relative
&
1.5%&1S (USP30) response factor as determined from the following table.
of total impurities is found.
TEST 2— Relative Response Factor (F) Relative Retention Time (RRT)
Acetate buffer—Prepare a 0.04 M 0.72 0.17–0.37
0.85 1.20–1.32
&
0.01 M&1S (USP31)
anhydrous sodium acetate solution, adjust with 1 N acetic acid to &
0.48–0.60&1S (USP30)
a pH of 5.0, and mix. 1.21 0.48–0.60
Solution A: filtered and degassed Acetate buffer.
Solution B: acetonitrile. &
0.67–0.79&1S (USP30)
Solution C: methanol. 0.96 1.14–1.18
Mobile phase—Use variable mixtures of Solution A, Solution B, 0.97 0.67–0.79
and Solution C as directed for Chromatographic system. Make
adjustments if necessary (see System Suitability under Chromatog- &
1.20–1.32&1S (USP30)
raphy h621i). 1.0 all other peaks
Diluent—Prepare a mixture of Acetate buffer and methanol
(84 : 16). Not more than 0.1% of any individual impurity is found; and not
Standard solution—Dissolve an accurately weighed quantity of more than 0.5% of total impurities is found.
USP Fluconazole RS in Diluent, and dilute quantitatively, and TEST 3—
stepwise if necessary, with Diluent to obtain a solution having Adsorbent: 0.25-mm layer of chromatographic silica gel mix-
a known concentration of about 0.01 mg per mL. ture.
System suitability solution—Dissolve suitable quantities of USP Test solution—Dissolve an accurately weighed quantity of
Fluconazole RS and USP Desacetyl Diltiazem Hydrochloride RS in Fluconazole in methanol to obtain a solution containing approxi-
Diluent. Dilute quantitatively, and stepwise if necessary, with mately 50 mg per mL.
Diluent to obtain a solution containing about 0.02 mg per mL and Standard solutions—Dissolve an accurately weighed quantity of
0.006 mg per mL, respectively. USP Fluconazole RS in methanol to obtain Standard solution A
Test solution—Transfer about 200 mg of Fluconazole, accurately having a known concentration of about 1 mg per mL (2.0%).
weighed, to a 100-mL volumetric flask, and dissolve in and dilute Quantitatively dilute portions of this solution with methanol to
with Diluent to volume. obtain Standard solution B and Standard solution C having known
Chromatographic system (see Chromatography h621i)—The concentrations of about 0.1 mg per mL (0.2%) and 0.05 mg per mL
liquid chromatograph is equipped with a 261-nm detector and (0.1%), respectively.
a 4.0-mm 6 10-cm column that contains packing L1. The flow rate Developing solvent system—Prepare a mixture of chloroform,
is 1 mL per minute. The chromatograph is programmed as follows. methanol, and ammonium hydroxide (80 : 20 : 1).
Time Solution Solution Solution Spray reagent A—Dissolve about 170 mg of silver nitrate in 100
(minutes) A (%) B (%) C (%) Elution mL of water.
0–10 80 5 15 isocratic Spray reagent B (Potassium iodoplatinate solution)—Dissolve
10–20 80?30 5?55 15 linear gradient about 375 mg of chloroplatinic acid in 5 mL of 1 N hydrochloric
(A and B) acid. Dissolve about 5 g of potassium iodide in 50 mL of water, and
20–23 30 55 15 isocratic store in a light-resistant container. Prepare a mixture of water, the
23–25 30?80 55?5 15 reset composition potassium iodide solution, and the chloroplatinic acid solution
25–30 80 5 15 re-equilibration (20 : 9 : 1).
Procedure—Proceed as directed for Thin-Layer Chromatography
Chromatograph the System suitability solution, and record the peak under Chromatography h621i. Spray the dry plate with Spray
responses as directed for Procedure: the relative retention times are reagent A, and expose the plate to 365-nm UV light for 10 to 20
1.0 for fluconazole and about 1.2 for desacetyl hydrochloride minutes. Dry the plate for 20 minutes between 808 and 908, then
spray the plate with Spray reagent B. Allow the plate to dry.
&
diltiazem;&1S (USP31) Examine the plate and compare the intensities of any secondary
the resolution, R, between fluconazole and desacetyl diltiazem spots observed in the chromatogram of the Test solution with those
hydrochloride is not less than 10.0; the column efficiency for of the principal spots in the chromatograms of the Standard
fluconazole is not less than 30,000 theoretical plates; and the tailing solutions: no spot from the chromatogram of the Test solution with
factor, T, is not more than 1.4. Chromatograph the Standard solution, an RF value of between 0.10 to 0.25 and 0.27 to 0.41 is larger or
and record the peak responses as directed for Procedure: the relative more intense than that obtained from Standard solution B (0.2%).
In-Process Revision
standard deviation for replicate injections is less than 5.0%.
Calculate the percentage of each impurity in the portion of
Fluconazole taken by the formula:
10,000(ri / rS)(C/W)(1/F)
in which ri is the peak response of each impurity obtained from the
Test solution; rS is the peak response of fluconazole obtained from
the Standard solution; C is the concentration, in mg per mL, of USP
Pharmacopeial Forum
USP Reference standards h11i—USP Formoterol Fumarate

BRIEFING
RS. USP Formoterol Fumarate System Suitability Mixture RS.
Formoterol Fumarate, page 1450 of PF 32(5) [Sept.–Oct. 2006]. USP Formoterol Related Compound I. USP Formoterol
The monograph has been revised to harmonize the Assay limits with
those in the European Pharmacopoeia. The USP Reference standards Fumarate Resolution Mixture RS.
section has also been revised to accommodate the change in the
Reference Standard for impurity I. At industry’s request, the test for Identification, Infrared Absorption h197Ki.
Content of related compound I (diastereoisomer) has been
harmonized with that in the European Pharmacopoeia by adding Specific rotation h781Si: between –0.108 and +0.108.
a second test (Test 2) under Content of related compound I
(diastereoisomer).
(AER: K. Zaidi) RTS—C50878; C52358 pH h791i: between 5.5 and 6.5, in a solution in water
containing 1 mg per mL.
Water, Method I h921i: not more than 5.0% between 4.0%

and 5.0%.
Add the following:
&Formoterol Fumarate
mined on 1 g.
Heavy metals, Method II h231i: not more than 0.002%.
Solution A—Dissolve 3.73 g of sodium dihydrogen phos-
phate monohydrate and 0.35 g of phosphoric acid in water,
dilute with water to 1000 mL, and mix. The pH of this
solution is 3.1 + 0.1.
(C19H24N2O4)2 C4H4O4 2H2O 804.88 840.91
Solution B—Use acetonitrile.
(+)-2’-Hydroxy-5’-[(R*)-1-hydroxy-2-[[(R*)-p-methoxy-a- Mobile phase—Use variable mixtures of Solution A and
methylphenethyl]amino]ethyl]formanilide fumarate Solution B as directed for Chromatographic system. Make
(2 : 1) (salt), dihydrate [43229-80-7]. adjustments if necessary (see System Suitability under
Solution C—Transfer 6.10 g of sodium dihydrogen phos-
» Formoterol Fumarate contains not less than 98.05
phate monohydrate and 1.03 g of disodium hydrogen
percent and not more than 102.0 101.5 percent of
In-Process Revision
phosphate dihydrate to a 1000-mL volumetric flask, add

(C19H24N2O4)2 C4H4O4, calculated on the anhy-
500 mL of water, and dissolve. Dilute with water to volume,
drous basis. and mix. The pH is 6.0 + 0.1.
Packaging and storage—Preserve in well-closed, light- Diluent—Prepare a filtered and degassed mixture of
resistant containers. Solution C and acetonitrile (84 : 16, v/v).

System suitability solution—Transfer about 5 mg of USP
Labeling—The labeling states with which Content of related
Formoterol Fumarate System Suitability Mixture RS (con-
compound I the test article complies if a test other than
taining formoterol fumarate, and formoterol related com-
Content of related compound I, Test 1 is used.
pounds A, B, C, D, E, F, G, and H), accurately weighed, to
a 25-mL volumetric flask, add 10 mL of Diluent, and sonicate
to dissolve. Dilute with Diluent to volume, and mix.
Pharmacopeial Forum
Test solution—Transfer about 20.0 mg of Formoterol in which F is the relative response factor for each formoterol
Fumarate, accurately weighed, to a 100-mL volumetric related compound according to Table 1; ri is the peak
flask, add 50 mL of Diluent, and sonicate to dissolve. response for each formoterol related compound; and rs is the
Dilute with Diluent to volume, and mix. sum of the responses for all the peaks.
Chromatographic system (see Chromatography h621i)— Content of related compound I (diastereoisomer)—
The liquid chromatograph is equipped with a 214-nm detector TEST 1—
and a 4.6-mm 6 15-cm column that contains packing L7. Standard solution—Dissolve 10 mg of USP Formoterol
The flow rate is about 1.0 mL per minute. The chromatograph Related Compound I USP Formoterol Fumarate Resolution
is programmed as follows. Mixture RS in 1 mL of dimethylformamide. Add 100 mL of
Time Solution A Solution B N-(trimethylsilyl)imidazole, and mix.
(minutes) (%) (%) Elution Test solution—Dissolve 10 mg of Formoterol Fumarate in

1 mL of dimethylformamide. Add 100 mL of N-(trimethyl-
silyl)imidazole, and mix.
The gas chromatograph is equipped with a flame-ionization
detector, a 0.32-mm 6 30-m fused-silica capillary column
coated with a 0.25-mm film of stationary phase G27, and
Chromatograph the System suitability solution, and record the
a split injection system. The carrier gas is helium, flowing at
a rate of about 2 mL per minute and a split ratio of about
between formoterol related compound G and formoterol
75 : 1. The injection port and the detector temperatures are
related compound A is not less than 1.5; the peak-to-valley
maintained at about 2808 and 3008, respectively. The column
ratio (HP / HV) of formoterol related compound C and
temperature is programmed as follows. Initially the column
formoterol fumarate is not less than 2.5, where HP is the
temperature is equilibrated at 2208 for 5 minutes, then the
height above the baseline of the peak due to formoterol
temperature is increased at a rate of 18 per minute to 2508,
related compound C, and HV is the height above the baseline
and maintained at 2508 for 20 minutes. Chromatograph the
of the lowest point of the curve separating this peak from the
peak due to formoterol fumarate; and the relative retention
for Procedure: the resolution, R, between formoterol related
times and limits are as provided in Table 1.
compound I and formoterol fumarate is not less than 2.0 1.2.
In-Process Revision
Procedure—Separately inject equal volumes (about 20 mL) Procedure—Separately inject equal volumes (about 2 mL)
of the System suitability solution and the Test solution into the of the Standard solution and the Test solution into the
chromatograph, record the chromatograms, and measure all of chromatograph, record the chromatograms, and measure the
the peak responses. Disregard any peak representing less than peak responses for formoterol related compound I and
0.05%. Calculate the percentage of each formoterol related formoterol fumarate. Disregard all other peaks. Calculate
compound in the portion of Formoterol Fumarate taken by the the percentage of formoterol related compound I in the
formula: portion of Formoterol Fumarate taken by the formula:
100F(ri / rs)
Pharmacopeial Forum
Table 1
Relative Relative
Related Retention Response Factor
Compound Related Compound Chemical Name Time (F) Limit (%)
G (2RS)-1-(4-methoxyphenyl)propan-2-amine 0.4 1.00 2.64 0.1
A 1-(3-amino-4-hydroxyphenyl)-2-[[2-(4-methoxy- 0.5 1.75 0.3
phenyl)-1-methylethyl]amino]ethanol
B N-[2-hydroxy-5-[(1RS)-1-hydroxy-2-[[2-(4-meth- 0.7 1.00 0.2
oxyphenyl)ethyl]amino]ethyl]phenyl]-
formamide
C N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy- 1.2 1.00 1.10 0.2
phenyl)-1-methylethyl]amino]ethyl]phenyl]-
acetamide
D N-[2-hydroxy-5-[1-hydroxy-2-[methyl[2-(4-meth- 1.3 1.00 1.12 0.2
oxyphenyl)-1-methylethyl]amino]ethyl]-
phenyl]formamide
E N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxy-3- 1.8 1.00 0.67 0.1
methylphenyl)-1-methylethyl]amino]ethyl]-
phenyl]formamide
F N-[2-hydroxy-5-[1-[[2-hydroxy-5-[1-hydroxy-2- 2.0 1.00 0.2
[[2-(4-methoxyphenyl)-1-methylethyl]amino]-
ethyl]phenyl]amino]-2-[[2-(4-methoxyphenyl)-
1-methylethyl]amino]ethyl]phenyl]formamide
H N-[5-[(1RS)-2-[benzyl[(1RS)-2-(4-methoxyphenyl)- 2.2 1.00 1.24 0.1
1-methylethyl]amino]-1-hydroxyethyl]-2-
hydroxyphenyl]formamide (monobenzyl
analogue)
In-Process Revision
Any other individual impurity 0.1

Total impurities 0.5
TEST 2—
100(ri / rs) Potassium phosphate solution—Dissolve 5.3 g of tribasic

potassium phosphate, trihydrate, in 1000 mL of water, and
in which ri is the peak response for formoterol related
mix. Adjust the pH with potassium hydroxide or phosphoric
compound I, and rs is the sum of the responses of both
acid to 12.0+0.1.
formoterol fumarate and formoterol related compound I
Mobile phase—Prepare a filtered degassed mixture of
peaks: not more than 0.3% of formoterol related compound I
Potassium phosphate solution and acetonitrile (88 : 12).
is found.
Pharmacopeial Forum
Standard solution—Dissolve 5 mg of USP Formoterol

BRIEFING
Fumarate Resolution Mixture RS in water, dilute with water
to 50 mL, and mix. Fosinopril Sodium Tablets, page 2004 of PF 30(6) [Nov.–Dec.
2004]. On the basis of comments received, in the Dissolution test it
Test solution—Dissolve 5 mg of Formoterol Fumarate in is proposed to include the preparation of the Standard solution from
the Standard stock solution, as both the Standard solution and the
water, dilute with water to 50 mL, and mix. Standard stock solution were omitted from the PF 30(6) publication.
In addition, minor editorial style changes have been made.
Diluted test solution—Dilute 1 mL of the Test solution with
water to 20 mL. Dilute 1 mL of this solution with water to 25 (MD-CV: S. Ramakrishna) RTS—C52185
mL.
Add the following:
and a 4.6-mm 6 15-cm column that contains packing L##
&Fosinopril Sodium Tablets
(see Chromatographic Reagents under Reagents, Indicators,
and Solutions). The flow rate is about 0.5 mL per minute.
responses as directed for the Procedure: the peak-to-valley » Fosinopril Sodium Tablets contain not less than
ratio (HP / HV) of formoterol related compound I and 90.0 percent and not more than 110.0 percent of the
formoterol fumarate is not less than 2.5, where HP is the labeled amount of fosinopril sodium
height above the baseline of the peak due to formoterol
(C30H45NNaO7P).
related compound I, and HV is the height above the baseline of
the lowest point of the curve separating this peak from the Packaging and storage—Preserve in tight containers, and
peak due to formoterol fumarate. store at controlled room temperature.
Procedure—Separately inject equal volumes (20 mL) of the USP Reference standards h11i—USP Fosinopril Sodium
Test solution and the Diluted test solution into the RS. USP Fosinopril Related Compound A RS. USP
chromatograph, record the chromatograms, and measure the Fosinopril Related Compound G RS.
peak responses for formoterol fumarate and formoterol Identification—
related compound I. The area due to formoterol related A: Infrared Absorption h197Fi—
compound I is not more than 1.5 times the area of the Test specimen—Transfer a portion of the finely powdered
principal peak in the chromatogram obtained with the Diluted Tablets equivalent to about 25 mg of fosinopril sodium to
In-Process Revision
test solution: not more than 0.3% of formoterol related a 100-mL beaker containing 40 mL of water. Heat at 258 for
compound I is found. 5 minutes with stirring, and pass through a medium-porosity
Assay—Transfer about 350 mg of Formoterol Fumarate, fritted-disk funnel. Centrifuge the filtrate at 2500 rpm for 30
accurately weighed, to a titration vessel, dissolve in 50 mL of minutes. Adjust the filtrate with phosphoric acid to a pH of
anhydrous acetic acid, and titrate with 0.1 M perchloric acid 3 to precipitate the fosinopril, and pass through a fritted-disk
VS, determining the endpoint potentiometrically. Perform funnel. Dissolve the precipitate by passing chloroform
a blank determination, and make any necessary correction. through the filter, and evaporate the chloroform solution to
Each mL of 0.1 M perchloric acid is equivalent to 40.24 mg dryness under a current of air. Proceed as directed, using the
of (C19H24N2O4)2 C4H4O4.&1S (USP31) oily residue so obtained and a similarly prepared residue from
25 mg of USP Fosinopril Sodium RS.
Pharmacopeial Forum
B: The retention time of the major peak in the the Standard solution, and record the peak responses as
chromatogram of the Assay preparation corresponds to that directed for Procedure: the resolution, R, between fosinopril
of the Standard preparation, as obtained in the Assay. sodium and fosinopril related compound G is not less than
1.7; and the relative standard deviation for replicate injections
Change to read:
of the Standard solution is not more than 2.0%.
Dissolution h711i— Procedure—Separately inject equal volumes (about 50 mL)
Medium: water; 900 mL. of the Test solution and the Standard solution having a known
Apparatus 2: 50 rpm. concentration of USP Fosinopril Sodium RS in the same
Time: 30 minutes. Medium, and record the chromatograms. Measure the
Mobile phase—Prepare a filtered and degassed mixture of responses for the major peaks, and calculate the amount of
acetonitrile and 0.2% phosphoric acid (64 : 36). Make C30H45NNaO7P dissolved.
adjustments if necessary (see System Suitability under Tolerances—Not less than 80% (Q) of the labeled amount
Chromatography h621i). of C30H45NNaO7P is dissolved in 30 minutes.
Resolution solution—Prepare a solution in Mobile phase
Uniformity of dosage units: meet the requirements.
containing about 0.02 mg per mL each of USP Fosinopril
Limit of related compound A—
Sodium RS and USP Fosinopril Related Compound G RS.
Mobile phase, Diluent, and Chromatographic system—
&
Standard stock solution—Accurately weigh about 20 mg
of USP Fosinopril Sodium RS into a 200-mL volumetric
flask, dissolve in 6-mL of methanol, sonicate briefly, and
tity of USP Fosinopril Related Compound A RS in methanol
dilute with Medium to volume.
Standard solution—Dilute the Standard stock solution with
0.1 mg per mL. Dilute with Diluent to obtain a solution
Medium as directed in the following table.
having a final known concentration of 0.0025 mg per mL.
Standard stock Final volume Test solution—Use the Assay preparation.
Label claim solution (mL) (Flask size) Procedure—Separately inject equal volumes (about 50 mL)
5 mg 5.0 100 of the Standard solution and the Test solution into the
10 mg 10 100 chromatograph, record the chromatogram, and measure the
20 mg 20 100 peak responses for the major peaks. Calculate the percentage
In-Process Revision
40 mg 40 100 of fosinopril related compound A in the portion of Tablets

&1S (USP31) taken by the formula:
passed through a 1.2-mm acrylic filter. [NOTE—Do not use 1000C(rU / rS)
glass filters.]
Chromatographic system (see Chromatography h621i)— in which C is the concentration, in mg per mL, of the
The liquid chromatograph is equipped with a 215-nm detector fosinopril related compound A in the Standard solution; and
and a 4.6-mm 6 15-cm column, maintained at a temperature rU and rS are the peak responses obtained from the Test
of 408, that contains 5-mm packing L1. The flow rate is about solution and the Standard solution, respectively. Not more
3 mL per minute. Chromatograph the Resolution solution and than 4% is found.
Pharmacopeial Forum
Assay— sodium peak. Calculate the quantity, in mg, of fosinopril

Mobile phase—Prepare a degassed mixture of methanol sodium (C30H45NNaO7P) in the portion of Tablets taken by
and 0.2% phosphoric acid (78 : 22). Make adjustments if the formula:
h621i). 50C(VA / VS)(rU / rS)
Diluent—Prepare a mixture of 0.2 M urea solution and
acetonitrile (80 : 20). in which C is the concentration, in mg per mL, of USP
Resolution solution—Prepare a solution in Diluent contain- Fosinopril Sodium RS in the Standard preparation; VA is the
ing 30 mg of USP Fosinopril Related Compound A RS and 70 volume, in mL, of the Assay preparation; VS is the volume, in
mg of USP Fosinopril Sodium RS per mL. mL, of supernatant taken for the Assay preparation; and rU
Standard preparation—Dissolve an accurately weighed and rS are the peak responses obtained from the Assay
quantity of USP Fosinopril Sodium RS to obtain a solution preparation and the Standard preparation, respec-
having a known concentration of about 0.1 mg per mL. tively.&1S (USP30)
Assay preparation—Transfer not fewer than 10 Tablets to

a 500-mL volumetric flask, add 400 mL of Diluent, and stir
BRIEFING
for 40 minutes. Dilute with Diluent to volume, mix, and
centrifuge. Quantitatively dilute an accurately measured Galantamine Tablets: Because there is no existing USP
monograph for this dosage form, a new monograph is being
volume (VS mL) of the clear supernatant with Diluent to proposed. The liquid chromatographic procedures in the test for
Related compounds and in the Assay are based on analyses
obtain a solution (VA mL) containing about 0.1 mg of performed with the YMC Pack Pro C18 brand of L1 column. The
typical retention time of the galantamine peak is about 16 minutes.
fosinopril sodium per mL.
Chromatographic system (see Chromatography h621i)— (MD-PP: R. Ravichandran; BPC: M. Marques) RTS—C44527

The flow rate is about 2 mL per minute. Chromatograph the
Resolution solution and the Standard preparation, and record Add the following:
the peak responses as directed for Procedure: the relative &Galantamine Tablets
retention time is 0.4 for fosinopril related compound A and
1.0 for fosinopril sodium; the resolution, R, between
In-Process Revision
fosinopril sodium and fosinopril related compound A is not
» Galantamine Tablets contain an amount of
less than 2.0; and the relative standard deviation for replicate
Galantamine Hydrobromide equivalent to not less
injections of the Standard preparation is not more than 2.0%.
of the labeled amount of galantamine (C17H21NO3).
the chromatograph, record the chromatograms, and measure Packaging and storage—Preserve in well-closed containers,
the responses for the major peaks. Continue the chromatog- and store at controlled room temperature.
raphy for up to 1.5 times the retention time of the fosinopril
Pharmacopeial Forum
USP Reference standards h11i—USP Galantamine Hydro-

bromide RS. USP Galantamine Hydrobromide Related
Compounds Mixture RS.
Identification—
A: Ultraviolet Absorption h197Ui—The spectrum of the
Test solution corresponds to that of the Standard solution, as in which AU and AS are the absorbances obtained from the Test
obtained in the test for Uniformity of dosage units. solution and the Standard solution, respecetively; CS is the
B: The retention time of the major peak in the concentration of galantamine, in mg per mL, in the Standard
chromatogram of the Assay preparation corresponds to that solution; 500 is the volume, in mL, of Medium; 100 is the
in the chromatogram of the Standard preparation, as obtained conversion factor to percentage; and LC is the Tablet label
in the Assay. claim in mg.
Dissolution h711i— Tolerances—Not less than 80% (Q) of the labeled amount
Medium: water; 500 mL. of galantamine is dissolved in 20 minutes.
Apparatus 2: 50 rpm. Uniformity of dosage units h905i—meets the requirements

Time: 20 minutes. for coated tablets.
Standard solution—Dissolve an accurately weighed quan- Standard solution—Dissolve an accurately weighed quan-
tity of USP Galantamine Hydrobromide RS in Medium, and tity of USP Galantamine Hydrobromide RS in a suitable
dilute quantitatively, and stepwise if necessary, to obtain volumetric flask, and dilute quantitatively with 0.1 N
a solution having a known concentration of about 0.008 mg hydrochloric acid to obtain a solution having a known
per mL of galantamine for Tablets labeled to contain 4 mg; concentration of about 0.04 mg of galantamine per mL.
about 0.016 mg per mL of galantamine for Tablets labeled to [NOTE—The concentration of galantamine (free base), in mg
contain 8 mg; and about 0.024 mg per mL of galantamine for per mL, can be calculated using the molecular weights of
Tablets labeled to contain 12 mg. [NOTE—The concentration galantamine (287.35) and galantamine hydrobromide
of galantamine (free base), in mg per mL, can be calculated (368.27).]
using the molecular weights of galantamine (287.35) and Test solution—Add one Tablet to each appropriately-sized
galantamine hydrobromide (368.27)] volumetric flask to obtain a final galantamine concentration of
Test solution—Use portions of the solution under test 0.04 mg per mL, add an appropriate amount of 0.1 N
In-Process Revision
passed through a suitable 0.2-mm filter. hydrochloric acid equivalent to 75% of the total volume of the
Procedure—Determine the amount of galantamine dis- volumetric flask, and mechanically shake for about 45
solved by employing UV absorption at the wavelength of minutes. Dilute with 0.1 N hydrochloric acid to volume,
maximum absorbance at about 288 nm on the Test solution in and mix. Pass a portion of this solution through a filter having
comparison with the Standard solution, using a 5-cm cell for a 0.2-mm or finer porosity, and use the filtrate.
Tablets labeled to contain 4 mg or 8 mg, or using a 1-cm cell Procedure—Determine the amount of galantamine
for Tablets labeled to contain 12 mg. Calculate the percentage (C17H21NO3) dissolved by employing UV absorption at the
of galantamine (C17H21NO3) dissolved, by the formula: wavelength of maximum absorbance at about 289 nm on
filtered portions of the Test solution in comparison with
Pharmacopeial Forum
a Standard solution. Calculate the quantity of galantamine impurities using the approximate relative retention times
(C17H21NO3) dissolved, in percent of the label claim, by the given in Table 1: the resolution, R, between 6b-hexahydro-
formula: galantamine and 6b-octahydrogalantamine is not less than
1.5. Chromatograph the Standard solution, and record the
(CS / CU)(AU / AS)100 responses as directed for Procedure: the relative standard
deviation for replicate injections is not more than 2.0% for the
in which CS is the concentration, in mg per mL, of
galantamine peak.
galantamine in the Standard solution; CU is the concentration,
in mg per mL, of galantamine in the Test solution based on
the label claim; and AU and AS are the absorbances at the
monitoring wavelength, obtained from the Test solution and
peak responses. [NOTE—Ignore the peak due to bromide near
the Standard solution, respectively.
the void volume.] Calculate the percentage of each of the
Related compounds— galantamine related compounds in the portion of Tablets
Buffer solution, Solution A, Solution B, Mobile phase, and taken by the formula:
Diluent—Prepare as directed in the Assay.
Resolution solution—Prepare a solution of USP Galanta- 100(Cs / CU)(rU / rS)(1/F)
mine Hydrobromide Related Compounds Mixture RS in
Diluent having a concentration of 0.6 mg per mL. in which CS and CU are the concentrations, in mg per mL, of
Standard solution—Use the Standard preparation, pre- galantamine in the Standard solution and Test solution,
pared as directed in the Assay. respectively; rU is the peak area of each impurity obtained
Test solution—Use the Assay preparation. from the Test solution; rS is the peak area of galantamine
Chromatographic system—Prepare as directed in the Assay. obtained from the Standard solution; and F is the Relative
Chromatograph about 20 mL of the Resolution solution, and Response Factor (see Table 1 for values) for each of the
record the responses as directed for Procedure. Identify the impurities relative to galantamine.
Table 1

Related Compound Time (RRT) Factor (F) Limit %
1
6b-Hexahydrogalantamine 0.73 1.1 0.30
In-Process Revision
6b-Octahydrogalantamine{2 0.86 — NA
Galantamine hydrobromide 1.00 1.0 NA
6a-Hexahydrogalantamine{3 1.15 — NA
Tetrahydrogalantamine{4 2.09 — NA
Individual unspecified degradation impurity — 1.0 0.20%
Total impurities — — 1.0%
[NOTE—The impurities marked with ‘‘{’’ are not quantified and are intended for system suitability evaluation only.]
1
[4aS-(4a,6b,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol, N-oxide.
2
[4aS-(4aa,6b,8aR*)]-4a,5,7,8,9,10,11,12-Octahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol.
3
[4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol.
4
[4aS-(4aR*,8aR*)]-9,10,11,12-Tetrahydro-3-methoxy-11-methyl-4aH-benzofuro[3a,3,2-ef][2]benzazepine.
Pharmacopeial Forum
Assay— The liquid chromatograph is equipped with a 230-nm detector
Buffer solution–Dissolve 5.34 g of dibasic sodium phos- and a 4.6-mm 6 10-cm column that contains 3-mm L1
phate dihydrate in 1 L of water. Adjust with phosphoric acid packing. The flow rate is about 1.5 mL per minute. The
to a pH of 6.5, and mix. column temperature is maintained at 358. The chromatograph
Solution A—Add 950 mL of Buffer solution to 50 mL of is programmed as follows.
methanol, and mix. Time Solution A Solution B

Solution B—Prepare a mixture of acetonitrile and methanol (minutes) (%) (%) Elution
(95 : 5).
0.0–40.0 100?75 0?25 linear gradient
40.0–45.0 75?60 25?40 linear gradient
Solution B as directed for Chromatographic system. Make
45.0–46.0 60?40 40?60 linear gradient
46.0–55.0 40 60 isocratic
55.0–56.0 40?100 60?0 linear gradient
Diluent—Dissolve about 35.4 g of edetate disodium in 950
56.0–61.0 100 0 re-equilbration
mL of water. Add 50 mL of methanol, and mix well.
Chromatograph the Standard preparation, and record the
quantity of USP Galantamine Hydrobromide RS in Diluent,
2.0%.
about 0.48 mg per mL of galantamine. [NOTE— The
concentration of galantamine (free base), in mg per mL, can
the chromatograph, and measure the responses for the
be calculated using the molecular weights of galantamine
galantamine hydrobromide peak. Calculate the quantity, in
(287.35) and galantamine hydrobromide (368.27)]
percentage of label claim, of galantamine (C17H21NO3) in the
Assay preparation—Weigh not fewer than 10 Tablets.
portion of Galantamine Tablets taken by the formula:
Transfer an accurately weighed portion to an appropriately-
sized volumetric flask, and dilute quantitatively, and stepwise
100(CS / CU)(rU / rS)
if necessary, with Diluent to obtain a solution having
In-Process Revision
a galantamine concentration of about 0.48 mg per mL,

in which CS and CU are the concentrations of galantamine, in
based on the label claim. Pass a portion of this solution
mg per mL, in the Standard preparation and the Assay
through a PTFE filter having a 0.45-mm or finer porosity, and
preparation, respectively; and rU and rS are the peak responses
use the filtrate.
obtained from the Assay preparation and the Standard
preparation, respectively.&1S (USP31)
Pharmacopeial Forum
Determine the amount of C24H34N4O5S dissolved by

BRIEFING
Glimepiride Tablets. Because there is no existing USP

Mobile phase—Prepare as directed in the Assay.
monograph for this dosage form, a new monograph, based on Diluting solution—Prepare a mixture of methanol and
validated methods of analysis, is being proposed. The liquid
chromatographic procedure in the test for Related compounds is water (50 : 50).
based on analyses performed with the LiChrospher C18 3-mm 100A
endcapped brand of L1 column. The typical retention time for Standard solution—Prepare a solution of USP Glimepiride
glimepiride is about 17 minutes. The liquid chromatographic
procedure in the test for Dissolution and in the Assay is based on RS in a mixture of acetonitrile and water (90 : 10) having
analyses performed with the LiChrospher C18 5-mm 100A end-
capped brand of L1 column. The typical retention time for a known concentration of about 0.125 mg of glimepiride per
glimepiride is about 8 minutes.
mL. Pipet 4.0 mL of this solution into a 200-mL volumetric
(MD-GRE: E. Gonikberg; BPC: M. Marques) RTS—C46582
flask, dilute with Medium to volume, and mix. Pipet 15.0 mL
of this solution into a 50-mL volumetric flask, dilute with
Diluting solution to volume, and mix. The final solution
contains about 0.00075 mg of glimepiride per mL.
Add the following:
&Glimepiride Test solution—Withdraw approximately 10 mL of the
Tablets
solution under test, and transfer to a centrifuge tube.
Centrifuge for 5 minutes at 2500 rpm. Pipet 3.0 mL of the
supernatant into a 10-mL volumetric flask, dilute with
» Glimepiride Tablets contain not less than 90.0 Diluting solution to volume, and mix.
percent and not more than 110.0 percent of the Chromatographic system (see Chromatography h621i)—
labeled amount of glimepiride (C24H34N4O5S). The liquid chromatograph is equipped with a 228-nm detector
and a 4.0-mm 6 12.5-cm column that contains packing L1.
Packaging and storage—Preserve in well-closed containers.
The flow rate is about 1.0 mL per minute. Chromatograph the
Store at controlled room temperature.
USP Reference standards h11i—USP Glimepiride RS. USP
for Procedure: the tailing factor is not more than 2.0, and the
Glimepiride Related Compound B RS. USP Glimepiride
Related Compound C RS.
than 2.0%.
Identification—The retention time of the major peak in the Procedure—Separately inject equal volumes (about 50 mL)
chromatogram of the Assay preparation corresponds to that in of the Standard solution and the Test solution into the
In-Process Revision
the chromatogram of the Standard preparation, as obtained in chromatograph, record the chromatograms, measure the
the Assay. responses for the major peaks, and determine the amount of
Dissolution h711i— C24H34N4O5S dissolved.
Medium: pH 7.8 phosphate buffer, prepared by dissolving Tolerances—Not less than 80% (Q) of the labeled amount
0.58 g of monobasic potassium phosphate and 8.86 g of of C24H34N4O5S is dissolved in 15 minutes.
dibasic sodium phosphate, anhydrous, in 1000 mL of water, Uniformity of dosage units h905i: meet the requirements.
and adjusting with 10% phosphoric acid or 1 N sodium Related compounds—[NOTE—Store the solutions containing
hydroxide to a pH of 7.8; 900 mL. glimepiride for no longer than 24 hours.]
Apparatus 2: 75 rpm. Mobile phase and Diluent—Prepare as directed in the
Time: 15 minutes. Assay.
Pharmacopeial Forum
System suitability solution—Prepare a solution in Diluent in which H is the measured height of the respective related
containing about 0.04 mg of USP Glimepiride RS per mL and compound peak, and h is the amplitude of the average
about 0.02 mg each of USP Glimepiride Related Compound measured baseline noise. The S/N for each peak is not less
B RS and USP Glimepiride Related Compound C RS per mL. than 10.
Pipet a 5.0-mL aliquot of this solution into a 50-mL Procedure—Inject a volume (about 10 mL) of the Test
volumetric flask, dilute with Diluent to volume, and mix. solution into the chromatograph, record the chromatograms,
Sensitivity solution—Pipet a 5.0-mL aliquot of the System and measure the peak responses. Continue the elution for at
suitability solution into a 100-mL volumetric flask, dilute least two times the retention time of the glimepiride peak.
with Diluent to volume, and mix. Calculate the percentage of each impurity in the portion of
Test solution—Weigh and finely powder not fewer than 10 Tablets taken by the formula:
Tablets, and transfer an accurately weighed portion of the
powder to a 50-mL centrifuge tube. Add Diluent to prepare 100(1 / F)(rU / rs)
a solution containing about 0.1 mg of glimepiride per mL,
based on the label claim. Sonicate in a water bath at in which F is the relative response factor, which is equal to
a temperature not to exceed 208 for not less than 5 minutes 1.3 for glimepiride related compound B and 1.0 for any other
and not more than 10 minutes, with occasional mixing. impurity; rU is the peak response for each impurity obtained
Centrifuge the samples, and use the clear supernatant. from the Test solution; and rs is the sum of the responses of all
Chromatographic system (see Chromatography h621i)— the peaks in the Test solution. Disregard any peak less than
The liquid chromatograph is equipped with a 228-nm detector 0.1%. Not more than 2.5% of glimepiride related compound
and a 4-mm 6 25-cm column that contains packing L1. The B is found, not more than 0.5% of any other individual
flow rate is about 1 mL per minute. Chromatograph the impurity is found, not more than 1.0% of total impurities
System suitability solution, and identify the glimepiride peak excluding glimepiride related compound B is found, and not
and the peaks due to the related compounds on the basis of more than 3.5% of overall total impurities (including
the relative retention times, which are about 0.2 for glimepiride related compound B) is found.
glimepiride related compound B, about 0.3 for glimepiride Assay—[NOTE—Store the solutions containing glimepiride no
related compound C, and 1.0 for glimepiride. Record the peak longer than 24 hours.]
responses as directed for Procedure: the resolution, R, Mobile phase—Dissolve 0.5 g of monobasic sodium
In-Process Revision
between glimepiride related compounds B and C is not less phosphate in 500 mL of water. Adjust with 10% phosphoric
than 4, and the relative standard deviation of the glimepiride acid to a pH of 2.1 to 2.7, add 500 mL of acetonitrile, and
peak for replicate injections is not more than 2.0%. mix.
Chromatograph the Sensitivity solution, and calculate the Diluent—Prepare a mixture of acetonitrile and water (9 : 1).
signal-to-noise ratio, S/N, for the peaks of glimepiride related System suitability preparation—Prepare a solution in
compounds B and C by the formula: Diluent containing 0.1 mg of USP Glimepiride RS per mL
and 0.02 mg each of USP Glimepiride Related Compound B
(2H)/h RS and USP Glimepiride Related Compound C RS per mL.
Pharmacopeial Forum
Standard preparation—Dissolve an accurately weighed in which CS is the concentration, in mg per mL, of glimepiride
quantity of USP Glimepiride RS in Diluent to obtain in the Standard preparation; CU is the concentration of
a solution having a known concentration of about 0.1 mg glimepiride in the Assay preparation, based on the labeled
per mL. quantity per Tablet and the extent of dilution; and rU and rS are
Assay preparation—Transfer five whole Tablets into the peak responses for glimepiride obtained from the Assay
a suitable volumetric flask to prepare a solution of preparation and the Standard preparation, respec-
approximately 0.1 mg of glimepiride per mL, based on the tively.&1S (USP31)
label claim. Add water to 10% of the volume of the flask.

Shake the flask to completely dissolve the tablets. Add
acetonitrile to about 70% of the volume of the flask, and BRIEFING
swirl. Sonicate the samples in a water bath not to exceed 208

Isosorbide Mononitrate Tablets, page 1700 of PF 32(6) [Nov.–
for not less than 5 minutes and not more than 10 minutes with Dec. 2006]. It is proposed to add a Dissolution test to this
monograph. The chromatographic procedure in this test was
occasional shaking. Allow the solutions to come to room validated using a Zorbax ODS brand of L1 packing.
temperature, dilute with acetonitrile to volume, mix, and filter. (BPC: M. Marques) RTS—C53197
and a 4-mm 6 12.5-cm column that contains packing L1. Add the following:
The flow rate is about 1 mL per minute. Chromatograph the &Isosorbide Mononitrate Tablets
System suitability preparation, and identify the glimepiride
peak and the peaks due to the related compounds based on
their relative retention times, which are about 0.25 for
» Isosorbide Mononitrate Tablets contain not less
glimepiride related compound B, about 0.35 for glimepiride
related compound C, and 1.0 for glimepiride. Record the peak
responses as directed for Procedure: the resolution, R, of the labeled amount of isosorbide mononitrate
between glimepiride related compounds B and C is not less (C6H9NO6).
than 1.5, and the tailing factor for the glimepiride peak is not
more than 2.0. Chromatograph the Standard preparation, and
at a temperature between 208 and 308.
record the peak responses as directed for Procedure: the
In-Process Revision
USP Reference standards h11i—USP Isosorbide RS.
[NOTE—The following Reference Standards are dry mixtures
than 2.0%.
of an active component and suitable excipients to permit safe
handling. For quantitative applications, calculate the concen-
tration of the active component on the basis of the content
stated on the label.] USP Diluted Isosorbide Dinitrate RS.
the areas for the major peaks. Calculate the percentage of the
USP Diluted Isosorbide Mononitrate RS. USP Diluted
labeled amount of glimepiride (C24H34N4O5S) in the portion of
Isosorbide Mononitrate Related Compound A RS.
Tablets taken by the formula:
Identification—
100(CS / CU)(rU / rS) A: Thin-Layer Chromatographic Identification Test

h201i—
Pharmacopeial Forum
well. Transfer 20.0 mL of this solution to a 100-mL

well.
powder, equivalent to about 120 mg of isosorbide mononi-
Test solution—Pass a portion of the solution under test
trate, to a suitable container, add 50.0 mL of absolute alcohol,
through a suitable filter having a porosity of 0.45 mm,
sonicate for 10 minutes, and centrifuge. Quantitatively dilute
discarding the first few mL.
the supernatant (10 in 50) with absolute alcohol.
Standard solution: 0.5 mg a solution of USP Diluted
Proceed as directed for Assay. Chromatograph the Standard
Isosorbide Mononitrate RS in absolute alcohol containing 0.5
mg of isosorbide mononitrate per mL.
Procedure: the relative standard deviation for replicate
Developing solvent system: a mixture of chloroform and
Procedure—Proceed as directed for Assay. Calculate the
methanol (95 : 5).
percentage of C6H9NO6 dissolved by the formula:
Spray reagent—Dissolve 1 g of soluble starch in 100 mL of
boiling water. Cool, add 0.5 g of potassium iodide, and mix to
dissolve.
Procedure—Examine the plate under short-wavelength UV
light, marking any observed spots. Visualize nitrates on the
plate by spraying with Spray reagent and illuminating with
in which rU and rS are the peak responses for the Test solution
short-wavelength UV light for about 10 minutes. Isosorbide
and the Standard solution, respectively; CS is the concentra-
mononitrate and other nitrates appear as a violet spot on
tion, in mg per mL, of the Standard solution; 900 is the
a white to light violet background.
volume, in mL, of Medium; 100 is the conversion factor to
percentage; and LC is the Tablet label claim, in mg.
of C6H9NO6 is dissolved in 15 minutes.&1S (USP31)
in the Assay.
Uniformity of dosage units h905i: meet the requirements
Change to read: for Content Uniformity.
In-Process Revision
Dissolution h711i—[To come.]
TEST 1—
&
Medium: water; 900 mL, deaerated.
Adsorbent, Standard solution 1, Standard solution 2,
Standard solution 3, Application volume, and Developing
Time: 15 minutes.
solvent system—Prepare as directed in Related compounds,
Determine the amount of C6H9NO6 dissolved by employing
Test 1, under Diluted Isosorbide Mononitrate.
Mobile phase—Proceed as directed for Assay.
Standard solution—Transfer 20 mg, accurately weighed, of
powder, equivalent to about 100 mg of isosorbide mononi-
USP Diluted Isosorbide Mononitrate RS to a 200-mL
trate, to a suitable container, add 20.0 mL of absolute alcohol,
sonicate for 10 minutes, and centrifuge. Use the supernatant.
Pharmacopeial Forum
Procedure—Proceed as directed for Thin-Layer Chroma- a volume of Isosorbide mononitrate related compound A
tography under Chromatography h621i. After developing, standard stock solution and a volume of Isosorbide dinitrate
dry the plate with warm air for about 10 minutes, dip the plate standard stock solution, and dilute with water to volume to
in a solution prepared by dissolving 1.25 g of potassium obtain a solution having a known concentration of about 0.1
permanganate and 10.0 g of sodium hydroxide in 500 mL of mg of USP Isosorbide Mononitrate RS isosorbide mononi-
water (prepared fresh for each plate), and heat at 1058 for trate per mL, 0.0005 mg of isosorbide mononitrate related
5 minutes. Any spot in the chromatogram obtained from the compound A per mL, and 0.0005 mg of isosorbide dinitrate
Test solution and corresponding to the RF value of the spots per mL. Filter a portion of the solution, discarding the first
obtained from the Standard solutions is not more intense than few mL of the filtrate.
the spot in the chromatogram obtained from Standard Test solution—Use the Assay preparation, prepared as
solution 3: not more than 1.0% of any individual impurity directed in the Assay.
is found. If the spot in the chromatogram obtained from the Chromatographic system (see Chromatography h621i)—
Test solution is nearly as intense as the spot obtained from The liquid chromatograph is equipped with a 220-nm detector
Standard solution 3, further dilute the Test solution (1 : 1) and a 4.6-mm 6 25-cm column that contains packing L1.
with absolute alcohol, repeat the test, and compare the The flow rate is about 1.0 mL per minute. Chromatograph the
intensity of the isosorbide spot in the diluted Test solution Resolution solution, and record the peak responses as directed
with the intensity of the spots obtained from the Standard for Procedure: the resolution, R, between isosorbide
solutions, correcting the percentage level for the additional mononitrate related compound A and isosorbide mononitrate
dilution of the Test solution. is not less than 1.5. Chromatograph the Standard solution,
TEST 2— and record the peak responses as directed for Procedure: the
Mobile phase and Resolution solution—Proceed as directed relative standard deviation for replicate injections is not more
in the Assay. than 10% for the isosorbide mononitrate related compound A
Isosorbide mononitrate related compound A standard stock and isosorbide dinitrate peaks.
solution—Dissolve an accurately weighed quantity of USP Procedure—Separately inject equal volumes (about 50 mL)
Diluted Isosorbide Mononitrate Related Compound A RS in of the Standard solution and the Test solution into the
methanol, and dilute quantitatively, and stepwise if necessary, chromatograph, record the chromatograms, and measure the
with methanol to obtain a solution having a known areas for the major peaks. Compare the peak areas of the
concentration of about 0.1 mg of isosorbide mononitrate corresponding impurity obtained from the Test solution and
In-Process Revision
related compound A per mL. the Standard solution, respectively. The average peak area of
Isosorbide dinitrate standard stock solution—Dissolve an the impurity in the Test solution is less than or equal to the
accurately weighed quantity of USP Diluted Isosorbide average peak area of the corresponding peak in the Standard
Dinitrate RS in methanol, and dilute quantitatively, and solution: not more than 0.5% of isosorbide mononitrate
stepwise if necessary, with methanol to obtain a solution related compound A is found; and not more than 0.5% of
having a known concentration of about 0.1 mg of isosorbide isosorbide dinitrate is found.
dinitrate per mL. Assay—
Standard solution—Transfer a quantity of USP Diluted Mobile phase—Prepare a filtered and degassed mixture of
Isosorbide Mononitrate RS, accurately weighed, to a suitable water and methanol (7 : 3). Make adjustments if necessary
volumetric flask. Dissolve in water, quantitatively add (see System Suitability under Chromatography h621i).
Pharmacopeial Forum
Resolution solution—Prepare a solution of USP Diluted in which C is the concentration, in mg per mL, of isosorbide
Isosorbide Mononitrate RS and USP Diluted Isosorbide mononitrate in the Standard preparation; and rU and rS are the
Mononitrate Related Compound A RS having a concentration peak responses obtained from the Assay preparation and the
of 0.0005 mg of each of isosorbide mononitrate and Standard preparation, respectively.&1S (USP30)
isosorbide mononitrate related compound A per mL.
quantity of USP Diluted Isosorbide Mononitrate RS in water, BRIEFING

Levalbuterol Hydrochloride, page 75 of PF 33(1) [Jan.–Feb.
water to obtain a solution having a known concentration of 2007]; Levalbuterol Inhalation Solution, page 79 of PF 33(1)
[Jan.–Feb. 2007]. A Sensitivity solution has been added to the test for
about 0.1 mg of isosorbide mononitrate per mL. Pass a portion Enantiomeric purity and chiral identity. The solution is used to
establish system suitability. A test for Microbial limits has also been
of this solution through a filter having a 0.45-mm or finer added, and a change was made to the test for the Related compounds.
porosity, and use the filtrate. (AER: K. Zaidi) RTS— C53466
Assay preparation—Weigh and finely powder not fewer
powder, equivalent to about 20 mg of isosorbide mononitrate, Add the following:
to a 200-mL volumetric flask, add 100 mL of water, and &Levalbuterol Hydrochloride
sonicate for about 10 minutes. Dilute with water to volume,
and mix. Pass a portion of this solution through a filter having
a 0.45-mm or finer porosity, and use the filtrate.
C13H21NO3 HCl 275.77
(R)-a1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-a,a’-
diol hydrochloride [50293-90-8].
Resolution solution, and record the peak responses as directed
for Procedure: the resolution, R, between isosorbide
mononitrate related compound A and isosorbide mononitrate » Levalbuterol Hydrochloride contains not less
is not less than 1.5. Chromatograph the Standard preparation, than 98.0 percent and not more than 102.0 percent
In-Process Revision
and record the peak responses as directed for Procedure: the of C13H21NO3 HCl, calculated on the anhydrous
relative standard deviation for replicate injections is not more basis.
than 1.5%.
containers, and store at controlled room temperature.
mg, of isosorbide mononitrate (C6H9NO6) in the portion of
Tablets taken by the formula:
200C(rU / rS)
Pharmacopeial Forum
USP Reference standards h11i—USP Albuterol RS. USP Chromatographic system (see Chromatography h621i)—
Dehydrated Alcohol RS. USP Ethyl Acetate RS. USP Heptane The liquid chromatograph is equipped with a 220-nm detector
RS. USP Levalbuterol Hydrochloride RS. USP Levalbuterol and a 4.6-mm 6 15-cm column that contains 5-mm packing
Related Compound A RS. USP Levalbuterol Related L1. The column temperature is maintained at 458. The flow
Compound B RS. USP Levalbuterol Related Compound C rate is about 1.0 mL per minute. The chromatograph is
RS. USP Levalbuterol Related Compound D RS. USP programmed as follows.
Levalbuterol Related Compound E RS. USP Levalbuterol
Related Compound F RS. USP Methyl Alcohol RS. USP 2-
Propanol RS.
Color of a 1% solution h631i: not more than 20 APHA 30–50 70?28 30?72 linear gradient
platinum cobalt units. 50–50.01 28?0 72?100 step gradient
50.01–55 0 100 isocratic
pH h791i: between 4.5 and 5.5, in a solution (1 in 100).
55–55.01 0?100 100?0 step gradient
Water, Method Ic h921i: not more than 0.3%.
Heavy metals, Method I h231i: not more than 10 ppm. areas as directed for Procedure: the resolution, R, between
levalbuterol and levalbuterol related compound A is not less
Microbial limits h61i: meets the requirements of the tests
than 4.9, and between levalbuterol related compound B and
for absence of Salmonella species, Staphylococcus aureus,
levalbuterol related compound C it is not less than 1.5; and
Escherichia coli, and Pseudomonas aeruginosa. The total
between levalbuterol related compound D and levalbuterol
aerobic bacterial count is less than 10 cfu per g. The total
related compound E is not less than 1.8; the column efficiency
combined molds and yeast count is less than 10 cfu per g.
determined from the levalbuterol peak is not less than 4000;
the tailing factor for the levalbuterol peak is not greater than
Solution A, Solution B, Mobile phase, and Diluent— 4.0; and the relative standard deviation for replicate injection
Proceed as directed in the Assay. is less than 20%, determined from any of the six related
Test solution—Use the Assay preparation. compound peaks.
In-Process Revision
Standard solution—Dissolve accurately weighed quantities Procedure—Separately inject equal volumes (about 50 mL)
of USP Levalbuterol Hydrochloride RS, USP Levalbuterol of the Standard solution and the Test solution into the
Related Compound A RS, USP Levalbuterol Related chromatograph, record the chromatograms, and measure the
Compound B RS, USP Levalbuterol Related Compound C peak responses. Determine the area of the levalbuterol peak,
RS, USP Levalbuterol Related Compound D RS, USP and integrate all peaks with an area greater than 0.05% of the
Levalbuterol Related Compound E RS, and USP Levalbuterol area corresponding to the levalbuterol peak. Calculate the
Related Compound F RS in Diluent to obtain a solution percentage of each impurity in the portion of Levalbuterol
having known concentrations of about 0.05 mg per mL of Hydrochloride taken by the formula:
each related compound and 100 mg per mL of USP
Levalbuterol Hydrochloride RS. 100(ri / rs F)
Pharmacopeial Forum
in which ri is the peak response for each impurity obtained Chromatographic system (see Chromatography h621i)—
from the Test solution; rs is the sum of the responses of all the The liquid chromatograph is equipped with a 225-nm detector
peaks (see Table 1 for limits of individual impurities); and F and a 4.6-mm 6 25-cm column that contains 5-mm packing
is the relative response factor for each impurity. Not more L##. The flow rate is about 1.0 mL per minute. Chromato-
than 0.5% of total impurities is found. graph the Standard Sensitivity solution, and record the peak
Table 1 between levalbuterol and (S)-albuterol is not less than 2.0;
the column efficiency calculated from either peak is not less
Relative Relative
than 4000; the tailing factor for levalbuterol and (S)-albuterol
is not more than 2.2; and the relative standard deviation for
Related Compound Time Factor (F) (%)
replicate injections is not more than 20% for (S)-albuterol.
A 1.2 1.0 0.1
B 1.5 1.0 0.10
of the Standard solution and the Test solution. The percentage
C 1.6 1.0 0.10
of (S)-albuterol is calculated using the following equation:
D 1.7 3.0 0.05
E 2.1 1.0 0.10 0.1
100(ri / rs)
F 3.5 1.2 0.10
Any unknown impu- — — 0.10
in which ri is the peak response for (S)-albuterol, and rs is the
rity
sum of the responses of both levalbuterol and (S)-albuterol
Total unknown impu- — — 0.1
peaks: not more than 0.2% of (S)-albuterol is found.
rities
Residual solvents—
Standard stock solution—Transfer 1.0 mL each of USP
Ethyl Acetate RS and USP Methyl Alcohol RS, 0.5 mL of
Enantiomeric purity and chiral identity—
USP 2-Propanol RS, 3.0 mL of USP Dehydrated Alcohol RS,
Mobile phase—Prepare a degassed mixture of acetonitrile,
and 0.1 mL each of toluene and USP Heptane RS into a
methanol, acetic acid, and triethylamine (500: 500: 3: 1).
25-mL volumetric flask, and dilute with butyl alcohol to
Diluent—Use the Mobile phase.
volume.
Sensitivity solution—Dissolve about 10 mg of USP
In-Process Revision
Low standard solution—Transfer 1 mL of water and 5 mL

Levalbuterol Hydrochloride RS and 4 mg of USP Albuterol
of butyl alcohol into an appropriate headspace vial, and seal.
RS in 100 mL of Diluent, and mix.
Using a 10-mL syringe, transfer 8.0 mL of the Standard stock
solution into the headspace vial through the septum, and mix.
tity of USP Albuterol RS in Diluent to obtain a solution
Middle standard solution—Transfer 1 mL of water and
5 mL of butyl alcohol into an appropriate headspace vial, and
Test solution—Transfer an accurately weighed quantity of
seal. Using a 25-mL syringe, transfer 20 mL of the Standard
Levalbuterol Hydrochloride to a suitable volumetric flask,
stock solution into the headspace vial through the septum, and
and quantitatively dilute with Diluent to obtain a solution
mix.
having a concentration of about 0.8 mg per mL of
Levalbuterol Hydrochloride.
Pharmacopeial Forum
High standard solution—Transfer 1 mL of water and 5 mL in which rU is the response of the Test solution; y-intercept is
of butyl alcohol into an appropriate headspace vial, and seal. from the equation of the line described by the Standard
Using a 50-mL syringe, transfer 30 mL of the Standard stock solutions; and WU is the weight, in mg, of Levalbuterol
solution into the headspace vial through the septum, and mix. Hydrochloride taken. The amount of each impurity in the Test
Test preparation solution—Transfer 500 mg of the article solution does not exceed the limit in the accompanying table:
under test into an appropriate headspace vial, add 1 mL of
Impurity Limit (%)
water, and 5 mL of butyl alcohol, seal, and mix.
Ethanol 0.2
Methanol 0.10
Ethyl acetate 0.10
detector, a headspace sampler, and a 0.32-mm 6 50-m fused
Isopropanol 0.050
silica column coated with a 1.0-mm layer of phase G16. The
n-Heptane 0.010
loop temperature is 1508. All samples are equilibrated for 30
Toluene 0.010
minutes at 908 in the headspace sampler. The carrier gas is
helium with a flow rate of 1.6 mL per minute and a split ratio
of 1.6 : 30. The column temperature is maintained at 508 for Assay—
5 minutes, then raised at a rate of 108 per minute to 2008. The Solution A—Prepare a 1 in 1000 solution of phosphoric
injection port and detector temperatures are maintained at acid in water, and degas.
2008 and 2508, respectively. Chromatograph the Low Solution B—Prepare a degassed mixture of acetonitrile,
standard solution, the Middle standard solution, and the methanol, water, and phosphoric acid (700: 700: 600: 2).
High standard solution, and record the peak responses as Mobile phase—Use variable mixtures of Solution A and
directed for Procedure. Calculate the correlation coefficient Solution B as directed for Chromatographic system. Make
for the line (r 2). The correlation coeffcient for each impurity adjustments if necessary (see System Suitability under
is equal to or greater than 0.99. Chromatography h621i).
Procedure—Separately inject equal volumes (about 1 mL) Diluent—Use Solution A.
of the Low standard solution, Middle standard solution, High Standard preparation—Dissolve an accurately weighed
standard solution, and the Test preparation solution into the quantity of USP Levalbuterol Hydrochloride RS in Diluent to
chromatograph, record the chromatogram, and measure the obtain a solution having a known concentration of about 100
responses for the major peaks. From the graph, calculate the mg per mL.
In-Process Revision
quantity, in percentage, of each impurity found in the portion Assay preparation—Transfer about 10 mg of Levalbuterol
of Levalbuterol Hydrochloride taken by the formula: Hydrochloride, accurately weighed, to a 100-mL volumetric
flask. Dissolve in and dilute with Diluent to volume, and mix.
100 [[(rU – y-intercept)/m (slope)] 6 6 / WU] Chromatographic system (see Chromatography h621i)—
L1. The column temperature is maintained at 358. The flow
rate is about 1.0 mL per minute. The chromatograph is
programmed as follows:
Pharmacopeial Forum
BRIEFING
Levalbuterol Inhalation Solution, page 79 of PF 33(1) [Jan.–
Feb. 2007]. Proposed revisions for this monograph include the
0 91.5 8.5 equilibration addition of a Sensitivity solution in the test for Enantiomeric purity
and chiral identity, which is used to establish system suitability, and
0–15 91.5 8.5 isocratic revisions in the tests for Particulate matter and Related compounds.
15–15.01 91.5?0 8.5?100 step gradient
(AER: K. Zaidi) RTS—C53604
15.01–20 0 100 isocratic
20–20.01 0?91.5 100?8.5 step gradient
20.01–30 9l.5 8.5 re-equilibration
Chromatograph the Standard preparation, and record the Add the following:
peak areas as directed for Procedure: the column efficiency is &Levalbuterol Inhalation Solution
greater than 5500 theoretical plates; the tailing factor is less
than 2.3; and relative standard deviation for replicate
» Levalbuterol Inhalation Solution is a sterile,
aqueous solution of Levalbuterol Hydrochloride,
prepared with Sodium Chloride. It contains not less
the responses for the major peaks. Calculate the quantity in than 90.0 percent and not more than 110.0 percent
mg of C13H21NO3 HCl in the portion of Levalbuterol of the labeled amount of levalbuterol hydrochloride
Hydrochloride taken by the formula: (C13H21NO3 HCl).
0.1CS (rU / rS) Packaging and storage—Preserve in low-density polyethyl-

ene single-use ampuls, with a multilayer foil overwrap. Store
in which CS is the concentration, in mg per mL, of USP at controlled room temperature.
Levalbuterol Hydrochloride RS in the Standard preparation; Labeling—The outer label indicates the dose and that the
and rU and rS are the peak responses of levalbuterol ampuls should be discarded if the solution is not colorless.
hydrochloride obtained from the Assay preparation and the
USP Reference standards h11i—USP Levalbuterol Hydro-
In-Process Revision
Standard preparation, respectively.&1S (USP31)

chloride RS. USP Levalbuterol Related Compound A RS.
USP Levalbuterol Related Compound B RS. USP Levalbu-
terol Related Compound C RS. USP Levalbuterol Related
Compound D RS. USP Levalbuterol Related Compound E RS.
USP Levalbuterol Related Compound F RS. USP Levalbu-
terol Related Compound G RS.
Identification—

observed in the chromatogram of the Standard preparation,
as obtained in the Assay.
Pharmacopeial Forum
Color h631i: not more than 20 APHA platinum cobalt the area corresponding to levalbuterol hydrochloride. Calcu-
units. late the percentage of each impurity in the portion of
Sterility h71i: meets the requirements. Inhalation Solution taken by the formula:
Uniformity of dosage units h905i: meets the require-

100(ri / rs)(1/F)
ments.
pH h791i: between 3.3 and 4.5. in which F is the relative response factor for each impurity
Particulate matter h788i: not more than 250 particles and is equal to 1.0 for related compounds A, B, C, E, and G
greater than or equal to 10 mm; and not more not more than 25 and all unknown peaks, 3.2 3.0 for related compound D, and
particles greater than or equal to 25 mm; not more than 1.2 for related compound F; ri is the peak response for each
2 particles greater than or equal to 100 mm; and not more than impurity obtained from the Test solution; and rs is the sum of
1 particle greater than or equal to 300 mm. the responses of all the peaks: not more than 0.10% of related
compound G is found; not more than 0.10% of related
compound D in each ampul is found (total content of related
compound D should not be more than 1 mg 1.0 mg per ampul);
directed for Related compounds under Levalbuterol Hydro-
not more than 0.25% of total unknown impurities are found;
chloride.
not more than 0.10% of any unknown impurity is found; and
Diluent—Dissolve about 9.0 + 0.05 g of sodium chloride
not more than 0.70% of total impurities is found.
in 950 mL of water. Adjust with dilute sulfuric acid to a pH of
4.0, and dilute with water to 1000 mL. Mix, and pass through Enantiomeric purity and chiral identity—
0.45-mm filter. Mobile phase, Sensitivity solution, and Standard solution—
Standard solution—Dissolve accurately weighed quantities Proceed as directed for Enantiomeric purity and chiral
of USP Levalbuterol Hydrochloride RS, USP Levalbuterol identity under Levalbuterol Hydrochloride.
Related Compound A RS, USP Levalbuterol Related Test solution—All sample concentrations are injected neat.
Compound B RS, USP Levalbuterol Related Compound C Chromatographic system (see Chromatography h621i)—
RS, USP Levalbuterol Related Compound D RS, USP The liquid chromatograph is equipped with a 225-nm detector
Levalbuterol Related Compound E RS, USP Levalbuterol and a 4.6-mm 6 25-cm column that contains 5-mm packing
Related Compound F RS, and USP Levalbuterol Related L## (see Chromatographic Reagents under Reagents,
Compound G RS in Diluent to obtain a solution having Indicators, and Solutions). The flow rate is about 1.0 mL
In-Process Revision
known concentrations of about 0.05 mg per mL of each per minute. The minimum run time is 30 minutes. Inject 10
related compound and 100 mg per mL of USP Levalbuterol mL of the Standard solution.Sensitivity solution. The
Hydrochloride RS. resolution, R, between levalbuterol and (S)-albuterol is not
Test solution—Use the Assay preparation, prepared as less than 3.0; and the tailing factor for levalbuterol and (S)-
directed in the Assay. albuterol are not more than 1.6 and 2.0, respectively. The
Procedure—Separately inject equal volumes (about 50 mL) Standard solution is injected three times and the relative
of the Standard solution and the Test solution into the standard deviation for The relative standard deviation
chromatograph, record the chromatograms, and measure the calculated from the peak area of (S)-albuterol is not greater
peak responses. Determine the area of the levalbuterol peak, than 20%.
and integrate all the peaks with an area greater than 0.05% of
Pharmacopeial Forum
Procedure—Inject equal volumes of the appropriate in which D is the dilution factor; C is the concentration of
Standard solution and the Test solution such that approxi- USP Levalbuterol Hydrochloride RS in the Standard
mately 4.2 mg of levalbuterol are injected. The percentage of preparation; and rU and rS are the peak responses obtained
(S)-albuterol is calculated using the following equation: from the Assay preparation and the Standard preparation,
respectively.&1S (USP31)
100(ri / rs)
in which ri is the peak response for (S)-albuterol, and rs is the BRIEFING

sum of the responses of both levalbuterol and (S)-albuterol
peaks. The Test solution contains not more than 2.50% (S)- Levothyroxine Sodium, USP 30 page 2468. It is proposed to
make the following changes.
albuterol.
1. To update the Definition.
2. To add two Identification tests: Identification test C, based on
Assay— HPLC retention time agreement of the major peak in the Assay
preparation and the Standard preparation; and Identification
Solution A, Solution B, Mobile phase, and test D for the counterion.
3. To replace the current Water, Method III (Loss on drying)
Chromatographic system—Proceed as directed in the Assay procedure with the Karl Fischer test for water determination,
using Water, Method I. Comments were received that the
under Levalbuterol Hydrochloride. current procedure does not adequately recover all of the water
of hydration contained in Levothyroxine Sodium.
Diluent—Dissolve about 9.0 + 0.05 g of sodium chloride 4. To delete the test and specification for the Limit of inorganic
iodides. From information received, the test does not provide
in 950 mL of water. Adjust with dilute sulfuric acid to a pH of any meaningful information on the quality of the drug
substance.
4.0, and dilute with water to 1000 mL. Mix, and pass through 5. To replace the test for Limit of liothyronine sodium with
a Related compounds section that is capable of quantitating
0.45-mm filter. liothyronine sodium and other related compounds in the drug
substance; and to tighten the specification for liothyronine
Standard preparation—Dissolve an accurately weighed sodium to not more than 1.0%. The new liquid chromato-
graphic procedure is based on analyses performed with the
portion of USP Levalbuterol Hydrochloride RS in Diluent to Zorbax SB C8 brand of L7 column. Typical retention times for
the liothyronine and levothyroxine peaks are about 3 and 4.8
obtain a solution having a known concentration of 100 mg per minutes, respectively.
6. In the Assay, to make changes in the Assay preparation that
mL. eliminate the use of glass beads, centrifuging, and filtering and
to delete the requirement to weigh out 100 mg of material; and
Assay preparation—Transfer an accurately measured in the Procedure, to clarify the numerical coefficient in the
calculation.
volume of Inhalation Solution to a suitable volumetric flask, In the Assay, in addition to the mBondapak CN 10-mm HPLC
column previously listed as acceptable for this method, the Agilent
and quantitatively dilute with Diluent to obtain a solution Zorbax CN brand of L10 5-mm column was also found to be
acceptable. A typical retention time for the levothyroxine peak is
having a concentration of about 100 mg of levalbuterol about 15 minutes.
In-Process Revision
hydrochloride per mL. (MD-GRE: E. Gonikberg) RTS—C48922

the responses for the major peaks. Calculate the concentra-
Levothyroxine Sodium
tion, in mg per mL, of C13H21NO3 HCl per ampul by the
formula:
DC(rU / rS)
C15H10I4NNaO4 xH2 O (anhydrous) 798.85
L-Tyrosine, O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-, monosodi-
um salt, hydrate.
Monosodium L-thyroxine hydrate [25416-65-3].
Anhydrous [55-03-8].
Pharmacopeial Forum
Change to read: Reference solution—Dissolve an accurately weighed quantity of

potassium iodide in water to obtain a stock solution containing 0.131
mg, equivalent to 0.100 mg of iodide per mL. Transfer 0.6 mL of this
» Levothyroxine Sodium is the sodium salt of the levo stock solution into a 1000-mL volumetric flask, dilute with the
isomer of thyroxine, an active physiological principle Extracting solution to volume, and mix. Each mL of the Reference
obtained from the thyroid gland of domesticated animals solution contains 0.06 mg of iodide. [NOTE—Prepare this solution on
used for food by man or prepared synthetically. the day of use.]
Test solution—Transfer 7.5 mg of Levothyroxine Sodium to
a beaker, add 100 mL of the Extracting solution, and sonicate for
&
L-3,3’,5,5’-tetraiodothyronine.&1S (USP31) 5 minutes.
It contains not less than 97.0 percent and not more than Electrode system—Use an iodide-specific, ion-indicating electrode
103.0 percent of C15H10I4NNaO4, calculated on the and a silver-silver chloride reference electrode connected to a pH
anhydrous basis. meter capable of measuring potentials with a minimum reproduc-
ibility of +1 mV (see pH h791i).
Packaging and storage—Preserve in tight containers, protected Procedure—Transfer the Reference solution to a beaker containing
from light. a magnetic stirring bar. Rinse and dry the electrodes, insert in the
solution, stir for 5 minutes or until the reading stabilizes, and read
USP Reference standards h11i—USP Levothyroxine RS. USP the potential, in mV. Repeat this process using the Test solution. The
Liothyronine RS. requirements of the test are met if the Test solution has a higher
potential, in mV, than the Reference solution: the limit is
Change to read: 0.08%.&1S (USP31)
Identification— Delete the following:

A: Ignite about 50 mg in a platinum dish over a flame: it
decomposes and liberates iodine vapors. &
Limit of liothyronine sodium—
Mobile phase, and Chromatographic system—Proceed as directed
&
[NOTE—Cool the residue obtained, and reserve it for use in in the Assay.
Standard solution—Prepare as directed for Standard preparation
Identification test D.]&1S (USP31) in the Assay.
B: To about 0.5 mg add 7.5 mL of acid sodium chloride solution Test solution—Proceed as directed for the Assay preparation.
(prepared by mixing 300 mL of water, 250 mL of alcohol, 100 mL of Procedure—Proceed as directed in the Assay. Calculate the
1 N sodium hydroxide, and 100 mL of hydrochloric acid) and 1 mL quantity, in mg, of liothyronine sodium (C15H11I3NNaO4) in the
of sodium nitrite solution (1 in 100). Allow to stand in the dark for sample taken by the formula:
20 minutes, and add 1.25 mL of ammonium hydroxide: a pink color
is produced. (672.96/650.98)(10C)(rU / rS)
&
C: The retention time of the major peak in the in which 672.96 and 650.98 are the molecular weights of
liothyronine sodium and liothyronine, respectively; C is the
chromatogram of the Assay preparation corresponds to that concentration, in mg per mL, of USP Liothyronine RS in the
Standard preparation; and rU and rS are the liothyronine peak
in the chromatogram of the Standard preparation, as obtained responses obtained from the Test solution and the Standard solution,
respectively: not more than 2.0% of liothyronine is found.&1S (USP31)
in the Assay.
Add the following:
D: To the residue retained from Identification test A, add
&
a 1 N potassium hydroxide solution dropwise until the residue Related compounds—
is dissolved: the solution meets the requirements of the flame Diluent—Prepare a mixture of equal volumes of water and
test for Sodium h191i.&1S (USP31) acetonitrile.
Specific rotation h781Si: between –58 and –68. Phosphoric acid solution—Prepare by diluting 5 mL of
Test solution: an amount equivalent to 30 mg of anhydrous
Levothyroxine Sodium per mL, in a mixture of alcohol and 1 N
In-Process Revision
phosphoric acid with Diluent to 100 mL.
sodium hydroxide (2 : 1).
Mobile phase—Dissolve 1.0 g of sodium 1-heptanesulfo-
nate in about 200 mL of water; add 200 mL of acetonitrile,
&
Water, Method III h921i—Dry about 500 mg, accurately weighed, 400 mL of methanol, and 1.0 mL of phosphoric acid; dilute
over phosphorus pentoxide at 608 and at a pressure not exceeding 10
mm of mercury for 4 hours: it loses not more than 11.0% of its with water to 1 L; and mix. Make adjustments if necessary
weight.&1S (USP31)
Add the following:
Levothyroxine standard stock solution—Transfer about 25
&
Water, Method I h921i: not more than 11.0%.&1S (USP31) mg of USP Levothyroxine RS, accurately weighed, to a
Delete the following: 100-mL volumetric flask. Add approximately 50 mL of
&
Limit of inorganic iodides—
Extracting solution—Prepare a 1 in 100 solution of sulfuric acid in
water.
Pharmacopeial Forum
Diluent and 1 drop of 10 N sodium hydroxide, and sonicate Procedure—Separately inject equal volumes (about 15 mL)
until dissolved. Add 7 mL of Phosphoric acid solution, dilute into the chromatograph in the following order: Blank
with Diluent to volume, and mix well. solution, Standard solution, and Test solution. Record the
Liothyronine standard stock solution—Transfer about 25 chromatograms for at least six times the retention time of the
mg of USP Liothyronine RS, accurately weighed, to a levothyroxine peak, and measure the peak area responses.
100-mL volumetric flask. Add approximately 50 mL of Verify that no peaks elute in the Blank solution at the
Diluent and 1 drop of 10 N sodium hydroxide, and sonicate expected retention times for levothyroxine and related
until dissolved. Add 7 mL of Phosphoric acid solution, dilute compounds. Calculate the percentage of each related
with Diluent to volume, and mix. compound in the portion of Levothyroxine taken by the
Resolution solution—Pipet 5.0 mL of the Levothyroxine formula:
standard stock solution and 5.0 mL of the Liothyronine
standard stock solution into a 100-mL volumetric flask. Add 100 (798.85/776.87)(CS / CU)(rU / rS) / (1–0.01L)
7 mL of Phosphoric acid solution, and dilute with Diluent to

volume.
levothyroxine sodium and levothyroxine, respectively; CS is
Standard solution—Pipet 4.0 mL of the Resolution solution
the concentration, in mg per mL, of levothyroxine in the
into a 100-mL volumetric flask. Add 7 mL of Phosphoric
Standard solution; CU is the concentration, in mg per mL, of
acid solution, and dilute with Diluent to volume.
levothyroxine sodium in the Test solution; rU is the peak area
Blank solution—Add 7 mL of Phosphoric acid solution to
for each impurity obtained from the Test solution; rS is the
a 100-mL volumetric flask, and dilute with Diluent to
peak area for levothyroxine obtained from the Standard
volume.
solution; and L is the percentage of water in Levothyroxine
Test solution—Transfer about 25 mg of Levothyroxine
Sodium, as determined separately in the test for Water h921i.
Sodium, accurately weighed, to a 100-mL volumetric flask.
[NOTE—The relative response factor for the impurities listed
Add approximately 50 mL of Diluent, and sonicate until
in Table 1 is 1.00. Any unspecified impurity peaks should be
dissolved. Add 7 mL of Phosphoric acid solution, dilute with
assigned a relative response factor of 1.00.] Disregard peaks
Diluent to volume, and mix well.
corresponding to those obtained from the Blank solution, and
disregard peaks corresponding to less than 0.03%.&1S (USP31)
In-Process Revision

Change to read:
L7. The column temperature is maintained at about 358, and
Assay—
the flow rate is about 1.5 mL per minute. Chromatograph the Mobile phase—Prepare a degassed and filtered mixture of water
and acetonitrile (60 : 40) that contains 0.5 mL of phosphoric acid in
Resolution solution, and record the peak responses as directed each 1000 mL. Make adjustments if necessary (see System
for Procedure: the resolution, R, between levothyroxine and 0.01 M Methanolic sodium hydroxide—Dissolve 400 mg of
sodium hydroxide in 500 mL of water. Cool, add 500 mL of
liothyronine is not less than 5.0. Chromatograph the Standard methanol, and mix.
Levothyroxine stock solution—Dissolve an accurately weighed
solution, and record the peak responses as directed for quantity of USP Levothyroxine RS in 0.01 M Methanolic sodium
hydroxide to obtain a solution having a known concentration of
Procedure: the relative standard deviation for replicate about 0.4 mg of levothyroxine per mL.
Liothyronine stock solution—Dissolve an accurately weighed
injections of the Standard solution is not more than 2.0% quantity of USP Liothyronine RS in 0.01 M Methanolic sodium
hydroxide to obtain a solution having a known concentration of
for the levothyroxine peak. about 0.4 mg of liothyronine per mL. Make a 1 : 100 dilution of this
solution, using Mobile phase.
Pharmacopeial Forum
Table 1
Approximate Relative
Retention Time (RRT) Impurity Limit (%)
0.65–0.70 Liothyronine 1.0
0.71–0.76 b-Hydroxy-T41 0.15
1.0 Levothyroxine N/A
1.13–1.28 T4-Hydroxyacetic acid2 0.15
1.47–1.53 N-Formyl-T43 and T4-Acetamide4 0.15
1.50–1.86 N-Acetyl-T45 0.20
2.42–2.51 T4-Acetic acid6 0.15
3.17–3.45 T4-Aldehyde7 0.15
3.46–3.70 T4-Benzoic acid8 0.15
N/A Individual unspecified impurity 0.10
N/A Total impurities 1.5
1
O-(4-Hydroxy-3,5-diiodophenyl)-3,5-diiodo-b-hydroxy-L-tyrosine
2
2-Hydroxy-2-(4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic acid
3
N-Formyl-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine
4
2-(4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetamide
5
N-Acetyl-O-(4-hydroxy-3,5-diiodophenyl)-3,5-diiodo-L-tyrosine
6
2-(4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic acid
7
4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzaldehyde
8
4-(4-Hydroxy-3,5-diiodophenoxy)-3,5-diiodobenzoic acid
Standard preparation—Transfer appropriate volumes of Levothy- Procedure—Separately inject equal volumes (about 100 mL) of the
roxine stock solution and Liothyronine stock solution to a suitable Standard preparation and the Assay preparation into the chromat-
container, and dilute quantitatively and stepwise, if necessary, with ograph, record the chromatograms, and measure the responses for
Mobile phase to obtain a solution having known concentrations of the major peaks. Calculate the quantity, in mg,
about 10 mg of levothyroxine per mL and 0.2 mg of liothyronine per
mL. &
percentage&1S (USP31)
Assay preparation—Transfer an accurately weighed portion of of C15H10I4NNaO4 in the portion of Levothyroxine Sodium taken by
about 100 mg of Levothyroxine Sodium into a centrifuge tube, add the formula:
2 glass beads, pipet 10 mL of Mobile phase into the tube, and mix
using a vortex mixer for 3 minutes. Centrifuge to obtain a clear (798.85/776.87)(10C)(rU / rS)
supernatant, filtering if necessary. &
100(798.85/776.87)(CS / CT)(rU / rS)&1S (USP31)
&
Prepare a solution of Levothyroxine Sodium in Mobile in which 798.85 and 776.87 are the molecular weights of
levothyroxine sodium and levothyroxine, respectively; C
phase having a known concentration of about 10 mg per
In-Process Revision
&
CS&1S (USP31)
mL.&1S (USP31) is the concentration, in mg per mL, of USP Levothyroxine RS in the
Chromatographic system (see Chromatography h621i)—The Standard preparation;
a 4.6-mm 6 25-cm column that contains packing L10. The flow rate &
CT is the concentration, in mg per mL, of levothyroxine
preparation, and record the peak responses as directed for sodium in the Assay preparation;&1S (USP31)
Procedure: the resolution, R, between liothyronine and levothyrox- and rU and rS are the levothyroxine peak responses obtained from the
ine is not less than 5.0; and the relative standard deviation for Assay preparation and the Standard preparation, respectively.
replicate injections is not more than 2.0% for levothyroxine.
Pharmacopeial Forum

BRIEFING Standard solution and the Test solution into the chromatograph,
record the chromatograms, and measure the levothyroxine peak
responses. Calculate the quantity, in mg,
Liothyronine Sodium, USP30 page 2480. It is proposed to (1) &
revise the preparation of the Assay preparation by eliminating use of of levothyroxine sodium (C15H10I4NNaO4) in the portion of
the glass beads, the centrifuging, and the filtering and by deleting the Liothyronine Sodium taken by the formula:
requirement to weigh out 100 mg of material; (2) add an
Identification test based on HPLC retention time agreement of the (798.85/776.87)(10C)(rU / rS)
major peaks obtained from the Assay preparation and the Standard
preparation in the Assay; (3) delete the test for Limit of inorganic
iodides (see the briefing under Levothyroxine Sodium, published
elsewhere in this issue of PF); and (4) revise the calculations in the
Assay and in the test for Limit of levothyroxine sodium.
&
100(798.85/776.87)(CS / CT)(rU / rS)&1S (USP31)
In addition to the mBondapak CN 10-mm HPLC column
previously listed as acceptable for the method in the Assay and in in which 798.85 and 776.87 are the molecular weights of
the test for Limit of levothyroxine, the Agilent Zorbax CN brand of levothyroxine sodium and levothyroxine, respectively; C
L10 5-mm column was also found to be acceptable. A typical
retention time for the liothyronine peak is about 11 minutes. &
CS&1S (USP31)
The MD-GRE Expert Committee encourages manufacturers of is the concentration, in mg per mL, of USP Levothyroxine RS in the
liothyronine sodium to review the newly proposed HPLC test for Standard solution;
Related compounds under Levothyroxine Sodium to evaluate whether
this new test could also be applicable to Liothyronine Sodium and to &
CT is the concentration, in mg per mL, of Liothyronine
submit comments to the Expert Committee.
Sodium in the Assay preparation;&1S (USP31)
(MD-GRE: E. Gonikberg) RTS—C48922 and rU and rS are the levothyroxine peak responses obtained from the
Test solution and the Standard solution, respectively: not more than
5.0% of levothyroxine sodium is found.
Change to read:
Change to read:
Identification—
A: The UV absorption spectrum of a 1 in 10,000 solution in Assay—
dilute hydrochloric acid (1 in 50) in 80 percent alcohol exhibits Mobile phase—Prepare a filtered and degassed mixture of water
maxima at the same wavelengths as that of a similar solution of USP and acetonitrile (60 : 40) that contains 0.5 mL of phosphoric acid in
Liothyronine RS, concomitantly measured; and the respective each 1000 mL. Make adjustments if necessary (see System
absorptivities, both calculated on the dried basis in terms of the Suitability under Chromatography h621i).
acid, at the wavelength of maximum absorbance at about 297 nm, do 0.01 M Methanolic sodium hydroxide—Dissolve 400 mg of
not differ by more than 5.0%. sodium hydroxide in 500 mL of water. Cool, add 500 mL of
B: Heat about 50 mg with a few drops of sulfuric acid in methanol, and mix.
a porcelain crucible: violet vapors of iodine are evolved. Liothyronine stock solution—Dissolve an accurately weighed
C: The residue from the ignition of it meets the requirements of quantity of USP Liothyronine RS in 0.01 M Methanolic sodium
the tests for Sodium h191i. hydroxide to obtain a solution having a known concentration of
about 0.4 mg of liothyronine per mL.
&
D: The retention time of the major peak in the Levothyroxine stock solution—Dissolve an accurately weighed
quantity of USP Levothyroxine RS in 0.01 M Methanolic sodium
chromatogram of the Assay preparation corresponds to that hydroxide to obtain a solution having a known concentration of
about 0.4 mg of levothyroxine per mL. Make a 1 : 100 dilution of
in the chromatogram of the Standard preparation, as obtained this solution using Mobile phase.
Standard preparation—Transfer appropriate volumes of Liothy-
in the Assay.&1S (USP31) ronine stock solution and Levothyroxine stock solution to a suitable
container, and dilute quantitatively and stepwise, if necessary, with
Mobile phase to obtain a solution having known concentrations of
In-Process Revision
about 10 mg of liothyronine per mL and 0.5 mg of levothyroxine per

mL.
&
Limit of inorganic iodide— Assay preparation—Transfer an accurately weighed portion of
Extracting solution, Reference solution, and Electrode system— 100 mg of Liothyronine Sodium to a centrifuge tube, add 2 glass
Proceed as directed in the Limit of inorganic iodide test under beads, pipet 10 mL of Mobile phase into the tube, and mix using
Levothyroxine Sodium. a vortex mixer for 3 minutes. Centrifuge to obtain a clear
Test solution—Transfer 7.5 mg of Liothyronine Sodium to supernatant, filtering if necessary.
a beaker, add 100 mL of Extracting solution, and sonicate for
5 minutes. &
Prepare a solution of Liothyronine Sodium in Mobile Phase
Procedure—Proceed as directed in the Limit of inorganic iodide
test under Levothyroxine Sodium: the limit is 0.08%.&1S (USP31) having a known concentration of about 10 mg per
mL.&1S (USP31)
Change to read: Chromatographic system (see Chromatography h621i)—The
Limit of levothyroxine sodium— a 4.6-mm 6 25-cm column that contains packing L10. The flow rate
Mobile phase and Chromatographic system—Proceed as directed is about 1.5 mL per minute. Chromatograph the Standard
in the Assay. preparation, and record the peak responses as directed for
Standard solution—Proceed as directed for Standard preparation Procedure: the resolution, R, between levothyroxine and liothyro-
in the Assay. nine is not less than 5.0; and the relative standard deviation for
Test solution—Proceed as directed for Assay preparation in the replicate injections is not more than 2.0% for liothyronine.
Assay.
Pharmacopeial Forum

&
The retention time of the major peak in the chromatogram of
ograph, record the chromatograms, and measure the responses for the Test preparation corresponds to that in the chromatogram
the major peaks. Calculate the quantity, in mg,
of the Standard preparation, as obtained in the
&
of C15H11I3NNaO4 in the portion of Liothyronine Sodium taken by Assay.&1S (USP31)
the formula:
(672.96/650.97)(10C)(rU / rS)
Change to read:
&
100(672.96/650.97)(CS / CT)(rU / rS)&1S (USP31) A: Dissolve Lorazepam in chloroform to obtain a Test prepa-
ration containing 2 mg per mL. Dissolve USP Lorazepam RS in
chloroform to obtain an Identification preparation having a known
in which 672.96 and 650.97 are the molecular weights of concentration of 2 mg per mL. Dissolve USP Lorazepam Related
liothyronine sodium and liothyronine, respectively; C Compound A RS (7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-ace-
toxy-2H-1,4-benzodiazepin-2-one) in chloroform to obtain a Stan-
&
CS&1S (USP31) dard preparation having a known concentration of 20 mg per mL.
is the concentration, in mg per mL, of USP Liothyronine RS in the Dilute portions of this Standard preparation quantitatively with
Standard preparation; chloroform to obtain solutions having concentrations of 10 mg per
mL (Diluted standard preparation A) and 4 mg per mL (Diluted
&
CT is the concentration, in mg per mL, of Liothyronine standard preparation B), respectively. Within 30 minutes after
preparation, apply separately 50 mL of the Test preparation, the
Sodium in the Assay preparation;&1S (USP31) Identification preparation, the Standard preparation, the Diluted
and rU and rS are the liothyronine peak responses obtained from the standard preparation A, and the Diluted standard preparation B to
Assay preparation and the Standard preparation, respectively. a suitable thin-layer chromatographic plate (see Chromatography
h621i) coated with a 0.25-mm layer of chromatographic silica gel
mixture and previously washed with a mixture of chloroform, ethyl
acetate, and methanol (2 : 1 : 1) and dried in air. Allow the spots to
dry, and develop the chromatograms in a solvent system consisting
of a mixture of chloroform, dioxane, and glacial acetic acid
BRIEFING (91 : 5 : 4) until the solvent front has moved to within 2 cm to
3 cm from the top of the plate. Remove the plate from the developing
chamber, mark the solvent front, and allow to air-dry for about 30
Lorazepam, USP 30 page 2496. It is proposed to replace the minutes. Examine the plate under short-wavelength UV light.
existing two TLC methods in the test for Related compounds with Compare the intensities of any secondary spots observed in the
one stability-indicating HPLC method. Consequently, the current chromatogram of the Test preparation with those of the principal
TLC Identification method is being replaced with HPLC as well. The spots in the chromatograms of the Standard preparation and the
proposed method was validated using the YMC brand of ODS A Diluted standard preparations: the sum of the intensities of all
5-mm L1 column. In addition, in the Assay, it is proposed to replace secondary spots obtained from the Test preparation corresponds to
the existing titration method with the HPLC method used in the test not more than 1.0%.
for Related compounds. Under the chromatographic conditions B: Transfer 50.0 mg of Lorazepam to a 10-mL conical flask, add
described, lorazepam elutes at approximately 6 minutes and 2.5 mL of acetone, and shake. Allow any undissolved particles to
lorazepam related compound B elutes at approximately 33 minutes. settle, and use the supernatant as the Test preparation. Dissolve USP
Lorazepam Related Compound B RS in acetone to obtain a Standard
(MD-PP: R. Ravichandran) RTS—C45600 preparation having a known concentration of 10 mg per mL. Apply
separately 50 mL of the Test preparation and 10 mL of the Standard
preparation to a suitable thin-layer chromatographic plate (see test A
under Related compounds). Allow the spots to dry, and develop the
chromatograms in a solvent system consisting of a mixture of
Change to read: chloroform, dioxane, and glacial acetic acid (91 : 5 : 4) until the
solvent front has moved not less than 10 cm from the origin. Remove
USP Reference standards h11i—USP Lorazepam RS. USP the plate from the developing chamber, mark the solvent front, and
In-Process Revision
Lorazepam Related Compound A RS. USP Lorazepam Related allow the solvent to evaporate. Lightly spray the plate with 2 N
Compound B RS. sulfuric acid, dry at 1058 for 15 minutes, and spray successively with
sodium nitrite solution (1 in 1000), ammonium sulfamate solution (1
&
USP Lorazepam Related Compound C RS. USP Lorazepam in 200), and N-(1-naphthyl)ethylenediamine dihydrochloride solu-
tion (1 in 1000), drying the plate with a current of air after each
Related Compound D RS. USP Lorazepam Related Com- spraying. Observe the plate under visible light: the spot produced by
the Test preparation is not greater in size or intensity than the
pound E RS.&1S (USP31) principal spot produced at the corresponding RF value by the
Standard preparation, corresponding to not more than 0.01% of 2-
amino-2’,5-dichlorobenzophenone (lorazepam related compound B).
Change to read: &
Mobile phase and Diluent—Prepare as directed in the
Identification— Assay.
B: The RF value of the principal spot observed in the
chromatogram of the Test preparation obtained as directed in
Related compounds test A corresponds to that obtained from the
Identification preparation.
Pharmacopeial Forum
Standard solution—Dilute a suitable volume of the Chromatographic system (see Chromatography h621i)—
Standard preparation, prepared as directed in the Assay, Proceed as directed in the Assay. Chromatograph the Peak
quantitatively, and stepwise if necessary, to obtain a solution identification solution, record the peak responses as directed
having a known concentration of about 0.032 mg per mL of for Procedure, and identify the peaks, using the retention
lorazepam. times given in Table 1. The resolution, R, between lorazepam
Peak identification solution—Dissolve accurately weighed related compound A and lorazepam related compound E is
amounts of USP Lorazepam RS, USP Lorazepam Related not less than 1.2. Chromatograph the Standard solution, and
Compound A RS, USP Lorazepam Related Compound B RS, record the peak responses as directed for Procedure: the
USP Lorazepam Related Compound C RS, USP Lorazepam tailing factor for lorazepam is not more than 2.0 and the
Related Compound D RS, and USP Lorazepam Related relative standard deviation for replicate injections is not more
Compound E RS in Diluent to obtain a solution having a final than 5% for lorazepam.
concentration of about 3.2 mg per mL of lorazepam and 0.032 Procedure—Separately inject equal volumes (about 100
mg per mL each of lorazepam related compound A, mL) of the Standard solution and the Test solution into the
lorazepam related compound B, lorazepam related compound chromatograph, collect the data for at least 50 minutes, and
C, lorazepam related compound D, and lorazepam related measure the responses for all the peaks. Calculate the
compound E. percentage of each impurity in the portion of Lorazepam
Test solution—Dissolve an accurately weighed quantity of taken by the formula:
Lorazepam in Diluent, and dilute quantitatively, and stepwise
if necessary, to obtain a solution having a known concentra- 100(1/F)(CS /CU)(ri / rS)
tion of about 3.2 mg per mL of lorazepam.
Table 1
Relative Response
Peak Identification Retention Time Factor Limit (%)
Lorazepam 1.0 1.0 —
Lorazepam related compound D1 1.4 1.0 0.15
Lorazepam related compound A2 1.7 1.0 0.10
In-Process Revision
Lorazepam related compound E3 1.9 1.3 0.15

Lorazepam related compound C4 2.1 1.0 0.15
Lorazepam related compound B5 5.5 1.0 0.01
Any individual unspecified impurity — 1.0 0.10
1
6-chloro-4-(o-chlorophenyl)-2-quinazolinecarboxylic acid
2
7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepin-2-one
3
6-chloro-4-(o-chlorophenyl)-2-quinazoline methanol
4
6-chloro-4-(o-chlorophenyl)-2-quinazolinecarboxaldehyde
5
2-amino-2’,5-dichlorobenzophenone
Pharmacopeial Forum
in which F is the relative response factor for any given Procedure—Separately inject equal volumes (about 20 mL)
impurity found in Table 1; CS and CU are the concentrations of of the Standard solution and the Test solution into the
lorazepam in the Standard solution and the Test solution, chromatograph, collect the data for at least 50 minutes, and
respectively; ri is the peak response for each impurity in the measure the responses for all the peaks. Calculate the
Test solution; and rS is the peak response for lorazepam percentage of Lorazepam in the portion of sample taken by
obtained from the Standard solution. The limit for each the formula:
related compound is given in Table 1.&1S (USP31)
100(CS / CU)(rU / rS)
Change to read:
Assay—Dissolve about 400 mg of Lorazepam, accurately weighed, in which CS and CU are the concentrations of lorazepam in the
in 50 mL of N,N-dimethylformamide. Titrate the solution with 0.1 N
tetrabutylammonium hydroxide VS, taking precautions against the Standard preparation and the Test preparation, respectively;
absorption of atmospheric carbon dioxide, determining the endpoint
potentiometrically, using a glass electrode and a calomel electrode and rU and rS are the peak responses for lorazepam obtained
containing a saturated solution of potassium chloride in methanol
(see Titrimetry h541i). Perform a blank determination, and make any from the Test preparation and the Standard preparation,
necessary correction. Each mL of 0.1 N tetrabutylammonium
hydroxide is equivalent to 32.12 mg of C15H10Cl2N2O2. respectively.&1S (USP31)
&
Mobile phase—Prepare a mixture of water, acetonitrile,
and glacial acetic acid (50 : 50 : 1.2). Make adjustments if
BRIEFING
h621i).
Diluent—Prepare a mixture of methanol and water (75 : 25). Lorazepam Tablets, USP 30 page 2498. It is proposed to replace
the existing TLC method in the test for Related compounds with
Standard preparation—Dissolve an accurately weighed a stability-indicating HPLC method. The proposed method was
validated using the YMC brand of ODS A 5-mm L1 column. Under
quantity of USP Lorazepam RS in Diluent, and dilute the chromatographic conditions described, lorazepam elutes at
approximately 6 minutes and lorazepam related compound B
quantitatively, and stepwise if necessary, to obtain a solution elutes at approximately 33 minutes.
having a known concentration of about 0.1 mg of lorazepam
per mL.
Test preparation—Dissolve an accurately weighed quantity Change to read:
of Lorazepam in Diluent, and dilute quantitatively, and Related compounds—

stepwise if necessary, to obtain a solution having a known A: Standard preparations— Prepare a solution in chloroform
having known concentrations of 1.0 mg each of USP Lorazepam
concentration of about 0.1 mg per mL of lorazepam. Related Compound C RS, USP Lorazepam Related Compound D
RS, and USP Lorazepam Related Compound E RS per mL. Dilute
In-Process Revision
Chromatographic system (see Chromatography h621i)— quantitatively with chloroform to obtain Standard preparations,
designated below by letter, having the following compositions:
The liquid chromatograph is equipped with a sample
Percentage (%,
compartment chiller maintained at 48, a UV detector set at Concentration for comparison
Standard (mg of each RS with test
230 nm, and a 4.6-mm 6 25-cm column that contains 5-mm preparation Dilution per mL) specimen)
A (1 in 25) 40 2.0
packing L1. The column temperature is maintained at 58. The B (1 in 50) 20 1.0
C (1 in 100) 10 0.5
Standard preparation, and record the peak responses as Test preparation—Transfer a quantity of finely powdered Tablets,
equivalent to 4.0 mg of lorazepam, to a sintered-glass funnel. Extract
directed for Procedure: the tailing factor for lorazepam is not with two 1-mL portions of chloroform followed by two 1-mL
portions of methanol, collecting the filtrate in a centrifuge tube.
more than 2.0, and the relative standard deviation for replicate Evaporate the filtrate with the aid of a stream of nitrogen at room
temperature to dryness. Dissolve the residue in 2.0 mL of
injections is not more than 2.0% for lorazepam. chloroform, and centrifuge. Use the clear supernatant as the Test
preparation.
Pharmacopeial Forum
Procedure—Within 30 minutes after preparation, apply separately Related Compound D RS, and USP Lorazepam Related
50 mL of the Test preparation and 50 mL of each Standard
preparation to a suitable thin-layer chromatographic plate (see Compound E RS in Diluent to obtain a solution having a final
Chromatography h621i) coated with a 0.25-mm layer of chromat-
ographic silica gel mixture and previously washed with a mixture of concentration of about 0.16 mg per mL of lorazepam and 1.6
chloroform, ethyl acetate, and methanol (2 : 1 : 1) and dried in air.
Allow the spots to dry, and develop the chromatograms in a solvent mg per mL each of lorazepam related compound A, lorazepam
system consisting of a mixture of chloroform, dioxane, and glacial
acetic acid (91 : 5 : 4) until the solvent front has moved to within related compound B, lorazepam related compound C,
2 cm to 3 cm from the top of the plate. Remove the plate from the
developing chamber, mark the solvent front, and allow to air-dry for lorazepam related compound D, and lorazepam related
about 30 minutes. Examine the plate under short-wavelength UV
light. Compare the intensities of any secondary spots observed in the compound E.
chromatogram of the Test preparation with those of the principal
spots in the chromatograms of the Standard preparations: [NOTE— Test solution—Grind the number of Tablets required in
The RF value and the intensity of the spot for the USP Lorazepam
Related Compound E RS in the Standard preparations correspond order to make the total amount of lorazepam in the final
closely, but not necessarily precisely, to those observed for one of the
secondary spots observed in the chromatogram of the Test composite powder about 25 mg. Accurately weigh and
preparation.] The sum of the intensities of all secondary spots
obtained from the Test preparation corresponds to not more than transfer an amount of powder equivalent to about 21.3 mg of
4.0%.
B: Transfer a quantity of finely powdered Tablets, equivalent to lorazepam to a 25-mL volumetric flask. Pipet 20 mL of
25.0 mg of lorazepam, to a tapered 15-mL centrifuge tube, add 2.5
mL of acetone, insert a stopper into the tube, mix by mechanical Diluent into the flask, and stir for 15 minutes. Do not dilute to
means, and centrifuge. Use the supernatant as the Test preparation.
Dissolve USP Lorazepam Related Compound B RS in acetone to volume. Centrifuge at 48 for 15 minutes at 2000 rpm. Pass the
obtain a Standard preparation having a known concentration of 100
mg per mL. Apply separately 50 mL of the Test preparation and 5 mL supernatant through a polyethersulfone membrane filter
of the Standard preparation to a suitable thin-layer chromatographic
plate (see Chromatography h621i) coated with a 0.25-mm layer of having a porosity of 0.45 mm. Quantitatively dilute the
chromatographic silica gel mixture and previously washed with
a mixture of chloroform, ethyl acetate, and methanol (2 : 1 : 1) and filtrate with Diluent to obtain a final solution having a known
dried in air. Proceed as directed in test B for Related compounds
under Lorazepam, beginning with ‘‘Allow the spots to dry.’’ The concentration of about 0.16 mg per mL of lorazepam, based
spot produced by the Test preparation is not greater in size or
intensity than the principal spot produced at the corresponding RF on the label claim.
value by the Standard preparation, corresponding to not more than
0.1% of 2-amino-2’,5-dichlorobenzophenone (lorazepam related Chromatographic system (see Chromatography h621i)—
compound B).
The liquid chromatograph is equipped with a sample
&
Mobile phase—Prepare a mixture of water, acetonitrile
compartment chiller maintained at 48, a UV detector set at
and glacial acetic acid (50 : 50 : 1.2). Make adjustments if
230 nm, and a 4.6-mm 6 25-cm column that contains 5-mm
packing L1. The column temperature is maintained at 58. The
h621i).
Buffer—Dissolve 67.7 g of sodium acetate trihydrate in 1 L
Peak identification solution, record the peak responses as
of water. Adjust with glacial acetic acid to a pH of
directed for Procedure, and identify the peaks, using the
5.0 + 0.05.
In-Process Revision
retention times given in Table 1. The resolution, R, between

Diluent—Prepare a mixture of methanol and Buffer
lorazepam related compound A and lorazepam related
(75 : 25).
compound E is not less than 1.2. Chromatograph the
Standard solution—Dissolve an accurately weighed
quantity of USP Lorazepam RS in Diluent, and dilute
for Procedure: the tailing factor for lorazepam is not more
quantitatively, and stepwise if necessary, to obtain a solution
than 2.0, and the relative standard deviation for replicate
having a known concentration of about 0.0016 mg per mL of
injections is not more than 5% for lorazepam.
lorazepam.
Peak identification solution—Dissolve accurately weighed
amounts of USP Lorazepam RS, USP Lorazepam Related
chromatograph, collect the data for at least 50 minutes, and
Compound A RS, USP Lorazepam Related Compound B RS,
USP Lorazepam Related Compound C RS, USP Lorazepam
Pharmacopeial Forum
Table 1
Relative Response
Peak Identification Retention Time Factor Limit (%)
Lorazepam 1.0 1.0 —
Lorazepam related compound D 1 1.4 1.0 0.5
Lorazepam related compound A*2 1.7 NA NA
Lorazepam related compound E3 1.9 1.3 0.5
Lorazepam related compound C4 2.1 1.0 3.0
Lorazepam related compound B5 5.5 1.0 0.1
Any individual unspecified degradation product — 1.0 0.2
*
Lorazepam related compound A is included only for peak identification purposes. It is not quantified and should not be included in the total
impurities calculation.
1
2
6-chloro-4-(o-chlorophenyl)-2-quinazolinecarboxylic acid
3
7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-acetoxy-2H-1,4-benzodiazepin-2-one
4
6-chloro-4-(o-chlorophenyl)-2-quinazoline methanol
5
6-chloro-4-(o-chlorophenyl)-2-quinazolinecarboxaldehyde
2-amino-2’,5-dichlorobenzophenone
measure the responses for all the peaks. Calculate the

BRIEFING
percentage of each impurity in the portion of Tablets taken
by the formula: Mirtazapine, USP 30 page 2671. It is proposed to delete the Test
preparation section from the Heavy Metals test to be consistent with
the sample size requirements stated in the currently official version
100(1/ F)(CS /CU)(ri / rS) of Heavy Metals h231i. Interested parties may submit comments to
USP no later than July 1, 2007. In the absence of any significant
adverse comments, it is proposed to implement this revision via the
Interim Revision Announcement pertaining to USP 30–NF 25, with
in which F is the relative response factor for any given an official date of October 1, 2007.
impurity found in Table 1; CS is the concentration of (MD-PP: R. Ravichandran) RTS—C53152

lorazepam in the Standard solution; CU is the concentration,
in mg per mL, of lorazepam in the Test solution, based on the Change to read:
label claim; ri is the peak response for each impurity obtained Heavy metals, Method II h231i: 0.001%.
In-Process Revision
~
Test preparation—Use a weighed quantity, approximately 4.0 g,
from the Test solution; and rS is the peak response for of Mirtazapine.~USP30
lorazepam obtained from the Standard solution. Table .
.5
1 shows the acceptance criteria for each impurity.&1S (USP31)
Pharmacopeial Forum
BRIEFING BRIEFING
Norethindrone Acetate and Ethinyl Estradiol Tablets, USP 30 Norethindrone Tablets, USP 30 page 2772 and page 1736 of PF
page 2776 and page 81 of PF 33(1) [Jan.–Feb. 2007]. It is proposed 32(6) [Nov.–Dec. 2006]. In Dissolution Test 2, in order to bring the
to revise the Dissolution test to provide additional information in the test into accordance with the validation reports, it is proposed to
Chromatographic system. revise the volume of Medium. In addition, it is proposed to add
a second chromatographic system, Chromatographic system 2,
which was developed and validated using the Symmetry C18 or
(BPC: M. Marques) RTS—C53551 Hypersil C18 brand of L1 packing.

Change to read:
Dissolution h711i— Add the following:

0.025 M Acetate buffer solution—Accurately weigh about 5.22 g
of anhydrous sodium acetate and 2.2 g of glacial acetic acid into a
4-L volumetric flask, add 3.5 L of water, and mix. Adjust with 1 N
&
Labeling—When more than one Dissolution test is given,
sodium hydroxide to a pH of 5.0 + 0.2, and dilute with water to
volume. the labeling states the Dissolution test used only if Test 1 is
Medium: 0.025 M pH 5.0 acetate buffer with 0.15% sodium
lauryl sulfate, prepared by accurately weighing about 6 g of sodium not used.&1S (USP31)
lauryl sulfate into a 4-L volumetric flask, adding 1.5 L of 0.025 M
Acetate buffer solution, mixing, and diluting with 0.025 M Acetate Delete the following:
buffer solution to volume; 600 mL.
Time: 60 minutes. &
Disintegration h701i: 15 minutes, the use of disks being
Determine the amounts of norethindrone acetate (C22H28O3) and omitted.&1S (USP31)
ethinyl estradiol (C20H24O2) dissolved by employing the following
method.
Mobile phase—Prepare a filtered and degassed mixture of 0.2% Add the following:
phosphoric acid, acetonitrile, and tetrahydrofuran (540 : 380 : 80).
Make adjustments if necessary (see System Suitability under &
Standard solution—Dissolve accurately weighed quantities of TEST 1—
USP Norethindrone Acetate RS and USP Ethinyl Estradiol RS in
a minimum amount of acetonitrile, and dilute quantitatively, and Medium: 0.09% sodium lauryl sulfate in 0.1 N hydro-
known concentrations equivalent to the expected concentrations of chloric acid; 500 mL, deaerated.
the solution under test.
Test solution—Withdraw a 2-mL aliquot, using a glass pipet or Apparatus 2: 75 rpm.
syringe, and centrifuge at about 2000 rpm for about 5 minutes. Use
the supernatant. Time: 30 minutes.
with a 242-nm detector, a fluorescent detector with an excitation Determine the amount of C20H26O2 dissolved by employing
wavelength set at 210 nm
~ the following method.
and an emission wavelength set at 310 nm,~USP31
a 6-mm 6 40-mm column that contains 3-mm packing L1 and a Mobile phase—Prepare a filtered and degassed mixture of
4-mm 6 12.5-mm guard column that contains 5-mm packing L1.
The flow rate is about 1 mL per minute. water and acetonitrile (3 : 2). Make adjustments if necessary
~
In-Process Revision
Chromatograph the Standard solution, and record the peak (see System Suitability under Chromatography h621i).
responses as directed for Procedure: the column efficiency is Standard solution—Transfer about 35 mg, accurately
not less than 500 theoretical plates for ethinyl estradiol and weighed, of USP Norethindrone RS to a 500-mL volumetric
not less than 1400 theoretical plates for norethindrone &ace- flask. Add approximately 100 mL of methanol, and sonicate
tate;&1S (USP31) the tailing factor is not more than 2.0 for both
&
until completely dissolved. Cool to room temperature. Dilute
norethindrone acetate and ethinyl estradiol;&1S (USP31) and the with methanol to volume, and mix well. Transfer 2.0 mL of
relative standard deviation for each analyte is not more than this solution to a 200-mL volumetric flask. Dilute with
2.5%.~USP31 Medium to volume, and mix well.
Standard solution and the Test solution into the chromatograph, Test solution—Pass the solution under test through
record the chromatograms, and measure the peak heights.
Tolerances—Not less than 80% (Q) of the labeled amounts of a suitable 0.45-mm filter.
C22H28O3 and C20H24O2 is dissolved in 60 minutes.
Pharmacopeial Forum
Chromatographic system (see Chromatography h621i)— Standard solution—Transfer about 14 mg, accurately
The liquid chromatograph is equipped with a 254-nm detector weighed, of USP Norethindrone RS to a 100-mL volumetric
and a 4.6-mm 6 15-cm column that contains 5-mm packing flask. Dilute with methanol to volume, and mix. Transfer 20.0
L7. The flow rate is about 1.5 mL per minute. Chromatograph mL of this solution to a 100-mL volumetric flask. Dilute with
the Standard solution, and record the peak responses as methanol to volume, and mix. Transfer 5.0 mL of this
directed for Procedure: the relative standard deviation for solution to a 200-mL volumetric flask. Dilute with Medium to
replicate injections is not more than 3.0%. volume, and mix.
Procedure—Separately inject equal volumes (about 100 Test solution—Pass the solution under test through
mL) of the Standard solution and the Test solution into the a suitable 0.45-mm filter.
chromatograph, record the chromatograms, and measure the Chromatographic system (see Chromatography h621i)—
peak responses. Calculate the percentage of norethindrone Use one of the following two chromatographic systems:
dissolved by the formula: Chromatographic system 1—The liquid chromatograph is
equipped with a 200-nm detector and a 4.6-mm 6 10-cm
column that contains 3-mm packing L1. The flow rate is about
1.0 mL per minute.
Chromatographic system 2—The liquid chromatograph is
equipped with a 240-nm detector and a 4.6-mm 6 10-cm
in which rU and rS are the peak responses for the Test solution column that contains 3- or 3.5-mm packing L1. The flow rate
and the Standard solution, respectively; CS is the concentra- is about 2.0 mL per minute.
tion, in mg per mL, of norethindrone in the Standard
Using either Chromatographic system 1 or 2, chromato-
graph the Standard solution, and record the peak responses as
conversion factor to percentage; and LC is the Tablet label
directed for Procedure: the relative standard deviation for
claim, in mg.
Procedure—Proceed as directed for Test 1. Calculate the
of C20H26O2 is dissolved in 30 minutes.
percentage of norethindrone dissolved by the formula:
Medium: 0.09% sodium lauryl sulfate in 0.1 N hydro-
In-Process Revision
chloric acid; 900 mL 500 mL, deaerated.
Time: 45 minutes. in which rU and rS are the peak responses for the Test solution
Determine the amount of C20H26O2 dissolved by employing and the Standard solution, respectively; CS is the concentra-
the following method. tion, in mg per mL, of norethindrone in the Standard
Mobile phase—Prepare a filtered and degassed mixture of solution; 500 is the volume, in mL, of Medium; 100 is the
0.02 M phosphate buffer pH 6.0 and acetonitrile (65 : 35). conversion factor to percentage; and LC is the Tablet label
Make adjustments if necessary (see System Suitability under claim, in mg.
Chromatography h621i). Tolerances—Not less than 80% (Q) of the labeled amount
of C20H26O2 is dissolved in 45 minutes.&1S (USP31)
Pharmacopeial Forum

BRIEFING
through a suitable 0.45-mm filter. Dilute a portion of the
Ofloxacin Tablets, page 1737 of PF 32(6) [Nov.–Dec. 2006]. It is filtrate with Medium in such a way as to obtain a final
proposed to add a Dissolution test to this new monograph.
theoretical concentration of about 8.8 mg per mL, considering
(BPC: M. Marques) RTS—C42637 complete dissolution of the label claim.
Procedure—Determine the amount of C18H20FN3O4 dis-
solved by employing UV absorption at the wavelength at
about 294 nm on the Test solution in comparison with the
Add the following: Standard solution, using a 1-cm cell and Medium as the
~
blank. Calculate the amount, in percentage, of C18H20FN3O4
Ofloxacin Tablets
dissolved by the formula:
» Ofloxacin Tablets contain not less than 90.0

labeled amount of ofloxacin (C18H20FN3O4).
solution and the Standard solution, respectively; CS is the
and store at controlled room temperature.
concentration, in mg per mL, of ofloxacin in the Standard
USP Reference standards h11i—USP Ofloxacin RS.
solution; DU is the dilution factor of the Test solution; 900 is
Identification—The retention time of the major peak in the the volume, in mL, of Medium; 100 is the conversion factor
chromatogram of the Assay preparation corresponds to that in to percentage; and LC is the Tablet label claim, in mg.
the chromatogram of the Standard preparation, as obtained in Tolerances—Not less than 80% (Q) of the labeled amount
the Assay. of C18H20FN3O4 is dissolved in 30 minutes.&1S (USP31)
Add the following: Uniformity of dosage units h905i: meet the requirements
for Content Uniformity.
&
Dissolution h711i—[To come.]
In-Process Revision
Phosphate buffer—Dissolve 2.72 g of monobasic potassium

phosphate in 1000 mL of water. Adjust with diluted
Time: 30 minutes.
phosphoric acid to a pH of 3.3 + 0.1.
Standard solution—Transfer about 44 mg, accurately
weighed, of USP Ofloxacin RS to a 100-mL volumetric
Phosphate buffer and acetonitrile (88 : 12).
flask, dissolve in and dilute with methanol to volume, and
Solution B—Prepare a filtered and degassed mixture of
mix well. Transfer 2.0 mL of this solution into a 100-mL
acetonitrile and Phosphate buffer (60 : 40).
well. The final concentration is about 8.8 mg per mL.
Solution B, as directed for Chromatographic system. Make
Pharmacopeial Forum
Standard solution—Dissolve an accurately weighed quan- Chromatograph the Standard solution, and record the peak
tity of USP Ofloxacin RS in methanol, and dilute quantita- responses as directed for Procedure: the tailing factor is not
tively, and stepwise if necessary, to obtain a solution having more than 2.0; and the relative standard deviation for replicate
a known concentration of about 4 mg per mL. injections is not more than 5.0%.
Test solution—Weigh and finely powder not fewer than 20 Procedure—Separately inject equal volumes (about 10 mL)
Tablets. Transfer an accurately weighed portion of the of the Standard solution and the Test solution into the
powder, equivalent to about 100 mg of ofloxacin, to a chromatograph, record the chromatograms, and measure the
100-mL volumetric flask, add 70 mL of methanol, and responses for the major peaks. Calculate the percentage of
sonicate for about 20 minutes. Dilute with methanol to each impurity in the portion of Tablets taken by the formula:
volume, and mix. Pass a portion of this solution through
a filter having a 0.45-mm or finer porosity, discarding the first 100(1/F)(rU / rS)(CS / CU)
5 mL. Use the filtrate.
Chromatographic system (see Chromatography h621i)— in which F is the relative response factor for each impurity; rU
The liquid chromatograph is equipped with a 294-nm detector is the peak response of the impurity obtained from the Test
and a 4.6-mm 6 10-cm column that contains packing L1. solution; rS is the peak response of ofloxacin obtained from
The flow rate is about 1.0 mL per minute. The chromatograph the Standard solution; CS is the concentration, in mg per mL,
is programmed as follows. of USP Ofloxacin RS in the Standard solution; and CU is the

concentration, in mg per mL, of ofloxacin in the Test solution,
based on the label claim. The impurity limits meet the
requirements specified in Table 1.
Assay—
Buffer solution—Dissolve 2.72 g of monobasic potassium
phosphate in 1000 mL of water, and adjust with diluted
phosphoric acid to a pH of 3.3 + 0.1.
Table 1
In-Process Revision
Relative Relative
Retention Response
Name Time Factor Limit (%)

Impurity A (2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido- 0.5 1 0.3
[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid)
Impurity B (9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- 3.6 0.22 0.3
benzoxazine-6-carboxylic acid)
Any other impurity — 1 0.2
All impurities — — 1.0
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of the responses for the major peaks. Calculate the quantity, in
Buffer solution and acetonitrile (88 : 12). Make adjustments if mg, of ofloxacin (C18H20FN3O4) in the portion of Tablets
necessary (see System Suitability under Chromatography taken by the formula:
h621i).
Diluent 1—Prepare a mixture of methanol and glacial acetic 5000C(rU / rS)
acid (75 : 25).

Diluent 2—Prepare a mixture of water and acetonitrile
Ofloxacin RS in the Standard preparation; and rU and rS are
(90 : 10).
the Standard preparation, respectively.~USP31
quantity of USP Ofloxacin RS in Diluent 1 to obtain
a solution having a known concentration of about 1 mg per
mL, and dilute quantitatively, and stepwise if necessary, with
BRIEFING
Diluent 2 to obtain a solution having a known concentration
of about 20 mg per mL. Omeprazole Magnesium. Because there is no existing USP
monograph for this drug substance, a new monograph, based on
Assay preparation—Weigh and finely powder not fewer validated methods of analysis, is being proposed. The liquid
chromatographic procedure in the test for Chromatographic purity
than 20 Tablets. Transfer an accurately weighed portion of the and in the Assay, while different, are both based on analyses
performed with the LiChrosorb brand of L7 column or with the
powder, equivalent to about 100 mg of ofloxacin, to a Nova-Pak C18 brand of L1 column. The typical retention time for
the omeprazole peak is about 8 to 10 minutes in the test for
100-mL volumetric flask, add 70 mL of Diluent 1, and Chromatographic purity and about 4 to 5 minutes for the Assay.
sonicate for about 20 minutes. Dilute with Diluent 1 to
volume, and mix. Pass a portion of this solution through
a filter having a 0.45-mm or finer porosity, and collect the
filtrate. Dilute 2.0 mL of the filtrate with Diluent 2 to 100 mL,
and mix well. Add the following:

&Omeprazole Magnesium
and 4.6-mm 6 10-cm column that contains packing L1. The
flow rate is about 1 mL per minute. Chromatograph the
In-Process Revision

directed for Procedure: the tailing factor is not more than 2.0;
and the relative standard deviation for replicate injections is
not more than 2.0%. C34H36MgN6O6S2 713.12
(RS)-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-
methyl]sulfinyl]-1H-benzimidazole, magnesium salt
(2 : 1).
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]-
sulfinyl]benzimidazole, (RS), magnesium salt (2 : 1)
[95382-33-5].
Pharmacopeial Forum
» Omeprazole Magnesium contains not less than System suitability solution—Dissolve about 1 mg of USP
97.5 percent and not more than 102.0 percent of Omeprazole RS and 1 mg of USP Omeprazole Related
Compound A RS in about 25 mL of the Mobile phase.
C34H36MgN6O6S2, calculated on the anhydrous
[NOTE—Omeprazole Related Compound A is omeprazole
basis.
sulfone.]
Packaging and storage—Preserve in tight containers, Chromatographic system (see Chromatography h621i)—
protected from light. Store at room temperature. The liquid chromatograph is equipped with a 280-nm detector
USP Reference standards h11i—USP Omeprazole RS. USP and a 4.0-mm 6 12.5-cm or 4.6-mm 6 15-cm column that
Omeprazole Magnesium RS. USP Omeprazole Related contains 5-mm packing L7. (Alternatively, a 3.9-mm 6
Compound A RS. 15-cm column that contains 4-mm packing L1 may also be
used.) The flow rate is about 0.8 to 1.0 mL per minute.
Identification—
B: The Test solution, prepared and tested as directed in
retention times for omeprazole related compound A and
the test for Content of magnesium, exhibits the emission
omeprazole are about 0.8 and 1.0, respectively; the capacity
maximum at about 285 nm.
factor, k ’, for the omeprazole peak is not less than 5.0; and the
Color of solution—Prepare a solution of Omeprazole
resolution, R, between omeprazole related compound A and
Magnesium in methanol having a concentration of 20 mg
omeprazole is not less than 3.
per mL, and filter. Determine the absorbance of this solution
Procedure—Inject a volume (about 50 mL) of the Test
at 440 nm, in 1-cm cells, using methanol as the blank: the
solution into the chromatograph, record the chromatogram for
absorbance is no greater than 0.1.
at least 4.5 times the retention time of the omeprazole, and
Water, Method I h921i: between 7% and 10%. measure the peak responses. Identify the impurities based on
Specific rotation h781Si: between +0.58 and –0.58, the relative retention times listed in Table 1.
measured at 208.
Table 1
Chromatographic purity— Relative

Phosphate buffer pH 7.6—Prepare as directed in the Assay. retention
Name time Limit (%)
In-Process Revision
Phosphate buffer pH 7.6 and acetonitrile (72.5 : 27.5). Make Omeprazole N-oxide1 0.45 0.1
adjustments if necessary (see System Suitability under Omeprazole Sulfone2 0.8 0.1
Chromatography h621i). [NOTE—To improve the resolution, (Omeprazole Related compound
the composition may be changed to 75 : 25, if necessary.] A)
Test solution—Dissolve about 4 mg of Omeprazole Omeprazole 1.0 —
Magnesium in 25 mL of the Mobile phase. [NOTE—Prepare 1
4-Methoxy-2-[[(RS)-(5-methoxy-1H-benzimidazol-2-yl)sulfinyl]-
methyl]-3,5-dimethylpyridine 1-oxide
this solution fresh.] 2
5-Methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfo-
nyl]-1H-benzimidazole
Calculate the percentage of any individual impurity in the

portion of Omeprazole Magnesium taken by the formula:
Pharmacopeial Forum
Blank solution—Transfer 4.0 mL of Lanthanum solution to

a 100-mL volumetric flask, and dilute with water to volume.
100(ri / rs)
Test solution—Transfer about 250 mg of Omeprazole
in which ri is the peak response of any individual impurity, Magnesium, accurately weighed, to a 100-mL volumetric
and rs is the sum of the responses of all the peaks: in addition flask, add 20 mL of 1 N hydrochloric acid, swirl until
to not exceeding the limits in Table 1, not more than 0.1% of dissolved, and dilute with water to volume. Allow to stand for
any other individual impurity is found; and not more than 30 minutes. Transfer 10.0 mL of this solution to a 200-mL
0.5% of total impurities is found. volumetric flask, and dilute with water to volume. Transfer
10.0 mL of the solution so obtained to another 100-mL
Content of magnesium—
volumetric flask, add 4.0 mL of Lanthanum solution, and
Lanthanum solution—Transfer 58.7 g of lanthanum oxide
dilute with water to volume.
to a 1000-mL volumetric flask, wet the substance with some
Procedure—Concomitantly determine the absorbances of
water, and dissolve by cautious addition of 250 mL of
the Standard solution, the Blank solution, and the Test
hydrochloric acid in 20 to 30 mL portions, cooling between
solution at the magnesium emission line at 285.2 nm with
additions. Add water while stirring, cool to room temperature,
a suitable atomic absorption spectrophotometer (see Spectro-
and dilute with water to volume. [NOTE—Store the solution in
photometry and Light-Scattering h851i) using an air–
a plastic bottle.]
acetylene flame. Determine the concentration, C, in mg per
Magnesium standard stock solution—Quantitatively dilute
mL, of magnesium in the Test solution using the calibration
a suitable amount of a commercially prepared atomic
graph. Calculate the content of magnesium, in percentage, in
absorption standard solution for magnesium with water to
the portion of Omeprazole Magnesium taken by the formula:
obtain a solution containing 1000 mg of magnesium per mL.
[NOTE—Store the solution in a plastic bottle.]
100(0.001CD / W)[100 / (100–L)]
Magnesium intermediate standard solution—Transfer 10.0
mL of Magnesium standard stock solution to a 500-mL in which C is as defined above; the multiplier 0.001 is for
volumetric flask, add 50 mL of 1 N hydrochloric acid, and
conversion of mg per mL to mg per mL; D is the dilution
dilute with water to volume. Transfer 20.0 mL of this solution
factor for the Test solution; W is the quantity of Omeprazole
to a 200-mL volumetric flask, and dilute with water to Magnesium, in mg, taken to prepare the Test solution; and L
volume. This solution contains 2 mg of magnesium per mL.
is the content of water, in percentage, as determined in the test
In-Process Revision
Standard solutions—Transfer 5.0, 10.0, 15.0, 20.0 and 25.0

for Water. The magnesium content, calculated on the
mL of Magnesium intermediate standard solution to separate
anhydrous basis, is between 3.30% and 3.55%.
100-mL volumetric flasks. To each flask, add 4.0 mL of
Assay—
Lanthanum solution, and dilute with water to volume. These
Standard solutions contain 0.1, 0.2, 0.3, 0.4 and 0.5 mg of
magnesium per mL, respectively. [NOTE—Concentrations of
phosphate in 300 mL of water, dilute with water to 1000 mL,
the Standard solutions and the Test solution may be modified
and mix. Dilute 250 mL of this solution with water to 1000
to fit the linear or working range of the instrument. When
mL. If necessary, adjust with phosphoric acid to a pH of 7.6.
using instruments with a linear calibration graph, the number
Mobile phase—Prepare a mixture of Phosphate buffer pH
of the Standard solutions can be reduced.]
7.6 and acetonitrile (650 : 350).
Pharmacopeial Forum
Phosphate buffer pH 11—Mix 11 mL of 0.25 M tribasic of omeprazole magnesium in the Assay preparation; and rU
sodium phosphate with 22 mL of 0.5 M dibasic sodium and rS are the peak responses obtained from the Assay
phosphate, and dilute with water to 100 mL. preparation and the Standard preparation, respec-
Standard preparation—Transfer about 10 mg of USP tively.&1S (USP31)
Omeprazole RS, accurately weighed, to a 200-mL volumetric

flask, and dissolve in about 10 mL of methanol. Add 10 mL
of Phosphate buffer pH 11, and dilute with water to volume. BRIEFING
This solution contains about 0.05 mg of omeprazole per mL.

Ondansetron Orally Disintegrating Tablets, USP 30 page 2803
Assay preparation—Transfer about 10 mg of Omeprazole and page 1463 of PF 32(5) [Sept.–Oct. 2006]. It is proposed a add
a Disintegration Test 2 to this monograph because FDA recently
Magnesium, accurately weighed, to a 200-mL volumetric approved a generic version of this product. In the absence of any
adverse comments, it is proposed to implement the inclusion of the
flask, dissolve in about 10 mL of methanol, add 10 mL of Disintegration Test 2 via the Interim Revision Announcement,
pertaining to USP 30–NF 25, with an official date of October 1,
Phosphate buffer pH 11, and dilute with water to volume. 2007. Also, modifications in the Dissolution test are being made to
accommodate all approved strengths.
This solution contains about 0.05 mg of omeprazole
magnesium per mL.
Add the following:
.Labeling—When more than one Disintegration test is given,
and a 4.0-mm 6 12.5-cm or 4.6-mm 6 15-cm column that
the labeling states the Disintegration test used only if Test 1 is
contains 5-mm packing L7. (Alternatively, a 3.9-mm 6
not used..5
15-cm column that contains 4-mm packing L1 may also be
used.) The flow rate is about 1 mL per minute. Chromato- Change to read:
graph the Standard preparation, and record the peak Disintegration—

responses as directed for Procedure: the capacity factor, k ’,
.TEST 1:
for the omeprazole peak is not less than 2; the column .5
not more than 10 seconds.
efficiency is not less than 2000 theoretical plates; and the .TEST 2—If the product complies with this test, the labeling
relative standard deviation for replicate injections is not more indicates that the product meets USP Disintegration Test 2.
than 2.0%. For Tablets labeled to contain 4 or 8 mg: not more than 30
Procedure—Separately inject equal volumes (about 20 mL) seconds. For Tablets labeled to contain 16 or 24 mg: not more
of the Standard preparation and the Assay preparation into than 40 seconds..5
In-Process Revision
Change to read:
the responses for the major peaks. Calculate the percentage of
C34H36MgN6O6S2 in the portion of Omeprazole Magnesium Medium: 0.1 N hydrochloric acid; 500 mL, deaerated.
taken by the formula: Time: 10 minutes.
Standard solution—Accurately weigh an amount of USP
Ondansetron RS, and dilute with Medium to obtain a solution
100[(713.12 / (2 6 345.42)](CS / CU)(rU / rS) having a final concentration of 0.01 mg per mL for Tablets labeled to
contain 4 mg, and a final concentration of 0.02 mg per mL for
Tablets labeled to contain 8 mg.
in which 713.12 and 345.42 are the molecular weights of .Stock standard solution—Transfer about 40 mg, accurately
omeprazole magnesium and omeprazole, respectively; CS is weighed, of USP Ondansetron RS to a 500-mL volumetric
the concentration, in mg per mL, of omeprazole in the flask. Add about 300 mL of Medium, and sonicate to dissolve.
Standard preparation; CU is the concentration, in mg per mL, Dilute with Medium to volume, and mix.
Pharmacopeial Forum
&
&2S (USP30)
Working standard solution—For Tablets labeled to contain 100 is the conversion factor to percentage; D is the dilution factor of
the Standard solution;
.
4 mg, transfer 10.0 mL of the Stock standard solution into .5
a 100-mL volumetric flask, dilute with Medium to volume,

&
and&2S (USP30)
L is the Tablet label claim, in mg. and MW2 is the molecular weight
and mix. For Tablets labeled to contain 8 mg, transfer 20.0 of ondansetron hydrochloride dihydrate (365.9).
&
mL of the Stock standard solution into a 100-mL volumetric &2S (USP30)
flask, dilute with Medium to volume, and mix. For Tablets C18H19N3O is dissolved in 10 minutes.
labeled to contain 16 mg, transfer 20.0 mL of the Stock

standard solution to a 50-mL volumetric flask, dilute with
BRIEFING
Medium to volume, and mix. For Tablets labeled to contain
24 mg, transfer 30.0 mL of the Stock standard solution to
Oxandrolone Tablets, USP 30 page 2811 and page 1464 of PF
a 50-mL volumetric flask, dilute with Medium to volume, and 32(5) [Sept.–Oct. 2006]. It is proposed to add a Dissolution Test
3 for a new generic product recently approved by FDA. The
mix..5 chromatographic procedure in this test was validated using a Luna
Test solution—Pass a portion of the solution under test through a C18 brand of L1 packing. In the absence of any adverse comments,
it is proposed to implement the inclusion of Dissolution Test 3 in PF
.suitable
.5
33(4) via the Interim Revision Announcement pertaining to USP 30–
filter. NF 25, with an official date of August 1, 2007.
Procedure—Determine the amount of C18H19N3O dissolved by UV
absorption at the wavelength of maximum absorbance at about 310 (BPC: M. Marques) RTS—C51044
nm on portions of the Test solution in comparison with the
.Working
.5 Change to read:
standard solution, using a 1-cm cell
.for Tablets labeled to contain 4 or 8 mg, a 0.5-cm cell for Dissolution h711i—
TEST 1—
Tablets labeled to contain 16 mg, or a 0.2-cm cell for Tablets Medium: a solution of water and isopropanol (7 : 3); 500 mL.
labeled to contain 24 mg..5 Time: 60 minutes.
Calculate the amount, in percentage, of ondansetron released by the Determine the amount of C19H30O3 dissolved by employing the
formula: following method.
Internal standard solution—Dissolve accurately weighed quantities
of 17a-methyltestosterone, and dilute quantitatively, and stepwise if
necessary, with acetonitrile to obtain a solution having a concentration
of about 0.2 mg per mL (for Tablets with a 2.5-mg label claim) and
about 0.8 mg per mL (for Tablets with a 10-mg label claim).
USP Oxandrolone RS, and dilute quantitatively, and stepwise if
necessary, with acetonitrile to obtain a solution having a concentra-
tion of about 1 mg per mL.
Working standard solution—Combine 100 mL of the Standard
solution, 400 mL of the Internal standard solution, and 1500 mL of
acetonitrile.
In-Process Revision
&
For Tablets labeled to contain 2.5 mg: combine 100 mL of
the Standard solution, 400 mL of the Internal standard
solution, and 1500 mL of acetonitrile. For Tablets labeled to
contain 10 mg: combine 100 mL of the Standard solution, 100
solution and the mL of the Internal standard solution, and 1800 mL of
.Working acetonitrile.&2S (USP30)
.5 Test solution—Withdraw 25 mL of the solution under test from the
standard solution, respectively; WS is the weight, in mg, of USP
Ondansetron RS taken vessel. Pass through a 0.45-mm polytef filter. Transfer 20 mL of the
filtrate to a separatory funnel, add 400 mL of the Internal standard
.C is the concentration, in mg per mL, of the Working solution, 40 mL of a 10% potassium chloride solution, and 8 mL of
S
chloroform. In separate separatory funnels, prepare an extraction
standard solution;.5 blank and an internal standard blank in a similar manner using 20
500 is the volume, in mL, of Medium; MW1 is the molecular weight mL of filtered Medium in place of the solution under test and
of ondansetron (293.4); P is the purity, expressed in decimal, of USP excluding the Internal standard solution from the extraction blank.
Ondansetron RS; Shake each funnel, and allow the layers to separate. Collect the
lower chloroform layer. Repeat the extraction procedure one more
Pharmacopeial Forum
time. Evaporate the solvents under a stream of nitrogen at 458 until

&
The column is maintained at 308, and the detector is
just dry. Reconstitute the dried residue with 2 mL of acetonitrile (for
Tablets with a 2.5-mg label claim) or with 8 mL of acetonitrile (for maintained at 508.&2S (USP30)
Tablets with a 10-mg label claim), and sonicate for 10 minutes. The flow rate is about 1.5 mL per minute. Chromatograph the
Chromatographic system (see Chromatography h621i)—The gas Working standard solution, and record the peak responses as directed
chromatograph is equipped with a flame-ionization detector and for Procedure: the tailing factor is not more than 2.0; the column
a 0.53-mm 6 30-m column coated with a 0.5-mm phase G27. The efficiency is not less than 4000 theoretical plates; and the relative
carrier gas is helium, flowing at a rate of about 16.8 mL per minute. standard deviation for replicate injections is not more than 5.0%.
The injection port and detector temperatures are maintained at 1908 Procedure—Separately inject equal volumes (about 100 mL) of the
and 3208, respectively. The chromatograph is programmed as Working standard solution and the Test solution into the chromat-
follows. Upon injection, the column temperature is increased at ograph, record the chromatograms, and measure the responses for
a rate of 258 per minute to 2808, and maintained at 2808 for the major peaks. Calculate the percentage of C19H30O3 released by the
3 minutes. Then the column temperature is increased at a rate of 108 formula:
per minute to 3208, and maintained at 3208 for 3 minutes.
Chromatograph the acetonitrile, the extraction blank, and the internal
standard blank, and record the peak responses as directed for
Procedure: the tailing factor is not more than 1.5. Make two
injections of the Working standard solution, and record the peak
responses. The average oxandrolone/Internal standard solution peak
area percent comparison is between 98.0% and 102.0%. The
resolution, R, between the oxandrolone peak and the nearest eluting in which rU and rS are the peak responses obtained from the Test
peak is equal to or greater than 1.5. solution and the Working standard solution, respectively; CS is the
Procedure—Separately inject equal volumes (0.5 mL) of the concentration, in mg per mL, of the Working standard solution; D is
Working standard solution and the Test solution into the chromat- the dilution factor of the Test solution; 500 is the volume, in mL, of
ograph, record the chromatograms, and measure the responses for Medium; 100 is the conversion factor to percentage; and LC is the
the major peaks. Calculate the percentage of C19H30O3 released by the Tablet label claim, in mg.
formula: Tolerances—Not less than 65% (Q) of the labeled amount of
C19H30O3 is dissolved in 120 minutes.
. TEST 3—If the product complies with this test, the labeling
Medium: 0.1 N hydrochloric acid containing 0.75% of
in which CS is the concentration, in mg per mL, of oxandrolone in
the Standard solution; sample ratio is the area ratio of oxandrolone sodium lauryl sulfate; 500 mL, deaerated with helium.
to 17a-methyltestosterone in the sample injection for each Test
solution; VUF is the final volume, in mL, of the sample after Apparatus 2: 75 rpm.
reconstitution of the dry residue; 500 is the volume, in mL, of
Medium; 100 is the conversion factor to percentage; standard ratio is Time: 90 minutes.
the mean area ratio of oxandrolone to 17a-methyltestosterone in all
injections of the Standard solution; VUI is the initial sample volume, Determine the amount of C19H30O3 released by employing
in mL, used in the extraction; and LC is the Tablet label claim, in mg.
Tolerances—Not less than 75% (Q) of the labeled amount of the following method.
oxandrolone (C19H30O3) is dissolved in 60 minutes.
TEST 2—If the product complies with this test, the labeling Mobile phase—Prepare a filtered and degassed mixture of
Medium: 1% polysorbate 80 in water; 500 mL, deaerated. water and acetonitrile (65 : 35). Make adjustments if neces-
Time: 120 minutes. sary (see System Suitability under Chromatography h621i).
Determine the amount of C19H30O3 dissolved by employing the
following method. Standard stock solution—Transfer about 20 mg, accurately
Mobile phase—Prepare a filtered and degassed mixture of water
and acetonitrile (55 : 45). Make adjustments if necessary (see System weighed, of USP Oxandrolone RS to a 100-mL volumetric
In-Process Revision
Standard stock solution—Transfer about 20 mg of USP Oxan- flask. Dissolve in approximately 5 mL of acetonitrile, and
drolone RS, accurately weighed, to a 200-mL volumetric flask. Add
about 20 mL of acetonitrile, and sonicate to dissolve. Dilute with sonicate for 10 minutes. Dilute with Medium to volume, and
Working standard solution—Quantitatively dilute the Standard mix.
stock solution with Medium to obtain a solution having a final
concentration of about 5 mg per mL for Tablets with a label claim of Working standard solution—Transfer 8.0 mL of the
2.5 mg, or a final concentration of about 20 mg per mL for Tablets
with a label claim of 10 mg. Standard stock solution to a 200-mL volumetric flask,
Test solution—Withdraw about 10 mL of the solution under test
from the vessel. Centrifuge in a glass tube at 2000 rpm for 10 dilute with Medium to volume, and mix.
minutes.
Chromatographic system (see Chromatography h621i)—The Test solution—Pass the solution under test through
liquid chromatograph is equipped with a reflective
a suitable filter having a porosity of 0.45 mm.
&
refractive&2S (USP30)
index detector and a 4.6-mm 6 25-cm column that contains 5-mm Chromatographic system—The liquid chromatograph is
packing L1.
equipped with a refractive index detector and a 4.6-mm
6 30-cm column that contains 5-mm packing L1. The flow
Pharmacopeial Forum
rate is about 1.0 mL per minute. The temperatures of the

BRIEFING
detector and the column are both maintained at 358.
Chromatograph the Working standard solution, and record Protein A. Because there is no existing USP monograph for this
ancillary material, a new monograph, based on validated methods of
the peak responses as directed for Procedure: the tailing analysis, is being proposed. As Protein A is used as an ancillary
material in the manufacture of recombinant therapeutic drugs,
factor is not more than 2.0; and the relative standard deviation regulatory requirements differ from those for therapeutic drug
products. The test methods for Protein A describe quality attributes
for replicate injections is not more than 5.0%. of the material rather than safety requirements as would be in an
active drug substance. The liquid chromatographic procedure in the
Procedure—Separately inject equal volumes (about 200 test for Chromatographic purity is based on analyses performed
using the Phenomenex Biosep 3000 SEC brand of L33 column;
mL) of the Working standard solution and the Test solution protein A elutes at approximately 15 minutes on this system.
into the chromatograph, record the chromatograms, and
(BB-PP: A. Szajek) RTS—C52464
measure the peak responses. Calculate the percentage of
C19H30O3 dissolved by the formula:
Add the following:

&Protein A
in which rU and rS are the peak responses for the Test solution C1995H3163N597O697S3 46,760
and the Working standard solution, respectively; CS is the
N-terminal Sequence AQHDEA
concentration, in mg per mL, of oxandrolone in the Working
standard solution; 500 is the volume, in mL, of Medium; 100 C-terminal Sequence IAADNK
is the conversion factor to percentage; and LC is the Tablet
label claim, in mg.
» Protein A is derived from Staphylococcus aureus.
of C19H30O3 is dissolved in 90 minutes..4
The structure is composed of a single polypeptide
chain containing four IgG binding domains. With
the exception of IgG3, all other human IgGs bind to
protein A. Each molecule of Protein A is capable of
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binding two IgG molecules. It is manufactured as

a bulk solution at a concentration of greater than 20
mg protein A per mL with an IgG-binding potency
of greater than 95%. Because Protein A is used as
an ancillary material in the manufacture of
recombinant therapeutic drugs, regulatory require-
ments differ from those for therapeutic drug
products.
Packaging and storage—Store in closed containers at the

temperature indicated on the label.
Pharmacopeial Forum
Labeling—Preserve in sealed containers, and store at control. The negative controls are wells coated with serum
a temperature of –208 or below. from nonimmunized sheep. The level of enterotoxin is
USP Reference standards h11i— USP Endotoxin RS. USP determined from the standard curve. The specification for
Protein A RS. the enterotoxin B level is 51 ng per mg of total protein.
Identification— Chromatographic purity—[NOTE—The size-exclusion chro-
A: SDS-PAGE—It meets the requirements of Identifica- matographic purity test resolves Protein A from high
tion test A under rProtein A using USP Protein A RS. molecular weight contaminants.]
B: IgG Binding—It meets the requirements of Identifica- Mobile phase—Prepare a solution of 50 mM sodium
tion test B under rProtein A using USP Protein A RS. dihydrogen phosphate, pH 6.5 in the following manner. Add
Microbial limits h61i—The total aerobic microbial count 6.9 + 0.1 g of sodium dihydrogen phosphate into a 1000-mL
does not exceed 100 cfu per mL, and the total yeasts and beaker. Dilute with water to 900 mL, and adjust with 5 M
molds count does not exceed 10 cfu per mL. sodium hydroxide to a pH of 6.50 + 0.05. Transfer the
solution into a 1000-mL volumetric flask, and dilute with
Bacterial endotoxins h85i—It contains not more than 1 USP
water to volume. Pass the solution through a 0.22-mm
Endotoxin Unit per mg of total protein. [NOTE—The Bacterial
membrane filter.
endotoxins test for Protein A is used to describe the quality of
Column regeneration solution—Prepare a solution of 0.1 M
this ancillary material. This test does not define the acceptable
sodium dihydrogen phosphate, pH 3.0 in the following
level of bacterial endotoxin in the preparation of injectable
manner. Add 13.8 + 0.1 g of sodium dihydrogen phosphate
dosage forms in which Protein A is used.]
into a 1000-mL beaker. Dilute with water to 900 mL, and
Total protein (see Spectrophotometry and Light-Scattering
adjust with hydrochloric acid to a pH of 3.0 + 0.1. Transfer
h851i)—Prepare triplicate samples for analysis by diluting
the solution into a 1000-mL volumetric flask, and dilute with
Protein A to 3.0 mg per mL in Water for Injection. Measure
the absorbance of each sample at 275 nm after correcting for
membrane filter.
the absorbance using Water for Injection as the blank.
Column storage solution—Mix 100 mL of methanol with
Determine the protein concentration using the equation:
900 mL of water.
Test solution—Dilute Protein A to approximately 1 mg per
Protein concentration (mg per mL) = (A275 / 0.149)
mL with Mobile phase.
Calibration standards—Using Mobile phase, prepare
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in which A is the absorbance of Protein A at the wavelength
of 275 nm and 0.149 is the molar absorptivity. Average the separate 1 mg per mL solutions of each of the following:
triplicate results, and determine a coefficient of variance thyroglobulin (670 kD), IgG (150 kD), beta lactoglobulin
(CV): the CV is 55%. (36 kD), and lysozyme (14 kD).
Limit of common contaminant protein and corresponding Standard solution—Prepare a solution containing 1 mg per
assay— mL of USP Protein A RS in Mobile phase.
Enterotoxin B—Enterotoxin B is determined using a com- Chromatographic system (see Chromatography h621i)—
mercially available microstrip enzyme-immunoassay kit.1 The liquid chromatograph is equipped with a 280-nm detector
Wells of the microstrips are coated with sheep antibodies to and a 7.8-mm 6 30-cm column that contains packing L33.
enterotoxin B. Standard curves are made using the ELISA kit

1
A suitable enzyme immunoassay kit is available from TECRA
International Pty Ltd., Australia (No. SETVIA96).
Pharmacopeial Forum
Equilibrate the column for approximately 30 minutes at 0.5

BRIEFING
mL of Mobile phase per minute or until a stable baseline is
achieved. rProtein A, C-Cys. Because there is no existing USP monograph
for this ancillary material, a new monograph, based on validated
Procedure—Separately inject 100 mL of each sample, and methods of analysis, is being proposed. As rProtein A, C-Cys is used
as an ancillary material in the manufacture of recombinant
run the samples in the following sequence: Calibration therapeutic drugs, regulatory requirements differ from those for
therapeutic drug products. The test methods for rProtein A, C-Cys
standards, thyroglobulin, IgG, beta lactoglobulin, and describe quality attributes of the material rather than safety
requirements as would be in an active drug substance. The liquid
lysozyme; the Standard solution; and the Test solution. Run chromatographic procedure in the test for Chromatographic purity is
based on analyses performed using the Superdex 200 10/300 GL
the sequence three times isocratically using Mobile phase at brand of L54 column; rProtein A, C-Cys elutes at approximately 35
minutes on this system.
0.5 mL per minute for 30 minutes. Absorbance is detected at
280 nm. Analyze the 280-nm peak data, and pick the (BB PP: A. Szajek) RTS—C52465
retention time (RT) with the largest peak area. Using the data
from the Calibration standards, plot the mean RT versus the
log molecular weight to produce the standard curve. The Add the following:
purity should be 95% in the main peak. Use the formula &rProtein A, C-Cys
from the standard curve to give the log molecular weights of
the Test solutions. Convert the log molecular weights of the
C1478H2320N432O503S4 34317.5 Da
Test solutions and the Standard solutions to actual molecular
weights. The apparent molecular weight of protein A from the N-terminal Sequence AQHDEAQQNA
Standard solution is between 156 and 205 kDa; and the
Protein A from the Test solution is within the same range.
» rProtein A, C-Cys is a recombinant Protein A
Column cleaning and storage—Rinse the column with 100
lacking the C-terminal membrane binding part;
mL of Column regeneration solution, and store by flushing
instead, a C-terminal cysteine has been introduced
with 100 mL of Column storage solution.&1S (USP31)
for directed immobilization purposes. It has five
homologous IgG binding domains identical to the
native Protein A and is produced using Escherichia
coli as the host cell followed by purification with
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conventional chromatography. rProtein A, C-Cys is

manufactured as a bulk solution with an IgG-
binding potency of greater than 95%. Because
rProtein A, C-Cys is used as an ancillary material in
the manufacture of recombinant therapeutic drugs,
regulatory requirements differ from those for
therapeutic drug products.
Pharmacopeial Forum
Packaging and storage—Store in closed containers at the Chromatographic purity—[NOTE—The size-exclusion chro-
temperature indicated on the label. matographic purity test resolves rProtein A, C-Cys from high
Labeling—Preserve in sealed containers, and store at molecular weight contaminants and low molecular weight
a temperature of –208 or below. contaminants.]

Mobile phase—Prepare a solution of 0.02 M sodium
phosphate, pH 7.2 containing 0.15 M sodium chloride in the
rProtein A, C-Cys RS.
following manner. Add 0.96 + 0.02 g of monobasic sodium
Identification—
phosphate hydrate, 2.32 + 0.02 g of dibasic sodium phos-
A: SDS-PAGE—It meets the requirements of Identifica-
phate dihydrate, and 8.76 g + 0.02 g of sodium chloride into
tion test A under rProtein A using USP rProtein A, C-Cys RS.
a 1000-mL beaker. Dilute with water to 900 mL, and adjust
B: IgG Binding—It meets the requirements of Identifica-
with 1 M sodium hydroxide to a pH of 7.2 + 0.05. Transfer
tion test B under rProtein A using USP rProtein A, C-Cys RS.
this solution into a 1000-mL volumetric flask, and dilute with
Microbial limits h61i—The total aerobic microbial count
does not exceed 100 cfu per mL, and the total yeasts and
membrane filter.
molds count does not exceed 10 cfu per mL.
EDTA solution—Prepare a 20 mM ethylenediaminetetraa-
Bacterial endotoxins h85i—It contains not more than 1 USP cetic acid (EDTA) solution by dissolving 0.74 + 0.02 g of
Endotoxin Unit per mg of total protein. [NOTE—The Bacterial EDTA in 100 mL of Mobile phase.
endotoxins test for rProtein A, C-Cys is used to describe the DTT solution—Prepare a 100 mM DL-dithiothreitol (DTT)
quality of this ancillary material. This test does not define the solution by dissolving 1.54 + 0.02 g of DTT in 100 mL of
acceptable level of bacterial endotoxin in the preparation of Mobile phase.
injectable dosage forms in which rProtein A, C-Cys is used.] Pretreatment solution—Prepare a solution containing
Total protein (see Spectrophotometry and Light-Scattering a mixture of EDTA solution and DTT solution (1 : 1, v/v).
h851i)—Prepare triplicate samples for analysis by diluting the [NOTE—Prepare fresh just before use.]
rProtein A, C-Cys to 3.0 mg per mL in Water for Injection. Test solution—Dilute rProtein A, C-Cys 1 to 5 in Pretreat-
Measure the absorbance of each sample at 275 nm after ment solution, and mix gently. Incubate the sample at 408 for
correcting for the absorbance using Water for Injection as the 60 minutes.
blank. Determine the protein concentration using the Chromatographic system (see Chromatography h621i)—
equation: The liquid chromatograph is equipped with a 214-nm detector
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and a 10-mm 6 30-cm column that contains packing L54.
Protein concentration (mg per mL) = (A275 / 0.22)
Equilibrate the column with at least two column volumes of
Mobile phase at a flow rate of 0.4 mL per minute.
in which A is the absorbance of rProtein A, C-Cys, at the
wavelength of 275 nm and 0.22 is the molar absorptivity.
Average the triplicate results, and determine a coefficient of
variance (CV): the CV is 52.5%.
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Procedure—Inject 100 mL of Pretreatment solution, and Add the following:

allow the chromatography to continue for at least two column &rProtein A
volumes. Repeat this twice before injecting 100 mL of the Test
solution. Absorbance is detected at 214 nm. Integrate the
C1917H3039N565O658S3 44,618
main peak from the Test solution run and all other peaks not
present in the Pretreatment solution runs. Calculate the N-terminal Sequence FLRPVE
percentage of impurities in the portion of the rProtein A,
C-Cys taken by the formula:
» Protein A is a component of the cell wall of
100(ri / rs) Staphylococcus aureus. Recombinant Protein A
(rProtein A) consists of five homologous immuno-
in which ri is the peak response for each impurity; and rs is the globulin (IgG) binding domains (E, D, A, B, C)
sum of the responses of all the peaks: the sum of all impurities
followed by a partial X domain sequence. It is
is not more than 5%; and the Test solution shows a major
expressed in Escherichia coli and purified via
peak at approximately 35 minutes.&1S (USP31)
a column chromatography process. IgG columns
are not used in the purification process. It is
BRIEFING manufactured as a bulk solution with an IgG-
binding potency greater than 95%. Release testing
rProtein A. Because there is no existing USP monograph for this
ancillary material, a new monograph, based on validated methods of methods and specifications are described below.
analysis, is being proposed. Because rProtein A is used as an
ancillary material in the manufacture of recombinant therapeutic Because rProtein A is used as an ancillary material
drugs, regulatory requirements differ from those for therapeutic drug
products. The test methods for rProtein A describe quality attributes in the manufacture of recombinant therapeutic
of the material rather than safety requirements as would be in an
active drug substance. The size exclusion HPLC procedure in the test
for Chromatographic purity is based on analyses performed using drugs, regulatory requirements differ from those
the Zorbax GF250 brand of L20 column; rProtein A elutes at
approximately 9 minutes on this system. The liquid chromatographic of therapeutic drug products.
procedure in the test for Limit of Triton X-100 is based on analyses
performed using the Vydac 219TP54 brand of L11 column; Triton
X-100 spike solution elutes at approximately 9 minutes on this Packaging and storage—Store in closed containers at the
system.
(BB PP: A. Szajek) RTS—C52463
Labeling—The labeling states that the material is of
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recombinant DNA origin along with the lot number, storage

conditions, and the statement ‘‘Formulated in Water for
Injection.’’
rProtein A RS.
Identification—
A: SDS-PAGE—
Molecular weight marker—Use a suitable molecular weight
marker (MWM) containing protein bands between 20 and
200 kD.
Pharmacopeial Forum
PBS solution—Prepare a solution that contains 8065.0 mg Standard preparation—Dilute USP rProtein A RS to 0.4
and 200.0 mg of sodium chloride and potassium chloride, mg per mL with PBS solution. Further dilute this solution 1 : 1
respectively, per L of 0.01 M sodium phosphate buffer, pH with 2X Reducing sample buffer, and incubate in a closed tube
7.4. for 5 minutes at 908. Mix, and quick spin prior to loading.
4X Sample buffer —Dissolve 0.666 g of tris-hydrochloride,
1 Test preparation—Dilute rProtein A with PBS solution to
0.682 g of tris base, 0.800 g of lithium dodecyl sulfate (LDS), 0.4 mg per mL. Proceed as directed under Standard
0.006 g of ethylenedinitrilotetraacetic acid (EDTA), and 4 g of preparation beginning with ‘‘Further dilute.’’
glycerol in 8 mL of water; add 0.75 mL of 1% Coomassie Comix solution—Dilute rProtein A and USP rProtein A RS
brilliant blue G-250 (see Coomassie Blue G-250 in Reagents with PBS solution to 0.8 mg per mL. This solution contains
under Reagents, Indicators, and Solutions) solution and 0.25 0.4 mg per mL of each protein. Proceed as directed under
mL of 1% phenol red solution. Mix well, and adjust the Standard preparation beginning with ‘‘Further dilute.’’
volume with water to 10 mL. SDS-PAGE gel and apparatus set-up—Assemble gel
2X Sample buffer—Prepare a mixture of 4X Sample buffer apparatus following the manufacturer’s instructions. Lock
and water (1 : 1). the gel tension wedge in place, and fill approximately 200 mL
1X Sample buffer—Prepare a mixture of 2X Sample buffer of 1X Running buffer into the inside chamber. If there are no
and water (1 : 1). leaks, pour 600 mL of 1X Running buffer into the outer
1 M Dithiothreitol solution—Dissolve 0.154 g of DL- chamber. Gently pull the comb out of the cassette to immerse
dithiothreitol (DTT) in 1 mL of water. the wells in 1X Running buffer. Load 10 mL of each
2X Reducing sample buffer—Mix 180 mL of 2X Sample preparation as directed below under Gel loading onto
buffer and 20 mL of 1 M Dithiothreitol solution. a 10% Bis-Tris SDS-PAGE gel.3
20X Running buffer2—Dissolve 104.6 g of 3-(N-morpholi- Gel loading—Use the following gel loading scheme when
no)propanesulfonic acid (MOPS), 60.6 g of tris base, 10 g of running one Test preparation (see Table 1). Each Test
sodium dodecyl sulfate (SDS), and 3.0 g of EDTA in 400 mL preparation is run by itself and as part of the Comix solution
of water. Mix well, and adjust with water to 500 mL. that contains the rProtein A and USP rProtein A RS.
1X Running buffer—Prepare a solution of water and 20X Table 1
Running buffer (19 : 1).
Load Load
Gel staining solution—Prepare a solution of Coomassie
Volume Amount
brilliant blue R-250 (see Coomassie Brilliant Blue R-250 in
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Lane Sample (mL) (mg)
Reagents under Reagents, Indicators, and Solutions) having
a concentration of 0.5 g per L in a mixture of water, 1 1X Sample buffer 10 N/A
isopropanol, and acetic acid (6.5 : 2.5 : 1.0). Filter, and store at 2 MWM 20 N/A
room temperature. Silver staining is not recommended. 3 Test preparation #1 10 2
Destaining solution—Mix 100 mL of acetic acid with 900 4 Comix solution #1 10 4 (total)
mL of water. 5 Test preparation #1 10 2

6 1X Sample buffer 10 N/A
7 Standard preparation 10 2
1
8 MWM 20 N/A
4X NuPAGE LDS sample buffer is available from Invitogen (No.
NP0007).
2 3
20X NuPAGE MOPS SDS Running Buffer is available from 10% Bis-Tris SDS-PAGE gel is available from Invitrogen (No.
Invitrogen (No. NP0001). NP0301).
Pharmacopeial Forum
distance should be the same for each lane on a gel. Calculate

Table 1 (Continued)
the percentage of the retention factor (RF) of each major peak
Load Load or band, and document on the report sheet using the following
Volume Amount equation:
Lane Sample (mL) (mg)

%RF = DM / DT 6 100
9 — — —
10 — — —
Also for each gel, record the number of bands and
approximate molecular weight of each band in each sample.
Running the gel—Set the voltage to 125 volts, and run at
System suitability—All bands between 20 kD and 70 kD are
a constant voltage. Run the gels until the bromophenol blue
present. The lane containing 1X Sample buffer does not
band is approximately 5 mm from the bottom of the gel
contain any bands.
(approximately 120 to 140 minutes).
Specificity—The rProtein A has one major band and
Gel staining—Pour approximately 100 mL of Gel staining
a similar molecular weight that corresponds to those of the
solution into the staining container. Place the gel into the
USP rProtein A RS. The Comix solution also shows a single
staining container, and allow the stain to completely cover the
major band.
gel. Cook the gel and container in a microwave for 30
B: IgG Binding—[NOTE—The IgG binding assay is
seconds. Place the staining container on an orbital shaker, and
a functional method for determining the percentage of
stain the gel for 1 hour with gentle shaking.
rProtein A capable of binding to immobilized human
Destaining—Drain the Gel staining solution, and add
polyclonal immunoglobulin. Since the percent of functional
enough Destaining solution to the container to cover the
rProtein A in each lot is not less than 95%, the assay measures
gel. Place the container on an orbital shaker, and shake at low
unbound protein versus total protein injected. This is done by
speed. Change the Destaining solution as necessary until
comparing the absorbance in the flow-through to absorbance
a clear background is obtained. After destaining, rinse the gel
from an injection bypassing the column.]
thoroughly with water, and leave the gel in water for 10
Sample pretreatment (desalting)—In order to remove any
minutes before scanning.
buffer components that may contribute to absorbance in the
Gel scanning—Apply some water to the glass plate of the
‘‘unbound’’ IgG column fraction, samples are desalted with
scanner, and place the gels on a wetted glass plate. Eliminate
Solution A. Desalting may be performed using a suitable
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any bubbles. Using appropriate settings, scan the gels.

desalting column4 depending on the volumes required.
Data analysis—Choose a band between the 20 kD and
IgG column—A 1-mL Sepharose column5 with immobi-
30 kD bands of the MWM to calculate the percentage of the
lized human polyclonal IgG (hIgG) is required to perform this
retention factor. Draw a line in one lane (lane containing 1X
assay. [NOTE—The IgG column requires washing when it is
Sample buffer) from the well to the apex (region of greatest
new, when it has performed several analysis cycles, or after
intensity) of the chosen band.
system suitability failure. Column washing procedure is not
The length of this line is denoted as the total distance (DT).
required for each sample injection.]
For the lanes containing samples draw a line from the well to
the apex of each band. For each band the length of this
4
distance is the migration distance (DM) in mm. Record the DT Zeba columns are available from Pierce; Nap-10 columns are
available from GE Healthcare.
5
and DM on the report sheet for each peak or band. The total HiTrap IgG Sepharose 6 FF column is available from GE
Healthcare (No. 90-1003-97).
Pharmacopeial Forum
Column washing solution A—Prepare a solution of 0.5 M Test preparation—Prepare a 4.0 to 6.0 mg per mL rProtein
acetic acid, pH 3.4 by adding 28.6 mL of acetic acid into A solution in Solution A.
a 1000-mL beaker, diluting to 900 mL with water, and Chromatographic system—The liquid chromatograph is
adjusting with ammonium acetate to a pH of 3.4. Transfer the equipped with a 280-nm detector and a 1-mL column with
solution into a 1000-mL volumetric flask, and dilute with immobilized hIgG. The chromatograph is equipped with
water to volume. Pass the solution through a 0.45-mm a bypass valve to allow flow to be diverted from the column.
membrane filter. Each analysis consists of a series of two injections, one where
Column washing solution B—Prepare a solution of 50 mM the sample is injected onto the column and one where the
Tris, pH 7.6, 150 mM sodium chloride, and 0.05% Tween 20 sample bypasses the column and flows directly into the
by the following procedure. Add 6.06 + 0.01 g of Tris and detector. Perform three replicate analyses. The chromatograph
8.77 + 0.01 g of sodium chloride into a 1000-mL beaker. is programmed as follows (see Table 2).
Dilute with water to 900 mL, and adjust with 0.5 M sodium Chromatograph the Standard preparation, record the peak
hydroxide to a pH of 7.60 + 0.05. Transfer the solution into responses, and calculate the percentage of hIgG binding as
a 1000-mL volumetric flask, and dilute with water to volume. directed for Procedure: the percentage of hIgG
Pass the solution through a 0.45-mm membrane filter (buffer binding 95% and the relative standard deviation for
solution). Add 0.5 mL of Tween 20 into 1 L of the buffer replicate analysis is not more than 1%.
solution and mix thoroughly. Procedure—Inject a volume (about 100 mL) of the Test
Solution A—Prepare a solution of 20 mM monobasic preparation. Record the chromatogram, and measure the peak
sodium phosphate and 150 mM sodium chloride, pH 7.6 by responses. Calculate the percentage of hIgG binding activity
the following procedure. Add 2.76 + 0.01 g monobasic by the following formula:
sodium phosphate hydrate and 8.77 + 0.01 g sodium chloride
into a 1000-mL beaker. Dilute with water to 900 mL, and 100 – 100(rC / rB)
adjust with 5 M sodium hydroxide to a pH of 7.60 + 0.05.
in which rC is the unbound material peak response from the
Transfer the solution into a 1000-mL volumetric flask, and
column injection and rB is the bypass peak response from the
dilute with water to volume. Pass the solution through a
bypass injection. Each replicate analysis of the Test
0.45-mm membrane filter.
preparation is not less than 95% of hIgG binding. Report
Solution B—Prepare a solution of 100 mM phosphoric acid
the average value from three replicate analyses.
pH 2.8 by the following procedure. Add 6.8 mL of
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phosphoric acid into a 1000-mL beaker. Dilute with water Microbial limits h61i—The total aerobic microbial count
to 900 mL, and adjust with 2 M potassium hydroxide to a pH does not exceed 100 cfu per mL, and the total yeasts and
of 2.80 + 0.05. Transfer the solution into a 1000-mL molds count does not exceed 10 cfu per mL.
volumetric flask, and dilute with water to volume. Bacterial endotoxins h85i—It contains not more than 0.5
Mobile phase—Use variable mixtures of Solution A and USP Endotoxin Unit per mg of total protein. [NOTE—The
Standard preparation—Thaw USP rProtein A RS, and use
directly.
Pharmacopeial Forum
Table 2
Flow Rate Time Solution A Solution B Valve

(mL per minute) (minutes) (%) (%) Position Elution
1.0 0–6 100 0 column re-equilibration
1.0 6–12 100?0 0?100 column re-equilibration
1.0 12–22 100 0 column equilibration
0.4 22–25 100 0 column equilibration
0.4 (sample 25–35 100 0 column isocratic
injected)
1.0 35–49 100?0 0?100 column regeneration
1.0 49–63 0?100 100?0 column re-equilibration
1 63–65 100 0 bypass equilibration
0.4 65–68 100 0 bypass equilibration
0.4 (sample 68–75 100 0 bypass isocratic
injected)
Bacterial endotoxins test for rProtein A is used to describe the absorbance at 270 to 250 nm (i.e., E270/E250): the
quality of this ancillary material. This test does not define the absorbance at 270 nm of a 1 mg per mL solution of rProtein
acceptable level of bacterial endotoxin in the preparation of A in Water for Injection is within the range 0.14–0.20.
injectable dosage forms in which rProtein A is used.] Chromatographic purity—[NOTE—The size-exclusion chro-
Total protein (see Spectrophotometry and Light-Scattering matographic purity test resolves rProtein A from high
h851i)—Prepare triplicate samples for analysis by diluting the molecular weight contaminants.]
rProtein A to 3.0 mg per mL in Water for Injection. Measure Mobile phase—A solution of 0.3 M sodium phosphate, pH
the absorbance of each sample at 275 nm after correcting for 7 is prepared by mixing monobasic and dibasic phosphate
the absorbance using Water for Injection as the blank. solutions in the following manner. Weigh 21.3 + 0.1 g of
Determine the protein concentration using the equation: dibasic anhydrous sodium phosphate, and dissolve in 500 mL
of water to obtain a 0.3 M dibasic sodium phosphate solution
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Protein concentration (mg per mL) = (A275 / 0.165) (Solution 1). Into a separate container, weigh 18.0 + 0.1 g
monobasic anhydrous sodium phosphate, and dissolve in 500
in which A is the absorbance of rProtein A at the wavelength
mL of water to obtain a 0.3 M monobasic sodium phosphate
of 275 nm and 0.165 is the molar absorptivity. Average the
solution (Solution 2). Calibrate a pH meter using pH
triplicate results, and determine a coefficient of variance
calibrators at a pH of 7 and 10. Add 400 mL of Solution
(CV): the CV is 55%.
1 to a 1-L beaker. Transfer the pH probe to the beaker. Slowly
UV spectral analysis—Dilute rProtein A to 1 mg per mL in add Solution 2 to the solution until the pH is 7.0 + 0.1. Pass
Water for Injection. Using a scanning UV spectrophotometer the solution through a 0.45-mm membrane filter.
and Water for Injection as the blank, obtain spectral scans Standard solution—Dilute USP rProtein A RS to 1 mg per
over the range of 240 to 360 nm. From the resulting data, mL in Mobile phase.
calculate the absorbance value at 270 nm and the ratio of
Pharmacopeial Forum
Test solution—Dilute rProtein A to 1 mg per mL in Mobile 20% trichloroacetic acid, then stain using a suitable stain for
phase. IEF gels.8 Finally, wash and dry the gel: the correlation
Chromatographic system (see Chromatography h621i)— coefficient of the best fit line for the pI Markers versus their
The liquid chromatograph is equipped with a 214-nm and migration in cm is 0.990, and the rProtein A from the
280-nm detector and a 4.6-mm 6 25-cm column that Standard solution shows a single major band within the pI
contains packing L35. The flow rate is 1 mL per minute. range of 4.6 to 5.2. A single band is seen in the Test solution
Chromatograph the Standard solution as directed for that corresponds to the pI range of the Standard solution.
Procedure: rProtein A shows a single major peak at Limit of Triton X-100—
approximately 9 minutes and the area percentage is 98% Mobile phase—Prepare a filtered and degassed mixture of
at 214 nm and 95% at 280 nm. water and acetonitrile (60 : 40).
Procedure—Inject 100 mL of the Test solution into the Test solution—Dilute rProtein A to 5 mg per mL in Water
chromatograph, run isocratically for 15 minutes, and record for Injection.
the chromatogram. The values for the rProtein A from the Triton X-100 spike solution—Combine 5 mg per mL of
Test solution correspond to the specifications of the USP USP rProtein A RS and 0.15% Triton X-100 (9 : 1) to obtain
rProtein A RS from the Standard solution. a solution having known concentrations of rProtein A and
Isoforms— 0.015% Triton X-100.
Standard solution—Thaw USP rProtein A RS, and use Chromatographic system (see Chromatography h621i)—
directly. The liquid chromatograph is equipped with a 214-nm and
Test solution—Dilute rProtein A to 4 mg per mL in Water a 280-nm detector and a 4.6-mm 6 25-cm column that
for Injection. contains 5-mm packing L11. The flow rate is 1 mL per minute.
pI Markers—Use a suitable marker set containing markers Chromatograph the Triton X-100 spike solution as directed for
between 3 and 10. 6
Procedure: Triton X-100 has a single major peak at
IEF gel—Use a suitable gel with the range of between approximately 9 minutes, and the rProtein A shows a smaller
3 and 10 and a size of 100 6 125 mm. 7
or undetectable peak at the same retention time.
Procedure—Apply 5-mL aliquots of the pI Markers, Test Procedure—Inject about 100 mL of the Test solution into
solution, and the Standard solution to the IEF gel, and run the chromatograph, run isocratically for 35 minutes, and
under 1W of power for approximately 10 minutes. Remove record the chromatogram. The absorbance is detected at 223
the sample mask, and apply power with concurrent cooling nm: the Triton X-100 peak is not more than 0.015%
In-Process Revision
between 58 to 108 of the focusing chamber for 40 minutes at (equivalent to the Triton X-100 spike solution).&1S (USP31)
a setting of 1000V, 20 mA, 25W. Fix the IEF gel for 1 hour in
6
pI markers in the 3–10 range are available from BioRad (No. 161-
0310).
7
IEF gels in the 3–10 range are available from Cambrex (No.
8
56015). ISS Pro-Blue is available from Integrated Separation Systems.
Pharmacopeial Forum
Labeling—Preserve in sealed containers, and store at

BRIEFING
a temperature of –208 or below.
rProtein A, B4, C-Cys. Because there is no existing USP USP Reference standards h11i—USP Endotoxin RS. USP
monograph for this ancillary material, a new monograph, based on
validated methods of analysis, is being proposed. As rProtein A, B4, rProtein A, B4, C-Cys RS.
C-Cys is used as an ancillary material in the manufacture of
recombinant therapeutic drugs, regulatory requirements differ from Identification—
those for therapeutic drug products. The test methods for rProtein A,
B4, C-Cys describe quality attributes of the material rather than A: SDS-PAGE—It meets the requirements of Identifica-
safety requirements as would be in an active drug substance. The
liquid chromatographic procedure in the test for Chromatographic tion test A under rProtein A using USP rProtein A, B4, C-Cys
purity is based on analyses performed using the Superdex 200 10/
300 GL brand of L54 column; rProtein A, B4, C-Cys elutes at RS.
approximately 37 minutes on this system.
B: IgG Binding—It meets the requirements of Identifica-
(BB PP: A. Szajek) RTS—C52466
tion test B under rProtein A using USP rProtein A, B4, C-Cys
RS.

Add the following:
does not exceed 100 cfu per mL, and the total yeasts and
&rProtein A, B4, C-Cys
molds count does not exceed 10 cfu per mL.
Bacterial endotoxins h85i—It contains not more than 1 USP

C1177H1854N326O384S1 26747.6 Da Endotoxin Unit per mg of total protein. [NOTE—The Bacterial
N-terminal Sequence AQGTVDAKFD endotoxins test for rProtein A, B4, C-Cys is used to describe
the quality of this ancillary material. This test does not define
the acceptable level of bacterial endotoxin in the preparation
» rProtein A, B4, C-Cys is a recombinant protein of injectable dosage forms in which rProtein A, B4, C-Cys is
derived from the B-domain of Protein A. The used.]
Protein A domain has been alkali-stabilized by site- Total protein (see Spectrophotometry and Light-Scattering
specific mutagenesis and multimerized to a tetramer h851i)—
with a C-terminal cysteine for directed immobili- Formulation buffer solution—Prepare a solution of 0.02 M
zation purposes. rProtein A, B4, C-Cys is produced potassium phosphate, pH 7.0, containing 0.15 M potassium
using Escherichia coli as the host cell followed by chloride and 2 mM of ethylenediaminetetraacetic acid
In-Process Revision
(EDTA) in the following manner. Add 2.72 + 0.01 g of

purification with conventional chromatography.
monobasic potassium phosphate anhydrous, 11.18 g + 0.22 g
rProtein A, B4, C-Cys is manufactured as a bulk
of potassium chloride, and 0.744 + 0.02 g of EDTA into
solution with an IgG-binding potency of greater
than 95%. Because rProtein A, B4, C-Cys is used as
an ancillary material in the manufacture of the solution into a 1000-mL volumetric flask, and dilute with
recombinant therapeutic drugs, regulatory require- water to volume. Pass the solution through a 0.45-mm
ments differ from those for therapeutic drug membrane filter.
products. Test preparation—Dilute the rProtein A, B4, C-Cys to 3.0
mg per mL with Formulation buffer solution.
Packaging and storage—Store in closed containers at the
Pharmacopeial Forum
Procedure—Prepare triplicate samples for analysis. Meas- Chromatographic system (see Chromatography h621i)—
ure the absorbance of each Test preparation at 275 nm after The liquid chromatograph is equipped with a 214-nm detector
correcting for the absorbance using the Formulation buffer and a 10-mm 6 30-cm column that contains packing L54.
solution as the blank. Determine the protein concentration Equilibrate the column with at least two column volumes of
using the equation: Mobile phase at a flow rate of 0.4 mL per minute.
Procedure—Inject 100 mL of Pretreatment solution, and
Protein concentration (mg per mL) = (A275 / 0.22) allow the chromatography to continue for at least two column
volumes. Repeat this twice before injecting 100 mL of the Test
in which A is the absorbance of rProtein A, B4, C-Cys, at the
solution. Absorbance is detected at 214 nm. Integrate the
wavelength of 275 nm and 0.22 is the molar absorptivity.
main peak from the Test solution run and all other peaks not
Average the triplicate results, and determine a coefficient of
present in the Pretreatment solution runs. Calculate the
variance (CV): the CV 52.5%.
percentage of impurities in the portion of rProtein A, B4,
Chromatographic purity—[NOTE—The size-exclusion chro- C-Cys taken by the formula:
matographic purity test resolves rProtein A, B4, C-Cys from
high molecular weight contaminants and low molecular 100(ri / rs)
weight contaminants.]
Mobile phase—Prepare a solution of 0.02 M sodium in which ri is the peak response for each impurity; and rs is the
phosphate, pH 7.2 containing 0.15 M sodium chloride in the sum of all the responses of all the peaks: the sum of all
following manner. Add 0.96 + 0.02 g of monobasic sodium impurities is not more than 5%; and the Test solution shows
phosphate hydrate, 2.32 + 0.02 g of dibasic sodium phos- a major peak at approximately 37 minutes.&1S (USP31)
phate dihydrate, and 8.76 g + 0.02 g of sodium chloride into

BRIEFING
this solution into a 1000-mL volumetric flask, and dilute with Reserpine Tablets, USP 30 page 3114. On the basis of comments
water to volume. Pass the solution through a 0.45-mm received, it is proposed to delete the Procedure for content
uniformity in the test for Uniformity of dosage units because (1)
membrane filter. the testing equipment is no longer available in the market and (2) the
Procedure in the Assay is validated for its use in testing the content
EDTA solution—Prepare a 20 mM EDTA solution by uniformity of the Tablets.
dissolving 0.74 + 0.02 g of EDTA in 100 mL of Mobile (MDCV: S. Ramakrishna) RTS—C51688
In-Process Revision
phase.
Change to read:
DTT solution—Prepare a 100 mM DL-dithiothreitol (DTT)
solution by dissolving 1.54 + 0.02 g of DTT in 100 mL of Uniformity of dosage units h905i: meet the requirements.
Procedure for content uniformity—
Mobile phase. Phosphoric acid-methanol solution—Dilute 20 mL of phosphoric
acid with 200 mL of methanol, then dilute with water to 1000 mL,
Pretreatment solution—Prepare a solution containing and mix.
Vanadium pentoxide reagent—Prepare a saturated solution of
a mixture of EDTA solution and DTT solution (1 : 1, v/v). vanadium pentoxide in phosphoric acid by shaking by mechanical
means for 1 hour 100 mg of vanadium pentoxide with 100 mL of
[NOTE—Prepare fresh just before use.] phosphoric acid. Allow undissolved solids to settle overnight, and
filter the supernatant through a medium-porosity, sintered-glass
Test solution—Dilute rProtein A, B4, C-Cys 1 to 5 in funnel.
Standard solution—Using an accurately weighed quantity of USP
Pretreatment solution, and mix gently. Incubate the sample at Reserpine RS, prepare a solution in Phosphoric acid-methanol
solution having a known concentration of about 0.002 mg per mL.
408 for 60 minutes.
Pharmacopeial Forum
Test preparation—Place 1 Tablet in a suitable container, and add Change to read:

an accurately measured volume of Phosphoric acid-methanol
solution so that the concentration of the final solution is about pH h791i—Place about 40 mL in a plastic beaker, add about 250 mg
0.002 mg of reserpine per mL. Shake by mechanical means until the of quinhydrone, and stir for 1 minute, leaving some of the
tablet is completely disintegrated. Filter before using. quinhydrone undissolved. Determine the pH using a hydrofluoric
Procedure—With the Apparatus set as described for Automated acid frit-junction calomel reference electrode and a hydrofluoric
Dissolution Test for Reserpine Tablets under Automated Methods of acid-resistant metallic electrode:
Analysis h16i, conduct determinations of one Standard per five
Tablets. Calculate the quantity, in mg, of reserpine (C33H40N2O9) in .and
the Tablet taken by the formula: determine the pH using a suitable electrode system:.5
the pH is between 3.0 and 4.5.
CD(IU / IS)
in which C is the concentration, in mg per mL, of USP Reserpine RS Change to read:
in the Standard solution; D is the dilution factor for the Test
preparation; and IU and IS are the fluorescence intensities obtained Assay—
from the Test preparation and the Standard solution, respectively.
.TEST 1—
& .5
&1S (USP31)
Buffer solution and Standard preparations—Prepare as directed in
the Assay under Sodium Fluoride Oral Solution.
Assay preparation—Transfer an accurately measured volume of
Topical Solution, equivalent to about 20 mg of fluoride ion, to
a 1000-mL volumetric flask, add water to dissolve, dilute with water
to volume, and mix.
BRIEFING Procedure—Proceed as directed for Procedure in the Assay under
Sodium Fluoride Oral Solution. Calculate the quantity, in mg, of
fluoride ion in each mL of the Topical Solution taken by the formula:
Sodium Fluoride and Acidulated Phosphate Topical Solution, C/V
USP 30 page 3195. Comments were received that the current Assay
method employing an ion-selective electrode has a history of poor in which C is the determined concentration of fluoride ion, in mg per
precision for some OTC formulations. To address this problem, mL, in the Assay preparation, and V is the volume, in mL, of Topical
a new Assay method based on ion chromatography is proposed. The Solution taken.
liquid chromatographic procedure in this test is based on analyses
performed with the Transgenomic AN1 brand of L## column. The .TEST 2—[NOTE—Use Purified Water (resistivity not less
typical retention time for the fluoride peak is about 5 minutes, and
a chloride peak (a typical impurity) elutes at about 5.7 minutes. than 18 megohm-cm) for the Mobile phase and all
Using a flexible monograph approach, it is proposed to add this new
method as Test 2 and to add a Labeling requirement for preparations.]
manufacturers using this method. Thus, parties currently using the
existing ion-selective electrode assay method would not be affected Mobile phase—Dissolve about 300 mg of anhydrous
by this revision.
In addition, comments were received that the type of calomel sodium carbonate in 2000 mL of water, add 2.0 mL of 1 N
reference electrode required in the test for pH is no longer available.
It is proposed to specify that a suitable electrode system can be used sodium hydroxide, mix, and pass through a 0.45-mm nylon
in the pH procedure. This proposal also affects the Sodium Fluoride
and Phosphoric Acid Gel monograph. filter.
In the absence of any adverse comments, it is proposed to
implement these revisions via the Interim Revision Announcement Standard stock preparation—Dissolve a suitable quantity
pertaining to USP 30–NF 25, with an official date of October 1,
2007. This approach is considered as a way for USP to support the of USP Sodium Fluoride RS in water to obtain a solution
fast pace of the OTC market as compared to prescription products,
and to address the OTC business need to implement method changes having a known concentration of about 0.11 mg per mL.
very quickly. Comments regarding these proposals should be
received by July 1, 2007. Standard preparation—Transfer 5.0 mL of the Standard
In-Process Revision
(MD-GRE: E. Gonikberg) RTS—C47631 stock solution to a 500-mL volumetric flask, dilute with water
to volume, and pass through a 0.45-mm nylon or PTFE filter.
Change to read: This solution contains about 1.1 mg of sodium fluoride per
Labeling—Label Topical Solution in terms of the content of sodium mL.
fluoride (NaF) and in terms of the content of fluoride ion.
Assay preparation—Transfer 10.0 mL of the Topical
.The labeling indicates the Assay test with which the article
Solution to a suitable volumetric flask, dilute with water
complies if a test other than Test 1 is used..5
quantitatively, and stepwise if necessary, to obtain a solution
having a known concentration of about 1.1 mg of sodium
fluoride per mL, based on the label claim, and pass through
a 0.45-mm nylon or PTFE filter.
Pharmacopeial Forum
Chromatographic system (see Chromatography h621i)— in which P is as defined above; 19.00 is the atomic weight of
The liquid chromatograph is equipped with a conductivity fluorine; and 41.99 is the molecular weight of sodium
detector with a suitable suppression unit and a 4.6-mm 6 fluoride..5
25-cm column and a 4.6-mm 6 50-mm guard column, both
containing packing L## (see Chromatographic Reagents
under Reagents, Indicators, and Solutions). The flow rate is
BRIEFING
about 1.0 mL per minute. [NOTE—It is recommended to use
polymethylpentene HPLC vials.] Chromatograph the Stan- Sodium Fluoride and Phosphoric Acid Gel, USP 30 page 3196.
Comments were received that the type of calomel reference electrode
dard preparation, and record the peak responses as directed required in the test for pH is no longer available. It is proposed to
specify that a suitable electrode system can be used in the pH
for Procedure: the tailing factor for the fluoride peak is not procedure. In the absence of any adverse comments, it is proposed to
implement this revision via the Interim Revision Announcement
more than 2.0, and the column efficiency is not less than 1500 pertaining to USP 30–NF 25, with an official date of October 1,
2007. Comments regarding this proposal should be received by July
theoretical plates; the elution order is fluoride, followed by 1, 2007.
the chloride peak; the resolution, R, between fluoride and (MD-GRE: E. Gonikberg) RTS—C47631
chloride is not less than 1.5; and the relative standard
deviation for six replicate injections is not more than 2.0% for Change to read:
the fluoride peak. [NOTE—Chloride is an impurity that is pH h791i—Place about 40 mL in a plastic beaker, add about 250 mg
of quinhydrone, and stir for 1 minute, leaving some of the
present in USP Sodium Fluoride RS.] quinhydrone undissolved. Determine the pH using a hydrofluoric
acid frit-junction calomel reference electrode and a platinum
Procedure—Separately inject equal volumes (about 20 mL) electrode:
of the Standard preparation and the Assay preparation into .and determine the pH using a suitable electrode system:.5
the pH is between 3.0 and 4.0.
the responses for the fluoride peaks. Calculate the percentage,
P (w/v), of sodium fluoride in the portion of Topical Solution
BRIEFING
Sulfamethoxazole, USP 30 page 3246. On the basis of stability
data submitted, it is proposed to revise the storage condition in
10060.0016CS (D / V)(rU / rS) Packaging and storage.

in which 0.001 is the conversion factor from mg to g; CS is the
concentration, in mg per mL, of sodium fluoride in the Change to read:
In-Process Revision
Standard preparation;D is the dilution factor for the Assay
Packaging and storage—Preserve in well-closed, light-resistant
preparation; V is the volume, in mL, of Topical Solution containers. Store at 258, excursions permitted between 158 and 308
taken to prepare the Assay preparation; and rU and rS are the &
room temperature.&1S (USP31)
fluoride peak responses obtained from the Assay preparation
and the Standard preparation, respectively.
Calculate the percentage (w/v) of fluoride ion in the portion
of Topical Solution taken by the formula
P619.00 / 41.99
Pharmacopeial Forum
potentiometrically. V1 and V2 are the volumes, in mL, of

BRIEFING
titrant needed to reach the first and second endpoints,
Sulisobenzone, USP 30 page 3258. On the basis of comments respectively. To determine the blank value caused by tertiary
received, it is proposed to (1) add a test for water because
Sulisobenzone is hygroscopic; (2) perform the calculations for the amines present as impurities in the titrant, dissolve V1/5 mL of
Assay and the UV absorptivities in the Identification section on the
anhydrous basis; and (3) add a blank value to the calculation in the 0.5 N hydrochloric acid VS in 50 mL of dehydrated isopropyl
Assay to take into account the tertiary amines present in the
tetrabutylammonium hydroxide. alcohol, and subsequently add (5 – V1/5) mL of water. Titrate
with 0.1 N tetrabutylammonium hydroxide VS, and determine
the two endpoints potentiometrically. V1B and V2B are the
Change to read: volumes, in mL, of titrant needed to reach the first and second
endpoints, respectively. The blank value VBV, in mL, is
» Sulisobenzone contains not less than 95.0
obtained by the formula:
&
97.0&1S (USP31)
percent and not more than 105.0
V2B – V1B
&
103.0&1S (USP31)
percent of C14H12O6S, calculated on the as-is
Calculate the percent of C14H12O6S in the portion of
&
anhydrous&1S (USP31)
basis. Sulisobenzone taken by the formula:
Change to read:
308.31C[2V1 – (V2 – VBV)](1/W)(0.001)100
Identification, Ultraviolet Absorption h197Ui—
Solution: 10 mg per mL.
Medium: water.
Absorptivities in which 308.31 is the molecular weight of Sulisobenzone; C
&
, calculated on the anhydrous basis,&1S (USP31) is the concentration, in moles per L, of the 0.1 N
do not differ by more than 3.0%.
tetrabutylammonium hydroxide VS; W is the weight, in g,
Add the following: of Sulisobenzone taken; 0.001 is the conversion factor for
&
Water, Method I h921i: not more than 2.0%.&1S (USP31) converting mL to L; and 100 is the conversion factor to
percentage.&1S (USP31)
Change to read:
Assay—Accurately weigh about 1 g of Sulisobenzone, and dissolve

in 20 mL of water in a conical flask. Add 200 mL of dehydrated
isopropyl alcohol, titrate a portion with 0.1 N tetrabutylammonium
hydroxide VS, and determine the two endpoints potentiometrically. BRIEFING
In-Process Revision
Calculate the amount, in mg, of C14H12O6S in the portion of

Sulisobenzone taken by the formula:
Sumatriptan Succinate. This new monograph, which appeared in
308.31C(2V1 – V2) Pharmacopeial Previews on page 3157 of PF 27(5) [Sept.–Oct.
in which 308.31 is the empirical weight of sulisobenzone; C is the 2001], was previously cancelled and is now being reproposed for In-
concentration, in moles per liter, of the 0.1 N tetrabutylammonium Process Revision, with changes to reflect the approved product. The
hydroxide VS; and V1 and V2 are the volumes, in mL, of titrant liquid chromatographic procedures in the test for Limit of
needed to reach the first and second endpoints, respectively. sumatriptan succinate related compound A are based on analyses
performed with the Spherisorb Silica brand of L3 column. The liquid
&
Accurately weigh about 0.25 g of Sulisobenzone and chromatographic procedures in the test for Related compounds and
in the Assay are based on analyses performed with the Spherisorb
dissolve in 5 mL of water in a conical flask. Add 50 mL of ODS1 brand of L1 column. In the Assay, the typical retention time
observed for sumatriptan is about 8 minutes.
dehydrated isopropyl alcohol, titrate with 0.1 N tetrabutyl-
ammonium hydroxide VS, and determine the two endpoints
Pharmacopeial Forum

Add the following:
methanol and 10 M Ammonium acetate solution (9 : 1). Make
&Sumatriptan Succinate
tity of USP Sumatriptan Succinate Related Compound A RS
in Mobile phase, and dilute quantitatively, and stepwise if
necessary, with Mobile phase to obtain a solution having
C14H21N3O2S C4H6O4 413.49
a known concentration of about 6.25 mg per mL.
1H-Indole-5-methanesulfonamide, 3-[2-(dimethylamino)eth- Test solution—Transfer about 70 mg of Sumatriptan
yl]-N-methyl-, butanedioate (1 : 1). Succinate, accurately weighed, to a 25-mL volumetric flask,
dissolve in and dilute with Mobile phase to volume, and mix.
3-[2-(Dimethylamino)ethyl]-N-methylindole-5-methanesul-
fonamide succinate (1 : 1) [103628-48-4].
» Sumatriptan Succinate contains not less than 98.0 L3. The flow rate is about 2.0 mL per minute. Chromatograph
percent and not more than 102.0 percent of the Standard solution, and record the peak responses as
C14H21N3O2S C4H6O4, calculated on the anhy- directed for Procedure: the relative standard deviation for
drous basis.
Packaging and storage—Preserve in tight, light-resistant of the Standard solution and the Test solution into the
containers. Protect from freezing, and store at a temperature chromatograph, record the chromatograms, and measure the
below 308. responses for the major peaks. Calculate the percentage of
USP Reference standards h11i—USP Sumatriptan Succi- sumatriptan related compound A free base in the portion of
nate RS. USP Sumatriptan Succinate Related Compound A sumatriptan free base taken by the formula:
RS. USP Sumatriptan Succinate Related Compound C RS.
USP Sumatriptan Succinate Related Impurities RS. 100(495.7/613.8)(413.5/295.4)(CS / CU)(rU / rS)
Identification—
In-Process Revision
A: Infrared Absorption h197Mi.
sumatriptan related compound A and sumatriptan succinate
related compound A, respectively; 413.5 and 295.4 are the
molecular weights of sumatriptan succinate and sumatriptan
respectively; CS is the concentration, in mg per mL, of
in the Assay.
sumatriptan succinate related compound A in the Standard
Water, Method I h921i: not more than 1.0%. solution; CU is the concentration, in mg per mL, of
Limit of sumatriptan succinate related compound A— sumatriptan succinate in the Test solution; and rU and rS are
10 M Ammonium acetate solution—Dissolve 77.1 g of the peak responses of sumatriptan succinate related com-
ammonium acetate in 100 mL of water. pound A obtained from the Test solution and the Standard
solution, respectively: not more than 0.6% is found.
Pharmacopeial Forum
Related compounds— Procedure—Inject a volume (about 10 mL) of the Test

Diluent and Resolution solution—Proceed as directed in the solution into the chromatograph, record the chromatogram,
Assay. and measure all of the peak responses. Calculate the
Buffer solution—Dissolve about 1.7 mL of dibutylamine, percentage of each impurity in the portion of Sumatriptan
about 0.6 mL of phosphoric acid, and about 3.9 g of Succinate taken by the formula:
monobasic sodium phosphate dihydrate in water. Adjust
with a solution of 50% (w/v) sodium hydroxide to a pH of 100(ri / rs)
about 7.5, dilute with water to 1000 mL, and mix.

in which ri is the peak response for each impurity, and rs is the
sum of the responses of all the peaks: meets the requirements
Buffer solution and acetonitrile (4 : 1). Make adjustments if
given in Table 1.
h621i). Assay—
Identification solution—Prepare a solution of USP Suma- Diluent—Dissolve 2.97 g of monobasic sodium phosphate
triptan Succinate Related Impurities RS in Mobile phase in 600 mL of water, adjust with a sodium hydroxide solution
having a concentration of about 3 mg per mL. (1 in 2) to a pH of 6.5, dilute with water to 750 mL, add 250
Test solution—Dissolve an accurately weighed quantity of mL of acetonitrile, and mix.
Sumatriptan Succinate in Diluent to obtain a solution having Mobile phase—Dissolve 1.7 mL of dibutylamine, 0.6 mL
a concentration of about 2.8 mg per mL. of phosphoric acid, and 3.9 g of sodium dihydrogen
Chromatographic system (see Chromatography h621i)— phosphate dihydrate in 750 mL of water, adjust with
Prepare as directed in the Assay. After making sure that the a sodium hydroxide solution (1 in 2) to a pH of 6.5, and
resolution criteria are met, chromatograph. Chromatograph dilute with water to 1000 mL. Mix 800 mL of this solution
the Identification solution, and record the peak responses as with 200 mL of acetonitrile, then filter and degas. Make
directed for Procedure. Identify the peaks according to Table adjustments if necessary (see System Suitability under
1. Chromatography h621i).
Table 1
In-Process Revision
Approx. Relative
Compound Name Retention Time Limit (%)
[3-[2-(Dimethylamino N-oxide)ethyl]-1H-indol-5-yl]-N-methylmethanesulfonamide 0.3 0.2
[3-[2-(Aminoethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide 0.4 0.1
[3-[2-(Methylamino)ethyl]-1H-indol-5-yl]-N-methylmethanesulfonamide 0.6 0.5
Sumatriptan succinate related compound C 0.9 0.5
Sumatriptan 1.0 —
Any individual unspecified impurity — 0.1
Total — 1.5
[NOTE—The calculation of total impurities includes the amount of sumatriptan related compound A, determined in the test for Limit of
sumatriptan related compound A.]
Pharmacopeial Forum
Resolution solution—Dissolve accurately weighed quan-

BRIEFING
tities of USP Sumatriptan Succinate RS and USP Sumatriptan
Succinate Related Compound C RS in Diluent to obtain Terbinafine Hydrochloride. Because there is no existing USP
monograph for this drug substance, this new monograph, based
solutions having known concentrations of about 0.28 mg per mainly on the Terbinafine Hydrochloride monograph in the
European Pharmacopoeia, is being proposed. The new improved
mL and 0.14 mg per mL, respectively. liquid chromatographic procedure in the test for Related compounds
is capable of separating additional potential impurities, and is
Standard preparation—Dissolve an accurately weighed supported by validation data. This procedure is based on analyses
performed with the Inertsil ODS-2 brand of L1 column. The typical
quantity of USP Sumatriptan Succinate RS in Diluent to retention time for terbinafine is about 16 minutes.
(MD-AA: E. Gonikberg; B. Davani) RTS— C49317
mg per mL.
tity of Sumatriptan Succinate in Diluent to obtain a solution
having a concentration of about 0.14 mg per mL.
Add the following:
Chromatographic system (see Chromatography h621i)— &Terbinafine Hydrochloride
L1. The flow rate is about 1.5 mL per minute. Chromatograph
the Resolution solution, and record the peak responses as
directed for Procedure: the relative retention times are about
0.9 for sumatriptan succinate related compound C and 1.0 for
C21H25N HCl 327.90
sumatriptan, and the resolution, R, between sumatriptan
succinate related compound C and sumatriptan is not less than 1-Naphthalenemethanamine, N-(6,6-dimethyl-2-hepten-4-
1.5. Chromatograph the Standard preparation, and record the ynyl)-N-methyl-, (E)-, hydrochloride.

(E)-N-(6,6-Dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphtha-
lenemethylamine, hydrochloride.
1.5%.
Procedure—Separately inject equal volumes (about 10 mL) (2E)-N,6,6-Trimethyl-N-(naphthalen-1-ylmethyl)hept-2-en-4-
of the Standard preparation and the Assay preparation into yn-1-amine hydrochloride [78628-80-5].
In-Process Revision
the areas for the major peaks. Calculate the quantity of
» Terbinafine Hydrochloride contains not less than
C14H21N3O2S C4H6O4, in percentage, in the portion of
Sumatriptan Succinate taken by the formula:
C21H25N HCl, calculated on the dried basis.
100(Cs / Cu)(rU / rS) Packaging and storage—Preserve in well-closed containers,

protected from light. Store at room temperature.
in which Cs and Cu are the concentrations, in mg per mL, of
USP Reference standards h11i—USP Terbinafine Hydro-
sumatriptan succinate in the Standard preparation and the
chloride RS.
Assay preparation, respectively; and rU and rS are the peak
responses obtained from the Assay preparation and the
Pharmacopeial Forum
Identification— Chromatographic system (see Chromatography h621i)—
A: Infrared Absorption h197Ki. The liquid chromatograph is equipped with a 280-nm detector
B: It meets the requirements of the test for Chloride and a 3.0-mm 6 15-cm column that contains 5-mm packing
h191i when using dehydrated alcohol as a solvent. L1. The flow rate is about 0.8 mL per minute. The column
temperature is maintained at 408. The chromatograph is
Loss on drying h731i—Dry it at 1058 to constant weight: it
programmed as follows.
loses not more than 0.5% of its weight.
Residue on ignition h281i: not more than 0.1%. Time Solution A Solution B
Related compounds—[NOTE—Protect all solutions contain-
ing Terbinafine Hydrochloride from light.] 0–4 100 0 isocratic
Methanol–acetonitrile mixture—Prepare a mixture of 4–25 100?0 0?100 linear gradient
methanol and acetonitrile (60 : 40). 25–30 0 100 isocratic
Buffer pH 7.5—Prepare a solution in water containing 2.0 30–30.1 0?100 100?0 linear gradient
mL of triethylamine per L. Adjust with diluted acetic acid to 30.1–38 100 0 re-equilibration
a pH of 7.5. Chromatograph the System suitability solution, and record the

Solution A—Prepare a mixture of Methanol–acetonitrile peak responses as directed for Procedure: the resolution, R,
mixture and Buffer pH 7.5 (70 : 30). between cis-terbinafine and terbinafine is not less than 2.0.
Solution B—Prepare a mixture of Methanol–acetonitrile Chromatograph the Standard solution, and record the peak
mixture and Buffer pH 7.5 (95 : 5). response as directed for Procedure: the relative standard
Mobile phase—Use variable mixtures of Solution A and deviation for replicate injections is not more than 10%.
Solution B as directed for Chromatographic system. Make Chromatograph the Sensitivity solution, and calculate the
adjustments if necessary (see System Suitability under signal-to-noise ratio, S/N, by the formula:
Diluent—Prepare a mixture of acetonitrile and water (2H)/h
(50 : 50).
Test solution—Dissolve an accurately weighed quantity of in which H is the measured height of the terbinafine peak, and
Terbinafine Hydrochloride in Diluent to obtain a solution h is the amplitude of the average measured baseline noise.
having a known concentration of about 0.5 mg per mL. The S/N ratio is not less than 10.
In-Process Revision
Standard solution—Dissolve an accurately weighed quan- Procedure—Separately inject equal volumes (about 20 mL)
tity of USP Terbinafine Hydrochloride RS in Diluent to obtain of the Standard solution and the Test solution into the
a solution having a known concentration of about 0.5 mg per chromatograph, record the chromatograms, identify the peaks
mL. based on their relative retetion times as given in Table 1, and
System suitability solution—Prepare a solution in Diluent measure the peak responses. Calculate the percentage of each
containing about 1 mg of terbinafine hydrochloride per mL, impurity in the portion of Terbinafine Hydrochloride taken by
and expose it to UV light at 254 nm for 1 hour. the formula:
Sensitivity solution—Dilute a portion of the Standard

100(1/F)(0.0016CS / CT)(rU / rS)
solution with Diluent to obtain a solution having a concen-
tration of about 0.25 mg of terbinafine hydrochloride per mL.
Pharmacopeial Forum
Table 1
Relative Response Limit

Name Relative Retention Time Factor (F) %
N-Methyl-C-(naphthalen-1-yl)methanamine 0.1 1.7 0.1
1
trans-Isoterbinafine 0.92 1.0 0.1
cis-Terbinafine2 0.94 1.0 0.1
Terbinafine 1.0 n/a n/a
4-Methylterbinafine3 1.1 1.0 0.1
Any other individual impurity n/a 1.0 0.1
Total impurities n/a n/a 0.3
1
(2E)-N,6,6-Trimethyl-N-(naphthalen-2-ylmethyl)hept-2-en-4-yn-1-amine.
2
(2Z)-N,6,6-Trimethyl-N-(naphthalen-1-ylmethyl)hept-2-en-4-yn-1-amine.
3
(2E)-N,6,6-Trimethyl-N-[(4-methylnaphthalen-1-yl)methyl]hept-2-en-4-yn-1-amine.
in which F is the relative response factor as listed in Table 1;

BRIEFING
0.001 is the conversion factor from mg per mL to mg per mL;
CS is the concentration, in mg per mL, of terbinafine Topiramate, page 1307 of PF 30(4) [Jul.–Aug. 2004]. The
following revisions are proposed:
hydrochloride in the Standard solution; CT is the concentra- 1. Using a flexible monograph approach, to add a Test 2 for
Related compounds by HPLC to capture the potential impurities
tion, in mg per mL, of terbinafine hydrochloride in the Test from a different synthetic route. This test is based on an
analytical method validated with the Spherisorb C6 brand of
solution; rU is the peak response for each impurity obtained L15 column. The typical retention time for topiramate is about
6 minutes. In addition, it is proposed to modify Test 1 in
from the Test solution; and rS is the peak response for the Related compounds by HPLC for increased clarity.
2. On the basis of comments received, to add the Related
terbinafine peak obtained from the Standard solution. compounds by TLC method to measure the limit of an impurity
that cannot be measured by either of the two HPLC tests. The
Disregard any peak observed in the blank, and any peak TLC method has been validated using the Whatman KC2 brand
of silica gel plates. The typical RF values for topiramate and
less than 0.05%. topiramate related compound A are about 0.65 and 0.70,
respectively.
Assay—Dissolve about 250 mg of Terbinafine Hydrochloride 3. To add a labeling statement to include the flexible monograph
approach and the caution statement.
in 50 mL of alcohol, and add 5 mL of 0.01 N hydrochloric 4. To revise the range for the limits in the test for Specific rotation
to reflect the currently marketed products.
acid VS. Titrate with 0.1 N sodium hydroxide VS determining 5. To add a test for Heavy metals.
6. To add USP Fructose RS to USP Reference standards h 11i
the endpoint potentiometrically. Read the volume added because it is used in Test 1 for Related compounds by HPLC to
In-Process Revision
quantitatively test for fructose.
between the two points of inflexion: 1 mL of 0.1 N 7. To modify for clarity several sections in the test for Limit of
sulfate/sulfamate.
sodium hydroxide is equivalent to 32.79 mg of 8. To modify the calculation formula in the Assay.
C21H25N HCl.&1S (USP31) (MD-PP: R. Ravichandran) RTS—C45565
Pharmacopeial Forum
Identification—
Add the following: A: Infrared Absorption h197Ki.
&Topiramate B: The retention time of the major peak in the
in the Assay.
Change to read:
C12H21NO8S 339.36 Specific rotation h781Si: between 298 and –358&–28.68

and –35.08,&1S (USP31) measured at 208.
b-D-Fructopyranose, 2,3 : 4,5-bis-O-(1-methylethylidene)-,
sulfamate.
Water, Method I h921i: not more than 0.5%.
2,3 : 4,5-Di-O-isopropylidene-b- D -fructopyranose sulfa- Residue on ignition h281i: not more than 0.2%.
mate [97240-79-4].
Add the following:
Change to read:
&
Heavy metals, Method II h231i: 0.001%.&1S (USP31)
Add the following:

» Topiramate contains not less than 98.0 percent
&
and not more than 102.0 percent of C12H21NO8S, Related compounds by TLC—
Adsorbent: 0.20-mm layer of chromatographic silica gel
calculated on the anhydrous basis.
mixture, prewashed with methanol and air-dried.
&
Caution—Great care must be exercised in
Test solution—Dissolve an accurately weighed quantity of
handling Topiramate because it is a suspected Topiramate in methanol to obtain a solution containing
teratogen.&1S (USP31) approximately 40 mg per mL.
Identification solution—Dissolve a weighed quantity of
USP Topiramate Related Compound A RS in methanol to
containers, and store at controlled room temperature.
obtain a solution containing about 0.2 mg per ml.
Add the following: Standard solution A—Dissolve an accurately weighed
In-Process Revision
&
Labeling—If a test for Related compounds by HPLC other quantity of USP Topiramate RS in methanol to obtain
than Test 1 is used, then the labeling states the test with which a final solution having a known concentration of about 40 mg
the article complies. The label also states that it is a suspected per mL of topiramate.
teratogen.&1S (USP31) Standard solution B—Quantitatively dilute Standard
Solution A with methanol to obtain a solution containing
Change to read:
0.08 mg per mL of topiramate.
USP Reference standards h11i— & USP Fructose Standard solution C—Quantitatively dilute Standard solu-
RS.&1S (USP31) USP Topiramate RS. USP Topiramate Related tion A with methanol to obtain a solution containing 0.04 mg
Compound A RS. per mL of topiramate.
Pharmacopeial Forum
Spray reagent—Prepare a 30 mg per mL solution of phenol Test solution—Transfer about 1 g of Topiramate, accurately
in a mixture of alcohol and concentrated sulphuric acid weighed, to a 25-mL volumetric flask, and dissolve in Mobile
(95 : 5, v/v). phase with the aid of sonication. Cool to room temperature,
Application volume: 20 mL. dilute with Mobile phase to volume, and mix.
Developing solvent system—Prepare a mixture of 0.5 M Chromatographic system (see Chromatography h621i)—
sodium chloride, acetonitrile, and methanol (50 : 35 : 15). The liquid chromatograph is equipped with a refractive index
Procedure—Proceed as directed for Thin-Layer Chroma- detector and a 4.6-mm 6 25-cm column that contains
tography under Chromatography h621i. After elution, air-dry packing L1. The column and the detector temperatures are
the plate, spray the plate with the Spray reagent, and let the maintained at 558. The flow rate is about 0.6 mL per minute.
plate air-dry. Then dry the plate for 10 minutes in an oven at Chromatograph the System suitability solution, and record the
1258. Examine the plate using visible light, and estimate the peak responses areas as directed for Procedure: the relative
percentage of all secondary spots observed in the chromat- retention times are about 0.45 for fructose, 0.9 for topiramate
ogram of the Test solution by comparing each spot with the related compound A, and 1.0 for topiramate; the resolution, R,
principal spot obtained from the chromatograms of the between topiramate related compound A and topiramate is
Standard solutions. [NOTE—Appoximate RF values for not less than 1.0; and the relative standard deviation for
topiramate and topiramate related compound A are 0.65 and replicate injections is not more than 2.0% for the topiramate
0.70, respectively. Disregard any spots observed at the origins peak.
of the chromatograms. Disregard any spot corresponding to Procedure—Separately inject equal volumes (about 50 mL)
topiramate related compound A because this impurity should of the Test solution and Mobile phase into the chromatograph,
be quantified using Related Compounds by HPLC Test 1 or record the chromatograms, and measure all of the peak
Test 2]: any single spot is not greater in size and intensity than responses areas. Record the chromatogram for a period of
the spot for Standard solution C; not more than 0.1% of any time equivalent to not less than five times the retention time
individual impurity is found; and not more than 0.5% of total of the topiramate peak. Calculate the percentage of each of
impurities by TLC is found.&1S (USP31) the impurities in the portion of Topiramate taken by the
formula:
Add the following:
&
Related compounds by HPLC—[NOTE—On the basis of
100(1/F)(rU / rs)
the synthetic route, perform either Test 1 or Test 2. Test 2 is
In-Process Revision
recommended if N-methyl topiramate is a potential related in which F is the relative response factor and is equal to 1.2
compound.] for topiramate related compound A and 1.0 for all the other
TEST 1— peaks; rU is the area of any peak at a relative retention time of
Mobile phase—Proceed as directed in the Assay. about 0.45 impurity peak; and rs is the sum of the responses
NOTE—Prepare all solutions fresh before use. areas of all of the impurity peaks and the topiramate peak. of
System suitability solution—Transfer about 3 mg each of all the peaks. Calculate the percentage of each impurity in the
USP Fructose RS and USP Topiramate Related Compound A portion of Topiramate taken by the formula:
RS, accurately weighed, to a 10-mL volumetric flask.
Dissolve in and dilute with Test solution to volume, and mix. 100(ri / rs)
Pharmacopeial Forum
in which ri is the peak response area for each impurity; and rs in which F is relative response factor, which has a value of
is the sum of the responses of all the peaks: Not more than 1.1 for topiramate related compound A and 1.0 for all other
0.3% of fructose is found; not more than 0.3% of topiramate impurities; CS and CU are the concentrations of topiramate in
related compound A is found; not more than 0.1% of any the Standard solution and the Test solution, respectively; ri is
other individual impurity is found; and not more than 0.5% of the peak response for each impurity in the Test solution; and
total impurities detected by Test 1 is found. rS is the peak response of topiramate in the Standard solution:
TEST 2— not more than 0.3% of topiramate related compound A is
Mobile phase—Prepare a mixture of water and methanol found; not more than 0.10% of any other individual impurity
(68 : 32). Make adjustments if necessary (see System is found; and not more than 0.5% total impurities detected by
Suitability under Chromatography h621i). Test 2 is found.&1S (USP31)
Change to read:
tity of USP Topiramate RS and USP Topiramate Related
Compound A RS in Mobile phase, and dilute quantitatively, Limit of sulfamate and sulfate—&[NOTE—Use Purified
and stepwise if necessary, to obtain a solution having a known Water (resistivity not less than 18 megohm-cm) for Mobile
concentration of about 10 mg of topiramate and 0.04 mg of phase and all solution preparations]&1S (USP31)
topiramate related compound A per mL. Diluent—Prepare a mixture of high-purity & Puri-
Test Solution—Dissolve an accurately weighed quantity of fied&1S (USP31) Water and acetonitrile (80 : 20).
Topiramate in Mobile phase, and dilute quantitatively, and Solution A—Transfer about 4 g of sodium hydroxide to
stepwise if necessary, to obtain a solution having a known a 1000-mL volumetric flask. Dissolve in and dilute with
concentration of about 10 mg per mL. High-Purity Water (see Reagents in Chemical Resistance—
Chromatographic system (see Chromatography h621i)— Glass Containers under Containers h661i) to volume, filter,
The liquid chromatograph is equipped with a refractive index and degas.
detector and a 4.6-mm 6 15-cm column that contains 5-mm Solution B—Use filtered and degassed High-Purity Water.
packing L15. The column temperature is maintained at 358. Solution C—Dilute 50 mL of Solution A to 100-mL with
The flow rate is about 1.5 mL per minute. Chromatograph the High-Purity Water, filter, and degas.
Standard solution, and record the peak responses as directed &
Solution A—Transfer about 4 g of sodium hydroxide to
for Procedure: the resolution, R, between topiramate and a 1000-mL volumetric flask. Dissolve in and dilute with water
In-Process Revision
topiramate related compound A is not less than 1.0; and the (see Reagents in Chemical Resistance—Glass Containers
relative standard deviation for six replicate injections is not under Containers h661i) to volume, filter, and degas.
more than 2.0 % for topiramate. Solution B—Use filtered and degassed water.
Procedure—Separately inject equal volumes (about 50 mL) Solution C—Dilute 50 mL of Solution A with water to 100
of the Standard solution and the Test solution into the mL, filter, and degas.&1S (USP31)
chromatograph, and measure the responses for all of the Mobile phase—Use variable mixtures of Solution A,
peaks. Calculate the percentage of each impurity in the Solution B, and Solution C as directed for Chromatographic
portion of Topiramate taken by the formula: system. Make adjustments if necessary (see System Suitability
100(1/F)(CS / CU)(ri / rS)
Pharmacopeial Forum
Sulfamic acid stock solution—Transfer about 60 mg, peak areas for the sulfate and sulfamate peaks. Calculate the
accurately weighed, of sulfamic acid to a 100-mL volumetric percentage of sulfate and sulfamate in the portion of
flask. Dissolve in and dilute with Diluent to volume. Topiramate taken by the formula:
Sulfate stock solution—Transfer about 90.7 mg, accurately
weighed, of potassium sulfate to a 100-mL volumetric flask. 1000F(C/W)(ri / rS)
Dissolve in and dilute with Diluent to volume.
Standard solution—Transfer 3.0 mL each of Sulfamic acid in which C is the concentration, in mg per mL, of potassium
stock solution and Sulfate stock solution to a 50-mL sulfate or sulfamic acid in the Standard solution; F is the
volumetric flask, dilute with Diluent to volume, and mix. correction factor and is equal to 0.551 for sulfate and 0.989
Test solution—Transfer about 100 mg, accurately weighed, for sulfamate; W is the weight, in mg, of Topiramate taken;
of Topiramate to a 10-mL volumetric flask. Dissolve in and and ri and rS are the peak areas of the sulfate or sulfamate ion
dilute with High-Purity Water&water&1S (USP31) to volume. obtained from the Test solution and the Standard solution,
Chromatographic system (see Chromatography h621i)— respectively: not more that 0.10% of sulfate ion is found; and
The liquid chromatograph is equipped with a conductivity not more than 0.10% of sulfamate ion is found.
detector, a 4.0-mm 6 5-cm guard column that contains

&
packing L46 and a 4.0-mm 6 25-cm column that contains mL) of the Standard solution and the Test solution into the
packing L46. The flow rate is about 2.0 mL per minute. The chromatograph, record the chromatograms, and measure the
chromatograph is programmed as follows. peak areas for the sulfate and sulfamate peaks. Calculate the
percentage of sulfate in the portion of Topiramate taken by
Solution Solution Solution
the formula:
Time A B C
(minutes) (%) (%) (%) Elution 1000(96.06/174.25)(C/W)(ri / rS)
0 0 95 5 equilibration
0–7.0 0 95 5 isocratic in which 96.06 and 174.25 are the molecular weights of the
7.0–15.0 0?20 95?0 5?80 linear gradient sulfate ion and potassium sulfate, respectively; C is the
15.0–20.0 20 0 80 isocratic concentration, in mg per mL, of potassium sulfate in the
20.0–20.1 20?0 0?95 80?5 linear gradient Standard solution; W is the weight, in mg, of Topiramate
re-equilibra- taken; and ri and rS are the peak areas of the sulfate ion
In-Process Revision
20.1–25.0 0 95 5 tion obtained from the Test solution and the Standard solution,
respectively: not more that 0.10% of sulfate ion is found.
Calculate the percentage of sulfamate in the portion of
areas as directed for Procedure: the relative retention time is
Topiramate taken by the formula:
1.0 for the sulfate peak and about 0.27 for the sulfamate peak;
and the relative standard deviation for replicate injections is
1000(96.08/97.09)(C/W)(ri / rS)
not more than 2.0% for both the sulfate and sulfamate peaks.
sulfamate ion and sulfamic acid respectively; C is the
concentration, in mg per mL, of sulfamic acid in the Standard
solution; W is the weight, in mg, of Topiramate taken; and ri
Pharmacopeial Forum
and rS are the peak areas of the sulfamate ion obtained from The injection port temperature is maintained at 1508; the
the Test solution and the Standard solution, respectively: not headspace sampler temperature is maintained at 808; and the
more than 0.10% of sulfamate ion is found.&1S (USP31) detector temperature is maintained at 2508. Nitrogen is used
as the carrier gas at a flow rate of about 5 mL per minute and
Delete the following: a split flow rate of about 15 mL per minute. Chromatograph
&
Limit of residual solvents— the Standard solution, and record the peak responses as
Standard stock solution—Dilute accurately measured directed for Procedure: the retention time for pyridine is
volumes of acetone, isopropyl alcohol, acetonitrile, methy- about 21 minutes; the relative retention times are about 0.4 for
lene chloride, n-hexane, ethyl acetate, and pyridine in acetone, about 0.46 for isopropyl alcohol, about 0.49 for
dimethylformamide to obtain a solution having known acetonitrile, about 0.51 for methylene chloride, about 0.58 for
concentrations, in mL per mL, of about 3.0, 3.2, 0.24, 0.20, n-hexane, about 0.71 for ethyl acetate, and 1.0 for pyridine;
0.22, 2.8, and 0.01, respectively. the resolution, R, between adjacent peaks is not less than 1.0;
Standard solution—Transfer 10.0 mL of Standard stock and the relative standard deviation for consecutive injections
solution to a 100-mL volumetric flask, dilute with dimeth- of the Standard solution for all analytes is not less than
ylformamide to volume, and mix. Transfer 5 mL to a 20-mL 15.0%. Chromatograph the Blank solution, and record the
headspace vial, and crimp immediately. peak responses as directed for Procedure: there are no
Blank solution—Use dimethylformamide. interfering peaks due to dimethylformamide.
Test solution—Transfer about 0.25 g of Topiramate to a 20- Procedure—Inject a volume (about 1 mL of the headspace,
mL headspace vial. Add 5.0 mL of dimethylformamide, and using a heated gas-tight syringe) of the Standard solution and
crimp immediately. the Test solution into the chromatograph, record the
Chromatographic system (see Chromatography h621i)— chromatogram, and measure the areas for the major peaks.
The gas chromatograph is equipped with a headspace injector, Calculate the percentage of each solvent per g of Topiramate
a flame-ionization detector, and a 0.53-mm 6 75-m capillary taken by the formula:
column, the internal wall of which is coated with a 0.3-mm
film of liquid phase G43. The column temperature is 500(CDU /W)(rU / rS)
programmed according to Table 1.
in which C is the concentration, in mL per mL, of each
solvent in the Standard solution; DU is the density, in mg per
In-Process Revision
Table 1. Column Temperature Program

mL, of each solvent; W is the weight, in mg, of Topiramate
Temperature taken to prepare the Test solution; and rU and rS are the peak
Initial Final Increase areas of the corresponding analyte obtained from the Test
Time Temperature Temperature (8 per solution and the Standard solution, respectively. Not more
(minutes) (8) (8) minute) than 0.50%, 0.50%, 0.04%, 0.05%, 0.029%, 0.05%, and
0–12 50 50 isothermal 0.02%, (w/w) of acetone, isopropyl alcohol, acetonitrile,
12–22 50 150 10 methylene chloride, n-hexane, ethyl acetate, and pyridine,
22–27 150 150 isothermal respectively, is found.&1S (USP31)
27–28.3 150 230 60

28.3–33.3 230 230 isothermal
Pharmacopeial Forum

Change to read:
Topiramate RS in the Standard preparation;&in which CS is
Assay— the concentration, in mg per mL, of USP Topiramate RS in
Mobile phase—Prepare a filtered and degassed mixture of the Standard preparation; CU is the concentration, in mg per
acetonitrile and water (1 : 1). Make adjustments if necessary mL, of Topiramate in the Assay preparation;&1S (USP31) and rU
(see System Suitability under Chromatography h621i). and rS are the peak responses areas for topiramate obtained
Standard preparation—Dissolve an accurately weighed from the Assay preparation and the Standard preparation,
quantity of USP Topiramate RS in Mobile phase, and dilute respectively.&1S (USP30)
quantitatively, and stepwise if necessary, with Mobile phase

BRIEFING
2.0 mg per mL.
Assay preparation—Transfer about 50 mg of Topiramate,
Valsartan, USP 30 page 3445. On the basis of comments
accurately weighed, to a 25-mL volumetric flask, and dissolve received, it is proposed to revise the preparation of the Standard
solution in Test 2 under Related compounds and to use the same
in and dilute with Mobile phase to volume. preparation for evaluating the system suitability requirements.
Chromatographic system (see Chromatography h621i)— (MD-CV: S. Ramakrishna) RTS—C52524

Change to read:
detector and a 4.6-mm 6 25-cm column that contains 5-mm
packing L1. The flow rate is about 0.6 mL per minute. The Related compounds—
TEST 1 (LIMIT OF VALSARTAN RELATED COMPOUND A)—
detector and column temperatures are maintained at 508. Mobile phase—Prepare a mixture of n-hexane, 2-propanol, and
trifluoroacetic acid (85 : 15 : 0.1). Make adjustments if necessary (see
Chromatograph the Standard preparation, and record the System Suitability under Chromatography h621i).
peak responses as directed for Procedure: the column USP Valsartan Related Compound A RS in Mobile phase, and dilute
quantitatively, and stepwise if necessary, to obtain a solution having
efficiency is not less than 1500 theoretical plates; the tailing a known concentration of about 0.01 mg per mL.
System suitability solution—Dissolve accurately weighed quan-
factor is not more than 2.0; and the relative standard deviation tities of USP Valsartan RS and USP Valsartan Related Compound A
RS in Mobile phase to obtain a solution having known concentra-
for replicate injections is not more than 2.0%. tions of about 0.04 mg per mL each of valsartan and valsartan related
compound A.
Procedure—Separately inject equal volumes (about 20 mL) Test solution—Transfer about 50 mg of Valsartan, accurately
weighed, to a 50-mL volumetric flask, add about 40 mL of Mobile
of the Standard preparation and the Assay preparation into phase, and sonicate for 5 minutes. Dilute with Mobile phase to
volume, and mix.
the chromatograph, record the chromatograms, and measure Chromatographic system (see Chromatography h621i)—The
the responses for the major peaks. Calculate the quantity, in a 4.6-mm 6 25-cm column that contains 5-mm packing L40. The
In-Process Revision
flow rate is about 0.8 mL per minute. Chromatograph the System
mg&percentage,&1S (USP31) of C12H21NO8S in the portion of suitability solution, and record the peak responses as directed for
Procedure: the resolution, R, between valsartan related compound A
Topiramate taken by the formula: and valsartan is not less than 2.0; and the relative standard deviation,
determined from the valsartan related compound A peak, for
replicate injections is not more than 5%.
25C(rU / rS) Standard solution and the Test solution into the chromatograph,
peaks. Calculate the percentage of valsartan related compound A in
the portion of Valsartan taken by the formula:
100(CS / CU)(rU / rS)
in which CS is the concentration, in mg per mL, of USP Valsartan
&
100(CS / CU)(rU / rS)&1S (USP31) Related Compound A RS in the Standard solution; CU is the
concentration, in mg per mL, of valsartan in the Test solution; and rU
and rS are the peak responses for valsartan related compound A
obtained from the Test solution and Standard solution, respectively:
not more than 1.0% is found.
Pharmacopeial Forum
TEST 2 (LIMIT OF VALSARTAN RELATED COMPOUND B, VALSARTAN Calculate the percentage of each other impurity in the portion of
RELATED COMPOUND C, AND OTHER RELATED COMPOUNDS)— Valsartan taken by the
Mobile phase—Proceed as directed in the Assay.
Resolution solution— &
same&1S (USP31)
formula,
&
Standard solution—&1S (USP31)
Dissolve accurately weighed quantities of USP Valsartan RS, USP 100(CS / CU)(ri / rS)
Valsartan Related Compound B RS, and USP Valsartan Related &
Compound C RS in Mobile phase, and dilute quantitatively, and &1S (USP31)
stepwise if necessary, with Mobile phase to obtain a solution having in which CS is the concentration, in mg per mL, of USP Valsartan RS
known concentrations of about 0.001 mg of valsartan per mL, 0.001 in the Standard solution; rS is the peak response for valsartan
mg of valsartan related compound B per mL, and 0.001 mg of obtained from the Standard solution; and the other terms are as
valsartan related compound C per mL. defined above: not more than 0.2% of valsartan related compound B
Standard solution—Dissolve an accurately weighed quantity of is found; not more than 0.1% of valsartan related compound C is
USP Valsartan RS in Mobile phase, and dilute quantitatively, and found; not more than 0.1% of any other individual impurity,
stepwise if necessary, to obtain a solution having a known excluding valsartan related compound A, is found; and not more
concentration of about 0.001 mg of valsartan per mL. than 0.3% of total impurities, excluding valsartan related compound
&
A, is found.
&1S (USP31)
Test solution—Transfer about 50 mg of Valsartan, accurately
weighed, to a 100-mL volumetric flask, dissolve in and dilute with
Mobile phase to volume, and mix.
Chromatographic system (see Chromatography h621i)—Prepare
as directed in the Assay, except to use a 225-nm detector. BRIEFING
Chromatograph the Resolution solution,
&
Standard solution,&1S (USP31) Warfarin Sodium, USP 30 page 3469. On the basis of comments
and record the peak responses as directed for Procedure: the received, it is proposed to make the following changes:
resolution, R, between valsartan related compound B and valsartan is
not less than 1.8; the relative standard deviation, determined from the 1. The chemical structure of Warfarin Sodium is added.
valsartan related compound B peaks, for replicate injections is not 2. The Identification test based on the melting range of warfarin is
more than 10.0%; and the relative standard deviation, determined deleted, and the cross-reference to this test is also deleted. An
from the valsartan peaks, for replicate injections is not more than Identification test based on the retention time agreement is
2.0%. added.
Procedure—Separately inject equal volumes (about 10 mL) of the 3. The internal standard is removed from the Assay on the basis of
Resolution solution, the recent submission of validation report. The system
&
suitability requirement under Chromatographic system in the
&1S (USP31) Assay is revised accordingly.
the Standard solution and the Test solution into the chromatograph,
peaks. Calculate the percentage of valsartan related compound B and (MD-OOD: F. Mao) RTS—C47674
valsartan related compound C in the portion of Valsartan taken by
the formula:
100(CS / CU)(ri / rS)
in which CS is the concentration, in mg per mL, of the appropriate Change to read:
USP Valsartan Related Compound RS in the Resolution solution
&
Standard solution;&1S (USP31)
CU is the concentration, in mg per mL, of valsartan in the Test
solution; ri is the peak response for the impurity obtained from the
Test solution; and rS is the peak response for the appropriate
valsartan related compound obtained from the Resolution solution
In-Process Revision
&
Standard solution.&1S (USP31)
C19H15NaO4 330.31
2H-1-Benzopyran-2-one, 4-hydroxy-3-(3-oxo-1-phenylbutyl)-,
sodium salt.
3-(a-Acetonylbenzyl)-4-hydroxycoumarin sodium salt
[129-06-6].
Change to read:
Identification—
A: Infrared Absorption h197Ki—The test specimen is the
residue of warfarin obtained in Identification test B.
&
Standard specimen—Use USP Warfarin RS.
Test specimen—Dissolve about 100 mg in 25 mL of water,
and adjust with hydrochloric acid to a pH of less than 3, using
short-range pH indicator paper. Stir the mixture and allow the
precipitate to coagulate. Filter the mixture, and retain the
Pharmacopeial Forum
filtrate for Identification test C. Wash the precipitate with four Procedure—Separately inject equal volumes (about 20 mL) of the
5-mL portions of water, and dry in vacuum over phosphorus ograph, record the chromatograms, and measure the responses for
the major peaks. Calculate the quantity, in mg, of C19H15NaO4 in the
pentoxide for 4 hours. Use the warfarin obtained to prepare portion of Warfarin Sodium taken by the formula:
the Test specimen.&1S (USP31) (330.32 / 308.34)C(RU / RS)
B: Dissolve about 100 mg in 25 mL of water, and adjust with

hydrochloric acid to a pH of less than 3, using short-range pH
indicator paper. Stir the mixture and allow the precipitate to &
(330.31 / 308.34)C(rU / rS)&1S (USP31)
coagulate. Filter the mixture, wash the precipitate with four 5-mL
portions of water, and dry in vacuum over phosphorus pentoxide for
4 hours: the warfarin so obtained melts between 1578 and 1678, but in which 330.31 and 308.34 are the molecular weights of warfarin
the range between beginning and end of melting does not exceed 48. sodium and warfarin, respectively; C is the concentration, in mg per
mL, of USP Warfarin RS in the Standard preparation; and RU and RS
&
The retention time of the major peak in the chromatogram of are the response ratios of warfarin
the Assay preparation corresponds to that in the Standard

&
and rU and rS are the peak responses of warfarin&1S (USP31)
preparation, as obtained in the Assay.&1S (USP31) respectively.
C: A solution of it responds to the tests for Sodium h191i. The
filtrate obtained in Identification test B
&
The filtrate obtained in Identification test A&1S (USP31)
responds to the flame test for Sodium h191i. BRIEFING
Change to read:
Warfarin Sodium for Injection, USP 30 page 3470. On the basis
Assay— of the recent submission of validation report, the internal standard is
pH 7.4 Buffer—Transfer 1.36 g of monobasic potassium phos- removed from the Assay.
phate to a 200-mL volumetric flask, and dissolve in 50 mL of water.
Add 39.1 mL of 0.2 N sodium hydroxide, and dilute with water to (MD-OOD: F. Mao) RTS—C47675
volume. Adjust with sodium hydroxide or phosphoric acid to a pH of
7.4 + 0.1.
Mobile phase—Prepare a degassed solution containing a mixture Change to read:
of methanol, water, and glacial acetic acid (64 : 36 : 1). Adjust the
ratio as necessary.
Internal standard solution—Dissolve propylparaben in a mixed Assay—
solvent consisting of acetonitrile and glacial acetic acid (988 : 12), to pH 7.4 Buffer, Mobile phase, and Chromatographic system—
obtain a solution having a concentration of about 0.2 mg per mL. Prepare as directed in the Assay under Warfarin Sodium.
Internal standard solution—Dissolve propylparaben in a solvent
&
&1S (USP31) consisting of a mixture of acetonitrile and glacial acetic acid
Standard preparation—Transfer about 94 mg of USP Warfarin (988 : 12) to obtain a solution having a concentration of about 1.0 mg
RS, accurately weighed, to a 250-mL volumetric flask, and dissolve per mL.
in 97.8 mL of 0.1 N sodium hydroxide. Add 62.5 mL of 0.2 M
&
monobasic potassium phosphate, dilute with water to volume, and &1S (USP31)
mix. Pipet 5 mL of this solution , 5 mL of pH 7.4 Buffer, and 10 mL Standard preparation—Transfer about 94 mg of USP Warfarin
of Internal standard solution RS, accurately weighed, to a 100-mL volumetric flask, and dissolve
in 39.1 mL of 0.1 N sodium hydroxide. Add 25.0 mL of 0.2 M
&
and 15 mL of pH 7.4 Buffer&1S (USP31) monobasic potassium phosphate, dilute with water to volume, and
into a conical flask, and mix. mix. Pipet 5 mL of this solution and 5 mL of Internal standard
Assay preparation—Using about 100 mg of Warfarin Sodium, solution
accurately weighed, prepare as directed under Standard preparation.
In-Process Revision
&
Chromatographic system (see Chromatography h621i)—The &1S (USP31)
liquid chromatograph is equipped with a 280-nm detector and into a 50-mL volumetric flask, dilute with pH 7.4 Buffer to volume,
a 4.6-mm 6 25-cm column that contains packing L7. The flow rate and mix.
is about 1.4 mL per minute. Chromatograph five replicate injections Assay preparation—Dissolve the contents of not fewer than 10
of the Standard preparation, and record the peak responses as containers of Warfarin Sodium for Injection in a sufficient volume,
directed for Procedure: the relative retention times of propylparaben accurately measured, of pH 7.4 Buffer to obtain a solution containing
and warfarin are about 0.75 and 1.0, respectively; the resolution of about 1 mg of warfarin sodium per mL. Pipet 5 mL of the resulting
the two peaks is not less than 2.0; and solution and 5 mL of Internal standard solution
& &
&1S (USP31) &1S (USP31)
the relative standard deviation of the warfarin responses is not more into a 50-mL volumetric flask, dilute with pH 7.4 Buffer to volume,
than 2.0%. and mix.
Procedure—Proceed as directed for Procedure in the Assay under
Warfarin Sodium. Calculate the average quantity, in mg, of warfarin
sodium (C19H15NaO4) in each container of Warfarin Sodium for
Injection taken by the formula:
10(330.32 / 308.34)(VC / N)(RU / RS)
Pharmacopeial Forum
Internal standard solution—Prepare a solution of propylparaben

in water containing, in each mL, an amount of propylparaben
&
10(330.31 / 308.34)(VC / N)(rU / rS)&1S (USP31) equivalent to 0.0025 times the labeled amount, in mg, of warfarin
sodium in each Tablet. [NOTE—A small amount of methanol may be
in which 330.31 and 308.34 are the molecular weights of warfarin used, if necessary, to dissolve the propylparaben.]
sodium and warfarin, respectively; V is the volume, in mL, of the &
&1S (USP31)
solution prepared from the contents of the 10 or more containers; C
is the concentration, in mg per mL, of USP Warfarin RS in the
Standard preparation; N is the number of containers taken; and RU Standard stock solution
and RS are the peak response ratios of warfarin to propylparaben &
Standard solution&1S (USP31)
&
and rU and rS are the peak responses of warfarin&1S —Dissolve an accurately weighed quantity of USP Warfarin RS in
(USP31)
obtained from the Assay preparation and the Standard preparation, water to obtain a solution having a known concentration of about
respectively. 0.0011L mg per mL,
&
0.0008L mg per mL,&1S (USP31)
L being the labeled amount, in mg, of warfarin sodium in the Tablets.
[NOTE—Use a small amount of 0.1 N sodium hydroxide to aid in
dissolution.]
BRIEFING Standard solution—To 3.0 mL of Standard stock solution, add 1.0
mL of Internal standard solution, and mix.
Test solution—To a filtered 3.0-mL aliquot of the solution under
Warfarin Sodium Tablets, USP 30 page 3471. On the basis of test, add 1.0 mL of Internal standard solution, and mix.
the recent submission of validation report, the internal standard is &
removed from the Dissolution and the Assay. The formula in the &1S (USP31)
Assay is also corrected by adding the volume of Assay preparation to Procedure—Separately inject equal volumes (about 40 mL) of the
calculate the quantity of warfarin sodium in mg. Standard solution and the Test solution
&
a filtered portion of the solution under test&1S (USP31)
(MD-OOD: F. Mao) RTS—C43224 into the chromatograph, record the chromatograms, and measure the
responses for the major peaks. Calculate the quantity, in mg, of
warfarin sodium dissolved by the formula:
Change to read:
(330.32 / 308.34)(900C)(RU / RS)
Identification—
A: The retention time of the major peak obtained from the Assay
preparation corresponds to that obtained from the Standard &
(330.31 / 308.34)(900C)(rU / rS)&1S (USP31)
preparation, both relative to the internal standard, obtained
&
&1S (USP31) in which 330.31 and 308.34 are the molecular weights of warfarin
as directed in the Assay. sodium and warfarin, respectively; C is the concentration, in mg per
B: Infrared Absorption h197Ki—Prepare the test specimen as mL, of USP Warfarin RS in the Standard stock solution; and RU and
follows. Triturate a quantity of finely powdered Tablets, equivalent RS are the ratios of the peak responses of warfarin to those of
to about 200 mg of warfarin sodium, with 50 mL of water, propylparabenvobtained from the Test solution
centrifuge, and filter the supernatant. Extract with 50 mL of ether,
transfer the aqueous layer to a second separator, and discard the &
Standard solution; and rU and rS are the peak responses of
ether. Adjust with hydrochloric acid to a pH of less than 3, using
short-range pH indicator paper, and extract with 50 mL of warfarin obtained from the solution under test&1S (USP31)
chloroform. Transfer the chloroform layer to another separator, and the Standard solution, respectively.
extract with 50 mL of sodium hydroxide solution (1 in 250), and Tolerances—Not less than 80% (Q) of the labeled amount of
discard the chloroform. Transfer the aqueous layer to a beaker, and C19H15NaO4 is dissolved in 30 minutes.
adjust with hydrochloric acid to a pH of less than 3 (using the pH
indicator paper) to precipitate the warfarin. Stir the mixture and
Change to read:
In-Process Revision
allow the precipitate to coagulate. Filter, and wash the precipitate

with four 5-mL portions of water. If the precipitate is not white or
practically white, dissolve it in a minimum volume of sodium Assay—
hydroxide solution (1 in 250), dilute with water to 50 mL, and repeat pH 7.4 Buffer and Chromatographic system—Proceed as directed
the foregoing procedure, beginning with ‘‘Extract with 50 mL of in the Assay under Warfarin Sodium.
ether.’’ Dry the warfarin so obtained in vacuum over phosphorus Solvent mixture—Prepare a mixture of pH 7.4 Buffer and
pentoxide for 4 hours. acetonitrile (85 : 15).
Change to read: methanol, water, and glacial acetic acid (68 : 32 : 1). Make adjust-
ments if necessary (see System Suitability under Chromatography
h621i).
Dissolution h711i— Internal standard solution—Prepare a solution of propylparaben
Medium: water; 900 mL. in acetonitrile having a concentration of 1 mg per mL.
Time: 30 minutes. &
&1S (USP31)
Mobile phase and Chromatographic system—Proceed as directed Standard preparation—Transfer about 62.5 mg of USP Warfarin
in the Assay. RS, accurately weighed, to a 200-mL volumetric flask, and dissolve
in 78 mL of 0.1 N sodium hydroxide. Add 50 mL of 0.2 M
monobasic potassium phosphate, dilute with water to volume, and
mix. Transfer 15.0 mL of this solution to a 50-mL volumetric flask, .
Add 5.0 mL of Internal standard solution,
Pharmacopeial Forum
&
&1S (USP31)
and dilute with Solvent mixture to volume. Add the following:
Tablets. Transfer an accurately weighed portion of the powder, &Fish
equivalent to about 5 mg of warfarin sodium, to a 50-mL volumetric Oil Containing Omega-3 Acids
flask, and add 5 mL of Internal standard solution and
&
&1S (USP31)
about 30 mL of Solvent mixture. Sonicate for 10 minutes, and then
shake by mechanical means for 60 minutes. Dilute with Solvent
mixture to volume, and filter. » Fish Oil Containing Omega-3 Acids is the
Standard preparation and the Assay preparation into the chromat- purified, winterized, and deodorized fatty oil
the major peaks. Calculate the quantity, in mg, of C19H15NaO4 in the
portion of Tablets taken by the formula: obtained from fish of the families Engraulidae,
(330.32 / 308.34)C(RU / RS) Carangidae, Clupeidae, Osmeridae, Scombroidae,
and Ammodytidae. The omega-3 acids are defined
as the following: alpha-linolenic acid (C18 : 3 n-3),
&
50(330.31 / 308.34)C(rU / rS)&1S (USP31) moroctic acid (C18 : 4 n-3), eicosatetraenoic acid
in which 330.31 and 308.34 are the molecular weights of warfarin (C20 : 4 n-3), eicosapentaenoic acid (EPA) (C20 : 5
sodium and warfarin, respectively; C is the concentration, in mg per
mL, of USP Warfarin RS in the Standard preparation; and RU and RS n-3), heneicosapentaenoic acid (C21 : 5 n-3), doc-
are the ratios of the peak responses of warfarin to those of
propylparaben osapentaenoic acid (C22 : 5 n-3), and docosahex-
&
and rU and rS are the peak responses of warfarin&1S (USP31) aenoic acid (DHA) (C22 : 6 n-3). It contains not
respectively.
less than 28.0 percent (w/w) of total omega-3 acids,
expressed as free acids, consisting of not less than
13.0 percent of EPA and not less than 9.0 percent of
MONOGRAPHS DHA. Suitable antioxidants in appropriate concen-
trations may be added.

BRIEFING
containers, and store at controlled room temperature. It may
Fish Oil Containing Omega-3 Acids; Fish Oil Containing be bottled or otherwise packaged in containers from which air
Omega-3 Acids Capsules. The previous proposals that appeared on
pages 474–481 of PF 31(2) [Mar.–Apr. 2005] have been cancelled. has been expelled by production of a vacuum or by an inert
New monographs are being proposed. The chromatographic
gas.
In-Process Revision
procedure in the Content of EPA and DHA and Content of total
omega-3 acids was validated using a CP-Wax 52 CB brand of
capillary G16 column. Typical retention times are 21.6 minutes for Labeling—The label states the average content of DHA and
eicosapentaenoic (EPA) methyl ester and 27.2 minutes for
docosahexaenoic acid (DHA) methyl ester. Oxidation indices and EPA in mg per g. It also states the name and concentration of
limits for heavy metals are based on the Council for Responsible
Nutrition’s voluntary monograph for omega-3 acids and the pesticide any added antioxidant.
limits are harmonized with recent European regulations.
USP Reference standards h11i—USP Docosahexaenoic
Ethyl Ester RS. USP Eicosapentaenoic Ethyl Ester RS. USP
Fish Oil RS. USP Methyl Tricosanoate RS.
Identification—The retention times of the peaks for

eicosapentaenoic acid methyl ester and docosahexaenoic
acid methyl ester obtained in the chromatogram of Test
solution 2 in the test for Content of EPA and DHA correspond
Pharmacopeial Forum
to those for the respective compounds in the chromatogram of 1% Palladium stock solution—Transfer 1 g of ultrapure
the Standard solution 1. The sum of the area for EPA and palladium metal, accurately weighed, into a Teflon beaker.
DHA methyl esters is not less than 22% of the total detected Add 20 mL of water and 10 mL of nitric acid, and warm on
area for the methyl esters, and no other peak in the a hot plate to dissolve. Allow the solution to cool to room
chromatogram has an area higher than 20% of the total temperature, transfer it into a 100-mL volumetric flask, and
detected area for the methyl esters. The chromatogram of Test dilute with deionized water to volume.
solution 2 exhibits at least 15 additional peaks at the retention 1% Magnesium nitrate stock solution—Transfer 1 g of
times of the methyl esters of unsaturated fatty acids exhibited ultrapure magnesium nitrate, accurately weighed, into
in the chromatogram of Standard solution 2. a Teflon beaker. Add 40 mL of water and 1 mL of nitric
acid, and warm on a hot plate to dissolve the solids. Allow the
Acid value h401i: not more than 3.
solution to cool to room temperature, transfer it into a 100-mL
Anisidine value h401i: not more than 20.0.
volumetric flask, and dilute with deionized water to volume.
Peroxide value h401i: not more than 5.0. Modifier working solution—Transfer 3 mL of 1% Palladi-
um stock solution and 2 mL of 1% Magnesium nitrate stock
Total oxidation value (TOTOX) h401i: not more than 26,
solution into a 10-mL volumetric flask, and dilute with 2%
calculated by the formula:
nitric acid to volume. A volume of 5 mL provides 0.015 mg of
palladium and 0.01 mg of magnesium nitrate.
(2 6 PV) + AV
Blank—Transfer 5 mL of nitric acid to a 100-mL
in which PV is the Peroxide value, and AV is the Anisidine volumetric flask, dilute with water to volume, and mix.
value. Standard stock solution—Transfer 10.0 mL of Standard

Arsenic Solution, prepared as directed in the test for Arsenic
Unsaponifiable matter h401i: not more than 1.5%.
h211i, to a 100-mL volumetric flask, add 40 mL of water and
Stearin: 10 mL remains clear after cooling at 08 for 5 mL of nitric acid, dilute with water to volume, and mix.
3 hours. This solution contains 0.10 mg of arsenic per mL.
Absorbance—Dilute 0.300 g to 50.0 mL with isooctane. Standard solutions—Dilute the Standard stock solution
Quantitatively transfer 2.0 mL of this solution to a 50-mL with the Blank to obtain solutions containing, respectively,
volumetric flask, and dilute with isooctane to volume. The 0.002, 0.005, 0.010, 0.025, and 0.050 mg of arsenic per mL.
In-Process Revision
absorbance is not more than 0.70, determined at 233 nm. Test solution—For preparation of the Test solution, use
a microwave oven with a magnetron frequency of about
Limit of arsenic—[NOTE—For the preparation of all aqueous
2455 MHz and a selectable output power of 0 to 950 watts in
solutions and for the rinsing of glass, polytef, and plastic
1% increments, equipped with advanced composite vessels
vessels before use, employ water that has been passed
with 100-mL polytef liners. Use rupture membranes to vent
through a strong-acid, strong-base, mixed-bed ion-exchange
vessels should the pressure exceed 125 psi. The vessels fit
resin before use. Select all reagents to have as low a content
into a turntable, and each vessel can be vented into an
of arsenic as practicable, and store all reagent solutions in
overflow container. Equip the microwave oven with an
containers of borosilicate glass. Cleanse glass, polytef, and
exhaust tube to ventilate fumes. [Caution—Wear proper eye
plastic vessels before use by soaking in warm 8 N nitric acid
protection and protective clothing and gloves.] Transfer
for 30 minutes and by rinsing with deionized water.]
approximately 500 mg of Fish Oil Containing Omega-
Pharmacopeial Forum
3 Acids, accurately weighed to the nearest 0.1 mg, into corrected peak areas of the Standard solutions versus their
a Teflon digestion vessel liner. Prepare samples in duplicate. contents of arsenic, in mg per mL, and calculate the regression
Add 15 mL of nitric acid, and swirl gently. Cover the vessels line best fitting the points. Determine the concentration, C, in
with lids, leaving the vent fitting off. Predigest overnight mg per mL, of arsenic in each mL of the Test solution by
under a hood. Place the rupture membrane in the vent fitting, interpolation from the regression line. Calculate the content of
and tighten the lid. Place all vessels on the microwave oven arsenic in the portion of Fish Oil Containing Omega-3 Acids
turntable. Connect the vent tubes to the vent trap, and connect taken by the formula:
the pressure-sensing line to the appropriate vessel. Initiate
a two-stage digestion procedure by heating the microwave at 25C/W
15% power for 15 minutes, followed by 25% power for 45

in which W is the weight, in g, of Fish Oil Containing Omega-
minutes. Remove the turntable of vessels from the oven, and
3 Acids taken to prepare the Test solution: not more than 0.1
allow the vessels to cool to room temperature. [NOTE—A cool
mg per g is found.
water bath may be used to speed the cooling process.] Vent
the vessels when they reach room temperature. Remove the Limit of lead—[NOTE—For the preparation of all aqueous
lids, and slowly add 2 mL of 30 percent hydrogen peroxide to solutions and for the rinsing of glass, polytef, and plastic
each. Allow the reactions to subside, and seal the vessels. vessels before use, employ water that has been passed
Return the vessels on the turntable to the microwave oven, through a strong-acid, strong-base, mixed-bed ion-exchange
and heat for an additional 15 minutes at 30% power. Remove resin before use. Select all reagents to have as low a content
the vessels from the oven, and allow them to cool to room of lead as practicable, and store all reagent solutions in
temperature. Transfer the cooled digests into 25-mL volu- containers of borosilicate glass. Cleanse glass, polytef, and
metric flasks, and dilute with water to volume. plastic vessels before use by soaking in warm 8 N nitric acid
Procedure—Program the graphite furnace as follows. Dry for 30 minutes and by rinsing with deionized water.]
at 1158, using a 1-second ramp, a 65-second hold, and an 10% Monobasic ammonium phosphate stock solution—
argon flow of 300 mL per minute; char the sample at 10008, Transfer 10 g of ultrapure monobasic ammonium phosphate,
using a 1-second ramp, a 20-second hold, and an airflow of accurately weighed, to a 100-mL volumetric flask. Add 40
300 mL per minute; cool down, and purge the air from the mL of water and 1 mL of nitric acid to dissolve the phosphate.
furnace for 10 seconds, using a 208 set temperature and an Dilute with deionized water to 100 mL.
argon flow of 300 mL per minute; atomize at 24008, using 1% Magnesium nitrate stock solution—Transfer 1 g of
In-Process Revision
a 0-second ramp and a 5-second hold with the argon flow ultrapure magnesium nitrate, accurately weighed, to a Teflon
stopped; and clean out at 26008 with a 1-second ramp and beaker. Add 40 mL of water and 1 mL of nitric acid, and
a 5-second hold. Separately inject equal volumes (about 20 warm on a hot plate to dissolve the solids. Allow the solution
mL) of the Standard solutions, the Test solution, and the to cool to room temperature, transfer it to a 100-mL
Blank, followed by an injection of 5 mL of the Modifier volumetric flask, and dilute with deionized water to volume.
working solution for each of the samples, into the graphite Modifier working solution—Transfer 4 mL of 10%
tube of a suitable graphite furnace atomic absorption Monobasic ammonium phosphate stock solution and 2 mL
spectrophotometer equipped with a hollow-cathode lamp for of 1% Magnesium nitrate stock solution to a 10-mL
arsenic. Determine the peak area at the arsenic emission line
at 193.7 nm, corrected for background absorption. Plot the
Pharmacopeial Forum
volumetric flask, and dilute with 2% nitric acid to volume. A mg per mL, of lead in each mL of the Test solution by
volume of 5 mL provides 0.2 mg of phosphate plus 0.01 mg of interpolation from the regression line. Calculate the content of
magnesium nitrate. lead in the portion of Fish Oil Containing Omega-3 Acids
Blank—Transfer 5 mL of nitric acid to a 100-mL taken by the formula:
volumetric flask, dilute with water to volume, and mix.
Standard stock solution—Transfer 10.0 mL of Lead Nitrate 25C/W
Stock Solution, prepared as directed in the test for Heavy

in which W is the weight, in g, of Fish Oil Containing Omega-
Metals h231i, to a 100-mL volumetric flask, add 40 mL of
3 Acids taken to prepare the Test solution: not more than 0.1
water and 5 mL of nitric acid, dilute with water to volume,
mg per g is found.
and mix. Transfer 1.0 mL of this solution to a second 100-mL
volumetric flask, add 50 mL of water and 1 mL of nitric acid, Limit of cadmium—[NOTE—For the preparation of all
dilute with water to volume, and mix. This solution contains aqueous solutions and for the rinsing of glass, polytef, and
0.10 mg of lead per mL. plastic vessels before use, employ water that has been passed
Standard solutions—Dilute the Standard stock solution through a strong-acid, strong-base, mixed-bed ion-exchange
with the Blank to obtain solutions containing, respectively, resin before use. Select all reagents to have as low a content
0.002, 0.005, 0.010, 0.025, and 0.050 mg of lead per mL. of cadmium as practicable, and store all reagent solutions in
Test solution—Prepare as directed for Test solution in the containers of borosilicate glass. Cleanse glass, polytef, and
test for Limit of arsenic. plastic vessels before use by soaking in warm 8 N nitric acid
Procedure—Program the graphite furnace as follows. Dry for 30 minutes and by rinsing with deionized water.]
at 1208, using a 1-second ramp, a 55-second hold, and an 10% Monobasic ammonium phosphate stock solution—
argon flow of 300 mL per minute; char the sample at 8508, Transfer 10 g of ultrapure monobasic ammonium phosphate,
using a 1-second ramp, a 30-second hold, and an airflow of accurately weighed, to a 100-mL volumetric flask. Add 40
300 mL per minute; cool down, and purge the air from the mL of water and 1 mL of nitric acid to dissolve the phosphate.
furnace for 10 seconds, using a 208 set temperature and an Dilute with deionized water to 100 mL.
argon flow of 300 mL per minute; atomize at 21008, using 1% Magnesium nitrate stock solution—Transfer 1 g of
a 0-second ramp and a 5-second hold with the argon flow ultrapure magnesium nitrate, accurately weighed, to a Teflon
stopped; and clean out at 26008 with a 1-second ramp and beaker. Add 40 mL of water and 1 mL of nitric acid, and
In-Process Revision
a 5-second hold. Separately inject equal volumes (about 20 warm on a hot plate to dissolve the solids. Allow the solution
mL) of the Standard solutions, the Test solution, and the to cool to room temperature, transfer it to a 100-mL
Blank, followed by an injection of 5 mL of the Modifier volumetric flask, and dilute with deionized water to volume.
working solution for each of the samples, into the graphite Modifier working solution—Transfer 4 mL of 10%
tube of a suitable graphite furnace atomic absorption Monobasic ammonium phosphate stock solution and 2 mL
spectrophotometer equipped with a hollow-cathode lamp for of 1% Magnesium nitrate stock solution to a 10-mL
lead. Determine the peak area at the lead emission line at volumetric flask, and dilute with 2% nitric acid to volume.
283.3 nm, corrected for background absorption. Plot the A volume of 5 mL provides 0.2 mg of phosphate and 0.01 mg
corrected peak areas of the Standard solutions versus their of magnesium nitrate.
contents of lead, in mg per mL, and calculate the regression Blank—Transfer 5 mL of nitric acid to a 100-mL
line best fitting the points. Determine the concentration, C, in volumetric flask, dilute with water to volume, and mix.
Pharmacopeial Forum
Standard stock solution—Transfer 137.2 mg of cadmium in which W is the weight, in g, of Fish Oil Containing Omega-
nitrate to a 1000-mL volumetric flask, dissolve in and dilute 3 Acids taken to prepare the Test solution: not more than 0.1
with water to volume, and mix. Transfer 2.0 mL of this mg per g is found.
solution to a second 100-mL volumetric flask, add 50 mL of Limit of mercury—Proceed as directed for Method IIa under
water and 1 mL of nitric acid, dilute with water to volume, Mercury h261i, except to use a Standard Mercury Solution
and mix. This solution contains 0.10 mg of cadmium per mL. having the equivalent of 0.1 mg of mercury per mL.
Standard solutions—Dilute the Standard stock solution Test solution—Prepare as directed for the Test solution in
with the Blank to obtain solutions containing, respectively, the test for Limit of arsenic combining the 2 duplicate cooled
0.002, 0.005, 0.010, 0.025, and 0.050 mg of cadmium per mL. digests into 1.0 mL of Potassium Permanganate Solution.
Test solution—Prepare as directed for Test solution in the The limit is 0.1 mg per g.
test for Limit of arsenic.
Limit of dioxins, furans, and polychlorinated biphenyls
Procedure—Program the graphite furnace as follows. Dry
(PCBs)—Determine the content of polychlorinated dibenzo-
at 1208, using a 1-second ramp, a 55-second hold, and an
para-dioxins (PCDDs) and polychlorinated dibenzofurans
argon flow of 300 mL per minute; char the sample at 8508,
(PCDFs) by method No. 1613 revision B of the Environ-
using a 1-second ramp, a 30-second hold, and an airflow of
mental Protection Agency. Determine the content of poly-
300 mL per minute; cool down, and purge the air from the
chlorinated biphenyls (PCBs) by method No. 1668 revision A
furnace for 10 seconds, using a 208 set temperature and an
of the Environmental Protection Agency. The sum of
argon flow of 300 mL per minute; atomize at 24008, using
polychlorinated dibenzo-para-dioxins (PCDDs) and poly-
a 0-second ramp and a 5-second hold with the argon flow
chlorinated dibenzofurans (PCDFs) is not more than 2.0 pg of
stopped; and clean out at 26008 with a 1-second ramp and
WHO toxic equivalents per g. The sum of polychlorinated
a 5-second hold. Separately inject equal volumes (about 20
dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofur-
mL) of the Standard solutions, the Test solution, and the
ans (PCDFs) and dioxin-like PCBs (polychlorinated biphen-
Blank, followed by an injection of 5 mL of the Modifier
yls, non-ortho IUPAC congeners PCB-77, PCB-81, PCB-126,
working solution for each of the samples, into the graphite
and PCB-169, and mono-ortho IUPAC congeners PCB-105,
tube of a suitable graphite furnace atomic absorption
PCB-114, PCB-118, PCB-123, PCB-156, PCB-157, PCB-
spectrophotometer equipped with a hollow-cathode lamp for
167, and PCB-189) is not more than 10.0 pg of WHO toxic
cadmium. Determine the peak area at the cadmium emission
equivalents per g.
line at 228.8 nm, corrected for background absorption. Plot
In-Process Revision
Content of EPA and DHA —
the corrected peak areas of the Standard solutions versus their
Antioxidant solution—Dissolve an accurately weighed
contents of cadmium, in mg per mL, and calculate the
amount of butylated hydroxytoluene in hexanes to obtain
regression line best fitting the points. Determine the
a solution having a concentration of 0.05 mg per mL.
concentration, C, in mg per mL, of cadmium in each mL of
Internal standard solution—Transfer an accurately weighed
the Test solution by interpolation from the regression line.
quantity of USP Methyl Tricosanoate RS to a volumetric
Calculate the content of cadmium in the Fish Oil Containing
flask. Dissolve in Antioxidant solution, and dilute with the
Omega-3 Acids taken by the formula:
same solvent to obtain a solution having a concentration of
25C/W about 7.0 mg per mL. [NOTE—Guard the solution against

evaporation during usage.]
Pharmacopeial Forum
Standard stock solution 1—Transfer 0.100 g each of USP Test solution 1—Proceed as directed for Standard solution
Docosahexaenoic Ethyl Ester RS and USP Eicosapentaenoic 1, except to use the Test stock solution.
Ethyl Ester RS, accurately weighed, to a 10-mL volumetric Test solution 2—Transfer 2.0 mL of the Internal standard
flask, and dissolve in and dilute with Internal standard solution into a glass tube. Then proceed as directed for Test
solution to volume. solution 1.
Standard stock solution 2—Transfer 0.300 g of USP Fish Chromatographic system (see Chromatography h621i)—
Oil RS accurately weighed to a 10.0-mL volumetric flask, and The gas chromatograph is equipped with a flame-ionization
dissolve in and dilute with Internal standard solution to detector and a 0.25-mm 6 25-m fused silica capillary column
volume. coated with a 0.2-mm film of G16. The temperature of the
Standard solution 1—Transfer 2.0 mL of Standard stock detector is maintained at 2708 and that of the injection port at
solution 1 to a glass tube, and evaporate the solvent with 2508. The column temperature is initially set at 1708 for
a gentle stream of nitrogen. Add 1.5 mL of a 2% (w/v) 2 minutes, then increased at a rate of 38 per minute to 2408,
solution of sodium hydroxide in methanol, cap tightly with and is maintained at this temperature for 2.5 minutes. The
a polytetrafluoroethylene-lined cap, mix, and heat in a boiling carrier gas is helium with a split flow ratio of 1 : 200 and
water bath for 7 minutes. Cool, add 2 mL of boron a flow rate of about 1 mL per minute. [NOTE—If splitless
trichloride–methanol solution (120 g in 1000 mL of metha- injection mode is used, solutions should be further diluted
nol), cover with nitrogen, cap tightly, mix, and heat in 1 in 200.] Chromatograph Standard solution 2, and record the
a boiling water bath for 30 minutes. Cool to 408 to 508, add peak responses as directed for Procedure: the resolution, R,
1 mL of 2,2,4-trimethylpentane, cap, and mix on a vortex between the peaks in Standard solution 2 due to methyl oleate
mixer or shake vigorously for at least 30 seconds. and methyl cis-vaccinate is not less than 1.3. The number of
Immediately add 5 mL of saturated sodium chloride solution fatty acid methyl ester peaks exceeding 0.05% of the total
containing 1 volume of sodium chloride and 2 volumes of area in the chromatogram of Standard solution 2 is at least 24,
water. [NOTE—Shake from time to time. Before use, decant and the 24 largest peaks of the methyl esters account for more
the solution from any undissolved substance and filter if than 90% of the total area. (These correspond, in common
necessary.] Cover with nitrogen, cap, and mix on a vortex elution order, to: 14 : 0, 15 : 0, 16 : 0, 16 : 1 n-7, 16 : 4 n-1,
mixer or shake thoroughly for at least 15 seconds. Allow the 18 : 0, 18 : 1 n-9, 18 : 1 n-7, 18 : 2 n-6, 18 : 3 n-3, 18 : 4 n-3,
upper layer to become clear, and transfer to a separate tube. 20 : 1 n-11, 20 : 1 n-9, 20 : 1 n-7, 20 : 2 n-6, 20 : 4 n-6, 20 : 3 n-
In-Process Revision
Shake the methanol layer once more with 1 mL of 2,2,4- 3, 20 : 4 n-3, 20 : 5 n-3, 22 : 1 n-11, 22 : 1 n-9, 21 : 5 n-3, 22 : 5
trimethylpentane, and combine the 2,2,4-trimethylpentane n-3, 22 : 6 n-3). Chromatograph Standard stock solution 1 and
extracts. Wash the combined extracts with two quantities, Standard solution 1, and record the peak responses as
each of 1 mL of water, and dry over anhydrous sodium directed for Procedure: the derivatization efficiency for the
sulfate. conversion of fatty acid ethyl ester to the fatty acid methyl
Standard solution 2—Proceed as directed for Standard ester is not less than 90.0% for each (DHA and EPA).
solution 1, except to use Standard stock solution 2. Procedure—Separately inject duplicate equal volumes
Test stock solution—Transfer 0.300 g of Fish Oil Contain- (about 1 mL) of Standard solution 1, Standard solution 2,
ing Omega-3 Acids, accurately weighed, to a 10-mL Test solution 1, and Test solution 2 into the chromatograph,
volumetric flask, and dissolve in and dilute with Antioxidant record the chromatograms, and measure the peak responses.
solution to volume. Identify the retention times of the relevant fatty acid methyl
Pharmacopeial Forum
esters by comparison of the chromatogram of Standard Content of total omega-3 acids—

solution 2 with the reference chromatogram supplied with the Antioxidant solution, Internal standard solution, Standard
USP Fish Oil RS. Identify the retention time for the internal stock solution 1, Standard stock solution 2, Standard solution
standard peak by comparing the chromatograms for Test 1, Standard solution 2, Test stock solution, Test solution 1,
solution 1 and Test solution 2. Calculate the percentage of Test solution 2, and Chromatographic system—Proceed as
EPA or DHA in the Fish Oil Containing Omega-3 Acids directed in the test for Content of EPA and DHA.
taken by the formula: Procedure—Proceed as directed in the test for Content of
EPA and DHA, except to calculate the content of the total
100FC / W(RU / RS)
omega-3 acids by the formula:
in which F is the factor to express the content of DHA (F =

0.921) and EPA (F = 0.915) as free fatty acids; C is the
concentration, in mg per mL, of either DHA or EPA in
Standard solution 1; W is the weight, in mg, of the Fish Oil
Containing Omega-3 Acids taken to prepare the Test stock in which EPA is the content of EPA, in mg per g, obtained
solution; RS is the ratio of peak responses of either EPA or from the test for Content for EPA and DHA; DHA is the
DHA relative to the internal standard in the chromatogram of content of EPA, in mg per g, obtained from test for Content
Standard solution 1; and RU is the corrected peak response of for EPA and DHA;An–3 is the sum of the areas of the peaks
either EPA or DHA relative to the internal standard in the corresponding to C18 : 3 n-3, C18 : 4 n-3, C20 : 4 n-3, C21 : 5
chromatogram of Test solution 2 calculated as follows: n-3, and C22 : 5 n-3 methyl esters in the chromatogram
obtained with Test solution 2;AEPA is the area of the peak
corresponding to the EPA methyl ester in the chromatogram
obtained with Test solution 2 and ADHA is the area of the peak
corresponding to the DHA methyl ester in the chromatogram
obtained with Test solution 2.&1S (USP31)
in which rU2 is the peak response of any peak at the locus of

the internal standard in the chromatogram of Test solution 2; BRIEFING
In-Process Revision
rU1 is the peak response of any peak at the locus of the internal
standard in the chromatogram of Test solution 1; rT1 is the Fish Oil Containing Omega-3 Acids Capsules—See briefing
under Fish Oil Containing Omega-3 Acids.
peak response of EPA or DHA in the chromatogram of Test
solution 1; and rT2 is the peak response of EPA or DHA in the
chromatogram of Test solution 2.
Pharmacopeial Forum
Add the following: the 2,2,4-trimethylpentane is completely evaporated. Weigh
&Fish the empty Capsules in the original tared weighing bottle, and
Oil Containing Omega-3 Acids
Capsules calculate the average net weight per Capsule.
Content of EPA and DHA and Content of total omega-

3 acids—Proceed as directed for in the Content of EPA and
» Fish Oil Containing Omega-3 Acids Capsules DHA and Content of total omega-3 acids under Fish Oil
contain not less than 95.0 percent and not more Containing Omega-3 Acids.
than 105.0 percent of the labeled amount of Fish Other requirements—The contents of the Capsules meet the
Oil Containing Omega-3 Acids. The oil contained requirements of the tests for Acid value, Anisidine value,
in Fish Oil Containing Omega-3 Acids Capsules Peroxide value, Total oxidation value, Unsaponifiable matter,
Stearin, Absorbance, Limit of arsenic, Limit of lead, Limit of
conforms to the definition for Fish Oil Containing
cadmium, Limit of mercury, and Limit of dioxins, furans, and
Omega-3 Acids.
polychlorinated biphenyls under Fish Oil Containing Omega-
Packaging and storage—Preserve in tight containers, and 3 Acids.&1S (USP31)
store at room temperature. Protect from light.
Labeling—The label states the amount of docosahexaenoic

BRIEFING
acid (DHA) and eicosapentaenoic acid (EPA) in mg per
Capsule.
Ginger, USP 30 page 931; Powdered Ginger, USP 30 page 933.
It is proposed to revise the Definition, Packaging and storage, and
USP Reference standards h11i—USP Docosahexaenoic the subsection Macroscopic under Botanic characteristics to reflect
the information provided in the general information chapter
Ethyl Ester RS. USP Eicosapentaenoic Ethyl Ester RS. USP Supplemental Information for Articles of Botanical Origin h2030i.
It is also proposed to revise the subsection Histology under Botanic
Fish Oil RS. USP Methyl Tricosanoate RS. characteristics to better describe the article.
Identification—Proceed as directed for Identification under (DSB: M. Sharaf) RTS—C50551

Fish Oil Containing Omega-3 Acids. The oil contained in the
Capsules meets the requirements. Change to read:
Weight variation h2091i: meet the requirements. » Ginger is the rhizome of Zingiber officinale Roscoe
(Fam. Zingiberaceae), scraped or unscraped. It is known
in commerce as unbleached ginger.
In-Process Revision
Disintegration and dissolution h2040i—Proceed as directed

in the chapter under Rupture Test for Soft Gelatin Capsules: &
Ginger is the dried rhizome of Zingiber officinale
meet the requirements. Roscoe (Fam. Zingiberaceae), scraped, partially
Content of Fish oil—Accurately weigh not fewer than 10 scraped, or unscraped. It is known in commerce as
Capsules in a tared weighing bottle. With a sharp blade, or by unbleached ginger.&1S (USP31)
other appropriate means, carefully open the Capsules, without
Change to read:
loss of shell material, and transfer the combined Capsule
contents to a 100-mL beaker. Remove any adhering substance Packaging and storage—Preserve~ in well-closed containers,
protected from light and moisture, and store at room tempera-
from the emptied Capsules by washing with several small ture.~USP30
portions of 2,2,4-trimethylpentane. Discard the washings, and &

and store in a cool area.&1S (USP31)
allow the empty Capsules to dry in a current of dry air until
Pharmacopeial Forum
Change to read: BRIEFING
Botanic characteristics—
Macroscopic—Ginger occurs in horizontal, laterally flattened, Powdered Ginger, USP 30 page 933—See briefing under Ginger.
sympodially branching pieces. Whole rhizomes are 5 to 15 cm long,
1.5 to 6 cm wide, and up to 2 cm thick, sometimes split (DSB: M. Sharaf) RTS—C50553
longitudinally; pale yellowish buff or light brown externally,
longitudinally striated, somewhat fibrous; branches flattish, obovate,
short, about 2 cm long, each ending with a depressed stem scar;
fracture, short with projecting fibers, or sometimes resinous; Change to read:
internally yellowish brown, showing a yellow endodermis separating
the narrow cortex from the wide stele, and numerous yellowish Packaging and storage—Preserve~ in well-closed containers,
points, secretion cells and numerous bigger greyish points, vascular protected from light and moisture, and store at controlled room
bundles, scattered on the whole surface. The unscraped rhizome temperature.~USP30
shows in addition an outer layer of dark brown cork.
&
and store in a cool area.&1S (USP31)
&
Morphological characteristics of different varieties and
forms of Ginger from different geographical areas are listed Change to read:
in Table 1 of general information chapter Supplemental Botanic characteristics—Under a microscope, Powdered Ginger
reveals mainly starch grains and parenchyma cells containing them;
Information for Articles of Botanical Origin h2030i.&1S (USP31) also parenchyma cells containing yellow-brown to dark brown
resinous substances or single crystals of calcium oxalate; fragments
Histology: Starch abundant in the thin-walled ground tissue, as of fibers with distinct pits; fragments of spiral, ring, and reticulate
flattened, ovate to subrectangular, transversely striated, simple vessels often accompanied by pigment cells; oleoresin in fragments
granules, each with the hilum in a projection toward one end, or droplets, staining with iodine TS and potassium iodide TS, and,
mostly up to about 50 mm long and up to about 25 mm wide and rarely, fragments of cork tissue; starch grains composed of simple,
7 mm thick. Oleoresin cells, with suberised cell walls and yellow compound or half-compound grains, spherical ovoid or globular with
contents, numerous in the ground tissue—pigment cells with dark, abaxial hilum, usually 20 to 30 mm in long axis. Sclerenchymatous
reddish brown contents occurring either singly in the ground tissue cells, trichomes, and calcium oxalate absent.
or in axial rows accompanying the vascular bundles. Irregularly
shaped, thin-walled fibers with delicate transverse septa, yielding &
Under a microscope, Powdered Ginger reveals mainly starch
only slightly the reaction characteristic of lignin. Vessels with spiral
or reticulate thickening in the scattered vascular bundles not yielding granules and parenchyma cells containing them; simple,
the reaction characteristic of lignin. In the unscraped ginger, varying
amounts of cork, composed of thin-walled cells. Sclereids and large, flattened, ovoid or sack-shaped starch granules, 5 to 15
calcium oxalate crystals absent.
mm wide and 30 to 60 mm long having an eccentric hilum,
&
The scraped rhizome in transverse section shows a cortex
some showing faint transverse striations; parenchyma cells
composed of multiple layers of parenchyma cells rich in
containing yellow-brown to dark brown resinous substances;
simple, large, flattened, ovoid or sack-shaped starch granules,
groups of large, thin-walled nonlignified septate fibers with
5 to 15 mm wide and 30 to 60 mm long having an eccentric
wide lumen; portions of sepate fibers with attached vessels;
hilum, some showing faint transverse striations. The cortex
large vessels with annular, spiral, or reticulate thickening and
also shows numerous oleoresin cells with a yellow or
often accompanied by parenchyma cells containing brown
yellowish-brown content and scattered collateral vascular
content; oleoresin in fragments or droplets, staining with
In-Process Revision
bundles; a single layer of endodermal cells free from starch;
iodine TS and potassium iodide TS; and, rarely, fragments of
a wide central stele composed of parenchyma cells rich in
brown cork tissue, usually seen in surface view. Scleren-
starch and oleoresin cells similar to those of the cortex, and
chymatous cells, trichomes, and calcium oxalate
containing scattered collateral vascular bundles, some
absent.&1S (USP31)
enclosed in a sheath of septate nonlignified fibers with wide
lumen. In addition to the above, the unscraped rhizome shows
an outer zone of dark brown cork cells.&1S (USP31)
Pharmacopeial Forum
BRIEFING ~
Fully Hydrogenated Rapeseed Oil~NF26
~
Excipients, USP and NF Excipients, Listed by Category, NF 25 Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26
page 1045 and page 257 of PF 33(2) [Mar.–Apr. 2007]. It is proposed Shellac
to add Hydrogenated Polydecene to the Emollient, Ointment Base, Starch, Pregelatinized Modified
Solvent, and Vehicle (Oleaginous) categories and Hydrogenated Sucrose
Starch Hydrolysate to the Humectant, Sweetening Agent, Tablet Bin- Titanium Dioxide
der, and Tablet and/or Capsule Diluent categories to complement the Wax, Carnauba
proposed new monographs for Hydrogenated Polydecene and Hydro- Wax, Microcrystalline
genated Starch Hydrolysate, respectively, which appear elsewhere in Zein
this issue of PF.
(EM1; EM2) RTS—C39325; C41492 Change to read:

Desiccant
Calcium Chloride
Calcium Sulfate
Change to read: &
Bulking Agent for Freeze-Drying Silicon Dioxide
Creatinine
Mannitol
Change to read:
&
Emollient
&
Trehalose&1S (NF26) Alkyl (C12-15) Benzoate
Change to read:
&
Hydrogenated Polydecene&1S (NF26)
Coating Agent
&
&
Ammonio Methacrylate Copolymer Change to read:
Ammonio Methacrylate Copolymer Dispersion
Carboxymethylcellulose, Sodium Emulsifying and/or Solubilizing Agent
Cellaburate Acacia
Cellacefate (formerly Cellulose Acetate Phthalate) Carbomer Copolymer
Cellulose Acetate Carbomer Interpolymer
Cellulose Acetate Phthalate (see Cellacefate) Cholesterol
&
Coconut Oil&1S (NF25) &
Copovidone Diethanolamine (Adjunct)
Diethylene Glycol Stearates
&
Corn Syrup Solids&2S (NF25) Ethylene Glycol Stearates
Glyceryl Distearate
&
Ethyl Acrylate and Methyl Methacrylate Copolymer Glyceryl Monolinoleate
Glyceryl Monooleate
Dispersion&1S (NF25) Glyceryl Monostearate
Ethylcellulose Lanolin Alcohols
In-Process Revision
Ethylcellulose Aqueous Dispersion Lecithin

Gelatin Mono- and Di-glycerides
Glaze, Pharmaceutical Monoethanolamine (Adjunct)
Hydroxypropyl Cellulose Oleic Acid (Adjunct)
Hydroxypropyl Methylcellulose (see Hypromellose) Oleyl Alcohol (Stabilizer)
Hydroxypropyl Methylcellulose Phthalate (see Hypromellose
Phthalate) &
Hypromellose Acetate Succinate &
Hypromellose Phthalate (formerly Hydroxypropyl Poloxamer
Methylcellulose Phthalate) Polyoxyethylene 50 Stearate
Maltodextrin Polyoxyl 10 Oleyl Ether
Methacrylic Acid Copolymer Polyoxyl 20 Cetostearyl Ether
Methacrylic Acid Copolymer Dispersion Polyoxyl 35 Castor Oil
Methylcellulose Polyoxyl 40 Hydrogenated Castor Oil
Polyoxyl 40 Stearate
&
Palm Kernel Oil&2S (NF25) Polyoxyl Lauryl Ether
Polyethylene Glycol Polyoxyl Stearyl Ether
Polysorbate 20
&
Polyvinyl Acetate&1S (NF25) Polysorbate 40
Polyvinyl Acetate Phthalate Polysorbate 60
Pharmacopeial Forum
Polysorbate 80 &
Ethyl Acrylate and Methyl Methacrylate Copolymer
&
Propylene Glycol Monocaprylate&1S (NF26) Dispersion&1S (NF25)
Propylene Glycol Monostearate
~
Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26
Sodium Cetostearyl Sulfate Change to read:
Sodium Lauryl Sulfate
Sodium Stearate Sequestering Agent
Sorbitan Monolaurate Beta Cyclodextrin (see Betadex)
Sorbitan Monooleate Betadex (formerly Beta Cyclodextrin)
Sorbitan Monopalmitate
Sorbitan Monostearate
&
Sorbitan Sesquioleate
Sorbitan Trioleate
&
Stearic Acid Sodium Tartrate
Trolamine
Wax, Emulsifying
Change to read:
Change to read: Solvent

Acetone
Humectant Alcohol
Alcohol, Diluted
&
Corn Syrup Solids&2S (NF25) Amylene Hydrate
Benzyl Benzoate
&
Erythritol&1S (NF25) Butyl
~
Alcohol
Glycerin Canola Oil~NF25
Hexylene Glycol Caprylocaproyl Polyoxylglycerides
Corn Oil
&
Hydrogenated Starch Hydrolysate&1S Cottonseed Oil
(NF26)
Maltitol Diethylene Glycol Monoethyl Ether
Ethyl Acetate
&
Glycerin
Propylene Glycol Hexylene Glycol
Sorbitol
Sorbitol Sorbitan Solution
&
Tagatose Isopropyl Alcohol
Lauroyl Polyoxylglycerides
Methyl Alcohol
Change to read: Methylene Chloride
Methyl Isobutyl Ketone
Ointment Base Mineral Oil
Caprylocaproyl Polyoxylglycerides Oleoyl Polyoxylglycerides
Diethylene Glycol Monoethyl Ether Peanut Oil
Polyethylene Glycol
&
Hydrogenated Polydecene&1S (NF26) Polyethylene Glycol Monomethyl Ether
Lanolin Propylene Glycol
Lauroyl Polyoxylglycerides Sesame Oil
Linoleoyl Polyoxylglycerides Stearoyl Polyoxylglycerides
Ointment, Hydrophilic Water for Injection
Ointment, White Water for Injection, Sterile
Ointment, Yellow Water for Irrigation, Sterile
Oleoyl Polyoxylglycerides Water, Purified
In-Process Revision
Polyethylene Glycol Monomethyl Ether
Petrolatum
Petrolatum, Hydrophilic
Petrolatum, White Change to read:
Rose Water Ointment
Squalane Stiffening Agent
Stearoyl Polyoxylglycerides Castor Oil, Hydrogenated
Vegetable Oil, Hydrogenated, Type II Cetostearyl Alcohol
Cetyl Alcohol
Cetyl Esters Wax
Cetyl Palmitate
Change to read: Hard Fat
Paraffin
Polymer Membrane Synthetic Paraffin
~
&
Amino Methacrylate Copolymer&1S (NF25) Fully Hydrogenated Rapeseed Oil~NF26
Ammonio Methacrylate Copolymer ~
Ammonio Methacrylate Copolymer Dispersion Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26
Cellaburate Stearyl Alcohol
Cellulose Acetate
Pharmacopeial Forum
Wax, Emulsifying Fructose

Wax, White Galactose
Wax, Yellow
&
Hydrogenated Starch Hydrolysate&1S (NF26)
Maltitol
Maltose
Saccharin
Agar Sorbitol
Bentonite Syrup
Bentonite, Purified Tagatose
Bentonite Magma
Carbomer 910 &
Trehalose&1S (NF26)
Carbomer 934
Carbomer 934P
Carbomer 940
Carbomer 1342
Carbomer Copolymer Tablet Binder
Carbomer Homopolymer Acacia
Carrageenan Ammonio Methacrylate Copolymer Dispersion
Cellulose, Microcrystalline, and Carboxymethylcellulose Carbomer Copolymer
Sodium Carbomer Homopolymer
Carbomer Interpolymer
&
Corn Syrup Solids&2S (NF25) Carboxymethylcellulose Sodium
Dextrin Cellulose, Microcrystalline
Gelatin Copovidone
Gellan Gum
Guar Gum &
Hydroxyethyl Cellulose Dextrin
Hydroxypropyl Cellulose
Hydroxypropyl Methylcellulose (see Hypromellose) &
Magnesium Aluminum Silicate Dispersion&1S (NF25)
Maltodextrin Ethylcellulose
Methylcellulose Gelatin
Pectin Glucose, Liquid
Polyethylene Oxide Guar Gum
Polyvinyl Alcohol
Povidone
Propylene Glycol Alginate &
Silicon Dioxide Low-Substituted Hydroxypropyl Cellulose
Silicon Dioxide, Colloidal Hydroxypropyl Methylcellulose (see Hypromellose)
Sodium Alginate Hypromellose (formerly Hydroxypropyl Methylcellulose)
In-Process Revision
Starch, Corn Hypromellose Acetate Succinate

Starch, Potato Maltodextrin
Starch, Tapioca Maltose
Starch, Wheat Methylcellulose
Tragacanth Polyethylene Oxide
Xanthan Gum
&
Povidone
Change to read: Starch, Corn
Starch, Potato
Sweetening Agent Starch, Pregelatinized
Acesulfame Potassium Starch, Pregelatinized Modified
Aspartame Starch, Tapioca
Aspartame Acesulfame Starch, Wheat
Syrup
&
Dextrates
Dextrose &
Trehalose&1S (NF26)
Dextrose Excipient
&
Pharmacopeial Forum
Tablet and/or Capsule Diluent Tonicity Agent

Calcium Carbonate
Calcium Phosphate, Dibasic
Calcium Phosphate, Tribasic &
Calcium Sulfate Dextrose
Cellulose, Microcrystalline Glycerin
Cellulose, Powdered Mannitol
Potassium Chloride
Sodium Chloride
&
Dextrates
Dextrin
Dextrose Excipient Change to read:
Fructose
Vehicle
FLAVORED AND/OR SWEETENED
&
Hydrogenated Starch Hydrolysate&1S (NF26) Aromatic Elixir
Kaolin Benzaldehyde Elixir, Compound
Lactitol
Lactose, Anhydrous
Lactose, Monohydrate
&
Maltitol Dextrose
Maltodextrin Peppermint Water
Maltose Sorbitol Solution
Mannitol Syrup
&
&
Trehalose&1S (NF26)
Sorbitol OLEAGINOUS
Starch Alkyl (C12-15) Benzoate
Starch, Corn Almond
~
Oil
Starch, Potato Canola Oil~NF25
Starch, Pregelatinized Corn Oil
Starch, Pregelatinized Modified Cottonseed Oil
Starch, Tapioca Ethyl Oleate
Starch, Wheat
Sucrose
Sugar, Compressible &
Sugar, Confectioner’s Isopropyl Myristate
Isopropyl Palmitate
Mineral Oil
&
Trehalose&1S (NF26) Mineral Oil, Light
Octyldodecanol
Olive Oil
Peanut Oil
Change to read: Safflower Oil
Sesame Oil
Tablet Disintegrant Soybean Oil
Alginic Acid Squalane
SOLID CARRIER
Croscarmellose Sodium
Crospovidone
In-Process Revision
Low-Substituted Hydroxypropyl Cellulose
Maltose
&
Polacrilin Potassium Sugar Spheres
Sodium Starch Glycolate STERILE
Starch Sodium Chloride Injection, Bacteriostatic
Starch, Corn Water for Injection, Bacteriostatic
Starch, Potato
Starch, Tapioca
Starch, Wheat
&
Trehalose&1S (NF26)
Pharmacopeial Forum
MONOGRAPHS (NF) trodes in the solution, stir on a magnetic stirrer having an insulated
top until equilibrium is attained (1 to 2 minutes), and record the
potential. Rinse and dry the electrodes between measurements,
taking care to avoid damaging the crystal of the ion-specific
electrode.] Plot the logarithms of the fluoride ion concentrations, in
mg per mL, of the Standard solutions versus potential, in mV. From
BRIEFING the measured potential of the Test solution and the standard response
line, determine the concentration, C, in mg per mL, of fluoride ion in
the Test solution. Calculate the quantity, in mg of fluoride per g of
Calcium Silicate by multiplying C by 20. The limit is 10 mg per g.
Calcium Silicate, NF 25 page 1075 and page 1417 of PF 31(5)
[Sept.–Oct. 2005]. On the basis of comments received, it is proposed &
NOTE—Store all solutions in plastic &
polytef&1S (NF26)
to change the acceptance criterion for the Limit of fluoride to 50 mg
from 10 mg, which resulted in an average increase in the amount of containers.
fluoride detected.
Buffer solution—Transfer 147 g of sodium citrate to a
(EM1: R. Lafaver) RTS—C52083
500-mL volumetric flask, dissolve in and dilute with water to
Change to read:
volume.
Ionic strength adjustment buffer—Transfer 42 mL of
» Calcium Silicate,
hydrochloric acid, 121 g of tris(hydroxymethyl)amino-
&
crystalline or amorphous,&1S (NF25) methane, and 115 g of sodium tartrate to a 500-mL volumetric
is a compound of calcium oxide and silicon dioxide. It
contains not less than 4.0 percent of calcium oxide and flask containing 250 mL of water. Stir to dissolve, and dilute
not less than 45.0
with water to volume.
&
35.0&1S (NF25)
percent of silicon dioxide. Electrode system—Use a fluoride-specific, ion-indicating
electrode and a calomel suitable reference electrode connect-
Change to read:
ed to a pH meter capable of measuring potentials with
pH h791i: between 8.4 and 10.2,
a reproducibility of +0.2 mV (see pH h791i).
&
11.2,&1S (NF25)
determined in a well-mixed aqueous suspension (1 in 20). Standard stock solution—Dissolve an accurately weighed
quantity of USP Sodium Fluoride RS in water to obtain
Change to read:
a solution containing 221 mg per mL. Each mL of this stock
Limit of fluoride—
NOTE—Store all solutions in plastic containers.
solution contains 100 mg of fluoride ion.
Buffer solution—Add 800 mL of hot water to 74.4 g of edetate
disodium and 24.2 g of tris(hydroxymethyl)aminomethane, and stir Test solution—Transfer about 2.0 g of Calcium Silicate,
until dissolved. Adjust with 5 N sodium hydroxide to a pH of 7.5 to
7.6. Allow the solution to cool, and adjust with 5 N sodium accurately weighed, to a 100-mL plastic polytef beaker
hydroxide to a pH of 8.0. Dilute with water to 1000 mL, and mix.
Electrode system—Use a fluoride-specific, ion-indicating electrode containing a magnetic stir bar. Add 20 mL of water and 2.0
and a calomel reference electrode connected to a pH meter capable
of measuring potentials with a reproducibility of +0.2 mV (see pH mL of hydrochloric acid. Cover with a watch glass, and heat
In-Process Revision
h791i).
Standard stock solution—Dissolve an accurately weighed quantity with stirring to a vigorous boil for 1 minute, stirring
of USP Sodium Fluoride RS quantitatively in water to obtain
a solution containing 221 mg per mL. Each mL of this stock solution continuously. Remove from heat, and cool. Transfer the
contains 100 mg of fluoride ion.
Standard solutions[NOTE—Prepare on the day of use.] Transfer cooled suspension to a 100-mL plastic polytef beaker. Add 25
10.0 mL of Standard stock solution to a 100-mL volumetric flask,
dilute with water to volume, and mix. This solution contains 10 mg mL of Buffer solution, and adjust with ammonium hydroxide
of fluoride ion per mL (Standard solution A). Transfer 1.0 mL of
Standard stock solution to a second 100-mL volumetric flask, dilute or hydrochloric acid to a pH between 5 and 6. Add 50 mL of
with water to volume, and mix. This solution contains 1.0 mg of
fluoride ion per mL (Standard solution B). Ionic strength adjustment buffer and water to make 100 mL of
Test solution—Transfer 5.0 g of Calcium Silicate to a 150-mL
polytef beaker. Add 40 mL of water and 20 mL of 1 N hydrochloric solution.
acid. Heat to near boiling for 1 minute, stirring continuously. Cool in
an ice bath, transfer the suspension to a 100-mL volumetric flask, Standard response line—Obtain a standard response line
dilute with water to volume, and mix.
Procedure—Transfer 20.0 mL of Standard solution A, Standard with four standard solutions containing 0, 0.10, 0.20, and
solution B, and the Test solution to separate polytef beakers, add 10.0
mL of Buffer solution to each beaker, and stir with a plastic-coated 0.40 mg per mL of fluoride as follows. Add 23 mL of water,
stirring bar. Concomitantly measure the potentials, in mV, of the
solutions. [NOTE—When taking measurements, immerse the elec- 2 mL of hydrochloric acid, and 25 mL of Buffer solution to
Pharmacopeial Forum
a 100-mL plastic &

polytef&1S (NF26) beaker. Adjust with to constant weight. Moisten the residue with 5 drops of sulfuric
ammonium hydroxide to a pH between 5 and 6, and add &

perchloric&1S (NF25)
acid, add 15 mL of hydrofluoric acid, heat cautiously on a hot plate
Ionic strength adjustment buffer to obtain 100 mL of solution. until all of the acid is driven off, and ignite at a temperature not
lower than 10008 to constant weight. Cool in a desiccator, and
Insert the electrode into the solution, stir for at least 15 weigh: the loss in weight represents the weight of SiO2. The
percentage of silicon dioxide in the Calcium Silicate is between
minutes, and record the potential for the standard solution 90.0% and 110.0% of the content stated in the labeling, or within the
range of percentages stated in the labeling.
containing 0 mg of fluoride per mL. When the electrode has
&
stabilized, add 100 mL of the Standard stock solution to the Table 2.
beaker, and stir. Allow the electrode to stabilize for 5 minutes,
Sample Weight Calcium Oxide Content
and measure the potential for the standard solution containing
about 400 mg greater than 25%
0.10 mg of fluoride per mL. Similarly add another 100 mL and
about 600 mg 11–25%
200 mL of the Standard stock solution and record the potential
about 1000 mg 4–10%
for the standard solutions containing 0.20 mg per mL of
&1S (NF25)
fluoride and 0.40 mg per mL of fluoride, respectively. After
each addition, continue to stir for 5 minutes before recording Change to read:
the reading. Assay for calcium oxide—Neutralize the combined filtrate and
washings retained from the Assay for silicon dioxide to litmus with
Procedure—Insert the calibrated electrode into the Test 1 N sodium hydroxide. Add, while stirring, about 30 mL
solution, stir for 5 minutes, and record the measurement. &

10 mL&1S (NF25)
of 0.05 M edetate disodium VS from a 50-mL buret. Add 15 mL of
From the measured potential of the Test solution and the 1 N sodium hydroxide and 300 mg of hydroxy naphthol blue, and
continue the titration to a blue endpoint. Each mL of 0.05 M edetate
Standard response line, determine the concentration, C, in mg disodium is equivalent to 2.804 mg of CaO. The percentage of CaO
in the Calcium Silicate is between 90.0% and 110.0% of the content
per mL, of fluoride ion in the Test solution. Calculate the stated in the labeling, or within the range of percentages stated in the
labeling.
quantity, in mg per g, of fluoride in Calcium Silicate by the
formula:
BRIEFING
100C/W
Hydrogenated Polydecene. The proposed new monograph for
Polydecene, which appeared on page 1331 of PF 30(4) [July–Aug.
in which W is the weight, in g, of Calcium Silicate taken. The 2004] was subsequently canceled. On the basis of comments and
data received and to replace that monograph, a new monograph for
limit is 10 &50&1S (NF26) mg per g.&1S (NF25) Hydrogenated Polydecene is now being proposed. The gas
chromatographic procedures in the tests for Limit of short-chain
Change to read: hydrocarbons and Content of decene oligomer are based on analyses
In-Process Revision
performed with a Supelco Petrocol B brand of G2 column.
Assay for silicon dioxide—Transfer about 400 mg of Calcium
Silicate, (EM2: H. Wang; NOM: L. Paul) RTS—C41492
&
the appropriate amount of Calcium Silicate (see Table
2.)&1S (NF25)
accurately weighed, to a beaker, add 5 mL of water and 10 mL of
perchloric acid, and heat until dense white fumes of perchloric acid
are evolved. Cover the beaker with a watch glass, and continue to Add the following:
heat for 15 minutes longer. &Hydrogenated Polydecene
&
2 hours.&1S (NF25)
Allow to cool, add 30 mL of water, filter, and wash the precipitate
with 200 mL of hot water. [NOTE—Retain the combined filtrate and
washings for use in the Assay for calcium oxide.] Transfer the filter
paper and its contents to a platinum crucible, heat slowly to dryness, C304n470H2n+2
then heat sufficiently to char the filter paper, . After cooling, add
a few drops of sulfuric acid, and ignite at about 13008
1-Decene, homopolymer, hydrogenated [68037-01-4].
&
and ignite at about 9008 to 10008&1S (NF25)
Pharmacopeial Forum
» Hydrogenated Polydecene is a mixture of hexamers, and possibly heptamers. The decene oligomer
saturated, synthetic hydrocarbons in the range content is within the range given in the accompanying table
for the labeled type of Hydrogenated Polydecene.
C30H62 through C70H142 made from direct oligo-
merization of 1-decene (C10 alpha olefin). The Specific gravity h841i: meets the requirements of the
oligomer mixture may be distilled to fractions of specific gravity range specified in the accompanying table, for
the labeled type, determined at 208.
a suitable calculated viscosity and hydrogenated to
reach saturation, or it may be hydrogenated to reach Viscosity h911i: meets the requirements of the viscosity
saturation and then distilled to the desired viscosity. range specified in the accompanying table for the labeled
type, determined using a capillary viscometer, in a liquid bath
The requirements for specific gravity, viscosity, and
maintained at 40.0 + 0.18.
content of decene oligomer differ for the various
types of Hydrogenated Polydecene, as set forth in Readily carbonizable substances h271i—Transfer 5 mL of
Hydrogeanted Polydecene to a glass-stoppered test tube
the accompanying table. Hydrogenated Polydecene
previously treated to remove organic matter (see Cleaning
may contain a suitable stabilizer.
Glass Apparatus h1051i), add 5 mL of sulfuric acid TS, and
Packaging and storage—Preserve in tight containers. No heat in a boiling water bath for 30 seconds. Quickly remove
storage requirements are specified. the test tube, and, while holding the stopper in place, shake
three times in a vertically reciprocating cycle with an
Labeling—Label it to indicate, as part of the official title, the
amplitude of about 13 cm. Repeat this procedure every 30
Hydrogenated Polydecene type (Type I, Type II, or Type III),
seconds for 10 minutes. Do not keep the test tube out of the
and label it to indicate the name and concentration of any
water bath any longer than 3 seconds for each shaking cycle.
added stabilizer.
Remove the test tube from the water bath, and let it cool for
Identification—The chromatogram of the Test solution
about 20 minutes to room temperature: the oil phase may turn
obtained from the test for Content of decene oligomer
hazy, but remains colorless; the interface between the two
exhibits major peaks for trimers, tetramers, pentamers,
layers is free from solids; and the acid layer does not become
darker than the standard color produced by mixing in a similar
test tube 3 mL of ferric chloride CS, 1.5 mL of cobaltous
In-Process Revision
Kinematic
Viscosity
Range,
Specific Centistokes
Gravity (mm2 s-1) Content of Decene Oligomer (%)

Type Range Range C30H62 C40H82 C50H102 C60H122 C70H142
Type I 0.814–0.819 16.0–20.0 70–93 5–25 0–5 0–1 0–1

Type II 0.823–0.827 28.0–34.0 13–40 35–70 9–25 0–7 0–2
Type III 0.828–0.832 40.0–52.0 3–15 25–55 25–40 13–28 0–10
Pharmacopeial Forum
chloride CS, and 0.5 mL of cupric sulfate CS, this mixture emission line of 232.0 nm, using a suitable graphite furnace
being overlaid with 5 mL of Hydrogenated Polydecene (see atomic absorption spectrophotometer (see Spectrophotometry
Readily Carbonizable Substances Test h271i). and Light-Scattering h851i) equipped with a deuterium
background corrector, a pyrolytically-coated tube with
Limit of nickel—
platform, and a nickel hollow-cathode lamp, using kerosene
Nickel stock solution—Immediately before use, dilute an
as the blank. Maintain the drying temperature of the furnace
appropriate quantity of organometallic standard1 with kero-
at 808 for 1 second, at 1208 for 10 seconds, and at 3008 for 20
sene to prepare a solution containing the equivalent of 1.0 mg
seconds; maintain the ashing temperature at 6008 for 20
of nickel per mL.
seconds and at 10008 for 20 seconds; and maintain the
Standard solutions—Transfer 0.5, 1.0, 2.0, and 4.0 mL of
atomization temperature at 25008 for 3 seconds and the
Nickel stock solution, respectively, to four identical 10-mL
cleaning temperature at 26008 for 5 seconds. [NOTE—The
volumetric flasks, dilute the contents of each flask with
temperature program may be modified to obtain optimum
kerosene to volume, and mix. These Standard solutions
furnace temperatures.] Plot the integrated absorbances of the
contain, respectively, about 0.05, 0.1, 0.2, and 0.40 mg of
Standard solutions versus concentration, in mg per mL, of
nickel per mL. [NOTE—The calibration range, especially the
nickel, and draw the straight line best fitting the four plotted
upper limit, can be adjusted for certain instruments, provided
points. From the graph so obtained, determine the concen-
that instrument validation and calibration linearity are
tration, C, in mg per mL, of nickel in the Test solution.
achieved.]
Calculate the quantity, in mg, of nickel in each g of
Test solution—Transfer about 3 g of Hydrogenated Poly-
Hydrogenated Polydecene taken by the formula:
decene, accuately weighed, to a 10-mL volumetric flask,
dilute with kerosene to volume, and mix. [NOTE—If necessary,
10C / W
dilute with an appropriate quantity of kerosene to obtain
a reading within the calibrated absorbance range.]
in which W is the weight, in g, of Hydrogenated Polydecene
Procedure—Place the Standard solutions and the Test
taken to prepare the Test solution: not more than 1 mg of
solution in an oven, setting the temperature at about 608 nickel per g is found.
during the period of determination, and shake these solutions
Limit of short-chain hydrocarbons—
vigorously before analysis. Use micropipettor and pipettor
Test solution, System suitability solution, Chromatographic
tips to make all injections. [NOTE—Positive displacement
system, and Procedure—Proceed as directed in the test for
In-Process Revision
pipets can be used when viscosity may become a problem.]
Content of decene oligomer. Calculate the percentage of each
Pretreat the pipettor tip by pipetting and then discarding 20
of the short-chain hydrocarbons present by the formula:
mL of heptane. [NOTE—The film of heptane remaining on the
wall of the tip facilitates a reproducible transfer of the oil
100(rU / rs)
sample.] The tip must be pretreated before each injection.
Separately inject equal volumes (20 mL) of the Standard in which rU is the response of any peak obtained from a peak
solutions and the Test solution into a graphite furnace, and eluting before the trimer but different from the solvent peak;
concomitantly determine the integrated absorbances of the and rs is the sum of the responses of all the peaks in the
Standard solutions and the Test solution at the nickel chromatogram, excluding the solvent peak: not more than
1
Suitable organometallic standards are available from, e.g.,
Continental Oil Co., Ponca City, OK (Conostan, 100 ppm), or 2.5% of total short-chain hydrocarbons is found.
Merck, D-6100 Darmstadt, Germany (metal in standard oil, 1000
ppm).
Pharmacopeial Forum
Content of decene oligomer—

Test solution—Dissolve about 0.1 mL of Hydrogenated
100(rO / rs)
Polydecene in about 10 mL of pentane.
System suitability solution—Dissolve accurately weighed in which rO is the response of each oligomer; and rs is the sum
quantities of hexadecane, squalane, and tetradecane in of the responses of all the peaks in the chromatogram,
pentane to obtain a solution having known concentrations excluding the solvent peak: the decene oligomer content is
of about 10 mg per mL, 10 mg per mL, and 1 mg per mL, within the limits specified in the accompanying table.&1S (NF26)
respectively.
The gas chromatograph is equipped with a flame-ionization BRIEFING
detector and a 0.52-mm 6 16-m fused-silica capillary
Hydrogenated Starch Hydrolysate. Because there is no existing
column coated with 0.1-mm stationary phase G2. The carrier NF monograph for this excipient, it is proposed to add a new
monograph based on validated methods of analysis submitted from
gas is helium, flowing at a rate of about 10 mL per minute. the manufacturer. Some additional tests were adopted from the
Hydrogenated Starch Hydrolysate monograph in Food Chemicals
The chromatograph is programmed as follows. Initially, the Codex, 5th edition, pages 221–222. The liquid chromatographic
procedures in the Assay are based on analyses performed with the
column is maintained at a temperature of 358, then Polymer Laboratories Hi-Plex brand of L58 column. The typical
retention times for maltose, maltitol, dextrose, and sorbitol are 29,
immediately after injection, the temperature is increased to 30, 34, and 36 minutes, respectively.
508 at a rate of 58 per minute, then increased to 1708 at a rate
(EM2: H. Wang; NOM: L. Paul; MSA: R. Tirumalai) RTS—
of 128 per minute, then increased to 3108 at a rate of 108 per C39325
minute, and maintained at 3108 for 18 minutes. The injection

port temperature is maintained isothermally at about 3108,
and the detector temperature is maintained isothermally at
about 3208. Chromatograph the System suitability solution, Add the following:
and record the responses as directed for Procedure: the &Hydrogenated Starch Hydrolysate
resolution, R, between tetradecane and hexadecane is not less
than 2.0; and the relative standard deviation for replicate
Hydrogenated Polysaccharides
injections for each peak is not more than 2.0%. [NOTE—For
information purposes only, the retention time for squalane is
In-Process Revision
about 18 minutes; and the relative retention times are about

0.5 for tetradecane, 0.6 for hexadecane, and 1.0 for squalane.]
Procedure—Inject a volume (about 2 mL) of the Test
C12H24O11(C6H10O5)n
solution into the chromatograph, record the chromatogram,
and measure the areas for the major peaks. [NOTE—For Polyglucitol [68425-17-2].
information purposes only, the tetramer oligomer has
a retention time of about 23 minutes. The trimer, pentamer,
» Hydrogenated Starch Hydrolysate is a mixture
hexamer, and heptamer oligomers, if present, have relative
retention times of about 0.8, 1.1, 1.3, and 1.4, respectively,
that contains less than 5% Sorbitol, less than 15%
relative to the tetramer.] Calculate the percentage of each Maltitol, and not less than 80% of hydrogenated
oligomer present by the formula: polysaccharides that contain more than 2 D-gluco-
Pharmacopeial Forum
pyranosyl units joined by a-1,4 linkages and Sulfur dioxide—Dissolve a quantity of Hydrognated Starch
terminated with a D-glucityl unit, calculated on Hydrolysate, equivalent to 50 g on the dried basis, in 150 mL
of water to obtain a homogenous solution. Cool the solution
the dried basis.
to 108 or lower. Stir the cold solution at a rate sufficient to
Packaging and storage—Preserve in well-closed containers. produce a small vortex at the solution surface. Add 10 mL of
No storage requirements specified. cold 1.5 N sodium hydroxide solution [NOTE—Keep acid and
USP Reference standards h11i—USP Dextrose RS. USP base solutions at 108 or lower], and stir for 15 to 20 seconds.
Maltitol RS. USP Maltose Monohydrate RS. USP Sorbitol RS. Add 10 mL of 1% starch solution as an indicator, and 10 mL
Identification—The retention times of the peaks for maltitol of cold 2.0 N sulfuric acid solution. Immediately titrate with
and sorbitol in the chromatogram of the Assay preparation 0.005 N iodine VS until a light blue or green color persists for
correspond to those in the chromatogram of the Standard a few seconds (see Titrimetry h541i). Perform a blank
preparation, as obtained in the Assay. determination, and make any necessary correction. Not more
than 12 mL of 0.005 N iodine is consumed, corresponding to
not more than 0.004% of sulfur dioxide.
does not exceed 1000 cfu per g, and the total combined molds
and yeasts count does not exceed 100 cfu per g. It meets the Limit of chloride—
requirements of the tests for absence of Salmonella species Test solution—Transfer a quantity of Hydrogenated Starch
and Escherichia coli. Hydrolysate equivalent to 25 g on the dried basis, to a beaker,
add 100 mL of water, and stir until the Hydrogenated Starch
pH h791i: between 3.0 and 7.0, in a 20% (w/w) solution in
Hydrolysate is completely dissolved.
carbon dioxide-free water.
Procedure—Add 1.0 mL of potasium chromate indicator
Loss on drying h731i—Dry 5 g of Hydrogenated Starch
solution (1 in 20) into the Test solution. Slowly titrate with
Hydrolysate at 1058 for 4 hours: it loses not more than 8% of
0.1 N silver nitrate VS until a reddish-orange color persists.
its weight.
Calculate the quantity, in mg, of chloride in each g of
Residue on ignition h281i: not more than 0.15%. Hydrogenated Starch Hydrolysate taken by the formula:
Reducing sugars—Dissolve a quantity of Hydrogenated

3545.3V / W
Starch Hydrolysate, equivalent to 1.0 g on the dried basis, in
6 mL of water with the aid of gentle heat, if necessary. Cool,
in which V is the volume, in mL, of 0.1 N silver nitrate
In-Process Revision
and add 20.0 mL of cupric citrate TS and a few glass beads.
solution consumed in the titration; and W is the weight, in g,
Heat so that boiling begins after 4 minutes, and maintain
of Hydrogenated Starch Hydrolysate taken to prepare the Test
boiling for 3 minutes. Cool rapidly, and add 40 mL of diluted
solution: not more than 50 mg of chloride per g is found.
acetic acid, 60 mL of water, and 20.0 mL of 0.05 N iodine
Limit of nickel—
VS. With continuous shaking, add 25 mL of a mixture of
Blank solution—Add 2.0 mL of saturated ammonium
6 mL of hydrochloric acid and 94 mL of water. When the
pyrrolidinedithiocarbamate TS to 150.0 mL of strong acetic
precipitate has dissolved, titrate the excess of iodine with
acid TS, and mix. Add 10.0 mL of methyl isobutyl ketone,
0.05 N sodium thiosulfate VS using 2 mL of starch TS as an
and shake for 30 seconds. Protect from bright light. Allow the
indicator, added towards the end of the titration. Not less than
12.8 mL of 0.05 N sodium thiosulfate is required, corre-
sponding to not more than 1% of reducing sugars.
Pharmacopeial Forum
two layers to separate, and use the methyl isobutyl ketone mL, in the Test solution. Calculate the content of nickel in the
layer. Several portions (10 mL each) of Blank solution are portion of Hydrogenated Starch Hydrolysate taken by the
prepared. formula:
Standard solutions—Add a quantity of Hydrogenated
Starch Hydrolysates, equivalent to 20.0 g on the dried basis, 10C / W
to each of three identical flasks, and dissolve in and dilute
in which W is the weight, in g, of Hydrogenated Starch
with strong acetic acid TS to 150.0 mL. Into these three flasks
Hydrolysate taken to prepare the Test solution: not more than
introduce respectively 0.5, 1.0, and 1.5 mL of nickel standard
1 mg per g is found.
solution TS, and mix. To each flask, add 2.0 mL of saturated
ammonium pyrrolidinedithiocarbamate TS and 10.0 mL of Limit of lead—[NOTE—For this test, use reagent-grade
methyl isobutyl ketone, and shake for 30 seconds. Protect chemicals, water, and gases that contain as low a lead content
from bright light. Allow the two layers to separate, and use as is practicable. Before use in this analysis, rinse all
the methyl isobutyl ketone layer. These Standard solutions glassware and plasticware twice with 5% nitric acid and twice
are fortified with the equivalent of 0.5, 1.0, and 1.5 mg of with 5% hydrochloric acid, and then rinse them thoroughly
nickel per mL from the nickel standard solution TS. with water.]
Test solution—Dissolve a quantity of Hydrogenated Starch Modifier stock solution—Transfer 20 g of magnesium
Hydrolysate equivalent to 20.0 g on the dried basis, in strong nitrate to a 100-mL volumetric flask, dilute with water to
acetic acid TS, and dilute with strong acetic acid TS to 150.0 volume, and mix.
mL. Add 2.0 mL of saturated ammonium pyrrolidinedithio- Modifier working solution—Just before use, pipet 1.0 mL
carbamate TS, and 10.0 mL of methyl isobutyl ketone, and of Modifier stock solution into a 10-mL volumetric flask,
shake for 30 seconds. Protect from bright light. Allow the two dilute with water to volume, and mix.
layers to separate, and use the methyl isobutyl ketone layer. Lead nitrate stock solution—Dissolve 16.0 mg of lead
Procedure—Concomitantly determine the absorbances of nitrate in 10 mL of 5% nitric acid, then dilute with 5% nitric
the Standard solutions and the Test solution at least three acid to 100 mL. Prepare and store this solution in glass
times each, at the wavelength of maximum absorbance at containers free from soluble lead salts.
232.0 nm, with a suitable atomic absorption spectrophotom- Standard lead solution—On the day of use, dilute 10.0 mL
eter (see Spectrophotometry and Light-Scattering h851i) of Lead nitrate stock solution with 5% nitric acid to 100.0
In-Process Revision
equipped with an air–acetylene flame and a nickel hollow- mL, and mix. Each mL of Standard lead solution contains the
cathode lamp, using the Blank solution to zero the instrument. equivalent of 10 mg of lead.
Record the average of the steady readings for each of the Standard solutions—Into 5 separate 100-mL volumetric
Standard solutions and the Test solution. Between each flasks, pipet 0.1, 0.25, 0.5, 1.0, and 5.0 mL, respectively, of
measurement, aspirate the Blank solution, and ascertain that Standard lead solution, dilute with 5% nitric acid, and mix.
the reading returns to its initial blank value. Plot the The Standard solutions contain, respectively, 0.01, 0.025,
absorbances of the Standard solutions and the Test solution 0.05, 0.1, and 0.5 mg of lead per mL. [NOTE—The calibration
versus the added quantity of nickel. Extrapolate the line range, especially the upper limit, can be adjusted for certain
joining the points on the graph until it meets the concentration instruments, provided that instrument validation and calibra-
axis. The distance between this point and the intersection of tion linearity are achieved.]
the axes represents the concentration of nickel, C, in mg per
Pharmacopeial Forum
Test solution—[Caution—Perform the procedure in a fume Standard blank—Use 5% nitric acid.

hood, and wear safety glasses.] Dissolve a quantity of Test blank—Transfer 3.0 g of water to a digestion tube.
Hydrogenated Starch Hydrolysate equivalent to 5.0 g on the Proceed in the same manner as directed for preparation of the
dried basis, in 5 g of water. Mix until completely dissolved. Test solution, beginning with ‘‘Add 0.75 mL of nitric acid.’’
Transfer 3.0 g of the solution to a digestion tube. Add 0.75 Procedure—Clean the furnace by running 5% nitric acid
mL of nitric acid. Heat the tube in a water bath (heat a quartz solution. [NOTE—The sample injection technique is the most
tube in a water bath or heating block), warming slowly to crucial step in controlling the precision of the analysis; the
between 908 and 958 to avoid spattering. Heat until all brown volume of each of the Standard solutions and the Test
vapors have dissipated and any rust-colored tint has solution must remain constant. Rinse the microliter pipet tip
disappeared (20 to 30 minutes), and allow the tube to cool. three times with either the Standard solutions or Test solution
Add 0.5 mL of 50% hydrogen peroxide dropwise. Heat to before injection. Use a fresh pipet tip for each injection, and
between 908 and 958 for 5 minutes, and allow the tube to start the atomization process immediately after injecting the
cool. Add a second 0.5-mL portion of 50% hydrogen Standard solutions and Test solution. Between injections,
peroxide, dropwise. Heat to between 908 and 1008 for 5 to flush the graphite tube of any residual lead by purging at
10 minutes until clear, and allow the tube to cool. Dilute with a high temperature as recommended by the manufacturer.]
water to a final volume of 10 mL. Concomitantly determine the absorbances of 20-mL aliquots
Spiked test solution—[Caution—Perform the procedure in of the five Standard solutions, a mixture of 5 mL of the
a fume hood, and wear safety glasses.] Dissolve a quantity of Modifier working solution and 20 mL of Test blank, a mixture
Hydrogenated Starch Hydrolysate equivalent to 5.0 g on the of 5 mL of the Modifier working solution and 20 mL of the
dried basis, in 5 g of water. Mix until completely dissolved. Test solution, and a mixture of 5 mL of the Modifier working
Transfer 3.0 g of the solution into a digestion tube. Add 0.75 solution and 20 mL of the Spiked test solution at least three
mL of nitric acid. Heat the tube in a water bath (heat a quartz times each, and average the results at the lead emission line at
tube in a water bath or heating block), warming slowly to 283.3 nm, with a suitable graphite furnace atomic absorption
between 908 and 958 to avoid spattering. Heat until all brown spectrophotometer (see Spectrophotometry and Light-
vapors have dissipated and any rust-colored tint has Scattering h851i) equipped with a pyrolytically-coated
disappeared (20 to 30 minutes), and allow the tube to cool. graphite tube, a solid pyrolytic graphite platform, and a lead
Add 0.5 mL of 50% hydrogen peroxide dropwise. Heat to hollow-cathode lamp, using a slit width of 0.7 mm (set low)
between 908 and 958 for 5 minutes, and allow the tube to and an adequate means of background correction, and using
In-Process Revision
cool. Add a second 0.5-mL portion of 50% hydrogen the Standard blank to zero the instrument. The furnace
peroxide, dropwise. Heat to between 908 and 1008 for 5 to program is operated by maintaining the drying temperature of
10 minutes until clear, and allow the tube to cool. Add 0.1 mL the furnace at 2008 for 30 seconds after a 20-second ramp
of Standard lead solution to the tube, and mix. Dilute with time using an argon flow rate of 300-mL per minute,
water to a final volume of 10 mL. This solution contains 0.1 maintaining the ashing temperature at 7508 for 40 seconds
mg of added lead per mL. after a 40-second ramp time using an air flow rate of 300 mL
per minute, maintaining the cooling down temperature at 208
and purging the air from the furnace for 60 seconds using an
argon flow rate of 300 mL per minute, and maintaining the
atomization temperature at 18008 for 10 seconds with the
Pharmacopeial Forum
argon flow stopped. Clean the graphite furnace at 26008 for Assay—
7 seconds after a 1-second ramp time using an argon flow rate Mobile phase—Use degassed water.
of 300 mL per minute, and recharge the graphite furnace at Standard preparation—Dissolve accurately weighed quan-
208 for 5 seconds after a 1-second ramp time using an argon tities of USP Maltose Monohydrate RS, USP Maltitol RS,
flow rate of 300 mL per minute. [NOTE—The temperature USP Dextrose RS, and USP Sorbitol RS in water to obtain
program may be modified to obtain optimum furnace a solution having known concentrations of about 1.0 mg per
temperatures.] Plot the integrated absorbance of each mL for each, calculated on the anhydrous basis.
Standard solution versus its content, in mg of lead per mL, Assay preparation—Transfer a quantity of Hydrogenated
and draw the best straight line fitting the five points. From this Starch Hydrolysate, equivalent to 100 mg on the dried basis,
plot, determine the concentrations, CT and CST, in mg per mL, to a 100-mL volumetric flask. Dilute with water to volume,
of lead in the Test solution and the Spiked test solution, and mix. Transfer approximately 10 mL of the solution into
respectively. [NOTE—Correct the integrated absorbance values a separate container, shake the solution for 30 seconds, and
of the Test solution and Spiked test solution by subtracting pass through a filter having a 0.45-mm or finer porosity into
from them the integrated absorbance value obtained from the a suitable autosampler vial, and seal.
Test blank.] Calculate the percentage recovery of lead in the Chromatographic system (see Chromatography h621i)—
portion of Hydrogenated Starch Hydrolysate taken by the The liquid chromatograph is equipped with a refractive index
formula: detector that is maintained at 408 and a 7.7-mm 6 30-cm
column that contains packing L58. The column temperature is
100[(CST – CT) / 0.1]
maintained at 808, controlled within +28, and the flow rate is
about 0.3 mL per minute. Chromatograph the Standard
in which 0.1 is the amount, in mg per mL, of lead added to the
preparation, and identify the components based on their
Spiked test solution. Calculate the content of lead, in mg per g,
relative retention times which are 0.80, 0.83, 0.94, and 1.00
in the portion of Hydrogenated Starch Hydrolysate taken by
for maltose, maltitol, dextrose, and sorbitol, respectively.
the formula:
Sorbitol is the last peak to elute on the chromatogram. Record
the peak responses as directed for Procedure: for the maltitol
10CT (W1 + W2) / W3W1
peak, the relative standard deviation for replicate injections is
in which W1 and W2 are the weights, in g, of Hydrogenated not more than 2.0%.
In-Process Revision
Starch Hydrolysate and water, respectively, taken to prepare

the Test solution before its digestion; and W3 is the weight, in
g, of the Test solution taken for digestion: not more than 1.0
mg of lead per g is found.
Pharmacopeial Forum

BRIEFING
of the Assay preparation and the Standard preparation into
the chromatograph, record the chromatograms, and measure Sodium Caprylate, NF 25 page 1207. On the basis of comments
received, it is proposed to clarify the test for Appearance of solution
the responses for the major peaks. Calculate the percentage of with the addition of a prepared reference solution when the resulting
solution is not clear and colorless.
each component, maltose (PM1), maltitol (PM2), dextrose (PD),
and sorbitol (PS), in the portion of Hydrogenated Starch (EM1: R. Lafaver) RTS—C50818
Hydrolysate taken by the formula:

Change to read:
(10,000C / W) / (rU / rS) Appearance of solution—Dissolve 2.5 g of Sodium Caprylate in

25.0 mL of freshly boiled and cooled water: the resulting solution is
clear and colorless,
in which C is the concentration, in mg per mL, of the &

and if not, not more intensely colored than a reference
respective component in the Standard preparation; W is the solution prepared as follows:
weight, in mg, of Hydrogenated Starch Hydrolysate taken to Reference stock solution—Pipet 30.0 mL of ferric chloride
prepare the Assay preparation; and rU and rS are the peak CS, 30.0 mL of cobaltous chloride CS, and 24.0 mL of cupric
responses obtained from the Assay preparation and the sulfate CS into a 100-mL volumetric flask. Dilute with 1%
Standard preparation, respectively: less than 15% of maltitol (w/v) hydrochloric acid to volume, and mix.
is found, less than 5% of sorbitol is found, and less than 1% Reference solution—Pipet 1.0 mL of the Reference stock
of maltose and dextrose (total) are found. Calculate the solution into a 100-mL volumetric flask. Dilute with 1%
percentage of hydrogenated polysaccharides other than the (w/v) hydrochloric acid to volume, and mix.&1S (NF26)
components of maltose, maltitol, dextrose, and sorbitol in the

portion of Hydrogenated Starch Hydrolysate taken by the
formula:
100 – PM1 – PM2 – PD – PS
Not less than 80% is found.&1S (NF26)
In-Process Revision
Pharmacopeial Forum
The labeling includes the following information if the complete

formula is not specified in the individual monograph: (1) In the case
GENERAL CHAPTERS of a liquid preparation, the percentage content of each ingredient or
the amount of each ingredient in a specified volume, except that in-
gredients added to adjust to a given pH or to make the solution iso-
tonic may be declared by name and a statement of their effect; and (2)
General Tests and Assays in the case of a dry preparation or other preparation to which a diluent
is intended to be added before use, the amount of each ingredient, the
composition of recommended diluent(s) [the name(s) alone, if the for-
mula is specified in the individual monograph], the amount to be used
General Requirements for to attain a specific concentration of active ingredient and the final vol-
ume of solution so obtained, a brief description of the physical ap-
Tests and Assays pearance of the constituted solution, directions for proper storage of
the constituted solution, and an expiration date limiting the period
during which the constituted solution may be expected to have the
required or labeled potency if it has been stored as directed.
Containers for Injections that are intended for use as dialysis, he-
mofiltration, or irrigation solutions and that contain a volume of more
than 1 L are labeled to indicate that the contents are not intended for
use by intravenous infusion.
Injections intended for veterinary use are labeled to that effect.
The container is so labeled that a sufficient area of the container
remains uncovered for its full length or circumference to permit in-
spection of the contents.
BRIEFING
h1i Injections, USP 30 page 33, the Interim Revision Announce-

ment on page 188 of PF 33(2) [Mar.–Apr. 2007], and page 402 of PF
&
STRENGTH AND TOTAL VOLUME FOR SINGLE- AND
32(2) [Mar.–Apr. 2006]. The Parenteral Products—Industrial, No-
menclature and Labeling, and Safe Medication Use Expert Commit- MULTIPLE-DOSE INJECTABLE DRUG PRODUCTS
tees have agreed on the appearance of identifying numbers or letters
on the side (skirt) surface of the ferrule on vials that contain injectable
products. For the prevention of counterfeiting, an additional state- For single-dose and multiple-dose injectable drug products,
ment that allows any anti-counterfeit scheme to be present if it does
not detract from or interfere with cautionary statements was included the strength per total volume should be the primary and prom-
in the new proposed text for Labeling on Ferrules and Cap Over-
seals, PF 31(5) [Sept.–Oct. 2005]. To clarify the intent of this section, inent expression on the principal display panel of the label,
the Parenteral Products Industrial Expert Committee has proposed a
new title and text, which will be targeted for the First Supplement to followed in close proximity by strength per mL enclosed by
USP 31 with an implementation date of February 1, 2009.
parentheses. For containers holding a volume of less than 1
(PPI: D. Hunt) RTS—C50935 mL, the strength per fraction of a mL should be the only ex-
pression of strength. Strength per single mL should be ex-
pressed as mg/mL, not mg/1 mL.
Change to read:
The following formats are acceptable for contents of
greater than 1 mL:
LABELS AND LABELING Total strength/total volume: 500 mg/10 mL
In-Process Revision
Labeling Strength/mL: (50 mg/mL)

NOTE—See definitions of ‘‘label’’ and ‘‘labeling’’ in Labeling in or
the section Preservation, Packaging, Storage, and Labeling of the
General Notices and Requirements. Total strength/total volume: 25,000 Units/5 mL
The label states the name of the preparation; in the case of a liquid
preparation, the percentage content of drug or amount of drug in a Strength/mL: (5,000 Units/mL)
specified volume; in the case of a dry preparation, the amount of ac-
tive ingredient; the route of administration; a statement of storage The following format is acceptable for contents of less
conditions and an expiration date; the name and place of business
of the manufacturer, packer, or distributor; and an identifying lot than 1 mL: 12.5 mg/0.625 mL
number. The lot number is capable of yielding the complete manufac-
turing history of the specific package, including all manufacturing, There are, however, some exceptions to expressing strength
filling, sterilizing, and labeling operations.
Where the individual monograph permits varying concentrations per total volume. In certain cases, the primary and prominent
of active ingredients in the large-volume parenteral, the concentration
of each ingredient named in the official title is stated as if part of the expression of the total drug content per container would not be
official title, e.g., Dextrose Injection 5%, or Dextrose (5%) and Sodi-
um Chloride (0.2%) Injection. effective in preventing medication errors (e.g., insulin). An ex-
ample is the use of lidocaine or other similar drugs used as a
Pharmacopeial Forum
local anesthetic where the product is ordered and administered neonates are particularly at risk because their kidneys are immature,
and they require large amounts of calcium and phosphate solutions
by percentage (e.g., 1%, 2%) or a local anesthetic in combina- which contain aluminum. Research indicates that patients with im-
paired kidney function, including premature neonates, who receive
tion with epinephrine that is expressed as a ratio (e.g., parenteral levels of aluminum at greater than 4 to 5 mg per kg per
day accumulate aluminum at levels associated with central nervous
1 : 100,000). In such cases, the total strength should be ex- system and bone toxicity. Tissue loading may occur at even lower
rates of administration of TPN products and of the lock flush solu-
pressed: for example, 1% (100 mg/10 mL). Dry solids, which tions used in their administration.’’
need to be reconstituted, should follow the same format, with &

&1S (USP30)
the exception that only the total strength of the drug should be
listed, not the strength/total volume or strength/mL.&1S (USP30) Change to read:
(Official February 1, 2009)

PACKAGING
Aluminum in Large-Volume Injections (LVIs), Small- Containers for Injections

Volume Injections (SVIs), and Pharmacy Containers, including the closures, for preparations for injections
Bulk Packages (PBPs) Used in Total Parenteral do not interact physically or chemically with the preparations in
Nutrition (TPN) Therapy any manner to alter the strength, quality, or purity beyond the official
requirements under the ordinary or customary conditions of handling,
(a) The aluminum content of LVIs used in TPN therapy must not shipment, storage, sale, and use. The container is made of material
exceed 25 mg per L. that permits inspection of the contents. The type of glass preferable
(b) The package insert of LVIs used in TPN therapy must state that for each parenteral preparation is usually stated in the individual
the drug product contains no more than 25 mg of aluminum per monograph. Unless otherwise specified in the individual monograph,
L. This information must be contained in the ‘‘Precautions’’ sec- plastic containers may be used for packaging injections (see Con-
tion of the labeling of all LVIs used in TPN therapy. tainers h661i).
(c) If the maximum amount of aluminum in SVIs and PBPs is 25 mg For definitions of single-dose and multiple-dose containers, see
per L or less, instead of stating the exact amount of aluminum Containers in the General Notices and Requirements. Containers
that each may contain, as in paragraph (d), the immediate con- meet the requirements under Containers h661i.
tainer label for SVIs and PBPs used in the preparation or in the Containers are closed or sealed in such a manner as to prevent con-
administration of TPN injections (with exceptions as noted be- tamination or loss of contents. Validation of container integrity must
low) and injectable emulsions may state: ‘‘Contains no more demonstrate no penetration of microbial contamination or chemical
than 25 mg/L of aluminum’’. If the SVI or PBP is a lyophilized or physical impurities. In addition, the solutes and the vehicle must
powder, the immediate container label may state the following; maintain their specified total and relative quantities or concentrations
if the SVI or PBP is a lyophilized powder used in the preparation when exposed to anticipated extreme conditions of manufacturing
of TPN injections and injectable emulsions, the immediate con- and processing, and storage, shipment, and distribution. Closures
tainer label must state the following: ‘‘When reconstituted in ac- for multiple-dose containers permit the withdrawal of the contents
cordance with the package insert instructions, the concentration without removal or destruction of the closure. The closure permits
of aluminum will be no more than 25 mg/L’’. penetration by a needle and, upon withdrawal of the needle, closes
(d) The maximum level of aluminum at expiry must be stated on the at once, protecting the container against contamination. Validation
immediate container label of all SVIs and PBPs used in the prep- of the multiple-dose container integrity must include verification that
aration or the administration of TPN injections and injectable such a package prevents microbial contamination or loss of product
emulsions. The aluminum content must be stated as follows: contents under anticipated conditions of multiple entry and use.
‘‘Contains no more than __ mg/L of aluminum’’. This maximum Piggyback containers are usually intravenous infusion containers
amount of aluminum may be stated as the highest one of the fol- used to administer a second infusion through a connector of some
lowing three levels: type or an injection port on the administration set of the first fluid,
1. The highest level for the batches produced during the last three thereby avoiding the need for another injection site on the patient’s
years body. Piggyback containers are also known as secondary infusion
2. The highest level for the latest five batches containers.
In-Process Revision
3. The maximum level in terms of historical levels, but only until
completion of production of the first five batches after the effec-
tive date of Potassium Chloride for Injection Concentrate
&
&1S (USP31) The use of a black closure system on a vial (e.g., a black flip-off
July 26, 2004. button and a black ferrule to hold the elastomeric closure) or the use
The package insert for all LVIs, SVIs, and PBPs used in the prep- of a black band or series of bands above the constriction on an ampul
aration or administration is prohibited, except for Potassium Chloride for Injection Concen-
trate.
&
&1S (USP30)
of TPN products must contain a warning statement. This warning
must be contained in the ‘‘Warnings’’ section of the labeling and must Neuromuscular Blocking and Paralyzing Agents
state the following: ‘‘WARNING: This product contains aluminum
that may be toxic. Aluminum may reach toxic levels with prolonged All injectable preparations of neuromuscular blocking agents and
parenteral administration if kidney function is impaired. Premature paralyzing agents must be packaged in vials with a cautionary state-
ment printed on the ferrules or cap overseals. Both the container cap
ferrule and the cap overseal must bear in black or white print (which-
ever provides the greatest color contrast with the ferrule or cap color)
the words: ‘‘Warning: Paralyzing Agent’’ or ‘‘Paralyzing Agent’’ (de-
Pharmacopeial Forum
pending on the size of the closure system). Alternatively, the overseal .Multi-Dose Containers— For Injections in multiple-dose con-
.2
may be transparent and without words, allowing for visualization of tainers labeled to yield a specific number of doses of a stated volume,
.
the warning labeling on the closure ferrule. select 1 container, and.2 proceed as directed .for single-dose con-
tainers,.2 using the same number of separate.syringe assemblies.2
as the number of doses specified. The volume is such that each sy-
Containers for Sterile Solids ringe delivers not less than the stated dose.
.Injections in Cartridges or Prefilled Syringes—Select 1 con-
Containers, including the closures, for dry solids intended for par- tainer if the volume is 10 mL or more, 3 containers if the nominal
enteral use do not interact physically or chemically with the prepara- volume is more than 3 mL and less than 10 mL, or 5 containers if
tion in any manner to alter the strength, quality, or purity beyond the the nominal volume is 3 mL or less. If necessary, fit the containers
official requirements under the ordinary or customary conditions of with the accessories required for their use (needle, piston, syringe)
handling, shipment, storage, sale, and use. and transfer the entire contents of each container without emptying
A container for a sterile solid permits the addition of a suitable sol- the needle into a dry tared beaker by slowly and constantly depressing
vent and withdrawal of portions of the resulting solution or suspen- the piston. Determine the volume in mL, calculated as the mass, in g,
sion in such manner that the sterility of the product is maintained. divided by the density.
Where the Assay in a monograph provides a procedure for the As- The volume measured for each of the containers is not less than the
say preparation, in which the total withdrawable contents are to be nominal volume..2
withdrawn from a single-dose container with a hypodermic needle .Large-Volume Intravenous Solutions—For intravenous solu-
and syringe, the contents are to be withdrawn as completely as pos-
sible into a dry hypodermic syringe of a rated capacity not exceeding tions, select 1 container. Transfer the contents into a dry measuring
three times the volume to be withdrawn and fitted with a 21-gauge cylinder of such a capacity that the volume to be determined occupies
needle not less than 2.5 cm (1 inch) in length, with care being taken at least 40% of the nominal volume of the cylinder. Measure the vol-
to expel any air bubbles, and discharged into a container for dilution ume transferred.
and assay. The volume is not less than the nominal volume..2
&
Labeling on Ferrules and Cap Overseals&1S (USP30)
Volume in Container
Each container of an injection is filled with sufficient excess of the &
Information on Ferrules and Cap Overseals&1S (USP31)
labeled ‘‘size’’ or that volume which is to be withdrawn. See Injec-
tions under Pharmaceutical Dosage Forms h1151i. &
Only cautionary statements are to appear on the top (circle)
surface of the ferrule or cap overseal of a vial containing an
DETERMINATION OF VOLUME OF INJECTION IN CONTAINERS
.Suspensions and emulsions must be shaken before withdrawal of injectable product. A cautionary statement is one intended to
the contents and before the determination of the density. Oily and vis- prevent an imminent life-threatening situation if the injectable
cous preparations may be warmed according to the instructions on the
label, if necessary, and thoroughly shaken immediately before remov- drug is used inappropriately. Examples of such statements in-
ing the contents. The contents are then cooled to 208–258C before
measuring the volume..2 clude but are not limited to the following: ‘‘Warning’’, ‘‘Dilute
.Single-Dose Containers— Select 1 .container if the volume
.2 .2
of the container is 10 mL or more, 3 .containers.2 if the .nominal.2 Before Using’’, ‘‘Paralyzing Agent’’, ‘‘I.M. Use Only’’, and
volume is more than 3 mL and less than 10 mL, or 5 .containers.2 if
the .nominal.2 volume is 3 mL or less. .Take up individually the to- ‘‘Chemotherapy’’.
tal.2 contents of each container selected into a dry syringe of a capa-
city not exceeding three times the volume to be measured and fitted The text must be in contrasting color and conspicuous under
with a 21-gauge needle not less than 2.5 cm (1 inch) in length. Expel
any air bubbles from the syringe and needle, and then discharge the ordinary conditions of use. The cautionary statement may ap-
contents of the syringe, without emptying the needle, into a standard-
ized, dry cylinder (graduated to contain rather than to deliver the des- pear solely on the ferrule, provided the cap overseal is con-
ignated volumes) of such size that the volume to be measured
occupies at least 40% of .its graduated.2 volume. Alternatively,.the structed so as to allow the cautionary statement beneath the
volume of the contents in mL may be calculated as the mass, in g,
cap to be readily legible.
In-Process Revision
divided by the density..2 For containers with a nominal volume of

2 mL or less, the contents of a sufficient number of containers may
be pooled to obtain the volume required for the measurement, pro- Identifying numbers or letters, such as code numbers, lot
vided that a separate, dry syringe assembly is used for each contain-
er.The contents of containers holding 10 mL or more may be numbers, etc., may appear on the side (skirt) surface of the fer-
determined by means of opening them and emptying the contents di-
rectly into the graduated cylinder or tared beaker. rule on vials containing injectable products. The appearance of
The volume is not less than the .nominal.2 volume in the case of
containers examined individually or, in the case of .containers with a such identifying data on the skirt surface of the ferrule, placed
nominal volume of 2 mL or less,.2 is not less than the sum of the
.nominal volumes of the containers taken collectively. where it does not detract from, or interfere with, the cautionary
.2
statement on the top surface, should be considered to be a ben-
eficial attribute of the in-process quality control of a product
throughout the manufacturing process. Any anti-counterfeit-
ing scheme must not detract from or interfere with the caution-
ary statements.
Pharmacopeial Forum
&
The following Injections are exempt from the 1-L restric-
Under no circumstances will advertising such as company
tion of the foregoing requirements relating to packaging:
names, logos, or product names be permitted to appear on
1. Injections packaged for extravascular use as irrigation so-
the top (circle) surface of any ferrule or cap overseal.&1S (USP30)
lutions or peritoneal dialysis solutions
&
Only cautionary statements or anti-counterfeiting features
2. Injections packaged for intravascular use as parenteral nu-
are to appear on the ferrules and cap overseals of vials contain-
trition or as replacement or substitution fluid to be admin-
ing an injectable product. A cautionary statement is one in-
istered continuously during hemofiltration
tended to prevent an imminent life-threatening situation if
Injections packaged for intravascular use that may be used
the drug is used inappropriately. Examples of such statements
for intermittent, continuous, or bolus replacement fluid admin-
may include, but are not limited to the following: ‘‘Dilute Be-
istration during hemodialysis or other procedures, unless ex-
fore Use’’, ‘‘Warning Paralyzing Agent’’, ‘‘I.M. Use Only’’,
cepted above, must conform to the 1-L restriction.&1S (USP30)
‘‘Chemotherapy’’, etc.
Injections labeled for veterinary use are exempt from packaging
The cautionary information must be in contrasting color and and storage requirements concerning the limitation to single-dose
containers and the limitation on the volume of multiple-dose con-
conspicuous under ordinary conditions of use. Cautionary in- tainers.
formation may be printed solely on the ferrule, providing the
cap overseal is clear (constructed so as to allow the cautionary
statement to be readily legible). Identifying information, such
BRIEFING
as a lot number, may appear on the side (skirt) surface of the
ferrule, placed where there is no detraction from, or interfer- h11i USP Reference Standards, USP 30 page 37, page 1832 of
PF 27(1) [Jan.–Feb. 2001], page 2022 of PF 29(6) [Nov.–Dec. 2003],
ence with, the cautionary statement on the top surface of the page 1338 of PF 30(4) [July–Aug. 2004], page 1674 of PF 30(5)
[Sept.–Oct. 2004], page 507 of PF 31(2) [Mar.–Apr. 2005], page
ferrule or cap overseal.&1S (USP31) 1154 of PF 31(4) [July–Aug. 2005], page 1433 of PF 31(5)
[Sept.–Oct. 2005], page 1680 of PF 31(6) [Nov.–Dec. 2005], page
181 of PF 32(1) [Jan.–Feb. 2006], page 407 of PF 32(2) [Mar.–
(Official February 1, 2009) Apr. 2006], page 829 of PF 32(3) [May–June 2006], page 1161 of
PF 32(4) [July–Aug. 2006], page 1491 of PF 32(5) [Sept.–Oct.
2006], page 1779 of PF 32(6) [Nov.–Dec. 2006], page 95 of PF
Packaging and Storage 33(1) [Jan.–Feb. 2007], and page 267 of PF 33(2) [Mar.–Apr. 2007].
The volume of injection in single-dose containers provides the (HDQ) RTS—C39916; C43961; C44030; C44055; C49317;
amount specified for parenteral administration at one time and in C52358; C52463; C52464; C52465; C52466
no case is more than sufficient to permit the withdrawal and admin-
istration of 1 L.
Preparations intended for intraspinal, intracisternal, or peridural
administration are packaged only in single-dose containers.
Unless otherwise specified in the individual monograph, a multi-
ple-dose container contains a volume of Injection sufficient to permit Add the following:
In-Process Revision
the withdrawal of not more than 30 mL.
Injections packaged for use as irrigation solutions, for hemofiltra- &
USP Acitretin Related Compound A RS [(2Z,4E,6E,8E)-
tion or dialysis, or for parenteral nutrition are exempt from the 1-L
restriction of the foregoing requirements relating to packaging. 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-
Containers for Injections packaged for use as hemofiltration or ir-
rigation solutions may be designed to empty rapidly and may contain 2,4,6,8-tetraenoic acid](C21H26O3 326.43).&1S (USP31)
a volume of more than 1 L.
Add the following:
&
USP Acitretin Related Compound B RS [(ethyl (all-E)-9-
(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-
2,4,6,8-tetraenoate)](C23H30O3 354.48).&1S (USP31)
Pharmacopeial Forum

&
USP Docosahexaenoic Ethyl Ester RS [all cis-4,7,10,13, &
USP rProtein A RS (C1917H3039N565O658S3
16,19-docosahexaenoic ethyl ester] (C24H36O2 44,618).&1S (USP31)
356.55).&1S (USP31)
Add the following:
USP rProtein A, B4, C-Cys RS (C1177H1854N326O384S1
&
USP Eicosapentaenoic Ethyl Ester RS [all cis-5,8,11,14, 26,747.6).&1S (USP31)
17-eicosapentaenoic ethyl ester] (C22H34O2

Add the following:
330.51).&1S (USP31)
&
USP rProtein A, C-Cys RS (C 1478 H 2320 N 432 O 503 S 4
Add the following: 34,317.5).&1S (USP31)
&
USP Esomeprazole Magnesium RS.&1S (USP31)
Add the following:
USP Terbinafine Hydrochloride RS.&1S (USP31)
&
USP Fish Oil RS.&1S (USP31)
Add the following: Chemical Tests and Assays

&
USP Formoterol Related Compound I Resolution Mix-
ture RS— This standard is a mixture of formoterol and formo-
terol fumarate impurity I. Impurity I is N-[2-hydroxy-5-
[(1RS)-1-hydroxy-2-[[(1SR)-2-(4-methoxyphenyl)-1-methy- OTHER TESTS AND
lethyl]amino]ethyl]phenyl]formamide fumarate salt
ASSAYS
(2 : 1)(diastereoisomer).&1S (USP31)
Add the following:

&
USP Methyl Tricosanoate RS [tricosanoic acid methyl BRIEFING
ester] (C24H48O2 368.64).&1S (USP31)
h525i Sulfur Dioxide. It is proposed to add this new general test
Add the following: chapter to be used for pharmaceutical excipients. Method I has been
introduced into the harmonized monographs of Corn Starch, Potato
&
USP Omeprazole Magnesium RS.&1S (USP31) Starch, and Wheat Starch and will be introduced into the Rice Starch
monograph through harmonization processes. Method II is currently
used in the Maltodextrin monograph. The other three methods are be-
Add the following: ing used in the monographs for some starch and starch-related mate-
In-Process Revision
rials. When this chapter becomes official, the detailed test procedures
&
USP Omeprazole Related Compound A RS [(omeprazole in these monographs will be removed, and readers will be referred to
this chapter.
sulfone, 5-methoxy-2-[[(4-methoxy-3,5-dimethylpyridin-2-
(EGC: H. Wang) RTS—C50635
yl)methyl]sulfonyl]-1H-benzimidazole)] (C17H19N3O4S
361.42 CAS-88546-55-8).&1S (USP31)
Add the following:

&
USP Protein A RS (C1995H3163N597O697S3
46,760).&1S (USP31)
Pharmacopeial Forum
Add the following: sealing surfaces of all the joints except the joint between the
separatory funnel and the boiling flask, and clamp the joints to
ensure tightness (see Figure 1).
&h525i SULFUR DIOXIDE
The following methods are provided for the determination

of sulfur dioxide in pharmaceutical excipients.
METHOD I
In this test, sulfur dioxide is released from the test specimen

in a boiling acid medium and is removed by a stream of carbon
dioxide. The separated gas is collected in a dilute hydrogen
peroxide solution, where the sulfur dioxide is oxidized to sul-
furic acid and titrated with standard alkali, using bromophenol
blue as an indicator.
Special Reagents
Figure 1. Apparatus for Method I

Carbon Dioxide—Use carbon dioxide with a flow regula-
tor that will maintain a flow of 100 + 10 mL per minute.
Hydrogen Peroxide Solution—Dilute a portion of 30 per-

Procedure
cent hydrogen peroxide with water to obtain a 3% solution.
Just before use, add 0.15 mL of bromophenol blue TS, and Add 150 mL of water to the boiling flask (A). Close the stop-
neutralize to a violet-blue endpoint with 0.01 N sodium hy- cock of the separatory funnel, and begin the flow of carbon
droxide. Do not exceed the endpoint. dioxide at a rate of 100 + 5 mL per minute through the appa-
ratus. Start the condenser coolant flow. Place 10 mL of Hydro-
gen Peroxide Solution in the receiving test tube (D). After 15
Apparatus minutes, without interrupting the flow of carbon dioxide re-
In-Process Revision
A suitable apparatus for sulfur dioxide determination is move the separatory funnel (B) from the boiling flask, and
shown in Figure 1. transfer 25.0 g of test specimen to the boiling flask with the
The apparatus consists of a 500-mL three-neck, round- aid of 100 mL of water. Apply stopcock grease to the outer
bottom boiling flask, A; a separatory funnel, B, having a ca- joint of the separatory funnel, and replace the separatory fun-
pacity of 100 mL or greater; a gas inlet tube of sufficient length nel in the boiling flask. Close the stopcock of the separatory
to permit introduction of the carbon dioxide within 2.5 cm of funnel, and add 80 mL of 2 N hydrochloric acid to the sepa-
the bottom of the boiling flask; a reflux condenser, C, having a ratory funnel. Open the stopcock of the separatory funnel to
jacket length of 200 mm; and a delivery tube, E, connecting permit the hydrochloric acid solution to flow into the boiling
the upper end of the reflux condenser to the bottom of a receiv- flask, guarding against the escape of sulfur dioxide into the
ing test tube, D. Apply a thin film of stopcock grease to the separatory funnel by closing the stopcock before the last few
mL of hydrochloric acid drain out. Boil the mixture for 1 hour.
Pharmacopeial Forum
Open the stopcock of the funnel, stop the flow of carbon diox- Nitrogen—Use high-purity nitrogen with a flow regulator
ide, discontinue heating the flask, and turn off the cooling wa- that will maintain a flow of 200 + 10 mL per minute. Guard
ter in the condenser. Remove the receiving test tube, and against the presence of oxygen by passing the nitrogen
transfer its contents to a 200-mL wide-necked, conical flask. through a scrubber, such as alkaline pyrogallol, prepared as
Rinse the receiving test tube with a small portion of water, follows: add 4.5 g of pyrogallol to a gas-washing bottle, purge
add the rinsing to the 200-mL conical flask, and mix. Heat the bottle with nitrogen for 3 minutes, and add a solution con-
on a water bath for 15 minutes, and allow to cool. Add 0.1 taining 85 mL of water and 65 g of potassium hydroxide while
mL of bromophenol blue TS, and titrate the contents with maintaining an atmosphere of nitrogen in the bottle.
0.1 N sodium hydroxide VS until the color changes from yel-
low to violet-blue, with the color change lasting for at least 20
Apparatus
seconds. Perform a blank determination and make any neces-
sary correction (see Titrimetry h541i). Calculate the content, in The apparatus (see Figure 2) is designed to effect the selec-
mg per g, of sulfur dioxide in the test specimen taken by the tive transfer of sulfur dioxide from the specimen in boiling
formula: aqueous hydrochloric acid to the Hydrogen Peroxide Solution
in vessel G. The backpressure is limited to the unavoidable
1000(32.03)VN / W pressure due to the height of the Hydrogen Peroxide Solution
above the tip of the bubbler, F. Keeping the backpressure as
in which 32.03 is the milliequivalent weight of sulfur dioxide; low as possible reduces the likelihood that sulfur dioxide will
the factor 1000 converts mg to mg; V is the volume, in mL, of be lost through leaks. Preboil vinyl and silicone tubing. Apply
titrant consumed; N is the normality of the titrant; and W is the a thin film of stopcock grease to the sealing surfaces of all the
weight, in g, of the test specimen taken. joints except the joint between the separatory funnel and the
flask, and clamp the joints to ensure tightness. The separatory
METHOD II funnel, B, has a capacity of 100 mL or greater. The inlet
In this method, similar to Method I, sulfur dioxide is re- adapter, A, with a hose connector, provides a means of apply-
leased from the test specimen in a boiling acid medium and ing headpressure over the solution. [NOTE—A pressure-equal-
is removed by a stream of nitrogen. The separated gas is col- izing dropping funnel is not recommended because
lected in a dilute hydrogen peroxide solution, where the sulfur condensate, which may contain sulfur dioxide, is deposited
dioxide is oxidized to sulfuric acid and titrated with standard in the funnel and the side arm.]
In-Process Revision
alkali, using methyl red as an indicator. The round-bottom flask, C, is a 1000-mL flask with three
24/40 tapered joints. The gas inlet tube, D, is long enough to
permit introduction of the nitrogen to within 2.5 cm of the bot-
Special Reagents
tom of the flask. The Allihn condenser, E, has a jacket length
Hydrogen Peroxide Solution—Dilute a portion of 30 per- of 300 mm. The bubbler, F (see Figure 3) is fabricated from
cent hydrogen peroxide with water to obtain a 3% solution. glass according to the dimensions given in Figure 3. The Hy-
Just before use, add 3 drops of methyl red TS, and neutralize drogen Peroxide Solution is contained in a vessel, G, having
to a yellow endpoint with 0.01 N sodium hydroxide. Do not an inside diameter of about 2.5 cm and a depth of about 18 cm.
exceed the endpoint. Circulate coolant, such as a mixture of water and methanol
(4 : 1) maintained at 58, to chill the condenser.
Pharmacopeial Forum
Procedure
Position the apparatus in a heating mantle controlled by a

power-regulating device. Add 400 mL of water to the flask.
Close the stopcock of the separatory funnel, and add 90 mL
of 4 N hydrochloric acid to the separatory funnel. Begin the
flow of nitrogen at a rate of 200 + 10 mL per minute. Start
the condenser coolant flow. Add 30 mL of Hydrogen Peroxide
Solution to the vessel (G). After 15 minutes, remove the sepa-
ratory funnel, and transfer a mixture of 50.0 g of the test spec-
imen, accurately weighed, and 100 mL of alcohol solution (5
in 100) to the flask. Apply stopcock grease to the outer joint of
the separatory funnel, return the separatory funnel to the ta-
pered joint flask, and concomitantly resume the nitrogen flow.
Apply headpressure above the hydrochloric acid solution in
the separatory funnel with a rubber bulb equipped with a
valve. Open the stopcock of the separatory funnel to permit
Figure 2. Apparatus for Method II
the hydrochloric acid solution to flow into the flask. Continue
to maintain sufficient pressure above the hydrochloric acid so-
lution to force it into the flask. [NOTE—The stopcock may be
temporarily closed, if necessary, to increase the pressure.] To
guard against escape of sulfur dioxide into the separatory fun-
nel, close the stopcock before the last few mL of hydrochloric
acid drain out. Apply power to the heating mantle sufficient to
cause about 85 drops of reflux per minute. After refluxing for
1.75 hours, remove the vessel (G), add 3 drops of methyl red
In-Process Revision
TS, and titrate the contents with 0.01 N sodium hydroxide VS,
using a 10-mL buret with an overflow tube and a hose connec-
tion to a carbon dioxide-absorbing tube, to a yellow endpoint
that persists for at least 20 seconds. Perform a blank determi-
nation, and make any necessary correction (see Titrimetry
h541i). Calculate the quantity, in mg, of SO2 in each g of the
test specimen taken by the formula:
Figure 3. Bubbler (F) for apparatus in Method II
1000(32.03)VN / W
Pharmacopeial Forum
in which 32.03 is the milliequivalent weight of sulfur dioxide; lution, prepared as follows: mix 10 g of soluble starch with 50
the factor 1000 converts mg to mg; V is the volume, in mL, of mL of cold water, transfer to 1000 mL of boiling water, stir
titrant consumed; N is the normality of the titrant; and W is the until completely dissolved, cool, and add 1 g of salicylic acid
weight, in g, of the test specimen taken. preservative. [NOTE—Discard the solution after 1 month.] Add
10 mL of 2.0 N sulfuric acid (at a temperature between 58 and
METHOD III 108), and titrate immediately with 0.005 N iodine VS until a
light blue color persists for 1 minute (see Titrimetry h541i).
Procedure Perform a blank determination, using 200 mL of water treated
similarly to the solution under test, and make any necessary
Mix 20 g of the test specimen, accurately weighed, with 200
correction. Each mL of 0.005 N iodine is equivalent to 0.16
mL of an appropriate solvent such as water, or a mixture of
mg of SO2.
alcohol and water, or a 1 in 5 solution of anhydrous sodium
sulfate, and stir until a smooth suspension is obtained. Allow
METHOD V
the test specimen mixture to remain undisturbed until most of
the test specimen has settled, and filter the aqueous portion
Procedure
through paper (Whatman No. 1 or equivalent). To 100 mL
of the clear filtrate add 100 mL of water, and mix, if necessary; Dissolve 20.0 g of the test specimen in 150 mL of hot water
otherwise, without adding 100 mL of water, add 3 mL of in a flask having a round bottom and a long neck, add 5 mL of
starch TS, and titrate with 0.01 N iodine solution VS to the first phosphoric acid and 1 g of sodium bicarbonate, and at once
permanent blue or purple color. Each 1.0 mL of 0.01 N iodine connect the flask to a condenser. [NOTE—Excessive foaming
solution VS consumed corresponds to 0.003% of sulfur diox- can be alleviated by the addition of a few drops of a suitable
ide found. antifoaming agent.] Distill 50 mL, receiving the distillate un-
der the surface of 50 mL of 0.1 N iodine. Acidify the distillate
METHOD IV with a few drops of hydrochloric acid, add 2 mL of barium
chloride TS, and heat on a steam bath until the liquid is nearly
Procedure colorless. The precipitate of barium sulfate, if any, when fil-
tered, washed, and ignited, weighs not more than 3 mg, corre-
Transfer about 50 to 100 g of the substance to be tested, ac-
sponding to not more than 0.004% of sulfur dioxide,
curately weighed, to a 250-mL conical flask, add 100 to 150
In-Process Revision
correction being made for any sulfate that may be present in

mL of water, and mix. Cool to between 58 and 108. While stir-
50 mL of the 0.1 N iodine.&1S (USP31)
ring with a magnetic stirrer, add 10 mL of cold 1.5 N sodium
hydroxide (at a temperature between 58 and 108). Stir for an
additional 20 seconds, and add 10 mL of starch indicator so-
Pharmacopeial Forum
where a standard material is included among the reagent specifica-

REAGENTS, INDICATORS, tions (e.g., Calcium Carbonate, primary standard; or Sodium
Carbonate, primary standard).
AND SOLUTIONS Reagents and solutions should be preserved in tight containers
made of resistant glass or other suitable material. Directions for
storage in light-resistant containers should be carefully observed.
Stoppers and stopcocks brought into contact with substances
capable of attacking or penetrating their surfaces may be given
a protective coating of a thin film of a suitable lubricant unless
Reagent Specifications specifically interdicted.
Where a particular brand or source of a material or piece of
equipment, or the name and address of a manufacturer, is mentioned,
this identification is furnished solely for informational purposes as
a matter of convenience, without implication of approval, endorse-
ment, or certification.
BRIEFING Atomic absorption and flame photometry require the use of
a number of metal-ion standard solutions. While the individual
monographs usually provide directions for preparation of these
solutions, use of commercially prepared standardized solutions of
Reagents, Indicators, and Solutions. USP 29 page 3102. It is the appropriate ions is permissible, provided that the analyst
proposed to include in the Water section the specifications for confirms the suitability of the solutions and has data to support
Particle-free water. their use.
Reagents are substances used either as such or as constituents of
(HDQ: M. Marques) RTS—C52250 solutions.
Indicators are reagents used to determine the specified end-point
in a chemical reaction, to measure hydrogen-ion concentration (pH),
or to indicate that a desired change in pH has been effected. They are
Change to read: listed together with indicator test papers.
Buffer Solutions are referred to separately.
This section deals with the reagents and solutions required in Colorimetric Solutions, abbreviated ‘‘CS,’’ are solutions used in
conducting the Pharmacopeial and the National Formulary tests and the preparation of colorimetric standards for comparison purposes.
assays. Test Solutions, abbreviated ‘‘TS,’’ are solutions of reagents in
As is stated in the General Notices, listing of reagents, indicators, such solvents and of such definite concentrations as to be suitable for
and solutions in the Pharmacopeia in no way implies that they have the specified purposes.
therapeutic utility; thus, any reference to the USP in their labeling is Volumetric Solutions, abbreviated ‘‘VS’’ and known also as
to include the term ‘‘reagent’’ or ‘‘reagent grade.’’ Standard Solutions, are solutions of reagents of known concentra-
Reagents required in the tests and assays for the Pharmacopeial tion intended primarily for use in quantitative determinations.
and National Formulary articles are listed in this section, generally Concentrations are usually expressed in terms of normality.
with specifications appropriate to their intended uses. Exceptions to Water—As elsewhere in the Pharmacopeia, where ‘‘water,’’
the latter include those reagents for which corresponding specifica- without qualification, is mentioned in the tests for reagents or in
tions are presented in the current edition of Reagent Chemicals, directions for preparing test solutions, etc., Purified Water (USP
published by the American Chemical Society, and reagents for which monograph) is always to be used. ‘‘Carbon dioxide-free water’’
specifications could not be drafted in time for inclusion here. Thus,
where it is directed to ‘‘Use ACS reagent grade,’’ it is intended that
&
Carbon dioxide-free water&1S (USP31)
a grade meeting the corresponding specifications of the current is Purified Water that has been boiled vigorously for 5 minutes or
edition of ACS Reagent Chemicals shall be used. Where no such more and allowed to cool while protected from absorption of carbon
specifications exist, and where it is directed to ‘‘Use a suitable dioxide from the atmosphere, or Purified Water that has a resistivity
grade,’’ the intent is that a suitable reagent grade available of not less than 18 Mohm-cm. ‘‘Deaerated water’’
commercially shall be used. Occasionally, additional test(s) augment
the designation ‘‘suitable grade,’’ as indicated in the text. Listed also
&
Deaerated water,&1S (USP31)
are some, but not all, reagents that are required only in determining for purposes other than dissolution and drug release testing, is
the quality of other reagents. For those reagents that are not listed, Purified Water that has been treated to reduce the content of
satisfactory specifications are available in standard reference works. dissolved air by suitable means, such as by boiling vigorously for
In those instances in which a reagent required in a Pharmacopeial 5 minutes and cooling or by the application of ultrasonic vibration.
or National Formulary test or assay need not be of analytical reagent
In-Process Revision
quality, it suffices to refer to the monograph for that article appearing
&
Particle-free water is water that has been passed through
in this Pharmacopeia or the National Formulary or the current edition
of the Food Chemicals Codex (FCC). In such cases it is to be a 0.22-mm filter.&1S (USP31)
understood that the specifications are minimum requirements and Chromatographic Solvents and Carrier Gases—The chromat-
that any substance meeting more rigid specifications for chemical ographic procedures set forth in the Pharmacopeia may require use
purity is suitable. of solvents and gases that have been especially purified for such use.
Where the name of a reagent specified in a test or assay is the The purpose may be (a) to exclude certain impurities that interfere
same as the title of a USP or NF article, and it does not appear with the proper conduct of the test procedure, or (b) to extend the life
among the following Reagent Specifications, a substance meeting the of a column by reducing the build-up of impurities on the column.
requirements of the USP or NF monograph is to be used (e.g., Where solvents and gases are called for in chromatographic
Benzocaine, USP; or Propylparaben, NF). However, reference is procedures, it is the responsibility of the analyst to ensure the
specifically made, under Reagent Specifications, to a reagent bearing suitability of the solvent or gas for the specific use. Solvents and
the name of a USP or NF article: (1) where there are requirements for gases suitable for specific high-pressure or other chromatographic
a reagent in addition to the USP or NF monograph requirements uses are available as specialty products from various reagent supply
(e.g., Sodium Salicylate, USP; or Isopropyl Myristate, NF), (2) houses, although there is no assurance that similar products from
where a source other than the USP or NF monograph is specified different suppliers are of equivalent suitability in any given
(e.g., Lactose, ACS reagent; or Hydrochloric Acid, ACS reagent), (3) procedure. The reagent specifications provided herein are for general
where complete reagent specifications differ from the USP or NF analytical uses of the solvents and gases and not for chromatographic
monograph standards (e.g., Calcium Lactate; or Thymol), or (4) uses for which the especially purified specialty products may be
required.
Pharmacopeial Forum
—White, shiny, crystalline flakes. Soluble in alcohol and in ether;

BRIEFING slightly soluble in water.
Assay—Dissolve 200 mg, accurately weighed, in 40 mL of boiling
water with vigorous stirring, and cool to room temperature. Stir the
Docusate Sodium, page 1190 of PF31(4) [July–Aug. 2005]. It is solution by mechanical means, add 5 mL of 2 N nitric acid, and
proposed to delete this reagent used in the test for Content of titrate with 0.1 N silver nitrate VS, determining the endpoint
benzalkonium chloride in the proposed new monograph for potentiometrically, using a glass–silver electrode system and
Fluticasone Propionate Nasal Spray. It will be available as a USP adding the titrant in 0.1-mL increments as the endpoint is
Reference Standard. approached. Perform a complete blank determination, and make
any necessary correction. Each mL of 0.1 N silver nitrate is
(HDQ: M. Marques) RTS—C52521 equivalent to 36.94 mg of (C4H9)4NI: not less than 99.0% is found.
Melting range h741i: between 1468 and 1478.
Delete the following: ~

Use a suitable grade with a content of not less than
&
99%.~USP31
&
Docusate Sodium—Use Docusate Sodium (USP mono-
graph).&1S (USP30)&1S (USP31)
&
Assay—Dissolve 370 mg, accurately weighed, in 60 mL
of acetone with vigorous stirring. Stir the solution by
BRIEFING mechanical means, add 10 mL of 16% sulfuric acid, and
titrate with 0.1 N silver nitrate VS, determining the endpoint
Tetrabutylammonium Iodide, USP 30 page 797 and page 1804
of PF 32(6) [Nov.–Dec. 2006]. It is proposed to revise this reagent to potentiometrically, using a glass–silver electrode system, and
change the procedure in the Assay. adding the titrant in 0.1-mL increments as the endpoint is
(HDQ: M. Marques) RTS—C53603 approached. Perform a blank determination, and make any
necessary corrections. Each mL of 0.1 N silver nitrate is
Change to read:
equivalent to 36.94 mg of (C4H9)4NI: not less than 99.0% is
Tetrabutylammonium Iodide, (C4H9)4NI369.37
found.&1S (USP31)
&
[311-28-4]&2S (USP30)
In-Process Revision
Pharmacopeial Forum

Container
Add the following:
&
BRIEFING
Add the following:
Container Specifications for Capsules and Tablets, USP 30 page
825, page 3730 of the First Supplement, and page 283 of PF 33(2)
&
[Jan.–Feb. 2007].
(HDQ) RTS—C39916; C43944; C44527; C46582; C48094

Add the following:
&
Didanosine Tablets T&2S (USP30)
The following table is provided as a reminder for the pharmacist
with the Packaging and storage requirements set forth in the individ- Add the following:
ual monographs. It lists the capsules and tablets that are official in the
&
Doxazosin Tablets T&1S (USP30)
well-closed (W), and light-resistant (LR) specifications applicable
to containers in which the drug that is repackaged should be dis- Add the following:
pensed.
This table is not intended to replace, nor should it be interpreted as &
Estradiol Vaginal Tablets T&2S (USP30)
replacing, the definitive requirements stated in the individual mono-
graphs.
Add the following:
Container Specifications for Capsules and Tablets

&
Container Tablets W&1S (USP30)

Add the following:
&
Acetaminophen, Chlorpheniramine, and
Add the following:
Dextromethorphan Tablets T&2S (USP30)
&
Fexofenadine Hydrochloride and Pseu-
Add the following: doephedrine Hydrochloride Tablets,
&
Acitretin Capsules W, LR&1S (USP31) Extended Release W&1S (USP30)

&
Capecitabine Tablets T&1S (USP31) &
Fish Oil Containing Omega-3 Acids
In-Process Revision
Add the following: Capsules T&1S (USP31)
~
Carprofen Tablets T~USP31 Add the following:
Add the following:

&
&
Cat’s Claw Capsules T, LR&2S (USP30) Add the following:
Add the following:

&
Fosinopril Sodium and Hydrochlorothi-
&
Cat’s Claw Tablets T, LR&2S (USP30)
azide Tablets T&1S (USP30)

~
&
Cilostazol Tablets T, LR&1S (USP31)
Gabapentin Tablets W~USP31
Pharmacopeial Forum
Container Container
&
Galantamine Tablets W&1S (USP31)
&
Isosorbide Mononitrate Tablets, Ex-
tended-Release T&2S (USP30)
Change to read:
Asian Ginseng Capsules T, LR Add the following:

&
&2S (USP30)
&
Ketoprofen Capsules, Extended-Re-
lease T&2S (USP30)
Add the following:

Add the following:
&
Glimepiride Tablets W&1S (USP31) ~
Loratadine and Pseudoephedrine Sul-
Add the following: fate Tablets, Extended-Release LR~USP31
&
Glipizide and Metformin Hydrochloride
Add the following:
&
Meloxicam Tablets W&2S (USP30)
Add the following:

Add the following:
&
Glucosamine, Chondroitin Sulfate Sodi-
&
Metformin Hydrochloride Tablets, Ex-
um, and Methylsulfonylmethane Tablets T, LR&2S (USP30)
tended-Release W, LR&2S (USP30)
Add the following:

Add the following:
&
Glucosamine and Methylsulfonyl-
&
methane Tablets T, LR&2S (USP30)
Add the following:

Add the following:
&
&
Hydrocodone Bitartrate and Homatro-
pine Methylbromide Tablets T, LR&1S (USP30)
Add the following:
&
Add the following:
&
Irbesartan Tablets W&1S (USP30)
Add the following:
&
Add the following:
In-Process Revision
&
Irbesartan and Hydrochlorothiazide Add the following:

&
Norgestimate and Ethinyl Estradiol
Add the following:
&
Isosorbide Mononitrate Tablets T&1S Add the following:
(USP30)
~
Ofloxacin Tablets W~USP31
Pharmacopeial Forum
Container Specifications for Capsules and Tablets (Continued)

Container BRIEFING
Add the following: Description and Relative Solubility of USP and NF Articles,
~ USP 30 page 832, page 8589 of PF 25(4) [July–Aug. 1999], page
Orlistat Capsules T~USP31 1908 of PF 27(1) [Jan.–Feb. 2001], page 554 of PF 28(2) [Mar.–
Apr. 2002], page 1953 of PF 28(6) [Nov.–Dec. 2002], page 266 of
Add the following: PF 29(1) [Jan.–Feb. 2003], page 1405 of PF 30(4) [July–Aug. 2004],
page 1822 of PF 30(5) [Sept.–Oct. 2004], page 2183 of PF 30(6)
&
Oxycodone Hydrochloride Tablets, Ex- [Nov.–Dec. 2004], page 122 of PF 31(1) [Jan.–Feb. 2005], page
591 of PF 31(2) [Mar.–Apr. 2005], page 861 of PF 31(3) [May–June
tended-Release T, LR&2S 2005], page 1193 of PF 31(4) [July–Aug. 2005], page 1491 of PF
(USP30)
page 188 of PF 32(1) [Jan.–Feb. 2006], page 662 of PF 32(2) [Mar.–
Add the following: Apr. 2006], page 942 of PF 32(3) [May–June 2006], page 1301 of PF
&
Pentazocine and Acetaminophen Tab- page 1811 of PF 32(6) [Nov.–Dec. 2006], page 110 of PF 33(1)
[Jan.–Feb. 2007], and page 283 of PF 33(2) [Mar.–Apr. 2007].
lets T, LR&1S (USP30)
(HDQ) RTS—C39325; C39916; C41492; C43961; C44030;
Add the following: C44055; C49317; C49323; C51226; C53482
&
Add the following:

&
Quinapril Tablets W&1S (USP30) Add the following:

Acitretin: Yellow or greenish, crystalline powder. Spar-
&
ingly soluble in tetrahydrofuran; slightly soluble in acetone
Add the following: and in alcohol; very slightly soluble in cyclohexane; practical-
&
Valerian Capsules T, LR&2S (USP30) ly insoluble in water.&1S (USP31)
Add the following: Change to read:

&
Valganciclovir Tablets T&2S (USP30) Adenosine: White, odorless, crystalline powder. Soluble
&
Slightly soluble&1S (USP31)
in water; practically insoluble in alcohol. Melts at about 2358.
Add the following:
&
Dehydroacetic Acid: White or nearly white, crystalline
In-Process Revision
powder. Soluble in aqueous solutions of alkalies; very slightly
soluble in water. One g of sample dissolves in about 35 mL of
alcohol and in 5 mL of acetone. NF category: Antimicrobial
preservative.&1S (NF26)
Add the following:
&
Esomeprazole Magnesium: White to slightly colored
powder. Soluble in methanol; slightly soluble in water; practi-
cally insoluble in heptane.&1S (USP31)
Pharmacopeial Forum
&
Fish Oil Containing Omega-3 Acids: Pale yellow liq-
&
Hydrogenated Starch Hydrolysate: Fine, white solid.
uid. Very soluble in acetone and in heptane; slightly soluble Very soluble in water; insoluble in alcohol. NF category:
in anhydrous alcohol; practically insoluble in water.&1S (USP31) Sweetening agent; humectant; tablet binder; tablet and/or cap-
sule diluent.&1S (NF26)
Add the following:
Add the following:
&
Omeprazole Magnesium: White to off-white powder.
Sparingly soluble in methanol; slightly soluble in alcohol;
&
Sumatriptan Succinate: White or almost white powder.
very slightly soluble in water and in dichloro- Freely soluble in water; sparingly soluble in methanol; practi-
methane.&1S (USP31)
cally insoluble in methylene chloride.&1S (USP31)
&
Hydrogenated Polydecene: Clear, colorless, odorless,
&
Terbinafine Hydrochloride: White or off-white pow-
tasteless liquid. Very slightly soluble in water. NF category: der. Freely soluble in dehydrated alcohol and in methanol;
Emollient; ointment base; solvent; vehicle (oleagi- slightly soluble in acetone; very slightly or slightly soluble
nous).&1S (NF26) in water.&1S (USP31)

In-Process Revision
Pharmacopeial Forum
Pending Proposals
published in the USP–NF, its Supplements, or an IRA. Those items that have not yet been adopted are marked as Pending Proposals.
monographs; Dietary Supplements Monographs; General Chapters; Reference Tables; Excipients; and NF Monographs. Each entry
in the Pending Proposals list contains the monograph title and the citation of the most recent publication of the monograph. When
the appropriate USP Expert Committee is considering advancing to official status a pending proposal that is more than 2 years old, it
is republished in PF for additional opportunity for public review and comment. Reprints of PF proposals may be purchased from
USP by sending a written request for information to custsvc@usp.org.
The briefing accompanying the monograph or general chapter lists the names of the Scientific Liaisons responsible for the proposed revisions.
The contact information (phone number and email) for the Scientific Liaison is available in the Staff Directory section of How to Use PF. For
USP–NF Online subscribers, the name and contact information for the assigned Scientific Liaison is available in the Auxiliary Information
portion of each monograph.
the email.
USP Monographs
(add)
In-Process Revision
Title (name change)
Tablets (new)
Title (name change)
(new)
Pharmacopeial Forum
and storage
Baclofen—Assay 33 2 211
compounds, Assay
Bupropion Hydrochloride—Identification, Content of chloride (delete) 33 2 211
Bupropion Hydrochloride Tablets—Identification 33 2 211
Dissolution
Calcium Carbonate and Magnesia Tablets (title change)—Labeling 33 2 211
Title (name change)
Tablets (new)
In-Process Revision
Carbachol—Identification 33 2 213
Carbachol Intraocular Solution—Identification 33 2 213
Carbachol Ophthalmic Solution—Identification 33 2 214
compounds
Pharmacopeial Forum
USP Reference standards, Identification,
Desogestrel (new) 28 6 1785
Assay
Title (name change)
Tablets (new)
Minimum fill (add)
In-Process Revision
Assay (add)
Pharmacopeial Forum
Enalapril Maleate and Hydrochlorothiazide Tablets— 33 2 220
Dissolution
Estradiol Benzoate (new) 33 2 220
Ethinyl Estradiol Tablets—Disintegration (delete), Dissolution (add) 31 4 1067
Flucytosine Oral Suspension (new) 32 1 92
Fludarabine Phosphate Injection (new) 33 2 232
Assay
Flumazenil Injection—Bacterial endotoxins 33 2 234
content (delete)
Fluvastatin Sodium—Labeling (add), 33 1 64
Identification, Water,
In-Process Revision

Galantamine Hydrobromide (new) 33 2 234
compounds, Assay
Dissolution (add)
Heparin Sodium—Definition, Anti-factor Xa 33 2 238
activity, Assay
Pharmacopeial Forum
Tablets (new)
Hydroxyzine Hydrochloride—Definition, 32 5 1456
dosage units (add)
Ipratropium Bromide (new) 33 2 241
Assay
Isosorbide Dinitrate Extended-Release Tablets—Labeling (add), 33 1 73
Dissolution
Ivermectin—Limit of alcohol and formamide 31 6 1645
Letrazole Tablets—Related compounds 33 2 244
In-Process Revision
to January 1, 2009)
Pharmacopeial Forum
to January 1, 2009)
Limit of lead (add)
Meclizine Hydrochloride—Chromatographic purity 33 2 244
Meclizine Hydrochloride Tablets—Identification, 33 2 245
Dissolution, Assay
Methylphenidate Hydrochloride Tablets—USP Reference 33 2 246
standards, Assay
Related compounds
Dissolution (add)
In-Process Revision

Octinoxate—Chromatographic purity, Assay 33 2 246
compounds (add)
Ondansetron—Packaging and storage 30 6 2021
Oxandrolone—Ordinary impurities (delete) 33 2 247
Oxybutynin Chloride Extended-Release Tablets—Drug release 32 6 1742
Pharmacopeial Forum
Pamidronate Disodium for Injection—Definition, 33 1 81
Paricalcitol—Identification, Chromatographic 33 2 252
purity, Assay
to January 1, 2009)
Assay
Identification
In-Process Revision
Related compounds
Related compounds
Pharmacopeial Forum
Related compounds
of ammonia
Sucralfate—Identification 33 2 254
Sulfadimethoxine Sodium—Loss on drying 33 2 254
standards, Assay
Thalidomide—Microbial limits 32 5 1467
In-Process Revision

Pharmacopeial Forum

Limit of fluoride
Fish Oil Containing Omega-3 Acids (new) 31 2 474
Fish Oil Containing Omega-3 Acids Capsules (new) 31 2 481
Asian Ginseng Capsules (new) 30 2 571
Lutein—Residue on ignition, Zeaxanthin and 33 2 255
other related compounds, Content of lutein
Lutein Preparation—Definition, Water, Residue on 33 2 255
ignition, Heavy metals, Zeaxanthin and other related
compounds, Content of lutein
In-Process Revision
Identification
Pharmacopeial Forum
Ubidecarenone Capsules—Labeling (add), Disintegration and dissolution 33 1 93
Ubidecarenone Tablets—Labeling (add), Disintegration and dissolution 33 1 94
Valerian Capsules (new) 27 1 1825
Definition
Definition
Definition
Definition
Definition
Definition
28 3 839
28 5 1468
29 3 710
29 5 1601
29 6 2022
30 2 613
30 4 1338
30 5 1674
30 6 2092
31 1 99
31 2 507
31 3 822
31 4 1154
31 5 1433
31 6 1680
32 1 181
32 2 407
32 3 829
32 4 1161
32 5 1491
32 6 1779
33 1 95
In-Process Revision
33 2 267
h381i Elastomeric Closures for Injections—(entire submission) 30 1 220
Harmonization
Procedure
Pharmacopeial Forum
h503i Acetic Acid in Peptides (new) 33 2 268
h644i Conductivity (new) 31 3 841
Emulsions (new)
In-Process Revision
Pharmacopeial Forum
Analysis (new)
h1082i Genotoxicity Testing (new) 30 1 264
h1087i Apparent Intrinsic Dissolution—Dissolution Testing 33 2 269
Procedures for Rotating Disk and Stationary Disk
(entire chapter revised)
In-Process Revision

Excipients (new)
Training and Safety
Pharmacopeial Forum
Waters (new)
Acetone 32 2 608
Alum 32 2 611
Aluminon 32 2 611
Aluminum 32 2 611
Amaranth 32 2 612
In-Process Revision
Aniline 32 2 619
Pharmacopeial Forum
Anisole 32 2 619
Anthracene 32 2 619
Anthrone 32 2 620
Benzene 32 2 623
Benzhydrol 32 2 623
Bibenzyl 32 2 625
Biphenyl 32 2 625
Boric Acid 32 2 628
In-Process Revision

Bromine 32 2 629
Pharmacopeial Forum
Carbazole 32 2 636
Casein 32 2 637
Cation-exchange Resin 30 1 1043
Catechol 32 2 637
Cedar Oil 32 2 637
Chlorine 32 2 638
Chloroform 32 2 640
Cholestane 32 2 641
In-Process Revision
Cinchonine 32 2 643
Congo Red 32 2 643
Copper 32 2 644
Cortisone 32 2 644
a-Cyclodextrin (new) 33 2 276
L-Cystine 32 2 646
Pharmacopeial Forum
Decanol 32 2 646
Dextrin 32 2 647
Digitonin 32 2 652
In-Process Revision

Pharmacopeial Forum
Dioxane 32 3 902
Dithizone 32 3 903
n-Eicosane 32 3 904
Eicosanol 32 3 904
Equilenin 32 3 904
Fluorene 32 3 909
Formamide 32 3 909
In-Process Revision
Gitoxin 32 3 910
Glucose 32 3 911
Glycerin 32 3 911
Guaiacol 32 3 912
Hematein 32 3 912
n-Hexane 32 3 913
Pharmacopeial Forum
Imidazole 32 3 918
Indene 32 3 918
Inosine 32 3 918
Inositol 32 3 918
Iodic Acid 32 3 919
Iodine 32 3 919
Kerosene 32 3 921
Lactose 33 1 100
In-Process Revision

Litmus 32 3 923
L-Lysine 32 3 923
Magnesium 32 3 923
Pharmacopeial Forum
Mercury 32 3 926
Methanol 32 3 927
Morpholine 32 3 933
In-Process Revision
1-Naphthol 32 3 934
2-Naphthol 32 3 934
Nickel 32 3 935
Ninhydrin 32 3 936
Pharmacopeial Forum
Nonadecane 32 3 939
Orange G 32 4 1240
Orcinol 32 4 1240
Pentane 32 4 1242
Pepsin 32 4 1242
Phenol 32 4 1243
In-Process Revision

Pharmacopeial Forum
Purine 32 4 1253
Pyrazole 32 4 1254
Pyrene 32 4 1254
Pyridine 32 4 1254
Pyrrole 32 4 1255
Selenium 32 4 1258
In-Process Revision
Sodium 32 4 1260
Pharmacopeial Forum
Sodium Phosphate, Dibasic, Dihydrate 33 1 101
Sodium Phosphate, Monobasic, Anhydrous (new) 33 2 276
Sodium Phosphate, Monobasic, Dihydrate (new) 33 2 276
In-Process Revision

Sudan III 32 4 1273
Sudan IV 32 4 1273
Pharmacopeial Forum
Tetrapropylammonium Chloride (new) 33 2 276
Thiourea 32 4 1279
Thymol 32 4 1280
Tin 32 4 1280
Toluene 32 4 1281
In-Process Revision
Uracil 32 4 1288
Urea 32 4 1288
Urethane 32 4 1288
Pharmacopeial Forum
Uridine 32 4 1288
Xanthine 32 4 1290
Xylene 32 4 1290
o-Xylene 32 4 1291
p-Xylene 32 4 1291
Xylose 32 4 1291
Zinc 32 4 1291
Test Solutions
Bismuth Nitrate, 0.01 mol/L (new) 32 4 1292
Ceric Sulfate, Tenth-Normal (0.1 N) 33 1 102
Mercuric Nitrate, Tenth Molar (0.1 M) 32 6 1805
Potassium Permanganate, Tenth-Normal (0.1 N) 33 1 103
Sodium Tetraphenylboron, Fiftieth Molar (0.02 M) 32 6 1807
Reference Tables
27 1 1908
28 2 554
28 6 1953
29 1 266
29 3 812
30 4 1405
In-Process Revision
30 5 1822
30 6 2183
31 1 122
31 2 591
31 3 861
31 4 1193
31 5 1491
31 6 1703
32 1 188
32 2 662
32 3 942
32 4 1301
32 5 1541
32 6 1811
33 1 110
33 2 285
Excipients 33 2 257
Pharmacopeial Forum
NF Monographs
Assay
Calcium Silicate—Definition, pH, Limit of fluoride, 31 5 1417
Assay for silicon dioxide, Assay for calcium oxide
Corn Syrup Solids (new) 28 6 1894
Dispersion (new)
Gamma Cyclodextrin (new) 31 3 812
Harmonization
In-Process Revision
Propylene Glycol (new)—Harmonization 33 2 317
Propylene Glycol Monocaprylate (new) 33 2 261
Trehalose (new) 33 2 263
Pharmacopeial Forum
[PF 33(1)–PF 33(6)]
USP Monographs
USP General Information Chapters
h1087i Intrinsic Dissolution (entire submission) 30 6 2130
In-Process Revision
HARMONIZATION
staff.
Stage 5: Consensus
A. Provisional
B. Final
Harmonization
Pharmacopeial Forum
536 HARMONIZATION Vol. 33(3) [May–June 2007]
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Carmellose [new] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
h85i Bacterial Endotoxins Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
h601i Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers . . . . . . . . . . . . . . . . . . . . . . . . . 550
Harmonization
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] HARMONIZATION 537
MONOGRAPHS (USP) B: Shake 5 mL of Sample solution with 1 mL of ferric

chloride TS: a brown, flocculent precipitate is produced.
C: Infrared Absorption h197Ki.
BRIEFING
D: pH h791i—The pH of a suspension, obtained by
shaking 1 g of Carmellose with 100 mL of water, is between
Carmellose. Because there is no existing USP or NF monograph
for this excipient, a new monograph is being proposed. The Japanese 3.5 and 5.0.
Pharmacopoeia is the coordinating pharmacopoeia for the interna-
tional harmonization of the compendial standards for the Carmellose
monograph, as part of the process of international harmonization of Loss on drying h731i—Dry 1 g at 1058 for 4 hours: it loses
monographs and general analytical methods of the European,
Japanese, and United States pharmacopeias. The following mono- not more than 8.0% of its weight.
graph, which represents the OFFICIAL INQUIRY STAGE 4 docu-
ment, is based in part on comments from the European Residue on ignition h281i: not more than 1.5% on 1 g.
Pharmacopoeia and the United States Pharmacopeia in response to
the Provisional Harmonized Text Stage 4 draft prepared by the
Japanese Pharmacopoeia Chlorides—
Test solution—Shake well 0.8 g of Carmellose with 50 mL
(EM2: K. Moore) RTS—C43991
of water, dissolve in 10 mL of sodium hydroxide TS, and add
water to make 100 mL. Heat 20 mL of this solution with 10
mL of nitric acid, diluted on a water bath until a flocculent
Add the following:
precipitate is produced, cool, centrifuge, and take out the
Carmellose
supernatant. Wash the precipitate with three 10-mL portions
of water by centrifuging each time, combine the supernatant
and the washings, and add water to make 100 mL. Take 25
Carboxymethylcellulose [9000-11-7].
mL of this solution and add 6 mL of nitric acid, diluted and
water to make 50 mL.
» Carmellose is a polycarboxymethyl ether of Control solution—Take 0.40 mL of 0.01 N hydrochloric
cellulose. acid VS and 6 mL of dilute nitric acid and add water to make
50 mL.
Packaging and storage—Preserve in tight containers.
Procedure—Add 1 mL of silver nitrate TS to the Test
Identification—
solution and to the Control solution, mix well, and allow to
Sample solution—Shake well 0.1 g of Carmellose with 10
stand for 5 minutes, protecting from direct sunlight. Compare
mL of water, add 2 mL of sodium hydroxide TS, shake, and
the opalescence developed in both solutions against a black
allow to stand for 10 minutes.
background by viewing downward or transversely. The
A: Take 1 mL of Sample solution, and add water to make
opalescence developed in the Test solution is not more than
5 mL. To 1 drop of this solution, add 0.5 mL of concentrated
that in the Control solution (not more than 0.36%).
disodium chlomotropate TS, and heat in a water bath for 10
minutes: a red-purple color develops.
Harmonization
Pharmacopeial Forum
Sulfates— Procedure—Add 2 mL of barium chloride TS to the Test
Test solution—Shake well 0.40 g of Carmellose with 25 mL solution and to the Control solution, mix well, and allow to
of water, dissolve in 5 mL of sodium hydroxide TS, and add stand for 10 minutes. Compare the turbidity developed in
20 mL of water. Heat this solution with 2.5 mL of both solutions against a black background by viewing
hydrochloric acid in a water bath until a flocculent precipitate downward or transversely. The turbidity produced in the
is produced. Cool, centrifuge, and take out the supernatant. Test solution is not thicker than that of the Control solution
Wash the precipitate with three 10-mL portions of water by (not more than 0.72%).
centrifuging each time, combine the supernatant and the Heavy metals, Method II h231i—Proceed with 1.0 g of
washings, and add water to make 100 mL. Filter this solution, Carmellose and perform the test. Prepare the Control solution
discard 5 mL of the first filtrate, take 25 mL of the subsequent with 2.0 mL of Standard lead solution (not more than 20
filtrate, and add 1 mL of hydrochloric acid, diluted and water ppm).
to make 50 mL. Description and solubility—
Control solution—Take 1.5 mL of 0.01 N sulfuric acid VS Propylene Glycol: Carmellose occurs as a white powder.
and 1 mL of dilute hydrochloric acid and add water to make Practically insoluble in ethanol (99.5%). Swells with water to
50 mL. form a suspension. Becomes viscid in sodium hydroxide TS.
Is hygroscopic.
Harmonization
Pharmacopeial Forum
GENERAL CHAPTERS In the gel-clot techniques, the reaction endpoint is determined

from dilutions of the material under test in direct comparison with
parallel dilutions of a reference endotoxin, and quantities of
endotoxin are expressed in USP Endotoxin Units (USP-EU).
[NOTE—One USP-EU is equal to one IU of endotoxin.]
General Tests and Assays Because LAL Reagents have been formulated to be used also for
turbidimetric or colorimetric tests, such tests may be used to comply
with the requirements. These tests require the establishment of
a standard regression curve; the endotoxin content of the test
Biological Tests and Assays material is determined by interpolation from the curve. The
procedures include incubation for a preselected time of reacting
endotoxin and control solutions with LAL Reagent and reading of
the spectrophotometric light absorbance at suitable wavelengths. In
the endpoint turbidimetric procedure the reading is made immedi-
ately at the end of the incubation period. In the endpoint colorimetric
procedure the reaction is arrested at the end of the preselected time
by the addition of an enzyme reaction-terminating agent prior to the
readings. In the turbidimetric and colorimetric kinetic assays the
absorbance is measured throughout the reaction period and rate
BRIEFING values are determined from those readings.
h85i Bacterial Endotoxins Test, USP 30 page 109. On the basis

APPARATUS AND GLASSWARE
of comments from EP, USP, and JP, this harmonized chapter has Depyrogenate all glassware and other heat-stable materials in
been revised to enhance user clarity. A harmonization STAGE a hot-air oven using a validated process.^2^Commonly used
4 document is presented for comments. minimum time and temperature settings are 30 minutes at 2508. If
employing plastic apparatus, such as microplates and pipet tips for
(MSA: R.Tirumalai) RTS—C49048 automatic pipetters, use only that which has been shown to be free of
detectable endotoxin and not to interfere with the test. [NOTE—In this
chapter, the term ‘‘tube’’ includes any other receptacle such as
Change to read: a micro-titer well.]
PREPARATION OF THE STANDARD

ENDOTOXIN STOCK SOLUTION AND
STANDARD SOLUTIONS
h85i BACTERIAL ENDOTOXINS The USP Endotoxin RS has a defined potency of 10,000 USP
Endotoxin Units (EU) per vial. Constitute the entire contents of
TEST 1 vial of the RSE with 5 mL of LAL Reagent Water^3^, mix
intermittently for 30 minutes, using a vortex mixer, and use this
concentrate for making appropriate serial dilutions. Preserve the
^
concentrate in a refrigerator for making subsequent dilutions for not
Portions of this general chapter have been harmonized with the more than 14 days. Mix vigorously, using a vortex mixer, for not less
corresponding texts of the European Pharmacopeia and/or the than 3 minutes before use. Mix each dilution for not less than 30
Japanese Pharmacopeia. Those portions that are not harmonized are seconds before proceeding to make the next dilution. Do not store
marked with symbols (^^) to specify this fact.^ dilutions, because of loss of activity by adsorption, in the absence of
This chapter provides a test to detect or quantify bacterial supporting data to the contrary.
endotoxins that may be present in or on the sample of the article(s) to
which the test is applied. It uses Limulus Amebocyte Lysate (LAL)
obtained from the aqueous extracts of circulating amebocytes of
horseshoe crab (Limulus polyphemus or Tachypleus tridentatus) Preparatory Testing
which has been prepared and characterized for use as an LAL Use an LAL Reagent of confirmed label sensitivity.
Reagent.^1^ The validity of test results for bacterial endotoxins requires an
There are two types of techniques for this test: the gel-clot adequate demonstration that specimens of the article or of solutions,
techniques, which are based on gel formation, and the photometric washings, or extracts thereof to which the test is to be applied do not
techniques. The latter include a turbidimetric method, which is based of themselves inhibit or enhance the reaction or otherwise interfere
on the development of turbidity after cleavage of an endogenous with the test. Validation is accomplished by performing the
substrate, and a chromogenic method, which is based on the inhibition or enhancement test described under each of the three
development of color after cleavage of a synthetic peptide- techniques indicated. Appropriate negative controls are included.
chromogen complex. Proceed by any one of these techniques, Validation must be repeated if the LAL Reagent source or the
unless otherwise indicated in the monograph. In case of dispute, the method of manufacture or formulation of the article is changed.
final decision is based on the gel-clot techniques, unless otherwise
indicated in the monograph.
Harmonization
^2
For a validity test of the procedure for inactivating endotoxins, see Dry-
Heat Sterilization under Sterilization and Sterility Assurance of Compendial
Articles h1211i. Use an LAL Reagent having a sensitivity of not less than
0.15 Endotoxin Unit per mL.^
^1 ^3
LAL Reagent reacts with some b-glucans in addition to endotoxins. Some Sterile Water for Injection or other water that shows no reaction with the
preparations that are treated will not react with b-glucans and must be used specific LAL Reagent with which it is to be used, at the limit of sensitivity of
for samples that contain glucans.^ such reagent.^
Pharmacopeial Forum
Preparation of Sample Solutions Preparatory Testing for the Gel-Clot Techniques

Prepare sample solutions by dissolving or diluting drugs or Test for Confirmation of Labeled LAL Reagent Sensitivity—
extracting medical devices using LAL Reagent Water. Some Confirm the labeled sensitivity using at least 1 vial of the LAL
substances or preparations may be more appropriately dissolved, Reagent lot. Prepare a series of two-fold dilutions of the USP
diluted, or extracted in other aqueous solutions. If necessary, adjust Endotoxin RS in LAL Reagent Water to give concentrations of 2l,
the pH of the solution (or dilution thereof) to be examined so that the l, 0.5l, and 0.25l, where l is as defined above. Perform the test on
pH of the mixture of the LAL Reagent and sample falls within the the four standard concentrations in quadruplicate and include
pH range specified by the LAL Reagent manufacturer. This usually negative controls. The test for confirmation of lysate sensitivity is
applies to a product with a pH in the range of 6.0 to 8.0. The pH may to be carried out when a new batch of LAL Reagent is used or when
be adjusted using an acid, base, or suitable buffer as recommended there is any change in the experimental conditions that may affect the
by the LAL Reagent manufacturer. Acids and bases may be prepared outcome of the test.
from concentrates or solids with LAL Reagent Water in containers Mix a volume of the LAL Reagent with an equal volume (such as
free of detectable endotoxin. Buffers must be validated to be free of 0.1-mL aliquots) of one of the Standard Endotoxin Solutions in each
detectable endotoxin and interfering factors. test tube. When single test vials or ampuls containing lyophilized
LAL Reagent are used, add solutions directly to the vial or ampul.
Incubate the reaction mixture for a constant period according to
DETERMINATION OF MAXIMUM VALID directions of the LAL reagent manufacturer (usually at 37 + 18 for
DILUTION (MVD) 60 + 2 minutes), avoiding vibration. To test the integrity of the gel,
take each tube in turn directly from the incubator and invert it
The Maximum Valid Dilution is the maximum allowable dilution through about 1808 in one smooth motion. If a firm gel has formed
of a specimen at which the endotoxin limit can be determined. It that remains in place upon inversion, record the result as positive. A
applies to injections or to solutions for parenteral administration in result is negative if an intact gel is not formed. The test is not valid
the form constituted or diluted for administration, or, where unless the lowest concentration of the standard solutions shows
applicable, to the amount of drug by weight if the volume of the a negative result in all replicate tests.
dosage form for administration could be varied. The general The endpoint is the last positive test in the series of decreasing
equation to determine MVD is: concentrations of endotoxin. Calculate the mean value of the
logarithms of the endpoint concentration and then the antilogarithm
MVD = (Endotoxin limit 6 Concentration of sample solution) / (l) of the mean value using the following equation:
where the concentration of sample solution and l are as defined Geometric Mean Endpoint Concentration = antilog (e / f)
below. Where the endotoxin limit concentration is specified in the
individual monograph in terms of volume (in EU per mL), divide the where e is the sum of the log endpoint concentrations of the
limit by l, which is the labeled sensitivity (in EU per mL) of the dilution series used, and f is the number of replicate test tubes. The
LAL Reagent, to obtain the MVD factor. Where the endotoxin limit geometric mean endpoint concentration is the measured sensitivity
concentration is specified in the individual monograph in terms of of the LAL Reagent (in EU/mL). If this is not less than 0.5l and not
weight or Units of active drug (in EU per mg or in EU per Unit), more than 2l, the labeled sensitivity is confirmed and is used in tests
multiply the limit by the concentration (in mg per mL or in Units per performed with this lysate.
mL) of the drug in the solution tested or of the drug constituted Interfering Factors Test for the Gel-Clot Techniques—Prepare
according to the label instructions, whichever is applicable, and solutions A, B, C, and D as shown in Table 1, and perform the
divide the product of the multiplication by l, to obtain the MVD inhibition/enhancement test on the Sample Solutions at a dilution
factor. The MVD factor so obtained is the limit dilution factor for the less than the MVD, not containing any detectable endotoxins,
preparation for the test to be valid. following the procedure in the Test for Confirmation of Labeled LAL
Reagent Sensitivity above. The geometric mean endpoint concentra-
tions of Solutions B and C are determined using the equation in that
ESTABLISHMENT OF ENDOTOXIN LIMITS test.
This test must be repeated when any condition that is likely to
The endotoxin limit for parenteral drugs, defined on the basis of influence the test results changes. The test is not valid unless
dose, is equal to K/M,^4^ where K is the threshold human pyrogenic Solutions A and D show no reaction and the result of Solution C
dose of endotoxin per kg of body weight, and M is equal to the confirms the labeled sensitivity.
maximum recommended human dose of product per kg of body If the sensitivity of the lysate determined in the presence of the
weight in a single hour period. sample solution under test of Solution B is not less than 0.5l and not
The endotoxin limit for parenteral drugs is specified in individual greater than 2l, the sample solution does not contain factors that
monographs in units such as EU/mL, EU/mg, or EU/Unit of interfere under the experimental conditions used. Otherwise, the
biological activity. sample solution to be examined interferes with the test.
If the sample under test does not comply with the test at a dilution
less than the MVD, repeat the test using a greater dilution, not
GEL-CLOT TECHNIQUES exceeding the MVD. The use of a more sensitive lysate permits
a greater dilution of the sample to be examined and this may
The gel-clot techniques detect or quantify endotoxins based on contribute to the elimination of interference.
clotting of the LAL Reagent in the presence of endotoxin. The Interference may be overcome by suitable treatment, such as
concentration of endotoxin required to cause the lysate to clot under filtration, neutralization, dialysis, or heating. To establish that the
standard conditions is the labeled sensitivity of the LAL Reagent. To chosen treatment effectively eliminates interference without loss of
ensure both the precision and validity of the test, tests for confirming endotoxins, perform the assay described below using the preparation
the labeled LAL Reagent sensitivity and for interfering factors are to be examined to which USP Endotoxin RS has been added and
described under Preparatory Testing for the Gel-Clot Techniques. which has been subjected to the selected treatment.
Harmonization
^4
K is 5 USP-EU/kg for any route of administration other than intrathecal
(for which K is 0.2 USP-EU/kg body weight). For radiopharmaceutical
products not administered intrathecally the endotoxin limit is calculated as
175/V, where V is the maximum recommended dose in mL. For intrathecally
administered radiopharmaceuticals, the endotoxin limit is obtained by the
formula 14/V. For formulations (usually anticancer products) administered on
a per square meter of body surface, the formula is K/M, where K = 5 EU/kg
and M is the (maximum dose/m2/hour 6 1.80 m2)/70 Kg. ^
Pharmacopeial Forum
Table 1. Preparation of Solutions for the Inhibition/Enhancement Test for Gel-Clot Techniques
Endotoxin Concentration/Solution to Dilution Initial Endotoxin Number of
Solution which Endotoxin is Added Diluent Factor Concentration Replicates
Aa none/sample solution — — — 4
Bb 2l/sample solution sample solution 1 2l 4
2 1l 4
4 0.5l 4
8 0.25l 4
Cc 2l/LAL Reagent Water LAL Reagent Water 1 2l 2
2 1l 2
4 0.5l 2
8 0.25l 2
Dd none/LAL Reagent Water — — — 2
a
Solution A: a Sample Solution of the preparation under test that is free of detectable endotoxins.
b
Solution B: test for interference.
c
Solution C: control for labeled LAL Reagent sensitivity.
d
Solution D: negative control of LAL Reagent Water.
Gel-Clot Limit Test Gel-Clot Assay

This test is used when a monograph contains a requirement for This assay quantifies bacterial endotoxins in sample solutions by
endotoxin limits. titration to an endpoint.
Procedure—Prepare Solutions A, B, C, and D as shown in Table Procedure—Prepare Solutions A, B, C, and D as shown in Table
2, and perform the test on these solutions following the procedure in 3, and test these solutions by following the procedure in the Test for
the Test for Confirmation of Labeled LAL Reagent Sensitivity under Confirmation of Labeled LAL Reagent Sensitivity underPreparatory
Preparatory Testing for the Gel-Clot Techniques. Testing for the Gel-Clot Techniques.
Calculation and Interpretation—The test is not valid unless the
Table 2. Preparation of Solutions for the Gel-Clot Limit Test following conditions are met: (1) both replicates of negative control
Solution D are negative; (2) both replicates of positive product
Endotoxin Concentration/Solution to Number of control Solution B are positive; and (3) the geometric mean endpoint
Solution* which Endotoxin is Added Replicates concentration of Solution C is in the range of 0.5l to 2l.
A none/diluted Sample Solution 2 To determine the endotoxin concentration of Solution A, calculate
B 2l/diluted Sample Solution 2 the endpoint concentration for each replicate series of dilutions by
C 2l/LAL Reagent Water 2 multiplying each endpoint dilution factor by l. The endotoxin
D none/LAL Reagent Water 2 concentration in the sample is the geometric mean endpoint
concentration of the replicates (see the formula given Test for
* Confirmation of Labeled LAL Reagent Sensitivity in the under
Prepare Solution A and positive product control Solution B using a dilution Preparatory Testing for the Gel-Clot Techniques). If the test is
not greater than the MVD and treatments as directed in the Interfering Factors
Test for the Gel-Clot Techniques under Preparatory Testing for the Gel-Clot conducted with a diluted Sample Solution, calculate the concentra-
Techniques. Positive control Solutions B and C contain the standard tion of endotoxin in the original Sample Solution by multiplying by
endotoxin preparation at a concentration corresponding to twice the labeled the dilution factor. If none of the dilutions of the Sample Solution is
LAL Reagent sensitivity. The negative control Solution D is LAL Reagent positive in a valid assay, report the endotoxin concentration as less
Water. than l (if the diluted sample was tested, less than l times the lowest
dilution factor of the sample.) If all dilutions are positive, the
endotoxin concentration is reported as equal to or greater than the
Interpretation—The test is not valid unless both replicates of greatest dilution factor multiplied by l (e.g., initial dilution factor
positive control Solutions B and C are positive and those of negative times 8 times l in Table 3).
control Solution D are negative. The preparation under test complies The articlemeets the requirements of the test if the concentration
with the test when a negative result is found for both tubes of endotoxin is less than that specified in the individual monograph.
containing Solution A. The preparation under test does not comply
with the test when a positive result is found for both tubes containing
Solution A.
Repeat the test when a positive result is found for 1 tube PHOTOMETRIC TECHNIQUES
containing Solution A and a negative result for the other one. The
preparation under test complies with the test when a negative result The turbidimetric method measures increases in turbidity.
is found for both tubes containing Solution A in the repeat result. If Depending on the test principle used, this technique is classified as
the test is positive for the preparation under test at a dilution less than either endpoint-turbidimetric or kinetic-turbidimetric. The endpoint-
the MVD, the test may be repeated at a dilution not greater than the turbidimetric technique is based on the quantitative relationship
MVD. between the concentration of endotoxins and the turbidity (absor-
bance or transmission) of the reaction mixture at the end of an
incubation period. The kinetic-turbidimetric technique is a method to
measure either the onset time needed to reach a predetermined
absorbance of the reaction mixture or the rate of turbidity
development.
The chromogenic method measures the chromophore released
from a suitable chromogenic peptide by the reaction of endotoxins
with the LAL Reagent. Depending on the test principle employed,
this technique is classified as either endpoint-chromogenic or
Harmonization
kinetic-chromogenic. The endpoint-chromogenic technique is

based on the quantitative relationship between the concentration of
endotoxins and the release of chromophore at the end of an
Pharmacopeial Forum
Table 3. Preparation of Solutions for the Gel-Clot Assay
Endotoxin Concentration/
Solution to which Endotoxin Dilution Initial Endotoxin Number of
Solution is Added Diluent Factor Concentration Replicates
Aa none/sample solution sample solution 1 — 2
2 — 2
4 — 2
8 — 2
Bb 2l/sample solution — 1 2l 2
Cc 2l/LAL Reagent Water 1 2l 2
2 1l 2
4 0.5l 2
8 0.25l 2
Dd none/LAL Reagent Water — — — 2
a
Solution A: a sample solution under test at the dilution, not to exceed the MVD, with which the Interfering Factors Test for the Gel-Clot Techniques was
completed. Subsequent dilution of the sample solution must not exceed the MVD. Use LAL Reagent Water to make dilution series of four tubes containing the
sample solution under test at concentrations ofInterfering Factors Test for the Gel-Clot Techniques was completed. Other dilutions 1, ½, ¼, and 18 relative to the
dilution with which the may be used as appropriate.
b
Solution B: Solution A containing standard endotoxin at a concentration of 2l (positive product control).
c
Solution C: two series of 4 tubes of LAL Reagent Water containing the standardendotoxin at a concentration of 2l, l, 0.5l, and 0.25l, respectively.
d
Solution D: LAL Reagent Water (negative control).
incubation period. The kinetic-chromogenic technique is a method to least in duplicate following the instructions for the LAL Reagent
measure either the onset time needed to reach a predetermined used (with regard to volume of sample and LAL Reagent, volume
absorbance of the reaction mixture or the rate of color development ratio of sample to LAL Reagent, incubation time, etc.)
All photometric tests are carried out at the incubation temperature Calculate the mean recovery of the added endotoxin by
recommended by the LAL Reagent manufacturer, which is usually subtracting the mean endotoxin concentration in the solution, (if
37 + 18. any) from that containing the added endotoxin. In order to be
considered free of interfering factors under the conditions of the test,
the measured concentration of the endotoxin added to the sample
Preparatory Testing for the Photometric Techniques solution must be within 50% to 200% of the known added endotoxin
concentration after subtraction of any endotoxin detected in the
To ensure the precision or validity of the turbidimetric and solution without added endotoxin.
chromogenic techniques, preparatory tests are conducted to verify When the endotoxin recovery is out of the specified ranges, the
that the criteria for the standard curve are valid and that the sample interfering factors must be removed as described in the Interfering
solution does not inhibit or enhance the reaction. Revalidation for the Factors Test for the Gel-Clot Techniques under Preparatory Testing
test method is required when conditions that are likely to influence for the Gel-Clot Techniques. Repeating the Interfering Factors Test
the test result change. for the Gel-Clot Techniques validates the treatment.
Verification of Criteria for the Standard Curve—Using the
Standard Endotoxin Solution, prepare at least three endotoxin
concentrations to generate the standard curve. Perform the test using Procedure for the Photometric Techniques
at least three replicates of each standard endotoxin concentration
according to the manufacturer’s instructions for the LAL Reagent Follow the procedure described in the Interfering Factors Test for
(with regard to volume ratios, incubation time, temperature, pH, the Photometric Techniques under Preparatory Testing for the
etc.). If the desired range in the kinetic methods is greater than two Photometric Techniques.
logs, additional standards should be included to bracket each log
increase within the range of the standard curve. The absolute value
of the correlation coefficient, |r|, must be greater than or equal to Calculation for the Photometric Techniques
0.980 for the range of endotoxin concentrations indicated by the
manufacturer of the LAL Reagent. Calculate the endotoxin concentration of each of the replicates of
Interfering Factors Test for the Photometric Techniques— test Solution A using the standard curve generated by positive
Select an endotoxin concentration at or near the middle of the control series C. The test is not valid unless the following conditions
endotoxin standard curve. Prepare Solutions A, B, C, and D as are met: (1) the results of control series C comply with the
shown in Table 4. Perform the test on Solutions A, B, C, and D at requirements for validation defined under Verification of Criteria for
the Standard Curve under Preparatory Testing for the Photometric
Table 4. Preparation of Solutions for the Inhibition/Enhancement Test for Photometric Techniques
Solution to which Endotoxin is

Solution Endotoxin Concentration Added Number of Replicates
Aa none sample solution not less than 2
Bb middle concentration of the standard curve sample solution not less than 2
Cc at least 3 concentrations (lowest concentration is LAL Reagent Water each not less than 2
designated l)
Dd none LAL Reagent Water not less than 2
Harmonization
a
Solution A: the sample solution may be diluted not to exceed MVD.
b
Solution B: the preparation under test at the same dilution as Solution A, containing added endotoxin at a concentration equal to or near the middle of the
standard curve.
c
Solution C: the standard endotoxin at the concentrations used in the validationof the method described in Verification of Criteria for the Standard Curve under
Preparatory Testing for the Photometric Techniques (positive control series).
d
Solution D: LAL Reagent Water (negative control).
Pharmacopeial Forum
Techniques; (2) the endotoxin recovery, calculated from the detectable endotoxin and which does not interfere in the test.
concentration found in Solution B after subtracting the endotoxin
concentration found in Solution A is within 50 to 200%; and (3) the [NOTE—In this chapter, the term ‘‘tube’’ includes any other
result of negative control series D does not exceed the limit of the
blank value required in the description of the LAL Reagent used. receptacle such as a microtiter well.]
Interpretation of Results from the Photometric

Techniques REAGENTS AND TEST SOLUTIONS
In photometric assays, the preparation under test complies with

the test if the mean endotoxin concentration of the replicates of Amoebocyte Lysate—A lyophilized product obtained
Solution A, after correction for dilution and concentration, is less
than the endotoxin limit for the product. from the lysate of amoebocytes (white blood cells) from the
^
Portions of this general chapter have been harmonized horseshoe crab (Limulus polyphemus or Tachypleus tridenta-
with the corresponding texts of the European Pharmacopoeia tus). This reagent refers only to a product manufactured in
and/or the Japanese Pharmacopoeia. Those portions that are accordance with the regulations of the competent authority.
not harmonized are marked with symbols (^^) to specify this [NOTE—Amoebocyte Lysate reacts to some b-glucans in
fact.^ addition to endotoxins. Amoebocyte Lysate preparations that
The Bacterial Endotoxins Test (BET) is a test to detect or do not react to glucans are available: they are prepared by
quantify endotoxins from Gram-negative bacteria using removing the G factor reacting to glucans from Amoebocyte
amoebocyte lysate from the horseshoe crab (Limulus poly- Lysate or by inhibiting the G factor reacting system of
phemus or Tachypleus tridentatus). Amoebocyte Lysate and may be used for the endotoxin testing
There are three techniques for this test: the gel-clot in the presence of glucans.]
technique, which is based on gel formation; the turbidimetric Water for Bacterial Endotoxins Test (BET)—Use Water
technique, based on the development of turbidity after for Injection or water produced by other procedures that
cleavage of an endogenous substrate; and the chromogenic shows no reaction with the lysate employed, at the detection
technique, based on the development of color after cleavage limit of the reagent.
of a synthetic peptide-chromogen complex. Proceed by any of Lysate TS—Dissolve Amoebocyte Lysate in Water for
the three techniques for the test. In the event of doubt or BET, or in a buffer recommended by the lysate manufacturer,
dispute, the final decision is made based upon the gel-clot by gentle stirring. Store the reconstituted lysate, refrigerated
technique unless otherwise indicated. The test is carried out in or frozen, according to the specifications of the manufacturer.
a manner that avoids endotoxin contamination.
PREPARATION OF SOLUTIONS
APPARATUS
Depyrogenate all glassware and other heat-stable materials Standard Endotoxin Stock Solution—A Standard Endo-
in a hot-air oven using a validated process.^1^ A commonly toxin Stock Solution is prepared from a USP Endotoxin
used minimum time and temperature is 30 minutes at 2508. If Reference Standard that has been calibrated to the current
employing plastic apparatus such as microplates and pipet WHO International Standard for Endotoxin. Follow the
tips for automatic pipetters, use apparatus shown to be free of specifications in the package leaflet and on the label for
preparation and storage of the Standard Endotoxin Stock
Solution. Endotoxin is expressed in Endotoxin Units (EU).
Harmonization
[NOTE—One USP Endotoxin Unit (EU) is equal to one

^1
For a validity test of the procedure for inactivating endotoxins, International Unit (IU) of endotoxin.]
see Dry-Heat Sterilization under Sterilization and Sterility Assur-
ance of Compendial Articleshh1211ii. Use Lysate TS having
a sensitivity of not less than 0.15 Endotoxin Unit per mL.^
Pharmacopeial Forum
Standard Endotoxin Solutions—After mixing the Stan- equal to the maximum recommended human bolus dose of
dard Endotoxin Stock Solution vigorously, prepare appropri- product per kg of body weight. When the product is to be
ate serial dilutions of Standard Endotoxin Solution, using injected at frequent intervals or infused continuously, M is the
Water for BET. Use dilutions as soon as possible to avoid loss maximum total dose administered in a single 1-hour period.
of activity by adsorption. The endotoxin limit for parenteral drugs is specified in units
Sample Solutions—Prepare the Sample Solutions by such as EU/mL, EU/mg, EU/Unit of biological activity, etc.,
dissolving or diluting drugs, or taking washes from medical in the individual monograph.
devices using Water for BET. Some substances or prepara- Concentration of Sample Solution: mg/mL, in the case
tions may be more appropriately dissolved, diluted, or of endotoxin limit specified by weight (EU/mg); Units/mL, in
extracted in other aqueous solutions. If necessary, adjust the the case of endotoxin limit specified by unit of biological
pH of the solution to be examined (or dilution thereof) so that activity (EU/Unit); mL/mL, in the case of endotoxin limit
the pH of the mixture of the lysate and Sample Solution falls specified by volume (EU/mL).
within the pH range specified by the lysate manufacturer, l: the labeled sensitivity in the Gel-Clot Technique (EU/
usually 6.0 to 8.0. The pH may be adjusted by the use of an mL) or the lowest point used in the standard regression curve
acid, base, or suitable buffer as recommended by the lysate for the Turbidimetric Technique or Chromogenic Technique.
manufacturer. Acids and bases may be prepared from
concentrates or solids with Water for BET in containers free GEL-CLOT TECHNIQUE
of detectable endotoxin. Buffers must be validated to be free
The Gel-Clot Technique is for detecting or quantifying
of detectable endotoxin and interfering factors.
endotoxins based on the clotting of the lysate reagent in the
presence of endotoxin. The concentration of endotoxin
DETERMINATION OF MAXIMUM VALID DILUTION
required to cause the lysate to clot under standard conditions
(MVD)
is the labeled sensitivity of the lysate reagent. To ensure both
The Maximum Valid Dilution is the maximum allowable the precision and validity of the test, perform the tests for
dilution of a specimen at which the endotoxin limit can be confirming the labeled lysate sensitivity and for interfering
determined. Determine the MVD from the following factors as described under Preparatory Testing.
equation:
MVD = (Endotoxin Limit 6 Concentration of Sample Preparatory Testing
Solution) / (l)
Test for Confirmation of Labeled Lysate Sensitivity—
Confirm in four replicates the labeled sensitivity, l, expressed
Endotoxin Limit—The endotoxin limit for parenteral in EU/mL of the Lysate TS prior to use in the test. The test for
drugs, defined on the basis of dose, equals K/M^2^, where confirmation of lysate sensitivity is to be carried out when
K is a threshold pyrogenic dose of endotoxin per kg, and M is a new batch of lysate is used or when there is any change in
^2
K is 5 USP-EU/kg for any route of administration other than the experimental conditions that may affect the outcome of
intrathecal (for which K is 0.2 USP-EU/kg body weight). For
Harmonization
radiopharmaceutical products not administered intrathecally, the the test. Prepare standard solutions having at least four
endotoxin limit is calculated as 175/V, where V is the maximum
recommended dose in mL. For intrathecally administered radio- concentrations equivalent to 2l, l, 0.5l, and 0.25l by
pharmaceuticals, the endotoxin limit is obtained by the formula 14/V.
For formulations (usually anticancer products) administered on a per diluting the USP Endotoxin RS with Water for BET.
square meter of body surface, the formula is K/M, where K = 5 EU/
kg and M is the (maximum dose/m2/hour 6 1.80 m2)/70 Kg. ^
Pharmacopeial Forum
Mix a volume of the Lysate TS with an equal volume (such

as 0.1-mL aliquots) of one of the Standard Endotoxin
Geometric Mean Endpoint Concentration = antilog (e / f)
Solutions in each test tube. When single test vials or
ampuls containing lyophilized Lysate are used, add solutions where e is the sum of the log endpoint concentrations of the
directly to the vial or ampul. Incubate the reaction mixture for dilution series used, and f is the number of replicate test tubes.
a constant period according to directions of the reagent The geometric mean endpoint concentration is the measured
manufacturer (usually at 37 + 18 for 60 + 2 minutes), sensitivity of the Lysate TS (in EU/mL). If this is not less than
avoiding vibration. To test the integrity of the gel, take each 0.5l and not more than 2l, the labeled sensitivity is
tube in turn directly from the incubator and invert it through confirmed and is used in tests performed with this lysate.
about 1808 in one smooth motion. If a firm gel has formed
Test for Interfering Factors—Usually prepare solutions
that remains in place upon inversion, record the result as
(A–D) in Table 1, and perform the inhibition/enhancement
positive. A result is negative if an intact gel is not formed.
test on the Sample Solutions at a dilution less than the MVD,
The test is not valid unless the lowest concentration of the
not containing any detectable endotoxins, operating as
standard solutions shows a negative result in all replicate
described for Test for Confirmation of Labeled Lysate
tests.
Sensitivity. The geometric mean endpoint concentrations of
The endpoint is the smallest concentration in the series of
Solutions B and C are determined using the formula described
decreasing concentrations of endotoxin. Calculate the mean
in the Test for Confirmation of Labeled Lysate Sensitivity.
value of the logarithms of the endpoint concentration and then
The test is not valid unless Solutions A and D show no
the antilogarithm of the mean value using the following
reaction and the result of Solution C confirms the labeled
formula:
sensitivity.
Table 1. Preparation of Solutions for the Inhibition/Enhancement Test for Gel-Clot Techniques
Endotoxin Concentration/Solution Dilution Initial Endotoxin Number of

Solution to which Endotoxin is Added Diluent Factor Concentration Replicates
Aa none/Sample Solution — — — 4
Bb 2l/Sample Solution Sample Solution 1 2l 4
2 1l 4
4 0.5l 4
8 0.25l 4
Cc 2l/Water for BET Water for BET 1 2l 2
2 1l 2
4 0.5l 2
8 0.25l 2
Dd none/Water for BET — — — 2
Harmonization
a
b
Solution A: a Sample Solution of the preparation under test that is free of detectable endotoxins.
c
Solution B: test for interference.
d
Solution C: control for labeled lysate sensitivity.
Solution D: negative control of Water for BET
Pharmacopeial Forum
If the sensitivity of the lysate determined in the presence of Interpretation—The test is valid when both replicates of
Solution B is not less than 0.5l and not greater than 2l, the Solution B and C are positive and those of Solution D are
Sample Solution does not contain factors that interfere under negative. When a negative result is found for both replicates
the experimental conditions used. Otherwise, the Sample of Solution A, the preparation under test complies with the
Solution to be examined interferes with the test. test. When a positive result is found for both replicates of
If the sample under test does not comply with the test at Solution A, the preparation under test does not comply with
a dilution less than the MVD, repeat the test using a greater the test.
dilution, not exceeding the MVD. The use of a more sensitive When a positive result is found for one replicate of Solution
lysate permits a greater dilution of the sample to be examined A and a negative result is found for the other, repeat the test.
and this may contribute to the elimination of interference. In the repeat test, the preparation under test complies with the
Interference may be overcome by suitable treatment, such test if a negative result is found for both replicates of Solution
as filtration, neutralization, dialysis, or heating. To establish A. The preparation does not comply with the test if a positive
that the chosen treatment effectively eliminates interference result is found for one or both replicates of Solution A.
without loss of endotoxins, perform the assay described However, if the preparation does not comply with the test at
below using the preparation to be examined to which USP a dilution less than the MVD, the test may be repeated using
Endotoxin RS has been added and which has then been a greater dilution, not exceeding the MVD.
submitted to the chosen treatment.
Semi-Quantitative Test
Limit Test
Procedure—The test quantifies bacterial endotoxins in
Procedure—Prepare Solutions A, B, C, and D as shown in Sample Solutions by titration to an endpoint. Prepare
Table 2, and perform the test on these solutions following the Solutions A, B, C, and D as shown in Table 3, and test
procedure for Test for Confirmation of Labeled Lysate these solutions by following the procedure in the Test for
Sensitivity under Preparatory Testing. Confirmation of Labeled Lysate Sensitivity under Preparatory
Testing.
Table 2. Preparation of Solutions for the Gel-Clot Limit Test
Endotoxin Concentration/Solution Number of Calculation and Interpretation—The test is not valid
Solution* to which Endotoxin is Added Replicates unless the following conditions are met: (1) both replicates of
negative control Solution D are negative; (2) both replicates
A none/diluted Sample Solution 2
of positive product control Solution B are positive; and (3) the
B 2l/diluted Sample Solution 2
geometric mean endpoint concentration of Solution C is in the
C 2l/Water for BET 2
range of 0.5l to 2l.
D none/Water for BET 2
To determine the endotoxin concentration of Solution A,
*
Prepare the Solution A and the positive product control Solution B
using a dilution not greater than the MVD and treatments as for the calculate the endpoint concentration for each replicate by
Test for Interfering Factors under Preparatory Testing. The positive
control Solutions B and C contain the Standard Endotoxin Solution at multiplying each endpoint dilution factor by l. The endotoxin
Harmonization
a concentration corresponding to twice the labeled lysate sensitivity.

The negative control Solution D consists of Water for BET. concentration in the Sample Solution is the geometric mean
endpoint concentration of the replicates (see the formula
given for Test for Confirmation of Labeled Lysate Sensitivity
Pharmacopeial Forum
Table 3. Preparation of Solutions for the Gel-Clot Assay
Endotoxin Concentration/
Solution to which Endotoxin Dilution Initial Endotoxin Number of
Solution is Added Diluent Factor Concentration Replicates
A a none/Sample Solution Water for BET 1 — 2
2 — 2
4 — 2
8 — 2
b
B 2l/Sample Solution — 1 2l 2
Cc 2l/Water for BET Water for BET 1 2l 2
2 1l 2
4 0.5l 2
8 0.25l 2
Dd none/Water for BET — — — 2
a
Solution A: Sample Solution under test at the dilution, not to exceed the MVD, with which the Test for Interfering Factors was completed.
Subsequent dilution of the Sample Solution must not exceed the MVD. Use Water for BET to make two replicates of four tubes containing the
Sample Solution under test at concentrations of 1, ½, ¼, and 18 relative to the dilution with which the Test for Interfering Factors was
completed.
b
Other dilutions within the MVD may be used as appropriate.
c
Solution B: Solution A containing standard endotoxin at a concentration of 2l (positive product control).
Solution C: Two replicates of four tubes of Water for BET containing the standard endotoxin at a concentration of 2l, l, 0.5l, and 0.25l,
respectively.
d
Solution D: Water for BET (negative control).
under Preparatory Testing). If the test is conducted with

a diluted Sample Solution, calculate the concentration of
PHOTOMETRIC QUANTITATIVE TECHNIQUES
endotoxin in the original Sample Solution by multiplying by
the dilution factor. If none of the dilutions of the Sample
Turbidimetric Technique
Solution is positive in a valid assay, report the endotoxin
concentration as less than l (if the diluted sample was tested, This technique is a photometric assay to measure the
report as less than l times the lowest dilution factor of the increase in turbidity. On the basis of the assay principle
sample.) If all dilutions are positive, the endotoxin concen- employed, this technique is classified into the endpoint-
tration is reported as equal to or greater than the greatest turbidimetric and kinetic-turbidimetric assays. The endpoint-
dilution factor multiplied by l (e.g., initial dilution factor turbidimetric assay is based on the quantitative relationship
times 8 times l in Table 3). between the concentration of endotoxins and the turbidity
The preparation under test meets the requirements of the (absorbance or transmission) of the reaction mixture at the
test if the concentration of endotoxin is less than that specified end of an incubation period. The kinetic-turbidimetric assay is
in the individual monograph. a method to measure either the time (onset time) needed to
reach a predetermined absorbance of the reaction mixture, or
the rate of turbidity development. The test is carried out at the
Harmonization
incubation temperature recommended by the lysate manufac-

turer (which is usually 37+18).
Pharmacopeial Forum
Chromogenic Technique
Assurance of Criteria for the Standard Curve—The test
This technique is an assay to measure the chromophore must be carried out for each lot of lysate reagent. Using the
released from a suitable chromogenic peptide by the reaction Standard Endotoxin Solution, prepare at least three endotoxin
of endotoxins with lysate. Based on the assay principle concentrations within the range indicated by the lysate
employed, this technique is classified into endpoint-chromo- manufacturer to generate the standard curve. Perform the
genic and kinetic-chromogenic assays. The endpoint-chro- assay using at least three replicates of each standard
mogenic assay is based on the quantitative relationship endotoxin concentration according to the manufacturer’s
between the concentration of endotoxins and the release of instructions for the lysate (volume ratios, incubation time,
chromophore at the end of an incubation period. The kinetic- temperature, pH etc.). If the desired range is greater than two
chromogenic assay is a method to measure either the time logs in the kinetic methods, additional standards should be
(onset time) needed to reach a predetermined absorbance of included to bracket each log increase in the range of the
the reaction mixture, or the rate of color development. The standard curve. The absolute value of the correlation
test is carried out at the incubation temperature recommended coefficient, r, must be greater than or equal to 0.980, for the
by the lysate manufacturer (which is usually 37+18). range of endotoxin concentrations set up.
Test for Interfering Factors—Select an endotoxin con-
Preparatory Testing centration at or near the middle of the endotoxin standard

curve. Prepare Solutions A, B, C, and D as shown in Table 4.
To assure the precision or validity of the turbidimetric and
Perform the test on Solutions A, B, C, and D at least in
chromogenic techniques, preparatory tests are conducted to
duplicate according to the instructions for the lysate
verify that the criteria for the standard curve are valid and that
employed, for example, concerning volume of Sample
the sample solution does not interfere with (inhibit or
Solution and Lysate TS, volume ratio of Sample Solution to
enhance) the reaction. Validation for the test method is
Lysate TS, incubation time, etc.
required when conditions that are likely to influence the test
The test is not valid unless the following conditions are
result change.
met.
Table 4. Preparation of Solutions for the Inhibition/Enhancement Test for Photometric Techniques
Solution to which Endotoxin

Solution Endotoxin Concentration is Added Number of Replicates
Aa none Sample Solution not less than 2
Bb middle concentration of the standard curve Sample Solution not less than 2
c
C at least 3 concentrations (lowest concentration Water for BET each not less than 2
is designated l)
D d none Water for BET not less than 2
Harmonization
a
b
Solution A: The sample solution may be diluted not to exceed MVD.
Solution B: The preparation under test at the same dilution as Solution A, containing added endotoxin at a concentration equal to or near the
middle of the standard curve.
c
Solution C: The standard endotoxin at the concentrations used in the validation of the method described for Assurance of Criteria for the
Standard
d
Curve under Preparatory Testing (positive controls).
Solution D: Water for BET (negative control).
Pharmacopeial Forum
1. The absolute value of the correlation coefficient of the Test Procedure

standard curve generated using Solution C is greater than or
Follow the procedure described for Test for Interfering
equal to 0.980.
Factors under Preparatory Testing.
2. The result with Solution D does not exceed the limit of
the blank value required in the description of the lysate
reagent employed, or it is less than the endotoxin detection Calculation
limit of the lysate reagent employed.
Calculate the endotoxin concentration of each of the
Calculate the mean recovery of the added endotoxin by
replicates of Solution A using the standard curve generated
subtracting the mean endotoxin concentration in the solution,
by the positive control Solution C. The test is not valid unless
if any (Solution A, Table 4), from that containing the added
the following three requirements are met.
endotoxin (Solution B, Table 4). In order to be considered free
1. The results of the control Solution C comply with the
of factors that interfere with the assay under the conditions of
requirements for validation defined for Assurance of Criteria
the test, the measured concentration of the endotoxin added to
for the Standard Curve under Preparatory Testing.
the sample solution must be within 50% to 200% of the
2. The endotoxin recovery, calculated from the concentra-
known added endotoxin concentration after subtraction of any
tion found in Solution B after subtracting the concentration of
endotoxin detected in the solution without added endotoxin.
endotoxin found in Solution A, is within the range of 50% to
When the endotoxin recovery is out of the specified range,
200%.
the Sample Solution under test is considered to contain
3. The result of the negative control Solution D does not
interfering factors. If the preparation under test does not
exceed the limit of the blank value required in the description
comply with the test, repeat the test using a greater dilution,
of the lysate employed, or it is less than the endotoxin
not exceeding the MVD. Furthermore, interference of the
detection limit of the lysate reagent employed.
Sample Solution or diluted Sample Solution not to exceed the
MVD may be eliminated by suitable validated treatment, such
as filtration, neutralization, dialysis, or heat treatment. Interpretation
In photometric assays, the preparation under test complies

with the test if the mean endotoxin concentration of the
replicates of Solution A, after correction for dilution and
concentration, is less than the endotoxin limit for the product.
Harmonization
Pharmacopeial Forum
Both EP and USP worked at the elaboration of a common text on

a new apparatus, the Next Generation Impactor. Both pharmacopeias
Physical Tests and have now published the text regionally but this new apparatus is not
subject to harmonization between EP, USP, and JP.
Determinations (AER: K. Moore) RTS—C42812
h601i AEROSOLS, NASAL

SPRAYS, METERED-DOSE
BRIEFING
INHALERS, AND DRY POWDER
INHALERS
h601i Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry
Powder Inhalers. The European Pharmacopoeia, a member of the
Pharmacopeial Discussion Group, is the coordinating pharmacopoe-
ia in the efforts toward the international harmonization of
compendial standards for this general test chapter. The presented Add the following:
text represents the Official Inquiry Stage 4 draft in the
harmonization process, based in part on comments received in PREPARATIONS FOR INHALATION:
response to the Stage 3 draft. Compared to the Stage 3 draft for
international harmonization, the following modifications have been AERODYNAMIC ASSESSMENT OF FINE
introduced:
(1) The paragraphs on cascade impactor stage mensuration, Re- PARTICLES
entrainment (for apparatus D, Andersen) and Mass balance
have been added or moved to the Introduction section of the
chapter. This test is used to determine the fine particle character-
(2) The paragraphs on discharge sequence have been clarified and
harmonized between the pharmacopeias throughout the text. istics of the aerosol clouds generated by preparations for
(3) The flow rate is now always defined with a tolerance of 5%.
(4) For powder inhalers, more information has been added to inhalation.
enable the calculation of the volumetric flow leaving the meter
(Qout) in the event that its original calibration was with respect to Unless otherwise justified and authorized, one of the
Qin.
(5) Figure 7 for the induction port has been modified to fit the USP following apparatus and test procedures is used.
design.
(6) Apparatus D, Andersen: critical dimensions are proposed Stage mensuration is performed periodically together with
(established together with a manufacturer).
(7) Apparatus D: in Stage 3 draft proposal, cut-off values at other confirmation of other dimensions critical to the effective
flow rates than 28.3 L/min were proposed; critical reviews
caused replacement of this by a more general sentence: ‘‘The operation of the impactor.
aerodynamic cut-off diameters of the individual stages of this
apparatus are currently not well-established at flow rates other Re-entrainment (for Apparatus D and E)—To ensure
than 28.3 L/min. Users must justify and validate the use of the
impactor in the chosen conditions, when flow rates other than efficient particle capture, coat each plate with glycerol,
28.3 L/min are selected.’’
(8) A large number of minor editorial modifications have been silicone oil or similar high viscosity liquid, typically
made to clarify the requirements.
Apparatus A (glass impinger) is not accepted by USP and thus has deposited from a volatile solvent. Plate coating must be part
been deleted from inclusion to the USP. Apparatus A will only be
harmonized between EP and JP. of method validation and may be omitted where justified and
Apparatus B (metal impinger) has been deleted from the earlier
harmonization text. authorized.
It is understood that Apparatus C (MSLI) is not considered as
suitable for the USA even though it is presently included in USP Mass balance—The total mass of the active substance is
chapter h601i.
Calculations—The cut-off diameter of 5 mm proposed in the text not less than 75% and not more than 125% of the average
to calculate the fine particle dose is not accepted by the USP: no such
figure will be included in that pharmacopeia. delivered dose determined during testing for uniformity of
delivered dose. This is not a test of the inhaler but it serves to
ensure that the results are valid.
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Fine particle dose and particle size distribution the axis of the jet tube and centrally aligned. The upper
surface of the impaction plate is slightly raised above the edge
APPARATUS C—MULTI-STAGE LIQUID IMPINGER
of the metal frame. A recess around the perimeter of the
horizontal partition wall guides the position of the glass
cylinder. The glass cylinders are sealed against the horizontal
partition walls with gaskets (M) and clamped together by
6 bolts (N). The sampling ports are sealed by stoppers. The
bottom-side of the lower partition wall of stage 4 has
a concentrical protrusion fitted with a rubber O-ring (P) which
seals against the edge of a filter placed in the filter holder. The
filter holder (R) is constructed as a basin with a concentrical
recess in which a perforated filter support (S) is flush-fitted.
The filter holder is dimensioned for 76-mm diameter filters.
The assembly of impaction stages is clamped onto the filter
holder by 2 snap-locks (T). Connect an induction port (see
Figure 7) onto the stage 1 inlet jet tube of the impinger. A
rubber O-ring on the jet tube provides an airtight connection
to the induction port. A suitable mouthpiece adapter is used to
provide an airtight seal between the inhaler and the induction
port. The front face of the inhaler mouthpiece must be flush
with the front face of the induction port.
Fig. 4. Apparatus C: Multi-Stage Liquid Impinger
The multi-stage liquid impinger consists of impaction stages

1 (preseparator), 2, 3, 4, and an integral filter stage (stage 5),
see Figures 4–6. An impaction stage comprises an upper
horizontal metal partition wall (B) through which a metal inlet
jet tube (A) with its impaction plate (D) is protruding. A glass
cylinder (E) with sampling port (F) forms the vertical wall of
the stage, and a lower horizontal metal partition wall (G)
through which the tube (H) connects to the next lower stage.
The tube into stage 4 (U) ends in a multi-jet arrangement. The Fig. 5. Apparatus C: Details of jet tube and impaction plate.
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impaction plate (D) is secured in a metal frame (J) which is Inserts show end of multi-jet tube U leading to stage 4.
fastened by 2 wires (K) to a sleeve (L) secured on the jet tube. (Numbers and lowercase letters refer to Table 3 and uppercase
The horizontal face of the collection plate is perpendicular to letters refer to Figure 4)
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should be minimized and typically would not be greater than

10. The number of discharges is sufficient to ensure an
accurate and precise determination of the fine particle dose.
After the final discharge, wait for 5 seconds and then switch
off the pump.
Dismantle the filter stage of the apparatus. Carefully
remove the filter, and extract the active substance into an
aliquot of the solvent. Remove the induction port and
mouthpiece adapter from the apparatus, and extract the
active substance into an aliquot of the solvent. If necessary,
rinse the inside of the inlet jet tube to stage 1 with the solvent,
Fig. 6. Apparatus C: Details of the filter stage (Stage 5).
allowing the solvent to flow into the stage. Extract the active
Numbers refer to dimensions (0 = diameter). Uppercase
substance from the inner walls and the collection plate of each
letters refer to Table 2. Dimensions are in millimeters unless
of the 4 upper stages of the apparatus into the solution in the
otherwise stated.
respective stage by carefully tilting and rotating the apparatus,
observing that no liquid transfer occurs between the stages.
Using a suitable method of analysis, determine the quantity
Procedure for Pressurized Inhalers—Dispense 20 mL of
of active substance contained in each of the aliquots of the
a solvent, capable of dissolving the active substance into each
solvent.
of stages 1 to 4, and replace the stoppers. Tilt the apparatus to
Calculate the fine particle dose (see Calculations).
wet the stoppers, thereby neutralizing electrostatic charge.
Procedure for Powder Inhalers—Place a suitable low
Place a suitable filter capable of quantitatively collecting the
resistance filter capable of quantitatively collecting the active
active substance in stage 5, and assemble the apparatus. Place
substance in stage 5, and assemble the apparatus. Connect the
a suitable mouthpiece adapter in position at the end of the
apparatus to a flow system according to the scheme specified
induction port so that the mouthpiece end of the actuator,
in Figure 8 and Table 4. Unless otherwise defined, conduct
when inserted, lines up along the horizontal axis of the
the test at the flow rate, Qout, used in the test for uniformity of
induction port and the inhaler is positioned in the same
delivered dose, drawing 4 L of air from the mouthpiece of the
orientation as intended for use. Connect a suitable vacuum
inhaler and through the apparatus.
pump to the outlet of the apparatus, and adjust the airflow
through the apparatus, as measured at the inlet to the
induction port, to 30 L per minute (+5%). Switch off the
pump. Unless otherwise prescribed in the patient instructions,
shake the inhaler for 5 seconds, and discharge one delivery to
waste. Switch on the pump to the apparatus, locate the
mouthpiece end of the actuator in the adapter, and discharge
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the inhaler into the apparatus, depressing the valve for

a sufficient time to ensure complete discharge. Wait for
5 seconds before removing the assembled inhaler from the Figure 8. Experimental set-up for testing powder inhalers
adapter. Repeat the procedure. The number of discharges
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Fig. 7. Induction port. Dimensions are in millimeters unless otherwise stated.
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Table 2. Component Specification for Apparatus C in Figures 4–6
Code* Item Description Dimensions**

A,H Jet tube Metal tube screwed onto partition wall sealed see Figure 5
by gasket (C), polished innersurface.
B,G Partition wall Circular metal plate
—diameter 120
—thickness see Figure 5
C Gasket e.g. PTFE to fit jet tube
D Impaction plate Porosity 0 sintered-glass disk
—diameter see Figure 5
E Glass cylinder Plane polished cut glass tube
—height, including gaskets 46
—outer diameter 100
—wall thickness 3.5
—sampling port (F) diameter 18
—stopper in sampling port ISO 24/25
J Metal frame L-profiled circular frame with slit
—inner diameter to fit impaction plate
—height 4
—thickness of horizontal section 0.5
—thickness of vertical section 2
K Wire Steel wire interconnecting metal frame
and sleeve (2 for each frame)
—diameter 1
L Sleeve Metal sleeve secured on jet tube by screw
—inner diameter to fit jet tube
—height 6
—thickness 5
M Gasket e.g. silicone to fit glass cylinder
N Bolt Metal bolt with nut (6 pairs)
—length 205
—diameter 4
P O-ring Rubber O-ring
—diameter 6 thickness 66.34 6 2.62
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Q O-ring Rubber O-ring

—diameter 6 thickness 29.1 6 1.6
R Filter holder Metal housing with stand and outlet see Figure 6
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Table 2. Component Specification for Apparatus C in Figures 4–6 (Continued)
Code* Item Description Dimensions**

S Filter support Perforated sheet metal
—diameter 65
—hole diameter 3
—distance between holes (center-points) 4
T Snap-locks
U Multi-jet tube Jet tube (H) ending in multi-jet arrangement see inserts Figure 5
*
**
Refers
to Figure 4.
Dimensions are in millimeters, with tolerances according to ISO 2768-m unless otherwise stated.
Connect a flowmeter to the induction port. Use a flowmeter Prepare the powder inhaler for use according to patient
calibrated for the volumetric flow leaving the meter, or instructions. With the pump running and the 2-way solenoid
calculate the volumetric flow leaving the meter (Qout) using valve closed, locate the mouthpiece of the inhaler in the
the ideal gas law. For a meter calibrated for the entering mouthpiece adapter. Discharge the powder into the apparatus
volumetric flow (Qin), use the following expression: by opening the valve for the required time, T (+5%). Repeat
the procedure. The number of discharges should be
minimized and typically would not be greater than 10. The
number of discharges is sufficient to ensure an accurate and
precise determination of fine particle dose.
Dismantle the filter stage of the apparatus. Carefully
Po = atmospheric pressure, P = pressure drop over the meter. remove the filter, and extract the active substance into an
Adjust the flow control valve to achieve steady flow aliquot of the solvent. Remove the induction port and
through the system at the required rate, Qout (+5%). Switch mouthpiece adapter from the apparatus, and extract the
off the pump. Ensure that critical flow occurs in the flow active substance into an aliquot of the solvent. If necessary,
control valve by the following procedure. rinse the inside of the inlet jet tube to stage 1 with the solvent,
With the inhaler in place and the test flow rate established, allowing the solvent to flow into the stage. Extract the active
measure the absolute pressure on both sides of the control substance from the inner walls and the collection plate of each
valve (pressure reading points P2 and P3 in Figure 8). A ratio of the 4 upper stages of the apparatus into the solution in the
P3/P2 of less than or equal to 0.5 indicates critical flow. respective stage by carefully tilting and rotating the apparatus,
Switch to a more powerful pump and re-measure the test flow observing that no liquid transfer occurs between the stages.
rate if critical flow is not indicated. Using a suitable method of analysis, determine the amount
Dispense 20 mL of a solvent, capable of dissolving the of active substance contained in each of the aliquots of the
active substance into each of the 4 upper stages of the solvent.
apparatus, and replace the stoppers. Tilt the apparatus to wet Calculate the fine particle dose (see Calculations).
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the stoppers, thereby neutralizing electrostatic charge. Place

a suitable mouthpiece adapter in position at the end of the
induction port.
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Table 3. Dimensions1 of Jet Tube With Impaction Plate of Apparatus C
Filter
Type Code2 Stage 1 Stage 2 Stage 3 Stage 4 (Stage 5)
Distance 1 9.5 5.5 4.0 6.0 n.a.
(–.0 +.5) (–.0 +.5) (–.0 +.5) (–.0 +.5)
Distance 2 26 31 33 30.5 0
Distance 3 8 5 5 5 5
Distance 4 3 3 3 3 n.a.
Distance 5 0 3 3 3 3
Distance 63 20 25 25 25 25
Distance 7 n.a. n.a. n.a. 8.5 n.a.
Diameter c 25 14 8.0 (+.1) 21 14

Diameter d 50 30 20 30 n.a.
Diameter e 27.9 16.5 10.5 23.9 n.a.
Diameter f 31.75 (–.0 +.5) 22 14 31 22
Diameter g 25.4 21 13 30 21
Diameter h n.a. n.a. n.a. 2.70 (+.5) n.a.
Diameter j n.a. n.a. n.a. 6.3 n.a.
Diameter k n.a. n.a. n.a. 12.6 n.a.
Radius4 r 16 22 27 28.5 0
Radius s 46 46 46 46 n.a.
Radius t n.a. 50 50 50 50
Angle w 108 538 538 538 538

Angle u n.a. n.a. n.a. 458 n.a.
Angle v n.a. n.a. n.a. 608 n.a.
1
2
Measures in millimeters with tolerances according to ISO 2768-m unles otherwise stated.
3
Refer to Figure 5.
4
Including gasket.
Relative centerline of stage compartment.
n.a. = not applicable
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APPARATUS D—ANDERSEN CASCADE IMPACTOR mouthpiece adapter is used to provide an airtight seal between
the inhaler and the induction port. The front face of the
The Andersen 1 ACFM non-viable cascade impactor
inhaler mouthpiece must be flush with the front face of the
consists of 8 stages together with a final filter. Material of
induction port.
construction may be aluminum, stainless steel, or other
In the configuration for powder inhalers, a preseparator is
suitable material. The stages are clamped together and sealed
placed above the top stage to collect large masses of non-
with O-rings. Critical dimensions applied by the manufacturer
respirable powder. It is connected to the induction port as
of Apparatus D are provided in Table 5. In use, some
shown in Figure 10. To accommodate high flow rates through
occlusion and wear of holes will occur. In-use mensuration
the impactor, the outlet nipple, used to connect the impactor
tolerances need to be justified. In the configuration used for
to the vacuum system is enlarged to have an internal diameter
pressurized inhalers (Figure 9) the entry cone of the impactor
of greater than or equal to 8 mm.
is connected to an induction port (see Figure 7). A suitable
Table 4. Component Specification for Figure 8
Code Item Description

A Connector ID 8 mm, e.g., short metal coupling, with low-diameter branch to P3.
B Vacuum tubing A length of suitable tubing having an ID 8 mm and an internal volume of
25 + 5 mL.
C 2-way solenoid valve A 2-way, 2-port solenoid valve having a minimum airflow resistance orifice with ID
8 mm and an opening time 5 100 ms. (e.g., type 256-A08, Bürkert GmbH,
D-74653 Ingelfingen), or equivalent.
D Vacuum pump Pump must be capable of drawing the required flow rate through the assembled
apparatus with the powder inhaler in the mouthpiece adapter (e.g., product type
1023, 1423 or 2565, Gast Manufacturing Inc., Benton Harbor, MI 49022),
or equivalent. Connect the pump to the 2-way solenoid valve using short and/or
wide (ID 10 mm) vacuum tubing and connectors to minimize pump capacity
requirements.
E Timer Timer capable to drive the 2-way solenoid valve for the required duration (e.g., type
G814, RS Components International, Corby, NN17 9RS, UK), or equivalent.
P2 P3 Pressure measurements Determine under steady-state flow condition with an absolute pressure transducer.
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F Flow control valve Adjustable regulating valve with maximum Cv 1, (e.g., type 8FV12LNSS, Parker
Hannifin plc, Barnstaple, EX31 1NP, UK), or equivalent.
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Table 5. Critical Dimensions for Apparatus D
Description Number Dimension (mm)

Stage 0 nozzle diameter 96 2.55 + 0.025
Procedure for Pressurized Inhalers—Assemble the

Andersen impactor with a suitable filter in place. Ensure
that the system is airtight. In that respect, follow the
manufacturer’s instructions. Place a suitable mouthpiece
adapter in position at the end of the induction port so that
the mouthpiece end of the actuator, when inserted, lines up
along the horizontal axis of the induction port and the inhaler
unit is positioned in the same orientation as the intended use.
Connect a suitable pump to the outlet of the apparatus, and
adjust the airflow through the apparatus, as measured at the
inlet to the induction port, to 28.3 L per minute (+5%). Switch
off the pump.
Unless otherwise prescribed in the patient instructions,
shake the inhaler for 5 seconds, and discharge one delivery to
waste. Switch on the pump to the apparatus, locate the
mouthpiece end of the actuator in the adapter, and discharge
the inverted inhaler into the apparatus, depressing the valve
for a sufficient time to ensure complete discharge. Wait for
5 seconds before removing the assembled inhaler from the
adapter. Repeat the procedure. The number of discharges
should be minimized and typically would not be greater than
Fig. 9. Apparatus D: Andersen cascade impactor used for
10. The number of discharges is sufficient to ensure an
pressurized inhalers
accurate and precise determination of the fine particle dose.
After the final discharge, wait for 5 seconds and then switch
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off the pump. Dismantle the apparatus. Carefully remove the

filter, and extract the active substance into an aliquot of the
solvent. Remove the induction port and mouthpiece adapter
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Fig. 10. Connection of the induction port to the preseparator of the Andersen cascade impactor
from the apparatus, and extract the active substance into an Assemble the Andersen impactor with the preseparator and
aliquot of the solvent. Extract the active substance from the a suitable filter in place, and ensure that the system is airtight.
inner walls and the collection plate of each of the stages of the Depending on the product characteristics, the preseparator
apparatus into aliquots of the solvent. may be omitted, where justified and authorized. Stages 6 and
Using a suitable method of analysis, determine the quantity 7 may also be omitted at high flow rates, if justified. The
of active substance contained in each of the aliquots of the preseparator may be coated in the same way as the plates or
solvent. may contain 10 mL of a suitable solvent. Connect the
Calculate the fine particle dose (see Calculations). apparatus to a flow system according to the scheme specified
Procedure for Powder Inhalers—The aerodynamic cut- in Figure 8 and Table 4.
off diameters of the individual stages of this apparatus are Unless otherwise defined, conduct the test at the flow rate,
currently not well-established at flow rates other than 28.3 L Qout, used in the test for uniformity of delivered dose drawing
per minute. Users must justify and validate the use of the 4 L of air from the mouthpiece of the inhaler and through the
impactor in the chosen conditions, when flow rates different apparatus.

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from 28.3 L per minute are selected.
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Connect a flowmeter to the induction port. Use a flowmeter mouthpiece adapter. Discharge the powder into the apparatus
calibrated for the volumetric flow leaving the meter, or by opening the valve for the required time, T (+5%). Repeat
calculate the volumetric flow leaving the meter (Qout) using the discharge sequence. The number of discharges should be
the ideal gas law. For a meter calibrated for the entering minimized and typically would not be greater than 10. The
volumetric flow (Qin), use the following expression: number of discharges is sufficient to ensure an accurate and
precise determination of fine particle dose.
Dismantle the apparatus. Carefully remove the filter, and
extract the active substance into an aliquot of the solvent.
Remove the preseparator, induction port, and mouthpiece
adapter from the apparatus, and extract the active substance
Po = atmospheric pressure, P = pressure drop over the meter. into an aliquot of the solvent. Extract the active substance
Adjust the flow control valve to achieve steady flow from the inner walls and the collection plate of each of the
through the system at the required rate, Qout (+5%). Ensure stages of the apparatus into aliquots of the solvent.
that critical flow occurs in the flow control valve by the Using a suitable method of analysis, determine the quantity
procedure described for Apparatus C. Switch off the pump. of active substance contained in each of the aliquots of the
Prepare the powder inhaler for use according to the patient solvent.
instructions. With the pump running and the 2-way solenoid Calculate the fine particle dose (see Calculations).
valve closed, locate the mouthpiece of the inhaler in the

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Fig. 11. Apparatus E (shown with the preseparator in place)
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APPARATUS E1
Apparatus E contains a terminal MOC that for most
Apparatus E is a cascade impactor with 7 stages and formulations will eliminate the need for a final filter as
a micro-orifice collector (MOC). Over the flow rate range of determined by method validation. The MOC is an impactor
30 L per minute to 100 L per minute the 50% efficiency cut- plate with nominally 4032 holes, each approximately 70 mm
off diameters (D50 values) range between 0.24 mm to 11.7 mm, in diameter. Most particles not captured on stage 7 of the
evenly spaced on a logarithmic scale. In this flow range, there impactor will be captured on the cup surface below the MOC.
are always at least 5 stages with D50 values between 0.5 mm For impactors operated at 60 L per minute, the MOC is
and 6.5 mm. The collection efficiency curves for each stage capable of collecting 80% of 0.14-mm particles. For
are sharp and minimize overlap between stages. formulations with a significant fraction of particles not
Material of construction may be aluminum, stainless steel, captured by the MOC, there is an optional filter holder that
or other suitable material. can replace the MOC or be placed downstream of the MOC (a
The impactor configuration has removable impaction cups glass fiber filter is suitable).
with all the cups in one plane (Figures 11–14). Procedure for Pressurized Inhalers—Place cups into the
There are 3 main sections to the impactor; the bottom frame apertures in the cup tray. Insert the cup tray into the bottom
that holds the impaction cups, the seal body that holds the frame, and lower into place. Close the impactor lid with the
jets, and the lid that contains the interstage passageways seal body attached, and operate the handle to lock the
(Figures 11–12). Multiple nozzles are used at all but the first impactor together so that the system is airtight.
stage (Figure 13). The flow passes through the impactor in Connect an induction port with internal dimensions defined
a saw-tooth pattern. in Figure 7 to the impactor inlet. Place a suitable mouthpiece
Critical dimensions are provided in Table 6. adapter in position at the end of the induction port so that the
In routine operation, the seal body and lid are held together mouthpiece end of the actuator, when inserted, lines up along
as a single assembly. The impaction cups are accessible when the horizontal axis of the induction port. The front face of the
this assembly is opened at the end of an inhaler test. The cups inhaler mouthpiece must be flush with the front face of the
are held in a support tray, so that all cups can be removed induction port. When attached to the mouthpiece adapter, the
from the impactor simultaneously by lifting out the tray. inhaler is positioned in the same orientation as intended for
An induction port with internal dimensions (relevant to the use. Connect a suitable pump to the outlet of the apparatus,
airflow path) defined in Figure 7 connects to the impactor and adjust the airflow through the apparatus, as measured at
inlet. A preseparator can be added when required, typically the inlet to the induction port, to 30 L per minute (+5%).
with powder inhalers, and connects between the induction Switch off the pump.
port and the impactor. A suitable mouthpiece adapter is used
to provide an airtight seal between the inhaler and the
induction port.
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1
See ‘‘Next Generation Pharmaceutical Impactor (A New Impactor
for Pharmaceutical Inhaler Testing) Part 1: Design’’ by Virgil A.
Marple and coll in J. Aerosol Med., 2003; 16(3):283-299 and ‘‘Next
Generation Pharmaceutical Impactor (A New Impactor for Phar-
maceutical Inhaler Testing) Part II: Archival Calibration’’ by Virgil
A. Marple and coll. in J. Aerosol Med., 2003; 16(3):301-324.
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Table 6. Critical Dimensions for Apparatus E
Description Dimension (mm)

Preseparator (dimension a – see Figure 15) 12.8 + 0.05
*
Stage 1 Nozzle diameter 14.3 + 0.05
Stage 2* Nozzle diameter 4.88 + 0.04
*
*
MOC* approx. 0.070
Cup depth (dimension b – see Figure 14) 14.625 + 0.10
Collection cup surface roughness (Ra) 0.5 – 2 mm
Stage 1 nozzle to seal body distance** – dimension c 0 + 1.18
Stage 2 nozzle to seal body distance** – dimension c 5.236 + 0.736
MOC nozzle to seal body distance** – dimension c 14.429 to 14.571
*
**
SeeFigure 13.
See Figure 14.
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Unless otherwise prescribed in the patient instructions, Dismantle the apparatus, and recover the active substance
shake the inhaler for 5 seconds, and discharge one delivery to as follows. Remove the induction port and mouthpiece
waste. Switch on the pump to the apparatus. Prepare the adapter from the apparatus, and recover the deposited active
inhaler for use according to the patient instructions, locate the substance into an aliquot of solvent. Open the impactor by
mouthpiece end of the actuator in the adapter, and discharge releasing the handle and lifting the lid. Remove the cup tray,
the inhaler into the apparatus, depressing the valve for with the collection cups, and recover the active substance in
a sufficient time to ensure a complete discharge. Wait for each cup into an aliquot of the solvent.
5 seconds before removing the assembled inhaler from the Using a suitable method of analysis, determine the quantity
adapter. Repeat the procedure. The number of discharges of active substance contained in each of the aliquots of the
should be minimized, and typically would not be greater than solvent.
10. The number of discharges is sufficient to ensure an Calculate the fine particle dose (see Calculations).
accurate and precise determination of the fine particle dose. Procedure for Powder Inhalers—Assemble the apparatus
After the final discharge, wait for 5 seconds and then switch with the preseparator (Figure 15). Depending on the product
off the pump. characteristics, the preseparator may be omitted, where
justified.
Fig. 12. Apparatus E showing component parts
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Fig. 13. Apparatus E: Nozzle configuration
Fig. 14. Apparatus E: Configuration of interstage passage ways

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Fig. 15. Apparatus E: Preseparator configuration
Place cups into the apertures in the cup tray. Insert the cup Connect an induction port with internal dimensions defined
tray into the bottom frame, and lower into place. Close the in Figure 7 to the impactor inlet or preseparator inlet. Place
impactor lid with the seal body attached, and operate the a suitable mouthpiece adapter in position at the end of the
handle to lock the impactor together so that the system is induction port so that the mouthpiece end of the inhaler, when
airtight. inserted, lines up along the horizontal axis of the induction
When used, the preseparator should be assembled as port. The front face of the inhaler mouthpiece must be flush
follows. Assemble the preseparator insert into the presepara- with the front face of the induction port. When attached to the
tor base. Fit the preseparator base to the impactor inlet. Add mouthpiece adapter, the inhaler is positioned in the same
15 mL of the solvent used for sample recovery to the central orientation as intended for use. Connect the apparatus to
cup of the preseparator insert. Place the preseparator body on a flow system according to the scheme specified in Figure 8
top of this assembly, and close the 2 catches. and Table 4.
Unless otherwise prescribed, conduct the test at the flow
rate, Qout, used in the test for uniformity of delivered dose
drawing 4 L of air from the mouthpiece of the inhaler and
through the apparatus.
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Connect a flowmeter to the induction port. Use a flowmeter Open the impactor by releasing the handle and lifting the
calibrated for the volumetric flow leaving the meter, or lid. Remove the cup tray, with the collection cups, and
calculate the volumetric flow leaving the meter (Qout) using recover the active substance in each cup into an aliquot of the
the ideal gas law. For a meter calibrated for the entering solvent.
volumetric flow (Qin), use the following expression: Using a suitable method of analysis, determine the quantity
of active substance contained in each of the aliquots of the
solvent.
Calculate the fine particle dose (see Calculations).
CALCULATIONS
Po = atmospheric pressure, P = pressure drop over the meter. From the analysis of the solutions, calculate the mass of
Adjust the flow control valve to achieve steady flow active substance deposited on each stage per discharge and
through the system at the required rate, Qout (+5%). Ensure the mass of active substance per discharge deposited in the
that critical flow occurs in the flow control valve by the induction port, mouthpiece adapter, and when used, the pre-
procedure described for Apparatus C. Switch off the pump. separator.
Prepare the powder inhaler for use according to the patient Starting at the final collection site (filter or MOC), derive
instructions. With the pump running and the 2-way solenoid a table of cumulative mass versus cut-off diameter of the
valve closed, locate the mouthpiece of the inhaler in the respective stage (see Table 7 for Apparatus C, Table 8 for
mouthpiece adapter. Discharge the powder into the apparatus Apparatus D, and Table 9 for Apparatus E). Calculate by
by opening the valve for the required time, T (+5%). Repeat interpolation the mass of the active substance less than 5 mm.
the discharge sequence. The number of discharges should be This is the Fine Particle Dose (FPD).
minimized and typically would not be greater than 10. The If necessary, and where appropriate (e.g., where there is
number of discharges is sufficient to ensure an accurate and a log-normal distribution), plot the cumulative fraction of
precise determination of fine particle dose. active substance versus cut-off diameter (see Tables 7–9) on
Dismantle the apparatus, and recover the active substance log probability paper, and use this plot to determine values for
as follows. Remove the induction port and mouthpiece the Mass Median Aerodynamic Diameter (MMAD) and
adapter from the preseparator, when used, and recover the Geometric Standard Deviation (GSD) as appropriate. Appro-
deposited active substance into an aliquot of the solvent. priate computational methods may also be used.
When used, remove the preseparator from the impactor, being
careful to avoid spilling the cup liquid into the impactor.
Recover the active substance from the preseparator.
Harmonization
Pharmacopeial Forum
p
Table 7. Calculations for Apparatus C. Use q = (60/Q), where Q is the test flow rate in L per minute (Qout for powder inhalers)
Cumulative mass of active

Cut-off diameter Mass of active substance substance deposited Cumulative fraction of
(mm) deposited per discharge per discharge active substance (%)
*
d4 = 1.7 6 q mass from stage 5, m5 c4 = m 5 f4 = (c4/c) 6 100
d3 = 3.1 6 q mass from stage 4, m4 c3 = c4 + m 4 f3 = (c3/c) 6 100
d2 = 6.8 6 q mass from stage 3, m3 c2 = c3 + m 3 f2 = (c2/c) 6 100
mass from stage 2, m2 c = c2 + m2 100
*
Stage 5 is the filter stage.
Table 8. Calculations for Apparatus D when used at a flow rate of 28.3 L per minute
Cumulative mass of active

Cut-off Mass of active substance substance deposited per Cumulative fraction of
diameter (mm) deposited per discharge discharge active substance (%)
d7 = 0.4 mass from stage 8, m8 c7 = m 8 f7 = (c7/c) 6 100
d6 = 0.7 mass from stage 7, m7 c6 = c7 + m 7 f6 = (c6/c) 6 100
Harmonization
Pharmacopeial Forum
Table 9. Calculations for Apparatus E. Use q = (60/Q)x, where Q is the test flow rate in L per minute, and x is listed in the table
Cumulative mass of
Mass of active active substance
Cut-off diame- substance deposited deposited per Cumulative fraction of
ter (mm) x per discharge discharge active substance (%)
d7 = 0.34 6 q 0.67 mass from MOC or terminal c7 = m 8 F7 = (c7 /c) 6 100
filter, m8
d6 = 0.55 6 q 0.60 mass from stage 7, m7 c6 = c7 + m 7 F6 = (c6 /c) 6 100
Harmonization

BRIEFING
STIMULI TO THE

REVISION PROCESS
commentaries
572 of the USPC or the USP Council of Experts Vol. 33(3) [May–June 2007]
Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing, Walter W. Hauck, Ronald
G. Manning, Todd L. Cecil, William Brown, and Roger L. Williams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Summary of Planned Revisions to Design and Analysis of Biological Assays h111i, Walter W. Hauck, Robert Singer,
and Larry N. Callahan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Vol. 33(3) [May–June 2007] of the USPC or the USP Council of Experts 573

be addressed to:
Pharmacopeial Forum
Rockville, MD 20852
Proposed Change to Acceptance Criteria for

Dissolution Performance Verification Testing
Walter W. Hauck,* Ronald G. Manning, Todd L. Cecil, William Brown, Roger L. Williams, USP
ABSTRACT USP Dissolution h711i specifies performance verification testing (PVT) of dissolution Apparatus 1 and 2.
Acceptance criteria are determined from a collaborative study and apply per tablet; i.e., each of the six tablets tested must fall
within the specified acceptance criteria in order to pass. In this Stimuli article, USP proposes changing the form of the acceptance
criteria to one that is consistent with the International Organization for Standardization’s (ISO’s) recommendations for proficiency
testing. The new criteria would apply to the laboratory’s average and standard deviation of the tablets tested. The article explains
the rationale and shows the criteria that would be applied to USP Lot P Prednisone Reference Standard (RS) Tablets and USP Lot
Q Salicylic Acid RS Tablets.
INTRODUCTION laboratories for specific tests or measurements and to monitor

laboratories’ continuing performance.’’ The USP PVT oper-
In either the private regulatory specification or the public ates at the interlaboratory level because the acceptance limits
monograph, the USP Performance test can be satisfied with are set from a collaborative study. Each laboratory conducting
approaches described in General Chapters Disintegration a PVT is thus comparing itself to the laboratories in the
h701i or Dissolution h711i. As described in h711i, dissolution collaborative study. USP PVT differs from a typical profi-
testing of non-solution oral drug products is complex, in- ciency test as described by Guide 43.1 because the PVT is con-
volving a preparatory apparatus, an analyst, and an analytical ducted in a single laboratory for comparison to an assigned
procedure. In 1979 at the request of industry and FDA, USP value from a collaborative study. ISO Guide 43-1 continues,
introduced reference standard (RS) tablets, formerly termed ‘‘Participation in proficiency testing schemes provides labora-
calibrator tablets, for use in periodic performance verification tories with an objective means of assessing and demonstrating
testing (PVT), formerly termed an apparatus suitability test. the reliability of the data they are producing,’’ and ‘‘One of the
This is typically conducted every six months. (1) main uses of proficiency testing schemes is to assess labora-
The acceptance criteria for the PVT are established on the tories’ ability to perform tests competently ... It thus supple-
basis of data from a collaborative study (Reference 2, for ex- ments laboratories’ own internal quality control procedures
ample) conducted for each new lot of reference standard tab- by providing an additional external measure of their testing
lets and are provided to the laboratory on the information sheet capability.’’
accompanying the tablets. The acceptance criterion is set per This describes well the intent of USP PVTs. Although pro-
tablet; i.e., the criterion is an interval and all six tested tablets ficiency testing to an external sample is not usually performed
must fall within that interval to be considered passing. Histori- in pharmaceutical QC laboratories, it is more common in offi-
cally, the acceptance interval was determined as X 2SDR, cial medicine control laboratories (e.g., check sample testing)
where X is the average (assigned value) and SDR the reprodu- and in other sectors (e.g., clinical chemistry laboratories). Its
cibility standard deviation for a single determination from the value in ensuring the integrity of the dissolution procedure is
collaborative study. important for at least two reasons: first, well-known sensitivity
Recently, this formula has been modified in two ways. First, of the dissolution procedure to various experimental variables;
the statistical analysis is now done in the natural log scale to and second, the importance of the dissolution procedure itself
better satisfy the assumption of normality. Second, the factor 2 in ensuring product performance over time. USP notes that the
corresponds, approximately, to 95% coverage and up to a 5% general ISO objectives of interlaboratory comparisons are not
false error rate per tablet. Because six tablets are tested, the satisfied by a manufacturer-specific tablet, which is sometimes
actual false positive rate is higher than the nominal 5%. To cor- proposed as a solution to the wide acceptance criteria arising
rect for this multiple testing, a 1% value is now used, so the from USP’s collaborative studies. Individual laboratories of
current formula is exp(X 2.576SDR), where X and SDR are course may set their own acceptance criteria for USP’s refer-
determined in the natural log scale. ence standard tablets if they believe that the acceptance criteria
Performance verification testing has the character of profi- set by USP are too wide.
ciency testing as described in guides published by the Interna- Other ISO guides address acceptance criteria. Table 3 of
tional Organization for Standardization (ISO). ISO Guide 43- ISO Guide 5725-6 titled Accuracy (Trueness and Precision)
1, Proficiency Testing by Interlaboratory Comparisons—De- of Measurement Methods and Results—Use in Practice of Ac-
velopment and Operation of Proficiency Testing Schemes curacy Values (4) lists the difference of the laboratory’s mean
(3), describes proficiency testing as the use of interlaboratory versus the consensus value from a collaborative study and the
comparisons to ‘‘determine the performance of individual laboratory’s reliability standard deviation as important pa-
*
rameters for checking trueness and precision. Both ISO
Correspondence should be addressed to Walter W. Hauck, Ph.D., Senior Guides 5725-6 and 21748, the latter titled Guidance for the
Scientific Fellow, U.S. Pharmacopeia, 12601 Twinbrook Parkway, Rockville,
MD 20852-1790; tel. 301.816.8390; e-mail wh@usp.org.
Use of Repeatability, Reproducibility, and Trueness To address these questions and gain some understanding of
Estimation in Measurement Uncertainty Estimation (5), give the likely interactions of the criteria, we determined variations
suggested acceptance criteria. Those from Guide 21748 are: on the ISO criteria for USP Lot P Prednisone RS Tablets and
A laboratory’s mean should be within two standard devia- USP Lot Q Salicylic Acid RS Tablets.
tions of the assigned value, where the standard deviation The first variation was to consider a tolerance interval for
is based on the reproducibility standard deviation of the the within-laboratory variability instead of the F-test. The
mean; and ISO criterion for the laboratory average is an approximate
Compare the laboratory’s reliability variability to the val- 95% tolerance interval for a laboratory average based on re-

ue from the collaborative study using an F test with 95% sults from the collaborative study. It is approximate in using
confidence. a factor of 2 rather than an exact tolerance interval factor,
For the variance comparison, Guide 21748 sets a minimum although the difference is not large with the degrees of free-
of 15 degrees of freedom for the laboratory. The Guide also dom for the within-laboratory error from the collaborative
requires that the number of determinations (tablets) be suffi- study. The corresponding approach for the standard deviation
ciently large that the repeatability standard error of the labo- would be a tolerance interval based on a chi-square distribu-
ratory’s mean is not more than 0.2 times the reproducibility tion, as in Guide 5725-6.
standard deviation for a single measurement. The criteria from The second variation was to consider the multiple testing
Guide 5725-6 differ from those of Guide 21748 only in using a issue. There are two acceptance criteria to meet. If each is at
chi-square rather than an F test to assess the within-laboratory 5%, then the maximum false positive rate would be approxi-
variability. mately 10%. To control the maximum false fail rate at 5%,
each of the two tests would be performed at 2.5%.
PRELIMINARY INVESTIGATION For acceptance limits for the standard deviation, low varia-
bility is desirable, so only one-sided limits are considered; i.e.,
ISO 5725-6 leaves some unanswered questions regarding failure is considered only as too large a standard deviation.
the USP PVT as specified in h711i: ISO specifies reliability as the particular variability to com-
The criterion for the mean is an approximate tolerance in- pare in proficiency testing. USP’s experience from its col-
terval, but the criterion for the variance is a statistical hy- laborative studies (see reference 2, for example) is that the pre-
pothesis test. Should these be more consistent in dominant component of reliability is the tablet-to-tablet varia-
structure? A priori, one expects that the difference is not bility in results. The tablet-to-tablet variability includes
large. The approximate tolerance interval for acceptance variability from the assay, position within the apparatus, loca-
criteria corresponds to the test if the variability in the col- tion of the tablet within the vessel, the vessels, and any varia-
laborative study is disregarded. Thus, for example, the bility in the tablets themselves. Reliability would add
chi-square test of Guide 5725-6 is a tolerance interval, additional variability associated with multiple runs conducted
in contrast to the F-test of Guide 21748. in a short period of time by the same analyst using the same
The variance test of Guide 21748 does not specify apparatus.
whether the test should be one- or two-sided. Which For the number of tablets, the ISO criteria are determined
should it be? The criterion in Guide 5725-6 is one-sided. based on one, two, and three sets of six tablets. With more than
Do we need full reliability standard deviations for the one set, the intralaboratory variability is pooled across sets.
PVT, or can we use the between-tablet variability? Results for the various options and sample sizes are shown
If we compare between-tablet variability, the ISO require- in Tables 1 and 2 for Lot P Prednisone RS Tablets and in Ta-
ment for degrees of freedom corresponds to three sets of bles 3 and 4 for Lot Q Salicylic Acid RS Tablets. The limits
six tablets (18 total) instead of the single set currently. shown as ‘‘Current USP’’ are the limits approved by the USP
Does the PVT need to be that much larger? Reference Standard and Biopharmaceutics Expert Committees
Because there are two acceptance criteria (mean and stan- for these lots. Figures 1 to 4 show the Prednisone limits with
dard deviation), should we adjust for multiple testing? the data from the collaborative study.
Table 1. Acceptance Limits, USP Lot P Prednisone RS Tablets, Apparatus 1

Limits for X %CV Upper Limits
Number of Limits for 2.5% Error
Approach Tablets Tablets 5% Error Rate 2.5% Error Rate 5% Error Rate Rate
Current 6 47–82
USP
ISO 6 53.5–72.3 52.6–73.6 12.3% 13.2%
12 53.9–71.8 53.0–73.0 11.2% 11.9%
18 54.1–71.6 53.2–72.8 10.7% 11.2%
Modified
ISO 6 12.1% 13.1%
12 11.0% 11.7%
18 10.5% 11.0%
Collaborative study results were a mean of 62.2 and an intralaboratory (residual) CV of 8.1%.
Table 2. Acceptance Limits, USP Lot P Prednisone RS Tablets, Apparatus 2
Number of Limits for
Approach Tablets Tablets 5% Error Rate 2.5% Error Rate 5% Error Rate 2.5% Error Rate
Current 6 37–70
USP
ISO 6 42.3–61.8 41.4–63.3 12.7% 13.7%
12 42.6–61.4 41.7–62.8 11.6% 12.3%

18 42.7–61.3 41.8–62.6 11.1% 11.7%
Modified
ISO 6 12.6% 13.6%
12 11.5% 12.1%
18 10.9% 11.5%
Figure 1. USP Lot P Prednisone RS Tablets, Laboratory Means from the Collaborative Study, Apparatus 1.
Figure 2. USP Lot P Prednisone RS Tablets, Laboratory %CVs from the Collaborative Study, Apparatus 1.

Figure 3. USP Lot P Prednisone RS Tablets, Laboratory Means from the Collaborative Study, Apparatus 2.
Figure 4. USP Lot P Prednisone RS Tablets, Laboratory %CVs from the Collaborative Study, Apparatus 2.
There is little difference between the ISO (F test) and mod- This is the probability that a lab whose variability is greater
ified ISO (tolerance interval) limits for the percent coefficient than that of the collaborative study will fail, i.e., obtain a
of variation (%CV). Increasing the number of tablets from 6 to %CV in the PVT outside the limits. Again, the largest change
12 does noticeably change the limits for the CV, and the is observed in power moving from six to 12 tablets. Although
further change to 18 tablets has little effect. Changing the the further increase to 18 tablets does increase the power
number of tablets also changes the power of the statistical test. further, it has much less an effect than increasing from 6 to 12.
Table 3. Acceptance Limits, USP Lot Q Salicylic Acid RS Tablets, Apparatus 1

Current 6 23–30
USP
ISO 6 24.2–28.9 24.0–29.2 3.1% 3.4%
12 24.2–28.9 24.0–29.2 2.8% 3.0%
18 24.2–28.9 24.0–29.2 2.7% 2.9%
Modified
ISO 6 3.1% 3.3%
12 2.8% 3.0%
18 2.7% 2.8%
Changing the number of tablets has little effect for the ment. The limits for the mean in Tables 1–4 assume that all
mean, but that partly depends on an assumption about how two or three sets would be done by the same analyst on the
the PVT would be conducted. The reproducibility standard de- same equipment, so the intermediate precision components
viation includes a component for experiment, corresponding are not reduced with the additional testing
to the intermediate precision components of analyst and equip-
Table 4. Acceptance Limits, USP Lot Q Salicylic Acid RS Tablets, Apparatus 2

Current 6 17–25
USP
ISO 6 18.4–23.0 18.1–23.3 7.8% 8.5%
12 18.5–22.9 18.2–23.2 7.2% 7.6%
18 18.5–22.9 18.2–23.2 6.8% 7.2%
Modified
ISO 6 7.8% 8.4%
12 7.1% 7.5%
18 6.7% 7.1%
PROPOSAL number of tablets tested but may reduce the number of cases
in which a test ‘‘fails’’ when only one of six tablets falls out-
To the extent possible, USP is interested in being consistent side specifications. Further work at USP is being done to de-
with practices set in ISO guides. From this perspective, USP termine the proper sample size for sound metrological
and its Biopharmaceutics Expert Committee envision chang- examination of testing tablets and acceptance criteria. In addi-
ing the PVT acceptance criteria to align them with recommen- tion, USP will conduct further collaborative testing of its Lot P
dations in cited ISO guides. Specifically, we propose to use the Prednisone RS Tablets using increased stringency in execution
general form of the criteria of Guide 21748, modified to com- to determine if the high interlaboratory variance can be re-

pare between-tablet variability based on 12 tablets. duced. USP welcomes comments on the approaches discussed
Another consideration is that when six tablets are tested and in this Stimuli article. They should be sent to Walter W. Hauck,
fail, often that failure is one tablet of the six falling just outside Ph.D., at wh@usp.org no later than August 15, 2007.
the acceptance range although the other five pass. Criteria
based on the mean and standard deviation should eliminate REFERENCES
many instances of this type of failure.
ISO is unambiguous about the need for a sufficient sample 1. USP Council of Experts Biopharmaceutics Expert Committee,
size—three sets of six tablets—for the variance comparison. Dissolution Advisory Panel, and USP Staff. The USP perfor-
Preliminary analyses in this report suggest little added benefit mance verification test, part I: proficiency testing and the USP
of 18 compared to 12 tablets. Twelve tablets would be a dou- dissolution procedure. Submitted for publication. 2007.
bling of effort for dissolution PVT if nothing else changes. 2. Glasgow M, Dressman S, Brown W, et al. The USP performance
One solution to this added burden might be to require for com- verification test, part II: collaborative study of USP’s Lot P
pliance in execution of the PVT use of only one USP tablet Prednisone Tablets. J Pharm Sci. In press.
(e.g., Salicylic Acid or Prednisone) per apparatus. The USP 3. ISO. Guide 43-1, Proficiency Testing by Interlaboratory Com-
Biopharmaceutics Expert Committee is exploring this option parisons—Development and Operation of Proficiency Testing
via the Dissolution Advisory Panel. Schemes. 2nd ed. Geneva, Switzerland: ISO; 1997.
4. ISO. Guide 5725-6, Accuracy (Trueness and Precision) of
Measurement Methods and Results—Use in Practice of Accu-
CONCLUSION
racy Values. Geneva, Switzerland: ISO; 1994.
USP believes that metrological understanding of ISO 5. ISO. Technical Specification 21748, Guidance for the Use of Re-
guides can improve manufacturers’ approaches to ensure in- peatability, Reproducibility, and Trueness Estimates in
tegrity of the dissolution procedure, including use of a PVT Measurement Uncertainty Estimation. Geneva, Switzerland:
and publicly available USP RS tablets that support interlabora- ISO; 2004.
tory comparisons. As this article suggests, metrological ap-
proaches to measuring variation may call for increasing the
Summary of Planned Revisions to

Design and Analysis of Biological Assays h111i
Walter W. Hauck, USP; Robert Singer, Chair, Ad Hoc Advisory Panel for the Revision of General Chapter h111i; and Larry N.
Callahan, USP *
ABSTRACT An ad hoc Advisory Panel to the USP Statistics Expert Committee has been charged with revising USP General
Chapter Design and Analysis of Biological Assays h111i. This revision is nearing readiness for publication in Pharmacopeial
Forum as an In-Process Revision that constitutes a complete rewrite of this Chapter and is substantially different in style and
content from the current h111i. The Advisory Panel anticipates that these sweeping changes may have both foreseen and
unforeseen consequences for industry. For example, companies that have relied on h111i may need to review and revise SOPs
that are related to this Chapter. The purpose of the current Stimuli article is to describe the substantive differences between the
revision and the current Chapter. The revisions are summarized in Table 1, and most are also described below. Stakeholders are
invited to comment on these changes.
CHANGES RELATED TO GENERAL STRUCTURE Currently, nine monographs and seven General Chapters
contain references to h111i and would need to be revised by
h111Revi{ is envisioned as less prescriptive than h111i. The USP to correspond to h111Revi. These are: chorionic gonado-
revision focuses on concepts and considerations that influence tropin; corticotropin; digitalis; glucagons; heparin sodium;
the design and analysis of bioassays rather than on formulas. iron dextran injection; menotropins; sincalide for injection;
The Chapter’s authors assume that bioassay practitioners have oil- and water-soluble vitamins with mineral tablets; Antibi-
access to sound and validated computer software that reliably otics—Microbial Assays h81i; Calcium Pantothenate Assay
performs requisite calculations. The revised chapter will in- h91i; Insulin Assays h121i; Vitamin B12 Activity Assay
clude several worked examples that illustrate particular meth- h171i; Vitamin D Assay h581i; Analytical Data—Interpreta-
ods of analysis but will not prescribe specific instructions tion and Treatment h1010i; and Biotechnology-Derived Arti-
about how to calculate potency or confidence intervals for spe- cles h1045i.
cific drug substances or products. General Chapter h111i contains specific information for a
The changes in general approach and style in h111Revi are total of 12 Monographs and General Chapters. General Chap-
sufficiently large that the Advisory Panel has recommended to ter h111Revi will not contain monograph-specific methods or
the Statistics Expert Committee that the chapter be renum- methods specific to other General Chapters. Specific methods
bered above 1000. As specified in the USP General Notices, of analysis for USP Monographs and General Chapters that
articles in USP must comply with General Chapters numbered are present in h111i will be moved into the Monographs and
below 1000. In contrast, General Chapters numbered above General Chapters.
1000 are considered interpretive and are intended to provide
information about or descriptive of a particular subject. Chap- SPECIFIC CHANGES
ters numbered above 1000 contain no official requirements ap-
plicable to any pharmacopeial article unless specifically The revised General Chapter will focus on the analysis of
referenced in a monograph or elsewhere in the pharmacopeia bioassays. Design considerations will be moved to a new
or otherwise required by law or regulation. chapter tentatively titled Design and Development of Bio-
logical Assays h1032i. Additionally, bioassay validation is-
CHANGES INTERNAL TO USP–NF sues will be addressed in Chapter h1033i, tentatively titled
Validation of Biological Assays.
General Chapter h111i is linked to USP monographs or General Chapter h111Revi will not contain procedures for
other General Chapters in two ways: either a monograph or outliers. Instead, it will discuss approaches to outlier identifi-
General Chapter contains reference to h111i for methods of cation and rejection and will refer to h1010i for statistical
analysis, or h111i refers directly to a drug monograph or Gen- methods to determine whether a data set contains outliers.
eral Chapter. The presence of either of these links for a parti- The section Combination of Independent Assays will stress
cular drug, product, or Chapter does not imply the presence or that the preferred method is to assume that the relative poten-
absence of a link in the other direction. cies differ by assay and that they will be averaged unweighted
to determine potency and the confidence interval. This differs
from the current method of h111i that assumes homogeneity of
relative potencies and weights the individual assays according
*
Correspondence should be addressed to: Larry N. Callahan, Ph.D., Senior to variance. The method that assumes homogeneity will be in-
Scientist, Standards Development, U.S. Pharmacopeia, 12601 Twinbrook cluded with a description of the required justification.
Parkway, Rockville, MD 20852-1790; tel. 301.816.8385; e-mail lnc@usp.org.
{
Note: In this Stimuli article h111i denotes the current official chapter in USP,
and h111Revi denotes the planned draft revision.
In h111Revi testing for parallelism and linearity will be natives. Also, h111Revi includes the four- and five-parameter
based on equivalence testing approaches. The current method logistic (nonlinear) models in addition to the linear models in
is to test the null hypothesis of no difference—i.e., detecting h111i. Given that most bioassay analysis currently is carried
no significant difference in slopes leads to the conclusion of out by computers and dedicated software, h111Revi will con-
parallelism. The current approach will no longer be acceptable tain data sets that may help validate software. Analysis of
for the determination of similarity in h111Revi. The procedure these data sets will give some indication that the software is
in the current version of h111i often fails bioassays that have performing correctly in the determination of similarity, po-
very little variance and minor differences in slope and passes tency, and confidence intervals.

assays that have large amounts of variation and considerable
differences in slope. This proposed change has been presented CONCLUSION
at a number of conferences and in the literature (1, and refer-
ences therein). Table 1 provides a summary of some important changes be-
General Chapter h111i was written more than 50 years ago, tween h111i and h111Revi. USP and the ad hoc Advisory Pan-
before the widespread availability of computer-assisted com- el believe that the proposed changes will improve the General
putation. General Chapter h111Revi will contain more modern Chapter and make it more suitable for modern bioassay appli-
statistical methods, such as nonlinear mixed effects models, cations. As always, USP welcomes public comments on the
and will describe their application as effective analytical alter- proposed changes.
Topic h111i h111Revi

Focus Algebraic manipulation of data Concepts and considerations
Placement in USP–NF Less than 1000 Greater than 1000
Links to monographs Included Not included
and General Chap-
ters
Bioassay design Some included Moved to new h1032i
Similarity Hypothesis test for linear case only Equivalence test for both linear and nonlinear case
Standard curve fit Linear only Linear and nonlinear (4- and 5-parameter logistic)
Computations No examples; formulas set up for Fewer formulas; numerous examples stressing use of
hand calculations validated computer software
Outliers Discussed in chapter with methods Discussed in chapter, but reference to h1010i for methods
Data imputation Discussed as viable means to handle Not discussed; stress use of modern statistical methods
missing or unbalanced data (e.g., nonlinear mixed effects models) instead
Combinations of Only method provided assumes Two methods given: preferred method assumes relative
independent assays homogeneous relative potencies potencies differ by assay
Validation data sets Not included Many of the data sets used as examples will be made
available on the USP Web site for use in checking
software determination of similarity, potency, and
the confidence intervals
REFERENCES
1. Hauck WW, et al. Assessing parallelism prior to determining rel-
ative potency. PDA J Pharm Sci Tech. 2005;59(2):127–137.
NOMENCLATURE
Nomenclature
Pharmacopeial Forum
584 NOMENCLATURE Vol. 33(3) [May–June 2007]
USP Dictionary of USAN and International Drug Names

2007 USP DICTIONARY SUPPLEMENT 1
IMPORTANT—Save this Supplement. This and all supplements appearing in PF are needed to keep the 2007 edition of the USP Dictionary
(USPD) up-to-date. The cumulative contents of the supplements to the current (2007) edition will be included in the next complete edition of the
Dictionary.
Revisions of United States Adopted Names (USAN)

The following are revisions of existing United States Adopted Names (USAN) and other names.
Ristianol Phosphate Sarmoxicillin

Change the chemical name to read: Change the chemical name to read:
(2) 2-(4-Pyridylmethyl)thioethanol phosphate (1:1) (salt). (1) 4-Thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-[4-(4-hy-

droxyphenyl)-2,2-dimethyl-5-oxo-1-imidazolidinyl]-3,3-dimethyl-7-
oxo-, methoxymethyl ester, [2S–(2a,5a,6b)]-;
Ritipenem
Nomenclature
Change the chemical name to read: Scarlet Red

Add the chemical name, formula, and molecular weight to
(5R,6S)-3-(Carbamoyloxymethyl)-6-((R)-1-hydroxyethyl)-7-oxo-4- read:
thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid.
C24H20N4O. 380.44. o-Tolylazo-o-tolylazo-b-naphthol.
Ropinirole Hydrochloride
Change the chemical name to read: Scopafungin

Add the chemical formula and molecular weight to read:
(1) 2H-Indol-2-one, 4-[2-(dipropylamino)ethyl]-1,3-dihydro-,
monohydrochloride;
C59H103N3O18. 1142.46
Rutin
Silodrate
Add the chemical names to read:
Delete the graphic
(1) 3-Rhamnoglucoside of 5,7,3’,4’-tetrahydroxyflavonol; (2) 2-(3,4-

Dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one-3-yl 6-O-a-L- Solimastat
rhamnopyranosyl-b-D-glucoside.
Change the chemical name to read:
Ruzadolone
(2S,3R)-3-[(1S)-(2,2-Dimethyl-1-(2-pyridylcarbamoyl)propyl)carba-
Change the chemical name to read: moyl]-2-methoxy-5-methylhexanohydroxamic acid.
3-[[2-[4-(2,4-Difluorophenyl)-1-piperazinyl]ethyl]thio]-S-triazo- Sorbitan Monolaurate

lo[4,3-a]pyridine.
Safrole
C18H34O6. 346.46.
Spiramycin
C10H10O2. 162.19.
Santonin
C43H74N2O14. 843.05.
Add the chemical name to read:
(3S,3aS,5aS)-3,5a,9-Trimethyl-3a,4,5,5a-tetrahydronaphtho[1,2-
b]furan-2,8(3H,9bH)-dione.
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] NOMENCLATURE 585
Stibophen Sulfasymazine
Add the chemical formula, molecular weight, and chemical Change the chemical name to read:
names to read:
N1-(4,6-Diethyl-s-triazin-2-yl)sulfanilamide.
C12H4Na5O16S4Sb 7H2O. 895.23. (1) Antimonate(5-), bis[4,5-dihy-
droxy-1,3-benzenedisulfonato(4-)-O4,O5]-, pentasodium heptahydrate;
(2) Pentasodium bis[4,5-dihydroxy-m-benzenedisulfonato Sulfur Hexafluoride
(4-)]antimonate(5-) heptahydrate.
Delete the graphic
Strontium Chloride Sr 89
Tafenoquine
Delete the graphic
Sulfabromomethazine
(RS)-N4-(2,6-Dimethoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)-
Add the chemical formula, molecular weight, cas number, quinolin-8-yl)pentane-1,4-diamine.
and chemical name to read:
Tebipenem Pivoxil
C12H12BrN4NaO2S H2O. 397.22. Sodium N1-(5-bromo-4,6-dimethyl-
2-pyrimidinyl)sulfanilamide, monohydrate. CAS-116-45-0 [sulfabro- Change the chemical name to read:
momethazine].
Nomenclature
(4R,5S,6S)-3-[[1-(4,5-Dihydro-2-thiazolyl)-3-azetidinyl]thio]-6-[(1R)-
1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-
carboxylic acid (2,2-dimethyl-1-oxopropoxy) methyl ester.
Tegafur
(2) 5-Fluoro-1-(tetrahydro-2-furyl)uracil.
Pharmacopeial Forum
586 NOMENCLATURE Vol. 33(3) [May–June 2007]
Proposed and Recommended International Nonproprietary Names

International Nonproprietary Names (INN) are devised by the tion reflects a belief that the proposal concerned is confusingly close
World Health Organization (WHO). to (i.e., conflicts with) a name already in use, perhaps in only a re-
Under its charter, the WHO is empowered simply to recommend stricted area in which the party has a proprietary interest in the form
specific actions or procedures to its Member States. This limitation of trademark rights. In the event that no objection is received, the
is incorporated into the WHO program concerned with the selection WHO proceeds with listing and publishing the names so devised as
of international nonproprietary names for pharmaceutical substances, recommendations (‘‘Recommended International Nonproprietary
in that the WHO first publishes the selected names as proposals Names’’), which many Member States then recognize as the sole or
(‘‘Proposed International Nonproprietary Names’’). A period of four preferred nonproprietary name for use within their respective terri-
months from the date of publication in WHO Drug Information is al- tories.
lowed for entering comments on, or objections to, any proposal on the
part of Member States or other interested parties. In general, an objec-
Proposed International Nonproprietary Names

The following 35 names have been selected by the World Health Any comments or formal objections to the proposed names should
Organization (WHO) as Proposed International Nonproprietary be addressed to Helene Biernacki, Research Associate, USAN Coun-
Names. This list, with chemical names or descriptions and the molec- cil, American Medical Association, 515 North State Street, Chicago,
ular formulae, appears in WHO Drug Information, Vol. 20, No. 4, Illinois 60610.
2006.
Proposed INN Therapeutic Indication Proposed INN Therapeutic Indication

Nomenclature
alogliptin antidiabetic nemonoxacin antibacterial

alvespimycin antineoplastic obinepitide neuropeptide Y receptor agonist
amifampridine potassium channel blocker ozenoxacin antibacterial
balamapimod antineoplastic padeliporfin laser-activated photosensitizer
bevirimat antiviral pamapimod immunomodulator
carisbamate anticonvulsant panobinostat antineoplastic
cevipabulin antineoplastic pardoprunox antiparkinsonian
dalcetrapib antihyperlipidaemic resatorvid toll-like receptor 4 inhibitor
firategrast nonsteroidal anti-inflammatory rusalatide thrombin receptor as an agonist,
giripladib cytosolic phospholipase A2 in- promoter of bone and skin
hibitor wound healing
imepitoin antiepileptic, anxiolytic (veteri- senicapoc calcium-activated potassium
nary drug) channel inhibitor
isavuconazole antifungal sergliflozin antidiabetic
isavuconazonium chloride antifungal tanespimycin antineoplastic
linaclotide guanylate cyclase-C agonist telatinib antineoplastic
litenimod antineoplastic - immunostimu- tesamorelin growth hormone release-stimu-
lant lating peptide
managlinat dialanetil antidiabetic ulipristal (already published in PL90)
masitinib antineoplastic vernakalant antiarrhythmic
methylnaltrexone bromide peripheral narcotic antagonist votucalis histamine-binding protein
naptumomab estafenatox antineoplastic
INDEX
Index
Pharmacopeial Forum
588 INDEX Vol. 33(3) [May–June 2007]
[Note—This index covers Vol. 33 No. 1, pp. 1–150; Vol. 33 No. Magnesium Chloride (USP) . . . . . . . . . . . . . . . . . . . . . 37
2 pp. 151–339; Vol. 33 No. 3 pp. 341–590] Meclizine Hydrochloride (USP) . . . . . . . . . . . . . . . . . . . 244
Meclizine Hydrochloride Tablets (USP) . . . . . . . . . . . . . . 245
MONOGRAPHS Metformin Hydrochloride Tablets (USP) . . . . . . . . . . . . . . 187
Acarbose . . . . . . . . . . . . . . . . . . . . . . . . . . ..
... . 388 Methdilazine Hydrochloride Oral Solution (USP erratum) . . . . 37
Acetaminophen Extended-Release Tablets (USP) . . . ..
... . 183 Methylphenidate Hydrochloride Tablets (USP) . . . . . . . . . . 246
Acitretin (USP) . . . . . . . . . . . . . . . . . . . . . . . ..
... . 390 Mirtazapine (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Acitretin Capsules (USP) . . . . . . . . . . . . . . . . . ..
... . 392 Norethindrone Acetate and Ethinyl Estradiol Tablets (USP) . . . 81, 432
Alprazolam Tablets . . . . . . . . . . . . . . . . . . . . ..
... . 41 Norethindrone Tablets (USP) . . . . . . . . . . . . . . . . . . . . . 432
Baclofen (USP) . . . . . . . . . . . . . . . . . . . . . . ..
... . 211 Octinoxate (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Benzonatate Capsules (USP) . . . . . . . . . . . . . . . ..
... . 394 Ofloxacin Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . 434
Bismuth Subsalicylate Oral Suspension (USP) . . . . . ..
... . 41 Omeprazole Magnesium (USP) . . . . . . . . . . . . . . . . . . . 436
Bisoprolol Fumarate Tablets (USP) . . . . . . . . . . . ..
... . 183 Ondansetron Orally Disintegrating Tablets (USP) . . . . . . . . . 439
Bupropion Hydrochloride (USP) . . . . . . . . . . . . . ..
... . 211 Oxandrolone (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . 247
Bupropion Hydrochloride Tablets (USP) . . . . . . . . ..
... . 211 Oxandrolone Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . 440
Bupropion Hydrochloride Extended-Release Tablets (USP) . . . 42, 184 Paclitaxel (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Calcitriol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Pamidronate Disodium for Injection (USP) . . . . . . . . . . . . . 81, 374
Calcium Carbonate and Magnesia Chewable Tablets (USP) . . . 212 Paricalcitol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Calcium Carbonate and Magnesia Tablets (USP) . . . . . . . . . 211 Phenylbutazone Boluses (USP) . . . . . . . . . . . . . . . . . . . 82
Calcium Silicate (NF) . . . . . . . . . . . . . . . . . . . . . . . . . 484 Phenylbutazone Tablets (USP) . . . . . . . . . . . . . . . . . . . . 82
Carbachol (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 Powdered Ginger (USP) . . . . . . . . . . . . . . . . . . . . . . . 479
Carbachol Intraocular Solution (USP) . . . . . . . . . . . . . . . . 213 Progesterone Vaginal Suppositories (USP) . . . . . . . . . . . . . 82
Carbachol Ophthalmic Solution (USP) . . . . . . . . . . . . . . . 214 Propylene Glycol (USP) . . . . . . . . . . . . . . . . . . . . . . . 317
Carmellose (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 Propylene Glycol Monocaprylate (NF) . . . . . . . . . . . . . . . 261
Cilostazol Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . 395 Protein A (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442
Citalopram Hydrobromide (USP) . . . . . . . . . . . . . . . . . . 214 rProtein A, C-Cys (USP) . . . . . . . . . . . . . . . . . . . . . . . 444
Citalopram Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . 46 rProtein A (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Cladribine (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 rProtein A, B4, C-Cys (USP) . . . . . . . . . . . . . . . . . . . . . 452
Clopidogrel Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . 50 Pygeum Extract (USP erratum) . . . . . . . . . . . . . . . . . . . 37
Clorazepate Dipotassium Tablets (USP erratum) . . . . . . . . . . 382 Ramipril (USP erratum) . . . . . . . . . . . . . . . . . . . . . . . . 37
Colchicine (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Ranitidine Injection (USP erratum) . . . . . . . . . . . . . . . . . 382
Cytarabine for Injection (USP) . . . . . . . . . . . . . . . . . . . . 51 Ranitidine Oral Solution (USP erratum) . . . . . . . . . . . . . . 382
Diclofenac Sodium Extended-Release Tablets (USP) . . . . . . . 218 Ranitidine in Sodium Chloride Injection (USP erratum) . . . . . 383
Dihydrocodeine Bitartate (USP) . . . . . . . . . . . . . . . . . . . 396 Ranitidine Tablets (USP erratum) . . . . . . . . . . . . . . . . . . 383
Diltiazem Hydrochloride Extended-Release Capsules (USP) . . . 184 Reserpine Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . 453
Dimethyl Sulfoxide Gel (USP) . . . . . . . . . . . . . . . . . . . . 52 Salicylic Acid (USP) . . . . . . . . . . . . . . . . . . . . . . . . . 83
Enalapril Maleate and Hydrochlorothiazide Tablets (USP) . . . . 220 Sodium Caprylate (NF) . . . . . . . . . . . . . . . . . . . . . . . . 493
Enoxaparin Sodium (USP) . . . . . . . . . . . . . . . . . . . . . . 52 Sodium Fluoride and Acidulated Phosphate Topical Solution
Enoxaparin Sodium Injection (USP) . . . . . . . . . . . . . . . . . 58 (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Eprinomectin (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Sodium Fluoride and Phosphoric Acid Gel (USP) . . . . . . . . . 455
Esomeprazole Magenesium (USP) . . . . . . . . . . . . . . . . . . 397 Sucralfate (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Estradiol and Norethindrone Acetate Tablets (USP) . . . . . . . . 220 Sulfadimethoxine Sodium (USP) . . . . . . . . . . . . . . . . . . 254
Estradiol Benzoate (USP) . . . . . . . . . . . . . . . . . . . . . . . 229 Sulfamethoxazole (USP) . . . . . . . . . . . . . . . . . . . . . . . 455
Sulisobenzone (USP) . . . . . . . . . . . . . . . . . . . . . . . . . 456
Index
Estradiol Transdermal System (USP) . . . . . . . . . . . . . . . . 225

Conjugated Estrogens Tablets (USP) . . . . . . . . . . . . . . . . 35 Sumatriptan Succinate (USP) . . . . . . . . . . . . . . . . . . . . . 456
Fish Oil Containing Omega-3 Acids (USP) . . . . . . . . . . . . 471 Terbinafine Hydrochloride (USP) . . . . . . . . . . . . . . . . . . 459
Fish Oil Containing Omega-3 Acids Capsules (USP) . . . . . . . 477 Topiramate (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Fluconazole (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 Trehalose (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Fludarabine Phosphate Injection (USP) . . . . . . . . . . . . . . . 232 Ubidecarenone Capsules (USP) . . . . . . . . . . . . . . . . . . . 93, 374
Flumazenil Injection (USP) . . . . . . . . . . . . . . . . . . . . . . 234 Ubidecarenone Tablets (USP) . . . . . . . . . . . . . . . . . . . . 94, 374
Fluvastatin Sodium (USP) . . . . . . . . . . . . . . . . . . . . . . 64 Valganciclovir Hydrochloride (USP) . . . . . . . . . . . . . . . . 84
Formoterol Fumarate (USP) . . . . . . . . . . . . . . . . . . . . . 402 Valganciclovir Tablets (USP) . . . . . . . . . . . . . . . . . . . . . 89
Fosinopril Sodium Tablets (USP) . . . . . . . . . . . . . . . . . . 405 Valsartan (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Fosinopril Sodium and Hydrochlorothiazide Tablets (USP) . . . 66 Warfarin Sodium (USP) . . . . . . . . . . . . . . . . . . . . . . . . 468
Galantamine Hydrobromide (USP) . . . . . . . . . . . . . . . . . 234 Warfarin Sodium for Injection (USP) . . . . . . . . . . . . . . . . 469
Galantamine Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . 407 Warfarin Sodium Tablets (USP) . . . . . . . . . . . . . . . . . . . 470
Ginger (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Ginkgo (USP erratum) . . . . . . . . . . . . . . . . . . . . . . . . 37 EXCIPIENTS
Glimepiride Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . 411 Excipients, USP and NF Excipients, Listed by Category (NF) . . 257, 480
Heparin Sodium (USP) . . . . . . . . . . . . . . . . . . . . . . . . 238
Hydrocortisone Tablets (USP) . . . . . . . . . . . . . . . . . . . . 72 GENERAL CHAPTERS
Acetic Acid in Peptides h503i (USP) . . . . . . . . . . . . . . . . 268
Hydrogenated Polydecene (NF) . . . . . . . . . . . . . . . . . . . 485
Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder
Hydrogenated Starch Hydrolysate (NF) . . . . . . . . . . . . . . . 488
Inhalers h601i (USP) . . . . . . . . . . . . . . . . . . . . . . . . 550
Hyoscyamine Sulfate (USP erratum) . . . . . . . . . . . . . . . . 382
Bacterial Endotoxins Test h85i (USP) . . . . . . . . . . . . . . . . 539
Ipratropium Bromide (USP) . . . . . . . . . . . . . . . . . . . . . 241
Bulk Pharmaceutical Excipients—Certificate of Analysis h1080i
Isosorbide Dinitrate Extended-Release Tablets (USP) . . . . . . . 73, 373
(USP erratum) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Isosorbide Mononitrate Tablets (USP) . . . . . . . . . . . . . . . . 413
Injections h1i (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . 188, 494
Letrozole Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . . 244
Intrinsic Dissolution h1087i (USP) . . . . . . . . . . . . . . . . . 269
Levalbuterol Hydrochloride (USP) . . . . . . . . . . . . . . . . . 75, 416
Microbiological Examination of Nonsterile Products: Acceptance
Levalbuterol Inhalation Solution (USP) . . . . . . . . . . . . . . . 79, 420
Criteria for Pharmaceutical Preparations and Substances for
Levothyroxine Sodium (USP) . . . . . . . . . . . . . . . . . . . . 422
Pharmaceutical Use h1111i (USP) . . . . . . . . . . . . . . . . . 207
Liothyronine Sodium (USP) . . . . . . . . . . . . . . . . . . . . . 426
Microbiological Examination of Nonsterile Products: Microbial
Lorazepam (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Enumeration Tests h61i (USP) . . . . . . . . . . . . . . . . . . . 189
Lorazepam Tablets (USP) . . . . . . . . . . . . . . . . . . . . . . . 429
Microbiological Examination of Nonsterile Products: Tests for
Lutein (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Specified Microorganisms h62i (USP) . . . . . . . . . . . . . . 193
Lutein Preparation (USP) . . . . . . . . . . . . . . . . . . . . . . . 255
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] INDEX 589
Organic Volatile Impurities h467i (USP) . . . . . . . .. . .... 375 Pharmacopeial Forum Public Review and Comment Period
Particulate Matter in Injections h788i (USP) . . . . . .. . .... 198 Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21,
. . 170, 360
Residual Solvents h467i (USP) . . . . . . . . . . . . .. . .... 378 Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . . . 18
Residual Solvents h467i (USP erratum) . . . . . . . . .. . .... 382 Policies and Announcements
Sulfur Dioxide h525i (USP) . . . . . . . . . . . . . . .. . .... 498 Catalog to Be Removed from Pharmacopeial Forum Print
USP Reference Standards h11i (USP) . . . . . . . . . .. . . .95,
. . 267, 497 Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Validation of Compendial Methods h1225i (USP) . . .. . .... 96 Eric B. Sheinin, Ph.D. Retires from USP . . . . . . . . . . . . 358
Extractable Volume, USP–NF General Chapter h1i, Injections:
REAGENTS, INDICATORS, AND SOLUTIONS Notice of Harmonized Text . . . . . . . . . . . . . . . . . . 168
Chromatographic Reagents (USP) . . . . . . . . . . . . . . . . . 104, 276 Harmonized Microbiology General Chapters: Notice of
Reagent Specifications Postponement . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Reagent Specifications Introduction . . . . . . . . . . . .. . . 503 How to Submit Comments . . . . . . . . . . . . . . . . . .20, . . 170, 360
2-Aminoheptane (USP) . . . . . . . . . . . . . . . . . . .. . . 100 Immediate Interim Revision Announcements for Ubidecarenone
Calconcarboxylic Acid (USP) . . . . . . . . . . . . . . . .. . . 100 Capsules and Ubidecarenone Tablets . . . . . . . . . . . . . 358
Calconcarboxylic Acid Triturate (USP) . . . . . . . . . .. . . 100 Immediate IRA Commentary USP Issues Immediate Interim
alpha-Cyclodextrin (USP) . . . . . . . . . . . . . . . . . .. . . 276 Revision Announcement for General Chapter h467i Residual
Dimethicone, Viscosity 500 Centistokes (USP) . . . . . .. . . 100 Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
Docusate Sodium (USP) . . . . . . . . . . . . . . . . . . .. . . 504 Implementation Period for Upcoming Official Revisions to the
Lactose (USP) . . . . . . . . . . . . . . . . . . . . . . . .. . . 100 USP–NF Extended . . . . . . . . . . . . . . . . . . . . . . . 19
Propylamine Hydrochloride (USP) . . . . . . . . . . . . .. . . 101 In Memoriam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Sodium Phosphate, Monobasic, Anhydrous (USP) . . . .. . . 276 International Correspondence . . . . . . . . . . . . . . . . .20, . . 170, 360
Sodium Phosphate, Monobasic, Dihydrate (USP) . . . .. . . 276 Pharmacopeial Education Courses . . . . . . . . . . . . . .19, . . 169, 359
Sodium Phosphate, Dibasic, Dihydrate (USP) . . . . . .. . . 101 Pharmacopeial Forum Public Review and Comment Period
Tetrabutylammonium Iodide (USP) . . . . . . . . . . . .. . . 504 Deadlines . . . . . . . . . . . . . . . . . . . . . . . . . . .21,
. . 170, 360
Tetrapropylammonium Chloride (USP) . . . . . . . . . .. . . 276 Pharmacopeial Harmonization . . . . . . . . . . . . . . . . . . 18
Triethylamine (USP) . . . . . . . . . . . . . . . . . . . . .. . . 101 Priority New Monograph Items . . . . . . . . . . . . . . . .22, . . 171, 361
Volumetric Solutions Revision Bulletins . . . . . . . . . . . . . . . . . . . . . . . . . 168
Ceric Sulfate, Tenth-Normal (0.1 N) (USP) . . . . . . . .... 101 Stimuli Articles Posted on USP’s Website . . . . . . . . . . . 169, 358
Potassium Permanganate, Tenth-Normal (0.1 N) (USP) .... 102 Stimuli Articles to be Posted on USP’s Website . . . . . . . . 19
USP Annual Scientific Meeting 2007 . . . . . . . . . . . . . . 168, 358
REFERENCE TABLES USP Catalog Available . . . . . . . . . . . . . . . . . . . . . . 169, 358
Container Specifications (USP) . . . . . . . . . . . . . . . . . . . 283, 505 2007 USP Dictionary . . . . . . . . . . . . . . . . . . . . . . . 170, 358
Description and Solubility (USP) . . . . . . . . . . . . . . . 110,
. . . 285, 507 USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . 19
USP Forms Stakeholder Forum to Address the Food Chemicals
GENERAL SUBJECTS Codex; First Meeting Set for February 2007 . . . . . . . . . 18
Canceled Revision Proposals . . . . . . . . . . . . . . . . . . 137, . . . 313, 534 USP Seeks Chair Candidate for Four Expert Comittees; Expert
Catalog to Be Removed from Pharmacopeial Forum Print Committee Members also Sought . . . . . . . . . . . . . . . 18
Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 USP to Establish Office and Laboratory Facility in China . . 168
Eric B. Sheinin, Ph.D. Retires from USP . . . . . . . . . . . . . . 358 USP to Verify the Quality of Pharmaceutical Ingredients
Errata List for USP30–NF25 Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Bulk Pharmaceutical Excipients—Certificate of Analysis h1080i Vice President of Pharmacopeial Education Named . . . . . . 18
(USP erratum) . . . . . . . . . . . . . . . . . . . . . . . . . . 382 Visit the USP Web Site at hhttp://www.usp.orgi . . . . . .20, . . 170, 360
Clorazepate Dipotassium Tablets . . . . . . . . . . . . . . . . . 382 Previews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141,
. . . 321, 569
Pending Proposals . . . . . . . . . . . . . . . . . . . . . . . . 111,
. . . 286,
Index
Ginkgo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 509
Hyoscyamine Sulfate . . . . . . . . . . . . . . . . . . . . . . . . 382 Priority New Monograph Items . . . . . . . . . . . . . . . . .22, . . 171, 361
Magnesium Chloride . . . . . . . . . . . . . . . . . . . . . . . . 37 Revision Bulletins .......................... 168
Methdilazine Hydrochloride Oral Solution . . . . . . . . . . . 37 Second Interim Revision . . . . . . . . . . . . . . . . . . . . . . . 179
Pygeum Extract . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Section Descriptions . . . . . . . . . . . . . . . . . . . . . . . .10,. . 160, 350
Ramipril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . .14,
. . 164, 354
Ranitidine Injection . . . . . . . . . . . . . . . . . . . . . . . . 382 Standards Development . . . . . . . . . . . . . . . . . . . . . . .5,. 155, 345
Ranitidine Oral Solution . . . . . . . . . . . . . . . . . . . . . . 382 Stimuli to the Revision Process
Ranitidine in Sodium Chloride Injection . . . . . . . . . . . . . 383 A New Validated Differential Calorimetric Procedure for
Ranitidine Tablets . . . . . . . . . . . . . . . . . . . . . . . . . 383 Monitoring the Less Active R,S Isomer of Ethambutol
Residual Solvents h467i . . . . . . . . . . . . . . . . . . . . . . 382 Dihydrochloride in Bulk Drug Samples and Anti-tuberculosis
Expert Committee Designations . . . . . . . . . . . . . . . . .12, . . 162, 352 Formulations, Bhagwat Prasad, Hemant Bhutani, Vijay
Extractable Volume, USP–NF General Chapter h1i, Injections: Kumar, and Saranjit Singh . . . . . . . . . . . . . . . . . . . 326
Notice of Harmonized Text . . . . . . . . . . . . . . . . . . . . 168 Instructions to Authors . . . . . . . . . . . . . . . . . . . . 145,
. . . 325, 573
First Interim Revision . . . . . . . . . . . . . . . . . . . . . . . . . 31 Proposed Change to Acceptance Criteria for Dissolution
Harmonization . . . . . . . . . . . . . . . . . . . . . . . . . . 139,
. . . 315, 535 Performance Verification Testing, Walter W. Hauck, Ronald
Harmonized Microbiology General Chapters: Notice of G. Manning, Todd L. Cecil, William Brown, and Roger L.
Postponement . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 Williams . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
How to Submit Comments . . . . . . . . . . . . . . . . . . . .20, . . 170, 360 Summary of Planned Revisions to Design and Analysis of
How to Use PF . . . . . . . . . . . . . . . . . . . . . . . . . . . .9,. 159, 349 Biological Assays h111i, Walter W. Hauck, Robert Singer,
Immediate Interim Revision Announcements for Ubidecarenone and Larry N. Callahan . . . . . . . . . . . . . . . . . . . . 580
Capsules and Ubidecarenone Tablets . . . . . . . . . . . . . . . 358 Stimuli Articles Posted on USP’s Website . . . . . . . . . . . . . 169, 358
Immediate IRA Commentary USP Issues Immediate Interim Stimuli Articles to be Posted on USP’s Website . . . . . . . . . . 19
Revision Announcement for General Chapter h467i Residual USP Annual Scientific Meeting 2007 . . . . . . . . . . . . . . . . 168, 358
Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 USP Catalog Available . . . . . . . . . . . . . . . . . . . . . . . . 169, 358
Implementation Period for Upcoming Official Revisions to the 2007 USP Dictionary . . . . . . . . . . . . . . . . . . . . . . . . . 170, 358
USP–NF Extended . . . . . . . . . . . . . . . . . . . . . . . . . 19 USP Discontinues Use of ‘‘Intent to Comment’’ Form . . . . . . 19
In Memoriam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 USP Forms Stakeholder Forum to Address the Food Chemicals
Interim Revision Announcements . . . . . . . . . . . . . . .31, . . 179,
. 369 Codex; First Meeting Set for February 2007 . . . . . . . . . . . 18
International Correspondence . . . . . . . . . . . . . . . . . . .20, . . 170, 360 USP Seeks Chair Candidate for Four Expert Comittees; Expert
Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . 147,. . . 335, 583 Committee Members also Sought . . . . . . . . . . . . . . . . . 18
Pharmacopeial Education Courses . . . . . . . . . . . . . . . .19, . . 169, 359 USP to Establish Office and Laboratory Facility in China . . . . 168
Pharmacopeial Forum
590 INDEX Vol. 33(3) [May–June 2007]
USP to Verify the Quality of Pharmaceutical Ingredients Vice President of Pharmacopeial Education Named ........ 18
Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . ..... 168 Visit the USP Web Site at hhttp://www.usp.orgi . . . . . . . .20,
. . 170, 360
Index
CHROMATOGRAPHIC REAGENTS
USED IN USP–NF AND
PHARMACOPEIAL FORUM
This is an update based on the proposals published in this issue of PF.
Pharmacopeial Forum
Vol. 33(3) [May–June 2007] CHROMATOGRAPHIC REAGENTS 1
Chromatographic Reagents Used in USP-NF and

Pharmacopeial Forum
May–June 2007
ARTEMETHER (USP International Standards) (DSD Mgh #2464)

0(0) L1 Purospher RP-18 Assay and Related com- 4 mm 6 12.5 cm, 5 mm, manufacturer Merck, KgaA
pounds
CURCUMINOIDS (DSD Mgh #2499)

33(1) L1 Luna C18 Identification and Content Identification Test B. Content of curcuminoids. 4.6 mm 6
of ...... 25 cm, 5 mm, manufacturer Phenomenex
CURCUMINOIDS CAPSULES (DSD Mgh #2492)

CURCUMINOIDS TABLETS (DSD Mgh #2493)

GRANISETRON HYDROCHLORIDE (DSD Mgh #35860)

0(0) L1 Hypersil BDS C-18 Assay and Related com- Related compounds, Test 2. 4.6 mm 6 25 cm, 5 mm,
pounds manufacturer Thermo Electron
IOPAMIDOL (DSD Mgh #41930)

32(6) L11 Zorbax SB Phenyl Related compounds 4.6 mm 6 25 cm, 5 mm, manufacturer Agilent
ISOSORBIDE MONONITRATE TABLETS (DSD Mgh #43615)

33(3) L1 Zorbax ODS Dissolution 4.6 mm 6 25 cm, manufacturer Agilent Technologies
LEVOTHYROXINE SODIUM (DSD Mgh #45000)

33(3) L7 Zorbax C8 Related compounds 4.6 mm 6 15 cm, 5 mm, manufacturer Agilent Technolo-
gies
LORAZEPAM (DSD Mgh #45900)

0(0) L1 YMC-Pack ODS-A Assay and Related com- 4.6 mm 6 25 cm, 5 mm, manufacturer YMC Inc.
pounds
LORAZEPAM TABLETS (DSD Mgh #45930)


0(0) L1 YMC-Pack ODS-A Related compounds 4.6 mm 6 25 cm, 5 mm, manufacturer YMC Inc.
LUMEFANTRINE (USP International Standards) (DSD Mgh #2465)

0(0) L1 Nucleosil 100 C18 Assay and Related com- 4 mm 6 12.5 cm, 5 mm, manufacturer Macherey-Nagel
pounds
Pharmacopeial Forum
2 CHROMATOGRAPHIC REAGENTS Vol. 33(3) [May–June 2007]
LUMEFANTRINE AND ARTEMETHER TABLETS (USP International Standards) (DSD Mgh #2466)
0(0) L1 Symmetry C-18 Assay, Identification, and 3.9 mm 6 15 cm, 5 mm, manufacturer Waters.
Content uniformity
0(0) L1 Nucleosil C18 Dissolution and Releated 4 mm 6 12.5 cm, 5 mm, manufacturer Macherey-Nagel
compounds
POWDERED SOY ISOFLAVONES EXTRACT (DSD Mgh #1453)

32(5) L1 YMC-Pack ODS- Content of . . . . . . . . Content of isoflavones. 3.0 mm 6 25 cm, 5 mm, manu-
AM facturer YMC Co. Ltd.
POWDERED TURMERIC (DSD Mgh #2490)

33(1) L1 Luna C18 Content of . . . . . . . . Content of curcuminoids. 4.6 mm 6 25 cm, 5 mm, man-
ufacturer Phenomenex
POWDERED TURMERIC EXTRACT (DSD Mgh #2491)

33(1) L1 Luna C18 Content (major) of . . . . Content of curcuminoids. 4.6 mm 6 25 cm, 5 mm, man-
SODIUM FLUORIDE AND ACIDULATED PHOSPHATE TOPICAL SOLUTION (DSD Mgh #76520)
33(3) L## Transgenomic AN1 Assay 4.6 mm 6 25 cm, manufacturer Transgenomic
SOY ISOFLAVONES CAPSULES (DSD Mgh #1454)

32(5) L1 YMC-Pack ODS- Content of . . . . . . . . Content of isoflavones. 3.0 mm 6 25 cm, 5 mm, manu-
AM facturer YMC Co. Ltd.
SOY ISOFLAVONES TABLETS (DSD Mgh #1455)

32(5) L1 YMC-Pack ODS- Identification and Content Content of isoflavones. 3.0 mm 6 25 cm, 5 mm, manu-
AM of ...... facturer YMC Co. Ltd.
TURMERIC (DSD Mgh #1126)

0(0) L1 Luna C18 Content (major) of . . . . Content of curcuminoids. 4.6 mm 6 25 cm, 5 mm, man-
XYLOSE (DSD Mgh #89350)

33(4) L8 Zorbax Carbohy- Assay and Identification 4.6 mm 6 15 cm, 5 mm, manufacturer Agilent
drate
Table of Contents*
PHARMACOPEIAL FORUM VOL. 33 NO. 4 JULY–AUG. 2007
STANDARDS DEVELOPMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595

HOW TO USE PF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
Staff Directory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Immediate IRA Commentary: Immediate Interim Revision Announcement for USP–NF General Chapter h711i,
Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Notice of Harmonized Text: USP–NF General Chapter h788i, Particulate Matter in Injections . . . . . . . . . . . . . . . . . 610
2007 USP Dictionary Now Available . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Visit the USP Website at http://www.usp.org . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 611
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Oxandrolone Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
GENERAL TEST CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
h711i Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Amiloride Hydrochloride and Hydrochlorothiazide Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Atovaquone (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Benazepril Hydrochloride Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Bismuth Subsalicylate Magma (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Bupropion Hydrochloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Bupropion Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Cefaclor Chewable Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
Ciclopirox (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
Ciclopirox Olamine (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Cyromazine [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Dantrolene Sodium Capsules [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
Ethionamide (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Etidronate Disodium (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Famotidine Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Formaldehyde Solution (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Glyburide Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Hydrocodone Bitartrate and Homatropine Methylbromide Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . 654
Hyoscyamine Sulfate (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Isosorbide Mononitrate Extended-Release Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Isotretinoin Capsules (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Mefloquine Hydrochloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Methylphenidate Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Nitrofurantoin Capsules (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Oxybutynin Chloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Paroxetine Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
Raloxifene Hydrochloride [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Raloxifene Hydrochloride Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Pharmacopeial Forum
592 Contents* Vol. 33(4) [July–Aug. 2007]
Ritonavir (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679

Tizanidine Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
Triclosan (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
Vecuronium Bromide (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Verapamil Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Powdered Bilberry Extract [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Chamomile (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
Glucosamine Hydrochloride ((2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Glucosamine Sulfate Potassium Chloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Glucosamine Sulfate Sodium Chloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Powdered Decaffeinated Green Tea Extract [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Excipients, USP and NF Excipients, Listed by Category (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
NF MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Agar (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Dehydroacetic Acid [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Egg Phospholipids [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Gamma Cyclodextrin [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Inositol [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
Poloxamer (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
GENERAL TEST CHAPTERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
h11i USP Reference Standards (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
h41i Weights and Balances (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
h191i Identification Tests—General (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
h643i Total Organic Carbon (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
h645i Water Conductivity (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
h1010i Analytical Data—Interpretation and Treatment (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
h1119i Near-Infrared Spectrophotometry (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
h1196i Pharmacopeial Harmonization (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
h1251i Weighing on an Analytical Balance (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
1-Butanesulfonic Acid Sodium Salt [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Butyrophenone [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Cetyltrimethylammonium Bromide [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Diethylamine Phosphate [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Fuchsin, Basic (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
n-Heptane, Chromatographic (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Hexadecyltrimethylammonium Bromide [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Octanesulfonic Acid Sodium Salt [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Potassium Pyroantimonate (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Selenium (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Triethylamine (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Test Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Alkaline Cupric Citrate TS 2 [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Cupric Citrate TS 2, Alkaline [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Sodium Hydroxide TS 2 [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Lithium Methoxide, Tenth-Normal, 0.1 N in Chlorobenzene (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . 770
Lithium Methoxide, Tenth-Normal, 0.1 N in Methanol (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Lithium Methoxide, Tenth-Normal, 0.1 N in Toluene (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Container Specifications (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
Description and Solubility (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
HARMONIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 803
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] Contents* 593
STIMULI TO THE REVISION PROCESS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807

Instructions to Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Assessing Antioxidant Activity in Botanicals and Other Dietary Supplements, Stephen Matthew Phipps,
Maged H. M. Sharaf, and Veronika Butterweck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
NOMENCLATURE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 815
INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
Pharmacopeial Forum
594 Contents* Vol. 33(4) [July–Aug. 2007]
Nancy Blum, M.P.H.
Director, Information Programs and pharmacy. It publishes the U.S. Pharmacopeia and National
Deborah G. Perfetto, Pharm.D. Formulary, the legally recognized compendia of standards for drugs
Director, Publications and products of other health care technologies. The USP and NF in-
Linda M. Guard clude assays and tests for the determination of strength, quality, and
Director, Scientific Reports purity and requirements for packaging and labeling.
Kate Meringolo
Project Manager
Shona Bramble
Irena Smith Our subscribers’ records and publication labels are computer-
Senior Editors generated. Please send your new address, and your latest label, or
Sandra Duverneuil; Anthony Owens; Lorraine M. Scheinman; an exact copy of it, to: USPC, PF Customer Service Dept., 12601
Melissa M. Smith Twinbrook Parkway, Rockville, MD 20852.
Editors Fax: (301) 816-8148.
Elizabeth Gould-Leger; Patricia von Brook
Rebecca Cambronero
Vivian Lazo
Pharmacopeial Forum
596 STANDARDS DEVELOPMENT Vol. 33(4) [July–Aug. 2007]
USP publishes Pharmacopeial Forum (PF) bimonthly and provides interested parties an opportunity to review and comment on
the new or revised standards of the United States Pharmacopeia and the National Formulary (USP–NF).
Previews)
USP welcomes comments and data on potential, proposed, or official standards. Comments, along with USP’s responses, will be
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] STANDARDS DEVELOPMENT 597
HOW TO USE PF
How to Use PF
Pharmacopeial Forum
600 HOW TO USE PF Vol. 33(4) [July–Aug. 2007]
The content of the different sections of PF are briefly described below. A more detailed description of each section is provided at
the beginning of that section. A general description of the types and amount of information expected in a Request for Revision is
available in the Guideline for Submitting Requests for Revision to the USP–NF on the USP website (www.usp.org/USPNF/
submitMonograph/subGuide.html).

How to Use PF
issues such as:
study; and
adoption the column used in developing the proposed procedure and the USP Staff Directory) identified at the end of
scientific staff liaison who handled the issue. the briefing accompanying each item.
New and revised standards that have been approved for publication For general inquiries or in cases where
by the appropriate USP Committee when it is considering whether to a particular liaison is not identified, use
advance standards to official status (see Standards Development). the general USP telephone number 301-
~
881-0666 or FAX number 301-816-
ify the tentative earliest date on which the revision would be officially 8373. Comment deadlines are found at
adopted. the end of the Policies and Announce-
ments section.
internationally nization. Individuals who wish to correspond
For In-Process Revision, new or revised text is marked with symbols with the European and Japanese Pharma-
(&&) to specify the tentative, earliest date on which the revision would copoeias concerning monographs in the
be officially adopted. Official Inquiry and Consensus stages
of international harmonization should ad-
dress their comments to the coordinating
pharmacopeia, with a copy to USP, for a
given article. The addresses for the Eu-
ropean and Japanese Pharmacopoeias
are as follows:
Technical Secretariat of the European
Pharmacopoeia Commission
B.P. 907
France
NAKASHIMA Nobumasa Evaluation
and Licensing Division Pharmaceutical
and Medical Safety Bureau Ministry of
Health, Labour and Welfare, Japan
Tel. +81-3-3595-2431, Fax +81-3-3597-
9535
E-mail: nakashima-nobumasa@mhlw.
go.jp
pending.
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] HOW TO USE PF 601

pending, but have since been canceled. Note that canceled proposals als.
may be republished to be considered in the future for adoption into the
USP–NF.
How to Use PF
Pharmacopeial Forum
Other Sections
Expert Committee Designations

Names of the Expert Committees (comprising volunteer scientific experts) that work with USP staff on the development of stan-
dards.
Staff Directory
Names of key USP Standards Division staff members, including scientific liaisons, with contact information.

How to Use PF

Guidelines on how to comments

Nomenclature
Index

Pharmacopeial Forum
2005–2010
AER Aerosols
How to Use PF
FA Food Additives
GC General Chapters
NOM Nomenclature
STAT Statistics
Pharmacopeial Forum

2005–2010
*
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Pharmacopeial Forum
STAFF DIRECTORY
number is (301) 816-8373.

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(MD-CCA)
Director, Patient Safety Initiatives
Affairs
Forms (PDF)
Senior Scientist
Development
Vice President, Healthcare Quality and
Information
(MD-AA)
Evaluation
Supplements—Non-
Botanicals (DSN)
Director, Dietary
Supplements
Scientist
Endocrine (MD-GRE)
Specialist
Scientist (P&S); Parenteral Products—
Industrial (PPI)
Pharmacopeial Forum

How to Use PF
Scientist
Vice President, Scientific Outreach
Scientist Ophthalmology, Oncology,
Manager
Biotechnology
Scientific Fellow,
Patient Safety
American Liaison
Scientific Fellow
Senior Drug Information Specialist
Director, Healthcare Information
Sujatha Ramakrishna, Ph.D., sxr@usp.org (301) 816-8349 Monograph Development—
Pharmacopeial Forum

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Statistics (STAT)
Senior Scientist
Scientist
(GTMDB); M icrobiology and
Scientist (EM2); Excipient General
Chapters (EGC)
Information (RI)
How to Use PF
POLICIES AND
ANNOUNCEMENTS
processes and announcements about issues being considered by USP. This section also includes publication and comment
schedules.

Pharmacopeial Forum
610 POLICIES AND ANNOUNCEMENTS Vol. 33(4) [July–Aug. 2007]
IMMEDIATE IRA COMMENTARY: IMMEDIATE Contact Kelly Coates, CMP (ktc@usp.org or 301-816-8510)
INTERIM REVISION ANNOUNCEMENT FOR USP– for further information.
NF GENERAL CHAPTER h711i, DISSOLUTION.
General Chapter h711i is being revised to replace the term USP CATALOG AVAILABLE. While no longer included in
‘‘Apparatus Suitability Test’’ with ‘‘Performance Verification the back of this publication, the USP Catalog is still available
Test’’ and ‘‘Calibrator Tablets’’ with ‘‘USP Reference in online and stand-alone print versions. The online bimonthly
Standard Tablets’’ in order to more accurately reflect the and daily catalogs can be accessed at www.usp.org/
purpose of the test and the nature of the tablets used in the referenceStandards/catalog.html. You can also sign up to
Apparatus Suitability section to confirm acceptable receive the USP Catalog in print (via postal mail) along with
performance. Please direct any comments or questions to monthly email alerts—which will keep you informed about
William Brown, Senior Scientist (301-816-8380 or new Reference Standards, availability, and current lots—by
web@usp.org). sending an email to marketing@usp.org or calling 301-816-
8237.
N O T I C E O F H A R M O N I Z E D T E X T: U S P – N F
G E N E R A L C H A P T E R h7 8 8 i, PA R T I C U L AT E STIMULI ARTICLES POSTED ON USP’S WEBSITE.
MATTER IN INJECTIONS. The harmonized text for The Stimuli articles that are published in Pharmacopeial
General Chapter h788i, Particulate Matter in Injections, was Forum are simultaneously published on USP’s website.
approved by the Parenteral Products—Industrial Expert L o o k f o r t h e m a t h t t p : / / w w w. u s p . o r g / U S P N F / p f /
Committee and became official on April 1, 2007. The
whatsInside.html. For more information about Stimuli

changes include verbatim harmonized text as proposed in articles, please contact Stefan Schuber, Ph.D., Director,
the European and Japanese pharmacopoeias, and reflect Scientific Reports (301-816-8551 or sps@usp.org).
alignment with the 2004 signed-off text of the
Pharmacopoeial Discussion Group (PDG). PHARMACOPEIAL EDUCATION COURSES. USP’s
Pharmacopeial Education (PE) courses offer specialized
The harmonized chapter, which became official via an Interim instruction for chemists, other scientists, and professionals in
Revision Announcement in PF 33(2), references a definition the pharmaceutical and allied industries. USP scientists and
for particle-free water in Reagents, Indicators, and Solutions, USP science experts, who play a key role in establishing
which did not appear in PF 33(2). That definition will read official USP standards, teach these courses and provide
‘‘Particle-Free Water: Filter water through a membrane with expert insights into the practical applications of official test
a pore size of 0.22 mm.’’ procedures and best practices in using the USP–NF and
The Evaluation subsections in the sections Light Obscuration opportunity to learn how to get involved in USP’s
Particle Count Test and Microscopic Particle Count Test were standards-setting processes and the benefits of participating
revised to show the correct testing criteria for preparations in standards development. Courses offered in 2007
supplied in containers with a nominal volume of 100 mL. are listed below. For more information and to register, visit
Questions should be directed to Dr. Desmond Hunt, Scientific w w w. u s p . o r g / g o t o / p e , o r c a l l C u s t o m e r S e r v i c e ,
Liaison, PPI Expert Committee (dgh@usp.org or 301-816- 1-800-227-8772. To discuss how USP can bring courses
8341). to a location of your choice or design a custom course
package for you, call 301-816-8589, or e-mail
2007 USP DICTIONARY NOW AVAILABLE. The new PharmacopeialEducation@usp.org.
USP Dictionary of USAN and International Drug Names Beginning in the 2007 calendar year, USP’s PE program will
was published on April 1, 2007. It is available in both print be initiating a significant expansion. Both the depth and
and online formats at $299 each. The 2007 edition features breadth of course offerings will grow as the Pharmacopeial
more than 9,000 updates, including over 3,700 new and Education staff works to make the science behind the stan-
revised graphic formulas and over 1,000 additional dards more accessible. As this process begins, the PE program
pronunciations! Order now at www.usp.org/products/ invites you to participate by suggesting titles, developing
dictionary/. course objectives, or even joining the teaching staff.
USP ANNUAL SCIENTIFIC MEETING 2007. The USP

Annual Scientific Meeting will be held in Tampa, Florida, at
the Hyatt Regency Tampa, September 25–28, 2007.
Information is available on USP’s website at www.usp.org.
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] POLICIES AND ANNOUNCEMENTS 611

Date Course Title Location Registration Information
2-Jul-07 USP eSymposium on Pharmacopeial Webinar Online registration available early June at
Forum 33(4) www.usp.org
4-Sep-07 USP eSymposium on Pharmacopeial Webinar Online registration available early June at
24-25 Sep 07 Effectively Using the USP–NF Tampa, Florida (ASM) Contact USP Customer Service to register,
(2-day course) 800-227-8772, or custsvc@usp.org
24-25 Sep 07 Essentials of USP Microbiological Tampa, Florida (ASM) Contact USP Customer Service to register,
Testing (2-day course) 800-227-8772, or custsvc@usp.org
25-Sep-07 Residual Solvents: Results in Practice Tampa, Florida (ASM) Contact USP Customer Service to register,
800-227-8772, or custsvc@usp.org
1-Nov-07 USP eSymposium on Pharmacopeial Webinar Online registration available early June at

VISIT THE USP WEBSITE AT http://www.usp.org. data regarding potential, proposed, or adopted (official)
Various resources related to Pharmacopeial standards are standards. In accordance with the Rules and Procedures of
presented, among them Highlights from PF, Notices relating the 2005–2010 Council of Experts, USP has implemented a
to USP–NF, USP policies, Commentary on upcoming 90-day comment period by providing a deadline for each
official revisions, and Reference Standard information. issue of PF unless otherwise stated in the individual
Briefing. The listing of comment period deadlines and the
PHARMACOPEIAL FORUM PUBLIC REVIEW AND targeted official publications appears below.
COMMENT PERIOD DEADLINES. The USP welcomes
and encourages interested parties to submit comments and
Targeted Official
PF 33(1) April 16, 2007
PF 34(1) April 15, 2008
All official revisions are published in the annual edition or not appear until Supplement 1. See table below. The electronic
Supplements to USP–NF (twice yearly). Between these publi- version of USP–NF is updated as each Supplement becomes
cations, official revisions are published in PF in the Interim available and, therefore, contains all official text up to and in-
Revision Announcement; these revisions are also incorporated cluding the contents of the latest Supplement. The new table
in the upcoming Supplement. The official publication in which below outlines the publications and their release and official
an IRA is incorporated depends on publication deadlines. The dates, and the book or Supplement that supersedes them.
IRAs appearing in PF Numbers 5 and 6 of each volume will
Pharmacopeial Forum
USP 30–NF 25 Nov. 1, 2006 May 1, 2007 1st Supplement
IRA [PF 33(1)] Jan. 1, 2007 Feb. 1, 2007 2nd Supplement
IRA [PF 33(2)] Mar. 1, 2007 Apr. 1, 2007 2nd Supplement
IRA [PF 33(3)] May 1, 2007 June 1, 2007 USP 31–NF 26
IRA [PF 33(4)] July 1, 2007 Aug. 1, 2007 USP 31–NF 26
USP 31–NF 26
USP 31–NF 26
USP 31–NF 26
* Tentative.
PRIORITY NEW MONOGRAPH ITEMS. USP is seeking Forum. (This list has been updated as of April 19, 2007.) For
monographs for the following drug substances and drug prod- additional information, contact Karen A. Russo, Ph.D., kar@
ucts that are or soon will be off patent and thus are of the high- usp.org. Monograph sponsors should consult USP’s Guideline
est priority. USP also is seeking monographs for the excipients for Submitting Requests for Revision to the USP–NF (http://
listed below. Monographs are marked received upon receipt of www.usp.org/USPNF/submitMonograph/subGuide.html).
the monograph proposal. Received monographs are removed
f r o m thi s l i s t up o n p u bl i ca t i o n in Ph ar mac o pe ia l

Acarbose Alfuzosin Hydrochloride Allopurinol Sodium
Aminopropazine Fumarate Aminopterin Sodium Anagrelide Hydrochloride
(Received)
Arsenic Trioxide Auranfoin Azelaic Acid
Balsalazide Disodium Bentoquatam Benzphetamine Hydrochloride
Bivalirudin Cabergoline Calcipotriene
(Received)
Calcium Trisodium Pentetate Calfactant Candesartan Cilexetil
Carmustine Cefdinir Cefditoren Pivoxil
Ceftibuten Ceftiofur Hydrochloride Cetrorelix
Cysteamine Bitartrate Cytarabine Liposome Dalfopristin
(Received)
Difloxacin Hydrochloride Entacapone Epoprostenol Sodium
(Received)
Erythromycin Phosphate Erythromycin Thiocyanate Esmolol Hydrochloride
Esomeprazole Magnesium Estazolam Estramustine Phosphate Sodium
(Received)
Ethanolamine Oleate Etomidate Etoposide Phosphate
(Received)
(Received)
Gadobenate Dimeglumine Gadopentetic Acid Gallium Nitrate
Pharmacopeial Forum
Ganirelix Glyceryl Aminobenzoate Granisetron Hydrochloride

(Received)
Guanidine Hydrochloride Halobetasol Propionate Haloperidol Decanoate
Hydrocodone Polistirex Ibandronate Sodium Imipramine Pamoate
Imiquimod Irinotecan Isosulfan Blue
Itraconazole Lamotrigine Latanoprost
Levetiracetam Lomustine Lopinavir
(Received)
Moexipril Hydrochloride Nalbuphine Hydrochloride Nalmefene Hydrochloride
Nateglinide Nedocromil Sodium Nicardipine Hydrochloride
(Received)
Nilutamide Nisoldipine Olopatadine

(Received)
Olsalazine Sodium Orbifloxacin Orlistat
Oxcarbazepine Oxiconazole Nitrate Pantoprazole Sodium
Pemirolast Potassium Pentamidine Isethionate Piperonyl Butoxide
(Received)
Pirbuterol Acetate Poractant Alpha Porfimer Sodium
Pramiprexole Dihydrochloride Proguanil Hydrochloride Quetiapine Fumarate
Ranitidine Rivastigmine Tartrate Rocuronium Bromide
(Received)
Rose Bengal Disodium Rosiglitazone Maleate Salmeterol Xinafoate
Sertraline Hydrochloride Sibutramine Hydrochloride Sodium Phenylbutyrate
Tacrolimus Tenofovir Disoproxil Fumarate Terbinafine Hydrochloride
Terconazole Tiludronate Disodium Tiopronin
(Received)
Trandolapril Tranexamic Acid Tranylcypromine Sulfate
(Received)
Trimetrexate Glucuronate Venlafaxine Hydrochloride Voriconazole
Zinc Tridosium Pentetate Zoledronic Acid

Albuterol for Inhalation Albuterol Inhalation Aerosol Albuterol Sulfate Inhalation Solution
Albuterol Sulfate Oral Solution Alendronate Sodium Oral Solution Alfuzosin Tablets
Allopurinol for Injection Alprazolam Extended-Release Tablets Alprostadil Urethral Suppository
Aminopropazine Fumarate and Neomycin Aminopropazine Fumarate Injection Aminopropazine Fumarate Tablets
Sulfate Tablets
Aminopterin Sodium Tablets Amlodipine and Benazepril Hydrochloride Amphotericin B Injection
Capsules
Anagrelide Hydrochloride Capsules Arsenic Trioxide Injection Atovaquone and Proguanil Hydrochloride
(Received) Tablets
Atovaquone Tablets Auranofin Capsules Azatadine Maleate and Pseudoephedrine Sul-
fate Extended-Release Tablets
Azelaic Acid Cream Azithromycin for Injection Azithromycin Tablets
(Received)
Pharmacopeial Forum

Baclofen Injection Balsalazide Disodium Capsules Beclomethasone Dipropionate Inhalation
Aerosol
Beclomethasone Dipropionate Nasal Sus- Bentoquatam Topical Suspension Benzocaine and Cetylpyridinium Chloride
pension Lozenges
Benzocaine and Menthol Lotion Benzphetamine Hydrochloride Tablets Bicalutamide Tablets
(Received)
Bivalirudin Injection Brompheniramine Maleate, Dextromethor- Budesonide Inhalation Aerosol
phan Hydrobromide, and Pseudoephedrine
HCl Oral Solution
Bupivacaine and Lidocaine Hydrochlorides Buprenorphine Hydrochloride Injection Butalbital and Acetaminophen Capsules
Injection
Butalbital and Acetaminophen Tablets Cabergoline Tablets Calcipotriene Cream
Calcipotriene Ointment Calcipotriene Topical Solution Calcitriol Capsules
Calcitriol Oral Solution Calcium Acetate Capsules Calcium Trisodium Pentetate Injection
Calfactant Intratracheal Suspension Carbidopa and Levodopa Extended- Carbidopa and Levodopa Tablets for Oral
Release Tablets Suspension
Carbidopa, Levidopa, and Entacapone Carmustine for Injection Carmustine Implant
Tablets (Received)
Carvedilol Tablets Cefdinir Tablets Cefditoren Pivoxil Tablets

(Received)
Ceftibuten Capsules Ceftibuten for Oral Suspension Ceftiofur Hydrochloride Oral Suspension
Cetirizine Hydrochloride Oral Solution Cetirizine Hydrochloride Tablets Cetrorelix Injection
Cevimeline Hydrochloride Capsules Chloroxine Cream Chlorpromazine Hydrochloride Extended-
Release Capsules
Choline and Magnesium Salicylates Oral Choline and Magnesium Salicylates Tablets Choline Salicylate Oral Solution
Solution (Received)
Ciclopirox Shampoo Ciclopirox Topical Gel Ciclopirox Topical Solution
(Received)
Cilostazol Tablets Cimetidine Oral Solution Ciprofloxacin Hydrochloride and Hydrocorti-
(Received) sone Otic Suspension
Ciprofloxacin Otic Solution Citalopram Hydrobromide Oral Solution Citric Acid, Gluconolactone, and Magnesium
Carbonate Irrigation
Cladribine Injection Clemastine Fumarate Syrup Clobetasol Propionate Gel
Clonazepam Orally Disintegrating Tablets Clorazepate Dipotassium Capsules Clorazepate Dipotassium Extended-Release
Tablets
Clotrimazole and Betamethasone Dipropio- Colestipol Hydrochloride Tablets Compound Undecylenic Acid Cream
nate Lotion (Received)
Release Tablets
Difloxacin Hydrochloride Tablets Dihydroergotamine Mesylate Metered Dinoprostone Vaginal Suppositories
Spray
Diphenhydramine Hydrochloride and Acet- Divalproex Sodium Delayed-Release Cap- Dorzolamide and Timolol Ophthalmic Solu-
aminophen Tablets sules tion
Dorzolamide Ophthalmic Solution Doxepin Hydrochloride Cream Doxycycline Oral Gel
Econazole Nitrate Cream Edrophonium Chloride and Atropine Sul- Enalapril Maleate and Diltiazem Malate
fate Injection Extended-Release Tablets
Enalapril Maleate and Felodipine Enalaprilat Injection Entacapone Tablets
Extended-Release Tablets (Received)
Ephedrine Sulfate and Guaifenesin Tablets Epoprostenol for Injection Epoprostenol Injection
Esmolol Hydrochloride Injection Esomeprazole Magnesium Capsules Estazolam Tablets
Estramustine Phosphate Sodium Capsules Ethanolamine Oleate Injection Etidronate Disodium Injection Concentrate
Etomidate Injection Exemestane Tablets Famotidine Orally Disintegrating Tablets
Felbamate Oral Suspension Felbamate Tablets Fentanyl Lozenges
Pharmacopeial Forum

Fentanyl Transdermal System Ferrous Fumarate and Docusate Sodium Flavoxate Hydrochloride Tablets
(Received) Extended-Release Capsules (Received)
Fluconazole Injection Fluconazole Tablets Flunisolide Inhalation Aerosol
Flunisolide Nasal Spray Fluocinolone Acetonide Shampoo Fluorescein Sodium Ophthalmic Solution
Fluorometholone Ointment Fluticasone Propionate Cream Fluticasone Propionate Inhalation Powder
(Received)
Fluticasone Propionate Ointment Fluticasone Propionate Pressurized Inhaler Foscarnet Sodium Injection
(Received)
Fosfomycin for Oral Solution Gabapentin Oral Solution Gadobenate Dimeglumine Injection
(Received)
(Received)
Guaifenesin and Pseudoephedrine Hydro- Guaifenesin and Salts of Dextromethorphan Guanidine Hydrochloride Tablets
chloride Extended-Release Tablets and Pseudoephedrine Oral Solution

othiazide Capsules
trate Oral Solution
tion
(Received)
(Received)
(Received)
Levetiracetam Tablets Levocabastine Ophthalmic Suspension Levofloxacin Solution
Lincomycin Hydrochloride and Spectino- Liothyronine Injection Lisinopril and Hydrochlorothiazide Tablets
mycin Sulfate Soluble Powder (Received)
Lomustine Capsules Lopinavir and Ritonavir Solution Lopinavir Capsules
Lopinavir Solution Loratadine Orally Disintegrating Tablets Losartan Potassium Tablets
(Received)
tion
trate
Methyclothiazide and Deserpidine Tablets Methylphenidate Hydochloride Chewable Metipranolol Ophthalmic Solution
Tablets
(Received)
Milrinone Injection Misoprostol Tablets Moexipril Hydrochloride and Hydrochlor-
(Received) othiazide Tablets
Pharmacopeial Forum

Nitroglycerin Extended-Release Transder- Nitroglycerin Solution in Acrylic Adhesive Nitroglycerin Transdermal System
mal Film
(Received)
Orbifloxacin Tablets Orphenadrine Citrate Extended-Release Orphenadrine Citrate, Aspirin, and Caffeine
(Received)
Tablets
Paroxetine Oral Suspension Pemirolast Potassium Ophthalmic Solution Penicillin G Potassium Tablets for Oral Solu-
tion
Pentamidine Isethionate for Inhalation Pentamidine Isethionate Injection Pentazocine Hydrochloride and Acetamino-
(Received) phen Tablets
Phendimetrazine Tartrate Extended-Release Phenobarbital Capsules Phentermine Resin Complex Capsules
Capsules
Phenylephrine Hydrochloride and Chlor- Phenylephrine Hydrochloride, Chlorphenir- Pilocarpine Hydrochloride Ophthalmic Gel
pheniramine Maleate Extended-Release amine Maleate, and Acetaminophen
Capsules Extended-Release Tablets
Pilocarpine Hydrochloride Ophthalmic Pilocarpine Hydrochloride Tablets Piperonyl Butoxide and Pyrethrins Aerosol
Ointment (Received) Foam
Pirbuterol Acetate Inhalation Aerosol Poractant Alpha Supension Porfimer Sodium for Injection
Povacrylate Solution Povacrylate-Iodine Topical Solution Povidone-Iodine Gauze
Povidone-Iodine Swabsticks Povidone-Iodine Topical Aerosol Foam Povidone-Iodine Vaginal Suppositories
Pramipexole Dihydrochloride Tablets Prednisolone Sodium Phosphate Oral Solu- Prochlorperazine Maleate Extended-Release
tion Capsules
Progesterone Capsules Promethazine and Phenylephrine Hydro- Promethazine and Phenylephrine Hydro-
chlorides and Codeine Phosphate Syrup chlorides Syrup
Promethazine Hydrochloride and Codeine Promethazine Hydrochloride and Dextro- Propafenone Hydrochloride Tablets
Phosphate Oral Solution methorphan Hydrobromide Syrup
Pseudoephedrine Hydrochloride and Brom- Pseudoephedrine Hydrochloride and Na- Pseudoephedrine Hydrochloride, Chlorphen-
pheniramine Maleate Extended-Release proxen Sodium Extended-Release Tablets iramine Maleate, and Codeine Phosphate Oral
Tablets Solution
Pseudoephedrine Hydrochloride, Guaifene- Pseudoephedrine Sulfate and Pseudoephedrine Sulfate and Dexbromphen-
sin, and Codeine Phosphate Oral Solution Dexbrompheniramine Maleate Extended- iramine Maleate Oral Solution
Release Tablets
Pseudoephedrine Sulfate, Dexbromphenira- Pyrilamine Maleate Injection Quinidine Sulfate Injection
mine Maleate, and Acetaminophen
zide Tablets
(Received)
Risperidone Orally Disintegrating Tablets Rivastigmine Tartrate Capsules Rivastigmine Tartrate Oral Solution
(Received)
Rocuronium Bromide Injection Ropinirole Hydrochloride Tablets Rosiglitazone Maleate Tablets
Salicylic Acid and Sulfur Cleansing Lotion Salicylic Acid and Sulfur Lotion Salicylic Acid and Sulfur Shampoo
Salicylic Acid Cream Salicylic Acid Ointment Salmeterol Inhalation Aerosol
Salmeterol Xinafoate Inhalation Powder Scopolamine Transdermal System Selegiline Hydrochloride Capsules
Sertraline Hydrochloride Oral Solution Sibutramine Hydrochloride Capsules Sodium Bicarbonate and Sodium Citrate for
Oral Solution
Sodium Bicarbonate, Sodium Citrate, and Sodium Iodide Injection Sodium Phenylbutyrate Oral Powder
Sodium Tartrate for Oral Suspension
Sodium Phenylbutyrate Tablets Sodium Phosphates for Oral Suspension Sodium Phosphates Tablets
Sodium Salicylate and Sulfur Shampoo Sterile Talc Aerosol Streptozocin for Injection
Sucralfate Oral Suspension Sulconazole Nitrate Cream Sulfacetamide Sodium and Fluorometholone
Ophthalmic Suspension
Pharmacopeial Forum

Sulfacetamide Sodium and Prednisolone Sulfasalazine Oral Suspension Sulisobenzone Lotion
Sodium Phosphate Ophthalmic Solution
(Received)
(Received)
Technetium Tc 99M Teboroxime Injection Tenofovir Disoproxil Fumarate Tablets Terbinafine Hydrochloride Cream
(Received)

Trolamine Salicylate Topical Emulsion Undecylenic Acid Topical Foam Aerosol Urea Cream
(Received)
Verapamil Hydrochloride Capsules Verapamil Hydrochloride Extended- Voriconazole Injection
Release Capsules
(Received)
Excipients
Butadiene- Styrene Rubber Butylated Hydromethylphenol Butylene Glycol
Calcium Phosphate Monobasic Calcium Propionate Calcium Pyrophosphate
Calcium Sorbate Calcium Stearoyl Lactylate Caldiamide Sodium
Calteridol Calcium Capric Acid Caprylic/Capric Diglyceryl Succinate
Carbon Carboxymethyl Starch Carboxymethylamylopectin Sodium
Carboxymethylcellulose Potassium Cetostearyl Isononanoate Chlorodifluoroethane
Cholic Acid Cinnamaldehyde Cocamide Diethanolamine
Cocamide Oxide Cocoyl Caprylocaprate Crystal Gum
Cutina Cystine Dammar Gum
Decanoic Acid Decyl Oleate Dehydroacetic Acid
(Received)
Desoxycholic Acid Dextrin Palmitate Dextrins Modified
Diacetyl Tartaric Acid Esters of Mono- and Dicetyl Phosphate Dichlorofluoromethane
Diglycerides
Diethyl Sebacate Difluoroethane Diglycol Stearate
Diisobutyl Adipate Diisopropyl Adipate Diisopropylbenzothiazyl-2-Sulfenamide
Dilauryl Thiodipropionate Dimethyl Dicarbonate Dimyristoyl Lecithin
Dimyristoyl Phosphatidylglycerol Dipropylene Glycol Disodium Edisylate
Pharmacopeial Forum
Disodium Guanylate Disodium Inosinate Disodium Monooleamide Sulfasuccinate
D-Mannose Docusate Sodium/Sodium Benzoate Erythorbic Acid
(Received)
Erythrosine Ethoxylated Mono- and Diglycerides Ethoxyquin
Ethyl Hexanediol Ethyl Linoleate Ethyl Maltol
Ethylene Dichloride Ethylurea Ferric Ammonium Citrate
Ferric Citrate Ferric Oxide, Brown Ferric Phosphate
Ferric Pyrophosphate Ferrous Citrate Ferrous Glycinate
Ferrous Lactate Fluorochlorohydrocarbons Formic Acid
Furcelleran Gentistic Acid Geraniol
(Received)
Hydroxylated Lecithin Indigotine Inositol
(Received)
Iron Carbonyl Iron Subcarbonate Isobutylated- Isoprene Copolymer
Isooctylacrylate Isopropyl Isostearate Isopropyl Stearate
Isostearic Acid Isostearyl Alcohol Lactobionic Acid
Lactose Ferrin, Bovine Lactylated Fatty Acid Esters of Glycerol and Lactylic Esters of Fatty Acids
Propylene Glycol
Lanolin (Wool Fat), Hydrogenated Lanolin Alcohols, Acetylated Lanolin Hydrous
L-Ascorbyl Stearate Lauramine Oxide Lauric Myristic Diethanolamide
Lauric Acid Lauric Diethanolamide Lavender Oil
L-Cysteine Monohydrochloride Lecithin, Hydroxylated L-Glutamic Acid
Linoleic Acid L-Leucine Macrogol Sorbitan Tristearate
(Received)
Macrogolglycerol Cocoates Macrogolglycerol Triisostearate Magnesium Aluminum Silicate Hydrate
Magnesium Aspartame Dihydrate Magnesium Aspartate Magnesium Phosphate Tribasic
Magnesium Phosphate, Dibasic, Trihydrate Magnesium Tartrate Malt Syrup
Maltitol Syrup Maltol Isobutyrate Manganese Chloride
Manganese Citrate Manganese Glycerophosphate Manganese Hypophosphite
Medical Antifoam Emulsion C Medronate Disodium Medronic Acid
Methyl Chloride Methylchloroisothiazolinone Methylisothiazolinone
Microcrystalline Cellulose, Silicified Mineral Spirits Monoisostearyl Glyceryl Ester
(Received)
Monopotassium Glutamate Monohydrate Monosodium Citrate Mullein Leaf
Myristyl Gamma-Picolinium Chloride Myristyl Lactate N,N-Bis(2-Hydroxyethyl)Stearamide
N-Acetyl-L- Methionine Naphtha N-Methylpyrrolidone
(Received)
Non-Pareil Seeds Nutmeg Oil Octanoic Acid
Oxystearin Palm Kernel Oil Pentasodium Triphosphate
(Received)
Pentetate Calcium Trisodium Pentetate Pentasodium Phenprobamate
Phenylmercuric Acetate Phenylmercuric Nitrate Pine Oil
Polacrilin Polyglycerol Esters of Fatty Acids Polyglycerol Polyricinoleic Acid
Polyoxyethylene Castor Oil (USP Has 35) Polyoxyl Stearate (USP Has 40) Polypropylene Oleate
Polypropylene Stearyl Ether Polysorbate 65 Polyvinylacetal Diethylanoacetate
Rice Bran Wax Rosin Silicone
Pharmacopeial Forum
Sodium Acid Pyrophosphate Sodium Aluminosilicate Sodium Aluminum Phosphate Acidic
(Received)
Sodium Aluminum Phosphate Basic Sodium Aspartate Sodium Bisulfate
Sodium Bisulfite Sodium Carbonate Hydrate Sodium Carboxymethyl Betaglucan
Sodium Caseinate Sodium Chlorate Sodium Citrate, Dibasic
Sodium Citrate, Monobasic Sodium Dehydroacetate Sodium Diacetate
Sodium Erythorbate Sodium Ferric Pyrophosphate Sodium Ferrocyanide
Sodium Hypophosphite Sodium Laureth Sulfate Sodium Lauroyl Sarcosinate
Sodium Lauryl Sulfoacetate Sodium Magnesium Aluminosilicate Sodium Magnesium Silicate
Sodium Malate Sodium Metaphosphate, Insoluble Sodium Metasilicate
Sodium Methylate Sodium Polyphosphates Glassy Sodium Potassium Tripolyphosphate
Sodium Pyrophosphate Sodium Pyrrolidone Carboxylate Sodium Sesquicarbonate
Sodium Sesquinoleate Sodium Stearoyl Lactylate Sodium Thiomalate
Sodium Trimetaphosphate Sodium Trioleate Sodium Tripolyphosphate
Soy Polysaccharides Stannous Chloride Stannous Tartrate
(Received)
Starch, Pregelatinized Corn Starch, Pregelatinized Tapioca Stearalkonium Chloride
Stearyl Citrate Stearyl Monoglyceridyl Citrate Succinylated Monoglycerides

Sucrose Acetate Isobutyrate Sucrose Fatty Acid Esters Sucrose Stearate
Sugar Fruit Fine Sulfobutyl Ether Beta Cyclodextran Tallow
Tallow Glycerides Tallow Oil Tetrafluoroethane
Thioglycerol Thyme Oil Tribehenin
Triceteareth-4 Phosphate Trichloroethylene Trimyristin
Trisodium Citrate Trolamine Lauryl Sulfate Vegetable Oil
Wheat Flour Wheat Germ Oil Wheat Gluten
(Received)
Whey
INTERIM REVISION
ANNOUNCEMENT
next page.)

Pharmacopeial Forum
622 INTERIM REVISION ANNOUNCEMENT Vol. 33(4) [July–Aug. 2007]

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Oxandrolone Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
h711i Dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
ERRATA LIST FOR USP 30–NF 25 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] INTERIM REVISION ANNOUNCEMENT 623
INTERIM REVISION
ANNOUNCEMENT


Official August 1, 2007 Released July 1, 2007

Pharmacopeial Forum
New USP Reference Standards USP Albumin Human RS

USP Alteplase RS
The following USP Reference Standards, which were not USP Amifostine RS
USP Amifostine Thiol RS
available when the associated monograph was made official, USP Antithrombin III Human RS
have since become available. The respective official date of USP Aprotinin RS
each USP 30 or NF 25 standard, test, or assay requiring the USP Aprotinin System Suitability RS
USP Copolymer Polypropylene RS
use of the following USP Reference Standards is indicated USP Cryopreserved Human Fibroblast-Derived Dermal
in parentheses after the name of the Reference Standard. Substitute Reference Photomicrographs RS
USP Diethylstilbestrol Diphosphate RS
USP Cetrimonium Bromide RS (November 1, 2007) USP Powdered Echinacea pallida Extract RS
USP Cladribine RS (August 1, 2007) USP Eucatropine Hydrochloride RS
USP Cladribine Related Compound A RS (November 1, 2007) USP Ginkgo Terpene Lactones RS
USP Decoquinate RS (November 1, 2007) USP Glyceryl Monooleate RS
USP Docosyl Ferulate RS (November 1, 2007) USP Gonadorelin Hydrochloride RS
USP Powdered American Ginseng Extract RS (November 1, 2007) USP Hemoglobin RS
USP Glyceryl Monolinoleate RS (January 1, 2008) USP Isosorbide Mononitrate RS
USP Irbesartan RS (August 1, 2007) USP Isosorbide Mononitrate Related Compound A RS
USP Irbesartan Related Compound A RS (November 1, 2007) USP Alpha Lipoic Acid RS
USP Polyoxyl 10 Oleyl Ether RS (August 1, 2007) USP Maritime Pine Extract RS
USP Quinapril Hydrochloride RS (November 1, 2007) USP Menotropins RS
USP Tizanidine Hydrochloride RS (August 1, 2007) USP Mibolerone RS
USP Narasin RS
USP Near Infrared Calibrator
Unavailable First-Time Official USP USP Pyrethrum Extract RS
USP Powdered St John’s Wort Extract RS
USP Sincalide RS
USP Valrubicin RS
availability of the respective Reference Standards. This listing USP Valrubicin Related Compound A RS
was updated as of April 20, 2007. USP Vasopressin RS
Pharmacopeial Forum
MONOGRAPHS (USP) in which CS is the concentration, in mg per mL, of oxandrolone in

the Standard solution; sample ratio is the area ratio of oxandrolone
to 17a-methyltestosterone in the sample injection for each Test
solution; VUF is the final volume, in mL, of the sample after
reconstitution of the dry residue; 500 is the volume, in mL, of
Medium; 100 is the conversion factor to percentage; standard ratio is
the mean area ratio of oxandrolone to 17a-methyltestosterone in all
Oxandrolone Tablets injections of the Standard solution; VUI is the initial sample volume,
in mL, used in the extraction; and LC is the tablet label claim, in mg.
oxandrolone (C19H30O3) is dissolved in 60 minutes.
Change to read: TEST 2—If the product complies with this test, the labeling
Dissolution h711i— Medium: 1% polysorbate 80 in water; 500 mL, deaerated.
TEST 1— Time: 120 minutes.
Medium: a solution of water and isopropanol (7 : 3); 500 mL. Determine the amount of C19H30O3 dissolved by employing the
Apparatus 2: 100 rpm. following method.
Time: 60 minutes. Mobile phase—Prepare a filtered and degassed mixture of water
Determine the amount of C19H30O3 dissolved by employing the and acetonitrile (55 : 45). Make adjustments if necessary (see System
following method. Suitability under Chromatography h621i).
Internal standard solution—Dissolve accurately weighed quan- Standard stock solution—Transfer about 20 mg of USP Oxan-
tities of 17a-methyltestosterone, and dilute quantitatively, and drolone RS, accurately weighed, to a 200-mL volumetric flask. Add
stepwise if necessary, with acetonitrile to obtain a solution having about 20 mL of acetonitrile, and sonicate to dissolve. Dilute with
a concentration of about 0.2 mg per mL (for Tablets with a 2.5-mg Medium to volume, and mix.
label claim) and about 0.8 mg per mL (for Tablets with a 10-mg label Working standard solution—Quantitatively dilute the Standard
claim). stock solution with Medium to obtain a solution having a final
Standard solution—Dissolve an accurately weighed quantity of concentration of about 5 mg per mL for Tablets with a label claim of
USP Oxandrolone RS, and dilute quantitatively, and stepwise if 2.5 mg, or a final concentration of about 20 mg per mL for Tablets
necessary, with acetonitrile to obtain a solution having a concentra- with a label claim of 10 mg.
tion of about 1 mg per mL. Test solution—Withdraw about 10 mL of the solution under test
Working standard solution—Combine 100 mL of the Standard from the vessel. Centrifuge in a glass tube at 2000 rpm for 10
solution, 400 mL of the Internal standard solution, and 1500 mL of minutes.
acetonitrile. Chromatographic system (see Chromatography h621i)—The
Test solution—Withdraw 25 mL of the solution under test from the liquid chromatograph is equipped with a reflective index detector
vessel. Pass through a 0.45-mm polytef filter. Transfer 20 mL of the and a 4.6-mm 6 25-cm column that contains 5-mm packing L1. The
filtrate to a separatory funnel, add 400 mL of the Internal standard flow rate is about 1.5 mL per minute. Chromatograph the Working
solution, 40 mL of a 10% potassium chloride solution, and 8 mL of standard solution, and record the peak responses as directed for

chloroform. In separate separatory funnels, prepare an extraction Procedure: the tailing factor is not more than 2.0; the column
blank and an internal standard blank in a similar manner using 20 efficiency is not less than 4000 theoretical plates; and the relative
mL of filtered Medium in place of the solution under test and standard deviation for replicate injections is not more than 5.0%.
excluding the Internal standard solution from the extraction blank. Procedure—Separately inject equal volumes (about 100 mL) of the
Shake each funnel, and allow the layers to separate. Collect the Working standard solution and the Test solution into the chromat-
lower chloroform layer. Repeat the extraction procedure one more ograph, record the chromatograms, and measure the responses for
time. Evaporate the solvents under a stream of nitrogen at 458 until the major peaks. Calculate the percentage of C19H30O3 released by the
just dry. Reconstitute the dried residue with 2 mL of acetonitrile (for formula:
Tablets with a 2.5-mg label claim) or with 8 mL of acetonitrile (for
Tablets with a 10-mg label claim), and sonicate for 10 minutes.
Chromatographic system (see Chromatography h621i)—The gas
chromatograph is equipped with a flame-ionization detector and
a 0.53-mm 6 30-m column coated with a 0.5-mm phase G27. The
carrier gas is helium, flowing at a rate of about 16.8 mL per minute.
The injection port and detector temperatures are maintained at 1908
and 3208, respectively. The chromatograph is programmed as in which rU and rS are the peak responses obtained from the Test
follows. Upon injection, the column temperature is increased at solution and Working standard solution, respectively; CS is the
a rate of 258 per minute to 2808, and maintained at 2808 for concentration, in mg per mL, of the Working standard solution; D is
3 minutes. Then the column temperature is increased at a rate of 108 the dilution factor of the Test solution; 500 is the volume, in mL, of
per minute to 3208, and maintained at 3208 for 3 minutes. Medium; 100 is the conversion factor to percentage; and LC is the
Chromatograph the acetonitrile, the extraction blank, and the internal tablet label claim, in mg.
standard blank, and record the peak responses as directed for Tolerances—Not less than 65% (Q) of the labeled amount of
Procedure: the tailing factor is not more than 1.5. Make two C19H30O3 is dissolved in 120 minutes.
injections of the Working standard solution, and record the peak .TEST 3—If the product complies with this test, the labeling
responses. The average oxandrolone/Internal standard solution peak indicates that it meets USP Dissolution Test 3.
area percent comparison is between 98.0% and 102.0%. The Medium: 0.1 N hydrochloric acid containing 0.75% of sodium
resolution, R, between the oxandrolone peak and the nearest eluting lauryl sulfate; 500 mL, deaerated with helium.
peak is equal to or greater than 1.5. Apparatus 2: 75 rpm.
Procedure—Separately inject equal volumes (0.5 mL) of the Time: 90 minutes.
Working standard solution and the Test solution into the chromat- Determine the amount of C19H30O3 released by employing the
ograph, record the chromatograms, and measure the responses for following method.
the major peaks. Calculate the percentage of C19H30O3 released by the Mobile phase—Prepare a filtered and degassed mixture of water
formula: and acetonitrile (65 : 35). Make adjustments if necessary (see System
Standard stock solution—Transfer about 20 mg, accurately
weighed, of USP Oxandrolone RS to a 100-mL volumetric flask.
Dissolve in approximately 5 mL of acetonitrile, and sonicate for 10
minutes. Dilute with Medium to volume, and mix.
Pharmacopeial Forum
Working standard solution—Transfer 8.0 mL of the Standard This test is provided to determine compliance with the dissolution
stock solution to a 200-mL volumetric flask, dilute with Medium to requirements ^where stated in the individual monograph^ for
volume, and mix. dosage forms administered orally. In this general chapter, a dosage
Test solution—Pass the solution under test through a suitable filter unit is defined as 1 tablet or 1 capsule or the amount specified. Ôf
having a porosity of 0.45 mm. the types of apparatus described herein, use the one specified in the
Chromatographic system—The liquid chromatograph is equipped individual monograph. Where the label states that an article is
with a refractive index detector and a 4.6-mm 6 30-cm column that enteric-coated, and where a dissolution or disintegration test that
contains 5-mm packing L1. The flow rate is about 1.0 mL per minute. does not specifically state that it is to be applied to delayed-release
The temperatures of the detector and the column are both maintained articles is included in the individual monograph, the procedure and
at 358. Chromatograph the Working standard solution, and record interpretation given for Delayed-Release Dosage Forms is applied
the peak responses as directed for Procedure: the tailing factor is not unless otherwise specified in the individual monograph. For hard or
more than 2.0; and the relative standard deviation for replicate soft gelatin capsules and gelatin-coated tablets that do not conform to
injections is not more than 5.0%. the Dissolution specification, repeat the test as follows. Where water
Procedure—Separately inject equal volumes (about 200 mL) of the or a medium with a pH of less than 6.8 is specified as the Medium in
Working standard solution and the Test solution into the chromat- the individual monograph, the same Medium specified may be used
ograph, record the chromatograms, and measure the peak responses. with the addition of purified pepsin that results in an activity of
Calculate the percentage of C19H30O3 dissolved by the formula: 750,000 Units or less per 1000 mL. For media with a pH of 6.8 or
greater, pancreatin can be added to produce not more than 1750 USP
Units of protease activity per 1000 mL.
Change to read:
USP Reference Standards h11i—USP Chlorpheniramine Male-

in which rU and rS are the peak responses for the Test solution and the ate Extended-Release Tablets RS. ..4 USP Prednisone Tablets RS. ..4
Working standard solution, respectively; CS is the concentration, in USP Salicylic Acid Tablets RS. ..4^
mg per mL, of oxandrolone in the Working standard solution; 500 is
the volume, in mL, of Medium; 100 is the conversion factor to
percentage; and LC is the Tablet label claim, in mg. Change to read:
C19H30O3 is dissolved in 90 minutes..4
APPARATUS
Apparatus 1 (Basket Apparatus)
GENERAL CHAPTERS The assembly consists of the following: a vessel, which may be
covered, made of glass or other inert, transparent material1; a motor;
a metallic drive shaft; and a cylindrical basket. The vessel is partially

immersed in a suitable water bath of any convenient size or heated
GENERAL TESTS AND by a suitable device such as a heating jacket. The water bath or
heating device permits holding the temperature inside the vessel at
ASSAYS 37 + 0.58 during the test and keeping the bath fluid in constant,
smooth motion. No part of the assembly, including the environment
in which the assembly is placed, contributes significant motion,
Physical Tests and agitation, or vibration beyond that due to the smoothly rotating
stirring element. An apparatus that permits observation of the
Determinations specimen and stirring element during the test is preferable. The
vessel is cylindrical, with a hemispherical bottom and ^with one of
the following dimensions and capacities: for a nominal^ capacity of
1 L, the height is 160 mm to 210 mm and its inside diameter is 98
mm to 106 mm; ^for a nominal capacity of 2 L, the height is 280
mm to 300 mm and its inside diameter is 98 mm to 106 mm; and for
a nominal capacity of 4 L, the height is 280 mm to 300 mm and its
inside diameter is 145 mm to 155 mm^. Its sides are flanged at the
top. A fitted cover may be used to retard evaporation.2 The shaft is
positioned so that its axis is not more than 2 mm at any point from
the vertical axis of the vessel and rotates smoothly and without
h711i DISSOLUTION significant wobble that could affect the results. A speed-regulating
device is used that allows the shaft rotation speed to be selected and
maintained at the specified rate ^given in the individual mono-
graph,^ within +4%.
This general chapter is harmonized with the corresponding texts Shaft and basket components of the stirring element are fabricated
of the European Pharmacopoeia and/or the Japanese Pharmaco- of stainless steel, type 316, or other inert material, to the
poeia. These pharmacopeias have undertaken not to make any specifications shown in Figure 1. A basket having a gold coating
unilateral change to this harmonized chapter. of about 0.0001 inch (2.5 mm) thick may be used. A dosage unit is
Portions of the present general chapter text that are national USP placed in a dry basket at the beginning of each test. The distance
text, and therefore not part of the harmonized text, are marked with between the inside bottom of the vessel and the bottom of the basket
symbols (^^) to specify this fact. is maintained at 25 + 2 mm during the test.
1
The materials should not sorb, react, or interfere with the specimen being
tested.
2
If a cover is used, it provides sufficient openings to allow ready insertion of
the thermometer and withdrawal of specimens.
Pharmacopeial Forum

Figure 1. Basket Stirring Element
Apparatus 2 (Paddle Apparatus) of suitable nonsorbing and nonreactive material and that are
designed to fit the tops and bottoms of the reciprocating cylinders;
Use the assembly from Apparatus 1, except that a paddle formed and a motor and drive assembly to reciprocate the cylinders
from a blade and a shaft is used as the stirring element. The shaft is vertically inside the vessels and, if desired, index the reciprocating
positioned so that its axis is not more than 2 mm from the vertical cylinders horizontally to a different row of vessels. The vessels are
axis of the vessel at any point and rotates smoothly without partially immersed in a suitable water bath of any convenient size
significant wobble that could affect the results. The vertical center that permits holding the temperature at 37 + 0.58 during the test. No
line of the blade passes through the axis of the shaft so that the part of the assembly, including the environment in which the
bottom of the blade is flush with the bottom of the shaft. The paddle assembly is placed, contributes significant motion, agitation, or
conforms to the specifications shown in Figure 2. The distance of vibration beyond that due to the smooth, vertically reciprocating
25 + 2 mm between the bottom of the blade and the inside bottom of cylinder. A device is used that allows the reciprocation rate to be
the vessel is maintained during the test. The metallic or suitably selected and maintained at the specified dip rate ^given in the
inert, rigid blade and shaft comprise a single entity. A suitable two- individual monograph^ within +5%. An apparatus that permits
part detachable design may be used provided the assembly remains observation of the specimens and reciprocating cylinders is
firmly engaged during the test. The paddle blade and shaft may be preferable. The vessels are provided with an evaporation cap that
coated with a suitable coating so as to make them inert. The dosage remains in place for the duration of the test. The components
unit is allowed to sink to the bottom of the vessel before rotation of conform to the dimensions shown in Figure 3 unless otherwise
the blade is started. A small, loose piece of nonreactive material, specified în the individual monograph^.
such as not more than a few turns of wire helix, may be attached to
dosage units that would otherwise float. An alternative sinker device
is shown in Figure 2a. Other validated sinker devices may be used.
Apparatus 3 (Reciprocating Cylinder)

NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA
The assembly consists of a set of cylindrical, flat-bottomed glass

vessels; a set of glass reciprocating cylinders; inert fittings (stainless
steel type 316 or other suitable material), and screens that are made
Pharmacopeial Forum
Figure 2. Paddle Stirring Element
Figure 2a. Alternative sinker. All dimensions are expressed in mm.
Pharmacopeial Forum

Figure 3. Apparatus 3 (reciprocating cylinder)
Apparatus 4 (Flow-Through Cell)

Figure 4. Large cell for tablets and capsules (top) Tablet holder for
The assembly consists of a reservoir and a pump for the the large cell (bottom) (All measurements are expressed in mm
Dissolution Medium; a flow-through cell; and a water bath that unless noted otherwise.)
maintains the Dissolution Medium at 37 + 0.58. Use the specified
cell size âs given in the individual monograph^.
The pump forces the Dissolution Medium upwards through the
flow-through cell. The pump has a delivery range between 240 and
960 mL per hour, with standard flow rates of 4, 8, and 16 mL per
minute. It must deliver a constant flow (+5% of the nominal flow
rate); the flow profile is sinusoidal with a pulsation of 120 + 10
pulses per minute.
The flow-through cell (see Figures 4 and 5), of transparent and
inert material, is mounted vertically with a filter system (specified in
the individual monograph) that prevents escape of undissolved
particles from the top of the cell; standard cell diameters are 12 and
22.6 mm; the bottom cone is usually filled with small glass beads of
about
1-mm diameter with one bead of about 5 mm positioned at the apex
to protect the fluid entry tube; and a tablet holder (see Figures 4 and
5) is available for positioning of special dosage forms, for example,
inlay tablets. The cell is immersed in a water bath, and the
temperature is maintained at 37 + 0.58.
Pharmacopeial Forum
The apparatus uses a clamp mechanism and two O-rings to

assemble the cell. The pump is separated from the dissolution unit in
order to shield the latter against any vibrations originating from the
pump. The position of the pump should not be on a level higher than
the reservoir flasks. Tube connections are as short as possible. Use
suitably inert tubing, such as polytef, with about 1.6-mm inner
diameter and chemically inert flanged-end connections.
APPARATUS SUITABILITY
The determination of suitability of a test assembly to perform

dissolution testing must include conformance to the dimensions and
tolerances of the apparatus as given above. In addition, critical test
parameters that have to be monitored periodically during use include
volume and temperature of the Dissolution Medium, rotation speed
(Apparatus 1 and Apparatus 2), dip rate (Apparatus 3), and flow rate
of medium (Apparatus 4).
Determine the acceptable performance of the dissolution test
assembly periodically. ^The suitability for the individual apparatus is
demonstrated by the .Performance Verification.4 Test.
.Performance Verification
.4 Test, Apparatus 1 and 2—
Individually test 1 tablet of the .USP Prednisone Tablets RS.4 and
1 tablet of .USP Salicylic Acid Tablets RS,.4 according to the
operating conditions specified. The apparatus is suitable if the results
obtained are within the acceptable range stated in the certificate for
that .Reference Standard tablet.4 in the apparatus tested.
.Performance Verification
.4 Test, Apparatus 3—Individually
test 1 tablet of the .USP Chlorpheniramine Maleate Extended-
Release Tablets RS.4 according to the operating conditions specified.
The apparatus is suitable if the results obtained are within the
acceptable range stated in the certificate.
.Performance Verification Test, Apparatus 4—[To come.]
.4 ^
Figure 5. Small cell for tablets and capsules (top) Tablet holder for
the small cell (bottom) (All measurements are expressed in mm
unless noted otherwise.)
Pharmacopeial Forum
ERRATA
official publication of USP–NF. If necessary, this list will be updated with every issue of PF. This information will also be available as a cumulative
table in future Supplements and will appear in its corrected form in a future annual edition of USP–NF. Errata are considered to be items erro-
neously published that have not received the approval of the Council of Experts and that do not reflect the official requirement. USP staff is
USP30–NF25
2003 Dronabinol Capsules Assay Change ‘‘Mobile phase, System suitability solution,
Standard preparation, and Chromatographic system—
Proceed as directed in the Assay under Dronabinol.’’ to:
Mobile phase—Prepare a filtered and degassed mixture

of methanol, water, and tetrahydrofuran (71:24:5), mak-
ing adjustments, if necessary (see System Suitability un-
der Chromatography h621i).
System suitability solution—Mix accurately measured
volumes of USP D 9 -Tetrahydrocannabinol RS and
USP D8-Tetrahydrocannabinol RS in dehydrated alco-
hol to obtain a solution having a known concentration
of about 0.5 mg per mL of each component.
Standard preparation—Dissolve an accurately meas-
ured volume of USP D9-Tetrahydrocannabinol RS in de-
hydrated alcohol to obtain a solution having a known
concentration of about 0.2 mg per mL.
Chromatographic system (see Chromatography
h621i)—The liquid chromatograph is equipped with a
228-nm detector, a 4.6- 6 30-mm guard column that

contains 5-mm packing L1, and a 4.6-mm 6 15-cm ana-
lytical column that contains 3-mm packing L1. The flow
rate is about 1 mL per minute. Chromatograph the Sys-
tem suitability solution, and record the peak responses
as directed for Procedure: the relative retention times
are about 1.0 for D9-tetrahydrocannabinol and 1.14 for
D8-tetrahydrocannabinol; the resolution, R, between
dronabinol and D8-tetrahydrocannabinol is not less than
2.0; and the tailing factor of the D9-tetrahydrocannabi-
nol peak is not more than 2.0. Chromatograph the Stan-
dard preparation, and record the peak responses as
directed for Procedure: the relative standard deviation
for replicate injections is not greater than 2.0%.
Line 1 under Procedure: Change ‘‘Proceed as directed
for Procedure in the Assay under Dronabinol.’’ to: Sep-
arately inject equal volumes (about 20 mL) of the Stan-
dard preparation and the Assay preparation into the
chromatograph, record the chromatograms, and mea-
sure the responses for all of the peaks.
2186 Fluvastatin Sodium Chromatographic purity Footnote 3 of Table 1 under Procedure: Change
‘‘[R*,S*-E]-(+)-’’ to: [R*,R*-E]-(+)-
First Supplement to USP30–NF25
3550 h11i USP Reference Standards USP Dantrolene Related Com- Change ‘‘[5-(4-nitrophenyl)furaldehyde azine]’’ to: [5-
pound A RS (4-nitrophenyl)-2-furaldehyde azine]
USP Dantrolene Related Com- Change ‘‘[5-(4-nitrophenyl)-1-furancarboxyaldehyde]’’
pound C RS to: [5-(4-nitrophenyl)-2-furancarboxyaldehyde]
3770 Dantrolene Sodium for Injec- Related compounds Line 1 under Procedure: Change ‘‘(about 20 mL)’’ to:
tion (about 10 mL)
Assay Line 1 under Buffer: Change ‘‘Dissolve 3.3 mg’’ to:
Dissolve 3.3 g
3773 Desmopressin Acetate Injection Assay Line 7 under Chromatographic system: Change ‘‘not
more than 1.0%.’’ to: not more than 5.0%.
Line 1 under Procedure: Change ‘‘(about 50 mL)’’ to:
(about 100 mL)
IN-PROCESS REVISION

BRIEFING
.
new text.
~
new text~USP31
&
new text&
In-Process Revision
~
&
revision will appear if approved. For example, .2 indicates that the revision is proposed for the Interim Revision Announcement that
will appear in issue 2 of a given PF volume, &2S (USP 30) indicates that the proposed revision is slated for the Second Supplement to
USP 30, and ~USP31 and ~NF26 indicate that the revisions are proposed for USP 31 and NF 26, respectively.
becomes official.
Pharmacopeial Forum
634 IN-PROCESS REVISION Vol. 33(4) [July–Aug. 2007]

MONOGRAPHS (USP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Amiloride Hydrochloride and Hydrochlorothiazide Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Atovaquone (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Benazepril Hydrochloride Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Bismuth Subsalicylate Magma (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Bupropion Hydrochloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Bupropion Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Cefaclor Chewable Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
Ciclopirox (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
Ciclopirox Olamine (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Cyromazine [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Dantrolene Sodium Capsules [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 645
Ethionamide (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Etidronate Disodium (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 648
Famotidine Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Formaldehyde Solution (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Glyburide Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Hydrocodone Bitartrate and Homatropine Methylbromide Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . 654
Hyoscyamine Sulfate (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Isosorbide Mononitrate Extended-Release Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
Isotretinoin Capsules (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Mefloquine Hydrochloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Methylphenidate Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . 667
Nitrofurantoin Capsules (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Oxybutynin Chloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Paroxetine Tablets (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 672
Raloxifene Hydrochloride [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Raloxifene Hydrochloride Tablets [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Ritonavir (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
Tizanidine Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
Triclosan (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
Vecuronium Bromide (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Verapamil Hydrochloride Extended-Release Tablets (Proposal for 6th IRA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Powdered Bilberry Extract [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 685
Chamomile (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
Glucosamine Hydrochloride ((2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Glucosamine Sulfate Potassium Chloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Glucosamine Sulfate Sodium Chloride (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Powdered Decaffeinated Green Tea Extract [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
EXCIPIENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Excipients, USP and NF Excipients, Listed by Category (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
NF MONOGRAPHS (NF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
Agar (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
In-Process Revision
Dehydroacetic Acid [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703

Egg Phospholipids [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Gamma Cyclodextrin [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Inositol [new] (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
Poloxamer (2nd Supp to NF26) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
h11i USP Reference Standards (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
h41i Weights and Balances (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
h191i Identification Tests—General (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
h643i Total Organic Carbon (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
h645i Water Conductivity (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
h1010i Analytical Data—Interpretation and Treatment (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
h1119i Near-Infrared Spectrophotometry (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
h1196i Pharmacopeial Harmonization (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
h1251i Weighing on an Analytical Balance (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
Pharmacopeial Forum
Vol. 33(4) [July–Aug. 2007] IN-PROCESS REVISION 635
REAGENTS, INDICATORS, AND SOLUTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766

Reagent Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
1-Butanesulfonic Acid Sodium Salt [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Butyrophenone [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Cetyltrimethylammonium Bromide [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Diethylamine Phosphate [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
Fuchsin, Basic (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
n-Heptane, Chromatographic (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Hexadecyltrimethylammonium Bromide [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Octanesulfonic Acid Sodium Salt [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Potassium Pyroantimonate (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Selenium (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Triethylamine (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Test Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Alkaline Cupric Citrate TS 2 [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Cupric Citrate TS 2, Alkaline [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Sodium Hydroxide TS 2 [new] (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Volumetric Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Lithium Methoxide, Tenth-Normal, 0.1 N in Chlorobenzene (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Lithium Methoxide, Tenth-Normal, 0.1 N in Methanol (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Lithium Methoxide, Tenth-Normal, 0.1 N in Toluene (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
REFERENCE TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
Container Specifications (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
Description and Solubility (2nd Supp to USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775
PREVIOUS PF PROPOSALS STILL PENDING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
CANCELED PROPOSALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
In-Process Revision
Pharmacopeial Forum
MONOGRAPHS (USP) Correction for the interference of amiloride is made using the
following equation:
BRIEFING
in which AUC is the corrected absorbance of Test solution 1 at 270

Amiloride Hydrochloride and Hydrochlorothiazide Tablets, nm; AU 270 is the absorbance of Test solution 2 at 270 nm; AU 363 is the
USP 30 page 1375. In the Dissolution test, it is proposed to add an absorbance of Test solution 1 at 363 nm; and F is as defined below.
HPLC procedure to quantitate the amount of drugs dissolved. This
procedure was validated using the Purospher RP-18 brand of L1
column. Using this column, the retention times of hydrochlorothi-
azide and amiloride are about 3 and 4 minutes, respectively.

in which ASAmiloride is the absorbance of the Amiloride standard
Change to read: solution.
Calculate the amount of hydrochlorothiazide (C7H8ClN3O4S2)
dissolved, in percentage, by the formula:
Time: 30 minutes.
&
Determine the amount of amiloride hydrochloride and
hydrochlorothiazide dissolved employing one of the follow- in which AUC is the corrected absorbance of Test solution 1 at 270
nm; AS is the absorbance of the Hydrochlorothiazide standard
ing procedures. solution; CS is the concentration, in mg per mL, of the
Hydrochlorothiazide standard solution; 900 is the volume, in mL,
SPECTROPHOTOMETRIC PROCEDURE—&2S (USP31)
of Medium; (25/5) is the dilution factor of Test solution 2; 100 is the
Amiloride standard solution—Transfer about 60 mg of USP conversion factor to percentage; and LC is the Tablet label claim, in
Amiloride Hydrochloride RS (equivalent to about 52 mg of mg, of hydrochlorothiazide.
anhydrous amiloride hydrochloride), accurately weighed, to a
200-mL volumetric flask. Dissolve in and dilute with methanol to &
CHROMATOGRAPHIC PROCEDURE—
volume. Transfer 2.0 mL of this solution to a 100-mL volumetric
flask, and dilute with Medium to volume. Standard solution—Dilute with Medium an accurately
Hydrochlorothiazide standard solution—Transfer about 100 mg of
USP Hydrochlorothiazide RS, accurately weighed, to a 100-mL measured volume of the Standard preparation prepared in
volumetric flask. Dissolve in and dilute with methanol to volume.
Transfer 5.0 mL of this solution to a 100-mL volumetric flask, and the Assay to obtain a solution having concentrations of 0.005
dilute with Medium to volume. Transfer 10.0 mL of the resulting
solution to a 50-mL volumetric flask, and dilute with Medium to mg per mL of amiloride hydrochloride and 0.05 mg per mL of
volume.
Test solution 1—Pass a portion of the solution under test through hydrochlorothiazide.
a 0.45-mm glass fiber filter.
Test solution 2—Transfer 5.0 mL of Test solution 1 to a 25-mL Test solution—Pass a portion of the solution under test
volumetric flask, and dilute with Medium to volume.
Procedure—Determine the amounts of amiloride hydrochloride through a suitable filter having a porosity of 0.45 mm.
(C6H8ClN7O HCl) and hydrochlorothiazide (C7H8ClN3O4S2) dis-
In-Process Revision
solved by employing UV absorption at the wavelengths of maximum Buffer solution and Mobile phase—Prepare as directed in
absorbance at about 363 nm for amiloride hydrochloride and 270 nm
for hydrochlorothiazide, using Medium as the blank. the Assay.
Calculate the amount of amiloride hydrochloride
(C6H8ClN7O HCl) dissolved, in percentage, by the formula: Chromatographic system (see Chromatography h621i)—
The flow rate is about 1 mL per minute. Chromatograph five
in which AU and AS are the absorbances obtained from Test solution replicate injections of the Standard solution, and record the
1 and the Amiloride standard solution, respectively; CS is the
concentration, in mg per mL, of the Amiloride standard solution; peak responses as directed for Procedure: the resolution, R,
900 is the volume, in mL, of Medium; 100 is the conversion factor to
percentage; and LC is the Tablet label claim, in mg, of amiloride. between hydrochlorothiazide and amiloride hydrochloride is
not less than 2.0; and the relative standard deviation for
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 50 mL) Blank preparation—Proceed as directed for Test preparation,
omitting the Atovaquone.
of the Standard solution and the Test solution into the Procedure—Transfer 12.0 mL of the Test preparation to a 50-mL
color-comparison tube, 10.0 mL of the Standard preparation to
chromatograph, record the chromatograms, and measure the another, and 10.0 mL of the Blank preparation and 2.0 mL of the
Test preparation to a third
responses for the major peaks. Calculate the amount of
&
to a third. Then add 2.0 mL of the Test preparation to the
amiloride hydrochloride and hydrochlorothiazide dissolved
Standard preparation as well as to the Blank prepara-
by the formula:
tion.&2S (USP31)
Add 2 mL of pH 3.5 Acetate Buffer (see Heavy Metals h231i) to each
of the three tubes, mix, add 1.2 mL of thioacetamide–glycerin base
TS, and mix. Allow to stand for 2 minutes, and view downward over
a white surface: the solution from the Standard preparation is
slightly brown when compared with the solution from the Blank
preparation, and the color of the solution from the Test preparation
is not darker than that of the solution from the Standard preparation
(10 mg per g).
in which rU and rS are the peak responses for amiloride

hydrochloride or hydrochlorothiazide in the Test solution and
BRIEFING
the Standard solution, respectively; CS is the concentration, in
mg per mL, of amiloride hydrochloride or hydrochlorothia- Benazepril Hydrochloride Tablets, USP 30 page 1492. It is
proposed to add Dissolution Test 2 because FDA recently approved
zide in the Standard solution; 900 is the volume, in mL, of a new generic version of this product. In the absence of any
significant adverse comments, it is proposed to implement this
Medium; 100 is the conversion factor to percentage; and LC is revision via the Interim Revision Announcement pertaining to USP
30–NF 25 in PF 33(6) [Nov.–Dec. 2007] with an official date of
the Tablet label claim, in mg, of amiloride hydrochloride or December 1, 2007.
hydrochlorothiazide.&2S (USP31)
Tolerances—Not less than 80% (Q) of the labeled amount of (BPC: M. Marques) RTS—C54936
C 6 H 8 ClN 7 O HCl and 75% (Q) of the labeled amount of
C7H8ClN3O4S2 are dissolved in 30 minutes.
Add the following:
.Labeling—
BRIEFING When more than one Dissolution test is given, the labeling
states the test used only if Test 1 is not used..6
Atovaquone, USP 30 page 1460. On the basis of information
received from the sponsor, it is proposed to revise the Procedure in Change to read:
the test for Heavy metals to correspond to the original submission for
this method.
(MD-AA: B. Davani) RTS—C52526 .TEST 1—
.6
Medium: water, 500 mL.
In-Process Revision
Change to read: Time: 30 minutes.
Determine the amount of C24H28N2O5 HCl dissolved by employ-
Heavy metals— ing the following method.
Test preparation—Thoroughly mix 1.0 g of Atovaquone with 0.5 g Tetrabutylammonium bromide solution, Mobile phase, System
of magnesium oxide in a silica crucible. Ignite to dull redness until suitability solution, and Chromatographic system—Proceed as
a homogeneous white or grayish-white mass is obtained. If the directed in the Assay under Benazepril Hydrochloride.
mixture remains colored after 30 minutes, allow to cool, mix using Procedure—Inject about 60 mL, or an amount of a filtered portion
a fine glass rod, and repeat the ignition. If necessary, repeat the of the solution under test, equivalent to about 1.2 mg of benazepril,
operation. Heat the residue at 8008 for about 1 hour. Cool, take up into the chromatograph. The amount of benazepril injected should
the residue in two 5-mL portions of 6 N hydrochloric acid, add 0.1 not exceed 1.5 mg. Record the chromatogram, and measure the
mL of phenolphthalein TS, and then add 13.5 N ammonium responses for the major peaks. Determine the quantity, in mg, of
hydroxide until a pink color is obtained. Cool, add glacial acetic C24H28N2O5 HCl dissolved in comparison with a Standard solution
acid until the solution is decolorized, and add 0.5 mL in excess. having a known concentration of USP Benazepril Hydrochloride RS
Filter, if necessary, and wash the filter with water. Dilute with water in the same Medium and similarly chromatographed.
to 20 mL. Tolerances—Not less than 80% (Q) of the labeled amount of
Standard preparation—Add 1.0 mL of Standard Lead Solution C24H28N2O5 HCl is dissolved in 30 minutes.
(see Special Reagents under Heavy Metals h231i) to 0.5 g of .TEST 2—If
magnesium oxide, and dry between 1008 and 1058. Proceed as the product complies with this test, the labeling
directed for Test preparation, starting with ‘‘Ignite to dull redness’’.
Pharmacopeial Forum
Medium, Apparatus, and Procedure—Proceed as directed Change to read:
for Test 1. Related compounds—

TEST 1—
Time: 45 minutes. Adsorbent: a 0.25-mm layer of high-performance silica gel,
previously washed with methanol.
Tolerances—Not less than 70% (Q) of the labeled amount Test solution—Prepare a solution of Bupropion Hydrochloride in
methanol having a concentration of about 100.0 mg per mL.
of C24H28N2O5 HCl is dissolved in 45 minutes..6 Standard solutions—Prepare a solution of m-chlorobenzoic acid in
methanol containing about 0.5 mg per mL. Dilute this solution
quantitatively, and stepwise if necessary, with methanol to obtain
solutions having known concentrations of about 0.3, 0.2, and 0.1 mg
per mL.
BRIEFING Developing solvent system: a mixture of toluene, cyclohexane,
and glacial acetic acid (47 : 47 : 6).
Procedure—Proceed as directed for Thin-Layer Chromatography
under Chromatography h621i. Locate and quantitate the spots
Bismuth Subsalicylate Magma, USP 30 page 1538. On the basis obtained by scanning the entire plate with a suitable densitometer at
of comments received, for consistency with the drug substance 235 nm. Plot a standard curve of area versus concentrations of the
monograph Bismuth Subsalicylate, it is proposed to revise the Standard solutions. From the standard curve, determine the
Packaging and storage section to include the description ‘‘light- percentages of m-chlorobenzoic acid and any other impurity present:
resistant’’. not more than 0.2% of m-chlorobenzoic acid is found; and not more
than 0.1% of any other individual impurity is found.
(MD-CCA: C. Anthony) RTS—C37376 TEST 2—
Diluent, 0.025 M Phosphate buffer, Mobile phase, System
suitability solution, and Chromatographic system—Proceed as
Change to read: directed in the Assay.
Standard solution—Use the Standard preparation, prepared as
directed in the Assay.
Packaging and storage—Preserve in tight, Test solution—Use the Assay preparation.
Procedure—Using the chromatograms obtained in the Assay,
&
light-resistant&2S (USP31) calculate the percentage of each impurity in the portion of Bupropion
containers. Hydrochloride taken by the formula:
5000(C/W)F(ri / rS)
n which C is the concentration, in mg per mL, of USP Bupropion
Hydrochloride RS in the Standard solution; W is the weight, in mg,
BRIEFING of sample take to prepare the Test solution; F is the relative response
factor for each impurity (see the accompanying table for values); ri is
the peak response for each impurity obtained from the Test solution;
Bupropion Hydrochloride, USP 30 page 1565 and page 211 of and rS is the peak response for bupropion hydrochloride obtained
PF 33(2) [Mar.–Apr. 2007]. On the basis of comments received, it is from the Standard solution.
proposed to revise the test for Related compounds to change the
calculation of the percentage of bupropion hydrochloride related
compound B by using the Standard solution instead of the System
suitability solution, as required in the currently official monograph.
It is also proposed to update the calculation of each impurity in the &
100(CS / CT)(ri / rS)(1/F)
portion of Bupropion Hydrochloride to be consistent with the
recommendations in the Stimuli articles ‘‘Common Pharmacopeial
Calculations in USP Monographs’’ (page 626 of PF 31(2) [Mar.–
Apr. 2005]) and ‘‘The Use of Relative Response Factors to in which CS and CT are the concentrations, in mg per mL, of
In-Process Revision
Determine Impurities’’ (page 960 of PF 31(3) [May–June 2005]).

Bupropion Hydrochloride in the Standard preparation and
(MD-PP: H. Ramanathan) RTS—C54824
the Assay preparation, respectively; ri is the peak response for
each impurity obtained from the Assay preparation; rS is the
Change to read:
peak response for bupropion hydrochloride obtained from the
Identification—
A: Infrared Absorption h197Ki. Standard preparation; and F is the relative response factor for
the Assay preparation corresponds to that in the chromatogram of each impurity relative to bupropion, as presented in the
accompanying table.&2S (USP31)
&
C: A solution of 1 mg per mL in water meets the The limits of impurities are also specified in the accompanying table:
not more than 0.3% of total unidentified impurities is found; and not
requirement of the silver nitrate precipitate test for Chloride more than 1.0% of total impurities is found, the results of Test 1 and
Test 2 being added.
h191i.&1S (USP31)
Pharmacopeial Forum
Relative Relative
Compound Name Retention Time Response Factor (F) Limit (%)
2-(tert-Butylamino)propio- about 0.38 0.68 0.5

phenone hydrochloride &
1.5&2S (USP31)
1-(3-Chlorophenyl)-1,2- about 0.58 0.96 0.2
propanedione &
1.0&2S (USP31)
2-(tert-Butylamino)-2’- about 0.71 2.22 0.1
chloropropiophenone
hydrochloride
&
0.45&2S (USP31)
3’-Chloropropiophenone about 0.78 0.82 0.1
&
1.2&2S (USP31)
Bupropion hydrochloride about 0.92 0.73 0.2
related compound A &
1.4&2S (USP31)
Bupropion 1.0 — —
Bupropion hydrochloride about 1.14 — 0.2*
related compound B
2-Bromo-3’-chloropropio- about 1.63 1.13 0.1
phenone &
0.88&2S (USP31)
2-(tert-Butylamino)-3’,4’- about 2.30 0.91 0.2
chloropropiophenone
hydrochloride
&
1.1&2S (USP31)
2-(tert-Butylamino)-3’,5’- about 2.74 1.45 0.2
chloropropiophenone
hydrochloride
&
0.69&2S (USP31)
Unknown all other peaks 1.00 0.1, individual
*
The percentage is determined by direct comparison to the area of the peak for bupropion hydrochloride related compound B obtained from the System suitability
solution.
&
Standard solution.&2S (USP31)
Delete the following: Change to read:
&
Content of chloride—Dissolve about 50.0 mg of Bupropion Dissolution h711i—
Hydrochloride, accurately weighed, in 50 mL of water, and titrate
&
with 0.1 N silver nitrate VS, determining the endpoint potentiomet- FOR PRODUCTS LABELED FOR DOSING EVERY 12
rically. Perform a blank determination, and make any necessary
corrections. Each mL of 0.1 N silver nitrate is equivalent to 3.545 mg HOURS—&1S (USP30)
of chloride (Cl): not less than 12.6% and not more than 13.1% of TEST 1—
chloride, calculated on the anhydrous basis, is found.&1S (USP31) Medium: water; 900 mL.
Procedure—Determine the amount of C13H18ClNO HCl dissolved
absorbance at about 298 nm, using a 1.0-cm cell, on filtered portions
BRIEFING of the solution under test, suitably diluted with Medium, if necessary,
In-Process Revision
in comparison with a Standard solution having a known concentra-
tion of USP Bupropion Hydrochloride RS in the same Medium.
Bupropion Hydrochloride Extended-Release Tablets, USP 30 Tolerances—The percentages of the labeled amount of
page 1567, the Interim Revision Announcement on page 184 of PF C13H18ClNO HCl dissolved at the times specified conform to
33(2) [Mar.–Apr. 2007], and page 42 of PF 33(1) [Jan.–Feb. 2007]. Acceptance Table 2.
It is proposed to add Dissolution Test 6 because FDA recently
approved a new generic version of this product with dosing every 24 Time (hours) Amount dissolved
hours. In the absence of any negative comments, it is proposed to 1 between 25% and 45%
implement the inclusion of this test in PF 33(6) [Nov.–Dec. 2007] 4 between 60% and 85%
via the Interim Revision Announcement pertaining to USP 30–NF 8 not less than 80%
25, with an official date of December 1, 2007.
(BPC: M. Marques) RTS—C54644 TEST 2—If the product complies with this test, the labeling
Medium: 0.1 N hydrochloric acid, pH 1.5
Pharmacopeial Forum
&
(prepared by transferring about 50 mL of concentrated Tolerances—The percentages of the labeled amount of
hydrochloric acid to 6000 mL of water, adding about 18 g of Acceptance Table 2.
sodium hydroxide, mixing, and adjusting with either diluted Time (hours) Amount dissolved
sodium hydroxide or hydrochloric acid to a pH of 1 between 35% and 55%
1.5 + 0.05.);&1S (USP30) 6 not less than 80%
900 mL,
.2
&
deaerated.&1S (USP30) &
Apparatus 1: 50 rpm. FOR PRODUCTS LABELED FOR DOSING EVERY 24 HOURS—
Determine the percentages of the labeled amount of TEST 4—If the product complies with this test, the labeling
C13H18ClNO HCl dissolved by employing the following method.
Buffer solution—Dissolve 3.45 g of sodium phosphate monobasic indicates that it meets USP Dissolution Test 4.
monohydrate in 996 mL of water, add 4.0 mL of triethylamine, and
mix. Adjust with phosphoric acid to a pH of 2.80 + 0.05. Medium: 0.1 N hydrochloric acid; 900 mL, deaerated.
solution and methanol (65 : 35). Make adjustments if necessary (see Apparatus 1: 75 rpm.
Standard solution—Dissolve an accurately weighed quantity of Times: 2, 4, 8, and 16 hours.
USP Bupropion Hydrochloride RS in Medium, and dilute quantita-
tively, and stepwise if necessary, with Medium to obtain a solution Procedure—Determine the amount of C13H18ClNO HCl
having a known concentration similar to the one expected in the Test
solution. dissolved by employing UV absorption at the wavelength of
through a 0.45-mm nylon filter. maximum absorbance at about 252 nm, using a 1.0-cm
&
1.0-mm&2S (USP30) cell, on filtered portions of the solution
a 4.6-mm 6 15-cm column that contains packing L1. The flow rate
is about 1.0 mL per minute. Chromatograph the Standard solution, under test, suitably diluted with Medium, if necessary, in
and record the peak responses as directed for Procedure: the column
efficiency is not less than 2000 theoretical plates; the tailing factor is comparison with a Standard solution having a known
not more than 2.0; and the relative standard deviation for replicate
injections is not more than 2.0%. concentration of USP Bupropion Hydrochloride RS in the
Standard solution and the Test solution into the chromatograph, same Medium.
Calculate the percentage of bupropion hydrochloride dissolved at Tolerances—The percentages of the labeled amount of
each time point.
Tolerances—The percentages of the labeled amount of C13H18ClNO HCl dissolved at the times specified conform to
Acceptance Table 2. Acceptance Table 2.
4 between 65% and 90% 2 not more than 20%
6 not less than 80%
TEST 3—If the product complies with this test, the labeling 8 between 65% and
In-Process Revision

Medium, Apparatus, and Procedure—Proceed as directed for Test 85%&90%&2S (USP30)
1, except using the wavelength at about 250 nm.
Times: 1, 2, 4, and 6 hours. 16 not less than 80%
Tolerances—The percentages of the labeled amount of &1S (USP30)
Acceptance Table 2.
1 between 30% and 55% indicates that it meets USP Dissolution Test 6.
4 between 70% and 90% Medium and Apparatus: Proceed as directed for Test 4.
6 not less than 80%
Times: 1, 2, 4, 8, and 12 hours.
.TEST 5—If the product complies with this test, the labeling Procedure—Determine the amount of C13H18ClNO HCl
Medium and Procedure—Proceed as directed for Test 1. dissolved by employing UV absorption at the wavelength of
Apparatus—Proceed as directed for Test 1, except to use a 0.5-cm
cell. maximum absorbance at about 298 nm, using a 1.0-cm cell,
on filtered portions of the solution under test, suitably diluted
Pharmacopeial Forum
with Medium, if necessary, in comparison with a Standard Add the following:
solution having a known concentration of USP Bupropion &Cefaclor Chewable Tablets

Hydrochloride RS in the same Medium.
» Cefaclor Chewable Tablets contain not less than
Acceptance Table 2.
90.0 percent and not more than 110.0 percent of the
Time (hours) Amount dissolved labeled amount of cefaclor (C15H14ClN3O4S).
at 258, excursions permitted between 158 and 308.
Labeling—Label chewable Tablets to include the word
‘‘chewable’’ in juxtaposition to the official name. The
labeling indicates that chewable Tablets are to be chewed
.6
before being swallowed. The product label and product
labeling indicate that the Chewable Tablets must be chewed
or crushed before administration.
BRIEFING
USP Reference standards h11i—USP Cefaclor RS. USP
Cefaclor Tablets, page 314 of PF 32(2) [Mar.–Apr. 2006]. The Cefaclor Delta-3 Isomer RS.
proposed change in the monograph title from Cefaclor Tablets to
Cefaclor Chewable Tablets is based on the Nomenclature Expert Identification—The retention time of the major peak in the
Committee policy for nomenclature and labeling of chewable tablets:
chromatogram of the Assay preparation corresponds to that in
1. The format ‘‘[DRUG] Tablets’’ will be used for tablets that are
swallowed whole or that MAY be chewed AND for which there the chromatogram of the Standard preparation, as obtained in
is no intended alternative method of administration. When
appropriate, there will also be a labeling statement indicting that the Assay.
the tablets MAY be chewed.
2. The format ‘‘[DRUG] Chewable Tablets’’will be used for
tablets that MUST be chewed AND for which there is no other Dissolution h711i—
alternative route of administration. There will also be a labeling
statement indicating that the tablets MUST be chewed. The Medium: water; 900 mL.
addition of the term Chewable in this monograph title
represents a significant improvement in that the consumer Apparatus 2: 50 rpm.
will now be provided with added information, along with the
labeling statement directing that tablets are to be chewed before Time: 30 minutes.
being swallowed, to hopefully assure that the product will be
used properly to achieve the benefit of the medication. Procedure—Determine the amount of cefaclor dissolved by
In-Process Revision
Also, USP Cefaclor Delta-3 Isomer RS is added to the Reference
standards section. employing UV absorption at the wavelength of maximum
(MD-ANT: S. Ramakrishna) RTS—C55249

absorbance at about 264 nm on filtered portions of the
solution under test, suitably diluted with Medium, if
necessary, in comparison with a Standard solution having
a known concentration of USP Cefaclor RS in the same
Medium. Calculate the amount of cefaclor dissolved by the
formula:
Pharmacopeial Forum
in which AU and AS are the absorbances obtained from the Assay—

solution under test and the Standard solution, respectively; CS Mobile phase, Standard preparation, Resolution solution,
is the concentration, in mg per mL, of the Standard solution; and Chromatographic system—Proceed as directed in the
900 is the volume, in mL, of Medium; 100 is the conversion Assay under Cefaclor.
factor to percentage; D is the dilution factor of the solution Assay preparation—Weigh and finely powder not fewer
under test; and LC is the tablet label claim, in mg. than 20 Chewable Tablets. Transfer an accurately weighed
Tolerances—Not less than 80% (Q) of the labeled amount portion of the powder, equivalent to about 75 mg of cefaclor,
of cefaclor is dissolved in 30 minutes. to a 250-mL volumetric flask, dilute with Mobile phase to
Uniformity of dosage units h905i: meet the requirements. volume, and mix. Sonicate, if necessary, to dissolve the
cefaclor. Filter to obtain a clear solution.
Procedure—Proceed as directed in the Assay under
Cefaclor. Calculate the quantity, in mg, of cefaclor
Solvent, Blank solution, Solution A, Solution B, Mobile
(C15H14ClN3O4S) in the portion of Chewable Tablets taken
phase, Standard solution, System suitability solution, and
by the formula:
Chromatographic system—Proceed as directed for Related
compounds under Cefaclor. 5WS (P/1000)(rU / rS)
Chewable Tablets. Transfer an accurately weighed portion of in which the terms are as defined therein.&2S (USP31)
the composite, equivalent to about 50 mg of cefaclor, to a 10-
mL volumetric flask. Dissolve in Solvent, using brief
sonication, if necessary, to dissolve. Avoid heating. Dilute BRIEFING
with Solvent to volume, mix, and filter. [NOTE—Use this Test

Ciclopirox, USP 30 page 1748. It is proposed to remove the
solution within 3 hours if stored at room temperature, or specified amounts of USP Ciclopirox Related Compound A RS and
USP Ciclopirox Related Compound B RS used in the preparation of
within 20 hours when stored under refrigeration.] the Standard stock solution in the test for Related compounds. This
will provide the flexibility to use proportionally smaller quantities or
Procedure—Separately inject equal volumes (about 20 mL) volumes to prepare the same final concentration of each Reference
Standard.
(MD-AA: B. Davani; H. Ramanathan) RTS—C50616
peak area responses for all the peaks. Calculate the quantity,
In-Process Revision
Change to read:
in mg, of each related compound in the portion of Chewable
Related compounds—[NOTE—Carry out the operations avoiding
Tablets taken by the formula: exposure to actinic light. All materials in direct connection with
ciclopirox, like column materials, reagents, solvents, and others
should contain only very low amounts of extractable metal cations.]
0.01CP(ri / rS) Mobile phase—Prepare a filtered and degassed mixture of an
edetate disodium solution (0.96 in 1000), acetonitrile, and glacial
acetic acid (770 : 230 : 0.1). Make adjustments if necessary (see
in which the terms are as defined for Related compounds Rinsing solution—Prepare a mixture of water, acetonitrile, glacial
acetic acid, and acetylacetone (500 : 500 : 1 : 1).
under Cefaclor. Not more than 1.0% of any individual Standard stock solution—Dissolve 15 mg of USP Ciclopirox
Related Compound A RS and 15 mg of USP Ciclopirox Related
cefaclor related compound is found; and the sum of all Compound B RS, accurately weighed, in 1 mL of acetonitrile and
7 mL of Mobile phase. Dilute the solution thus obtained with Mobile
cefaclor related compounds found is not more than 3.0%, not phase to 10.0 mL in order to obtain a solution having a known
concentration of 1.5 mg each per mL.
including the contribution of any peak that gives a result of
less than 0.1%.
Pharmacopeial Forum
&
Dissolve USP Ciclopirox Related Compound A RS and USP
BRIEFING
Ciclopirox Related Compound B RS, accurately weighed, in
an appropriate volume of acetonitrile/Mobile phase solution
Ciclopirox Olamine, USP 30 page 1749. It is proposed to remove
(approximate ratio, 1 : 7). Further dilute with Mobile phase to the specified amounts of USP Ciclopirox Related Compound A RS
and USP Ciclopirox Related Compound B RS used in the
obtain a solution having a known final concentration of about preparation of the Standard stock solution in the test for Related
compounds. This will provide the flexibility to use proportionally
1.5 mg each per mL.&2S (USP31) smaller quantities or volumes to prepare the same final concentration
Standard solution A—Dilute 1.0 mL of Standard stock solution to of each Reference Standard.
200.0 mL with a mixture of Mobile phase and acetonitrile (9 : 1).
Standard solution B—Dilute 2.0 mL of Standard solution A to (MD-AA: B. Davani; H. Ramanathan) RTS—C50617
10.0 mL with a mixture of Mobile phase and acetonitrile (9 : 1).
Test solution—Dissolve 30 mg of ciclopirox, accurately weighed,
in a mixture of 2 mL of acetonitrile and 15 mL of Mobile phase. If Change to read:
necessary, use an ultrasonic bath. Dilute with Mobile phase to 20.0
mL.
Resolution solution—Mix 5 mL of Standard stock solution with Related compounds—[NOTE—Carry out the operations avoiding
5 mL of the Test solution. exposure to actinic light. All materials that are in direct contact with
Chromatographic system (see Chromatography h621i)—The Ciclopirox Olamine (e.g., column materials, reagents, solvents, etc.)
liquid chromatograph is equipped with a detector capable of should contain only very low amounts of extractable metal cations.]
recording at both 220 nm and 298 nm and a 4.0-mm 6 8-cm Mobile phase—Prepare a filtered and degassed mixture of an
column that contains packing L10. [NOTE—Ciclopirox related edetate disodium solution (0.96 in 1000), acetonitrile, and glacial
compound A has an intense absorbance at 220 nm, and acetic acid (770 : 230 : 0.1). Make adjustments if necessary (see
6-cyclohexyl-4-methyl-2(1H)-pyridone, ciclopirox related com- System Suitability under Chromatography h621i).
pound B, and ciclopirox have intense absorbances at 298 nm.] The Rinsing solution—Prepare a mixture of water, acetonitrile, glacial
flow rate is about 0.7 mL per minute. Chromatograph the Resolution acetic acid, and acetylacetone (500 : 500 : 1 : 1).
solution, and record the peak responses as directed for Procedure at Standard stock solution—Dissolve 15 mg of USP Ciclopirox
298 nm: the resolution, R, between the ciclopirox related compound Related Compound A RS and 15 mg of USP Ciclopirox Related
B peak and ciclopirox peak is not less than 2.0. Chromatograph the Compound B RS, accurately weighed, in 1 mL of acetonitrile and
Standard solution B, and record the peak responses as directed for 7 mL of Mobile phase. Dilute the solution thus obtained with Mobile
Procedure at 298 nm: the chromatogram obtained shows at 298 nm phase to 10.0 mL to obtain a solution having a known concentration
a peak corresponding to ciclopirox related compound B with of 1.5 mg of each USP Reference Standard per mL.
a signal-to-noise ratio of not less than 3. Chromatograph the Test
solution, and record the peak responses as directed for Procedure at &
Dissolve USP Ciclopirox Related Compound A RS and USP
298 nm: the tailing factor for the ciclopirox peak is less than 2.0.
Procedure—Separately inject equal volumes (about 10 mL) of Ciclopirox Related Compound B RS, accurately weighed, in
Standard solution A, Standard solution B, and the Test solution into
the chromatograph, and record the chromatograms. [NOTE—In order an appropriate volume of acetonitrile/Mobile phase solution
to ensure desorption of disruptive metal ions, every new column
must be rinsed with the Rinsing solution over a period of not less (approximate ratio, 1 : 7). Further dilute with Mobile phase to
than 15 hours and then with the Mobile phase for not less than
5 hours with a flow rate of 0.2 mL per minute. The chromatographic obtain a solution having a known final concentration of about
run time is not less than 2.5 times the retention time of the ciclopirox
peak.] The relative retention times are about 0.5 for ciclopirox 1.5 mg of each per mL.&2S (USP31)
related compound A, 0.9 for 6-cyclohexyl-4-methyl-2(1H)-pyridone, Standard solution A—Dilute 1.0 mL of Standard stock solution to
1.0 for ciclopirox, and 1.3 for ciclopirox related compound B. The 200.0 mL with a mixture of Mobile phase and acetonitrile (9 : 1).
peak response at 220 nm of the ciclopirox related compound A peak Standard solution B—Dilute 2.0 mL of Standard solution A to
in the chromatogram obtained from the Test solution is not more than 10.0 mL with a mixture of Mobile phase and acetonitrile (9 : 1).
the peak response at 220 nm of the corresponding peak in the Test solution—Dissolve 40 mg of Ciclopirox Olamine, accurately
chromatogram obtained from Standard solution A (0.5%). The sum weighed, in a mixture of 2 mL of acetonitrile, 20 mL of glacial acetic
of responses at 298 nm of the peaks in the chromatogram obtained acid, and 15 mL of Mobile phase. If necessary, use an ultrasonic bath
from the Test solution is not more than the peak response at 298 nm to dissolve. Dilute with Mobile phase to 20.0 mL, and mix.
In-Process Revision
of the ciclopirox related compound B peak in the chromatogram Resolution solution—Mix 5 mL of Standard stock solution with
obtained from Standard solution A (0.5%). At 298 nm disregard any 5 mL of the Test solution.
peak due to the solvent and any peak with a response less than the Chromatographic system (see Chromatography h621i)—The
response of the ciclopirox related compound B peak in the liquid chromatograph is equipped with a detector capable of
chromatogram obtained from Standard solution B at 298 nm (0.1%). recording at both 220 nm and 298 nm and a 4.0-mm 6 8-cm
column that contains packing L10. [NOTE—Ciclopirox related
compound A has an intense absorbance at 220 nm, and
6-cyclohexyl-4-methyl-2(1H)-pyridone, ciclopirox related com-
pound B, and ciclopirox have intense absorbances at 298 nm.] The
flow rate is about 0.7 mL per minute. Chromatograph the Resolution
solution at 298 nm, and record the peak responses as directed for
Procedure: the resolution, R, between the ciclopirox related
compound B peak and the ciclopirox peak is not less than 2.0.
Chromatograph Standard solution B at 298 nm, and record the peak
responses as directed for Procedure: the chromatogram obtained
shows at 298 nm a peak corresponding to ciclopirox related
compound B with a signal-to-noise ratio of not less than 3.
Chromatograph the Test solution at 298 nm, and record the peak
responses as directed for Procedure: the tailing factor for the
ciclopirox peak is less than 2.0.
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 10 mL) of » Cyromazine contains not less than 98.0 percent
Standard solution A, Standard solution B, and the Test solution into
the chromatograph, and record the chromatograms. [NOTE—In order and not more than 102.0 percent of C6H10N6,
to ensure desorption of disruptive metal ions, every new column
must be rinsed with the Rinsing solution over a period of not less
than 15 hours and then with Mobile phase for not less than 5 hours calculated on the dried basis.
with a flow rate of 0.2 mL per minute. The chromatographic run time
is not less than 2.5 times the retention time of the ciclopirox peak.]
The relative retention times are about 0.5 for ciclopirox related Packaging and storage—Preserve in well-closed containers.
compound A, 0.9 for 6-cyclohexyl-4-methyl-2(1H)-pyridone, 1.0 for
ciclopirox, and 1.3 for ciclopirox related compound B. The peak Labeling—Label it to indicate that it is for veterinary use
response at 220 nm of the ciclopirox related compound A peak in the
chromatogram obtained from the Test solution is not more than the only.
peak response at 220 nm of the corresponding peak in the
chromatogram obtained from Standard solution A (0.5% with
reference to ciclopirox). The sum of responses at 298 nm of the USP Reference standards h11i—USP Cyromazine RS.
impurity peaks in the chromatogram obtained from the Test solution
is not more than the peak response at 298 nm of the ciclopirox Identification—
related compound B peak in the chromatogram obtained from
Standard solution A (0.5% with reference to ciclopirox). At 298 nm A: Infrared Absorption h197Ki.
disregard any peak due to the solvent and any peak with a response
less than the response of the ciclopirox related compound B peak in B: The retention time of the major peak in the
the chromatogram obtained from Standard solution B at 298 nm
(0.1% with reference to ciclopirox). chromatogram of the Assay preparation corresponds to that
in the Assay.
BRIEFING
Melting range h741i: between 2198 and 2268.
Cyromazine. Because there is no existing USP monograph for Loss on drying h731i—Dry it at 1058 to a constant weight: it
this article, a new monograph is being proposed. This article is used
in veterinary medicine as the active ingredient in Cyromazine loses not more than 1.0% of its weight.
Premix and Cyromazine Soluble Powder, used to control fly larvae
populations associated with poultry operations. It is regulated as
a pesticide by EPA. The Assay is an HPLC method, developed using Residue on ignition h281i: not more than 0.1%.
a Phenomenex Prodigy ODS3 brand of 4.6-mm 6 25-cm column
that contains 5-mm packing L1. The typical retention time for Assay—
cyromazine under the chromatographic conditions described in the
Assay is about 9 to 10 minutes. USP has received minimal validation Mobile phase—Mix 930 mL of water, 3.72 g of dibasic
data in support of the suitability of the methods described below;
additional verification of the suitability of the methods will be potassium phosphate, and 6.48 g of monobasic potassium
performed as part of the Reference Standard collaborative study.
Interested parties are invited to submit comments. phosphate. Add 50 mL of methanol and 20 mL of acetonitrile,
(VET: I. DeVeau) RTS—C49277 and mix. Make adjustments if necessary (see System
quantity of USP Cyromazine RS in methanol to obtain
In-Process Revision
Add the following: a solution having a known concentration of about 0.50 mg per
&Cyromazine mL. Dilute an aliquot of the resulting solution with Mobile
phase to obtain a solution having a known concentration of
about 10 mg per mL.
tity of Cyromazine in methanol to obtain a solution having
a known concentration of about 0.50 mg per mL. Dilute an
C6H10N6 166.18
aliquot of the resulting solution with Mobile phase to obtain
N-Cyclopropyl-1,3,5-triazine-2,4,6-triamine.
a solution having a known concentration of about 10 mg per
2-Cyclopropylamino-4,6-diamino-s-triazine [66215-27-8]. mL.
Pharmacopeial Forum
Chromatographic system (see Chromatography h621i)— Add the following:

The liquid chromatograph is equipped with a 214-nm detector &Dantrolene Sodium Capsules
the Standard preparation, and record the peak responses as
» Dantrolene Sodium Capsules contain not less
directed for Procedure: the column efficiency is not less than
3000 theoretical plates; and the relative standard deviation for
replicate injections is not more than 2.0%. of the labeled amount of dantrolene sodium
Procedure—Separately inject equal volumes (about 20 mL) (C14H9N4NaO5 3½H2O).
containers.
the responses for the major peaks. Calculate the content, in
USP Reference standards h11i—USP Dantrolene RS. USP
percentage, of C6H10N6 in the portion of Cyromazine taken by
Dantrolene Related Compound B RS. USP Dantrolene
the formula:
Sodium RS.
100(CS / CU)(rU / rS) Identification—

in which CS is the concentration, in mg per mL, of USP B: The retention time of the major peak in the
Cyromazine RS in the Standard preparation; CU is the chromatogram of the Assay preparation corresponds to that
concentration, in mg per mL, of Cyromazine in the Assay in the chromatogram of the Standard preparation, as obtained
preparation; and rU and rS are the peak responses obtained in the Assay.
from the Assay preparation and the Standard preparation,
Change to read:
respectively.&2S (USP31)
Medium: 0.5% methylbenzethonium chloride in water,
BRIEFING pH 6.8 (adjusted with 0.1 N potassium hydroxide or 0.1 N
&
hydrochloric acid);&2S (USP31) 900 mL, deaerated.

Dantrolene Sodium Capsules, page 1063 of PF 32(4) [July–
Aug. 2006]. It is proposed to add instructions on how to adjust the Apparatus 1: 100 rpm.
pH of the Medium in the Dissolution test.
In-Process Revision
Time: 40 minutes.
Determine the amount of C14H9N4NaO5 3½H2O dissolved
by employing the following method.
Standard solution 1 (for capsules labeled to contain 100
mg)—Accurately weigh 25 mg of USP Dantrolene RS into
a 250-mL volumetric flask. Dissolve in 5.0 mL of
dimethylformamide. Add 200 mL of Medium and 10.0 mL
of 0.1 N potassium hydroxide. Mix, dilute with Medium to
volume, and mix. Pass through a 0.45-mm polytetrafluoro-
ethylene (PTFE) filter, previously wetted with a few drops of
isopropyl alcohol, discarding the first 5 mL.
Pharmacopeial Forum

mg)—Transfer 25.0 mL of Standard solution 1 to a 50-mL
volumetric flask containing 0.5 mL of 0.1 N potassium
hydroxide. Dilute with Medium to volume, and mix. Pass
through a 0.45-mm PTFE filter, previously wetted with a few
drops of isopropyl alcohol, discarding the first 5 mL.
solution and the Standard solution, respectively; CS is the
concentration, in mg per mL, of dantrolene in the Standard
mg)—Transfer 25.0 mL of Standard solution 1 to a 100-mL
volumetric flask containing 1.0 mL of 0.1 N potassium
conversion factor to percentage; 0.79186 is the correction for
hydroxide. Dilute with Medium to volume, and mix. Pass
water of hydration and sodium contained in the dantrolene
through a 0.45-mm PTFE filter, previously wetted with a few
sodium monohydrate form of the drug, assuming that the bulk
drops of isopropyl alcohol, discarding the first 5 mL.
drug contains 15% of water and 6.84% of sodium; and LC is
Test solution—Withdraw 10 mL of the solution under test.
the capsule label claim, in mg.
Pass through a 0.45-mm PTFE filter, previously wetted with
a few drops of isopropyl alcohol. Discard the first 5 mL.
of C14H9N4NaO5 3½H2O is dissolved in 40 minutes.
Collect the filtered solution in a tube that contains 1 drop of
1 N potassium hydroxide, and mix.
System suitability—[NOTE—All absorbance values should Related compounds—
be obtained on solutions within 2 hours of their preparation.] Diluent, Solution A, Solution B, Mobile phase, and
Using a 0.1-cm cell, measure the absorbance of Medium, Chromatographic system—Proceed as directed in the Assay.
using water as the blank, and measure the absorbance of each Standard solution—Transfer 5 mg, accurately weighed, of
of the three Standard solutions using Medium as the blank, at USP Dantrolene Related Compound B RS into a 50-mL
the wavelength of maximum absorbance at about 395 nm. volumetric flask, and dissolve in 2.5 mL of dimethylform-
The system is considered suitable for use if the following amide. Add 2.5 mL of glacial acetic acid, and dilute with
criteria are met: the absorbance of Medium is less than 10% of acetone to volume. The final concentration is about 0.1 mg
the absorbance of Standard solution 1; the absorbance of per mL. Quantitatively dilute this solution with Diluent to
Standard solution 2 is between 0.3 and 0.5; and the ratio of obtain a solution having a known concentration of about
In-Process Revision
the absorbance of Standard solution 1 to that of Standard 0.0005 mg per mL of dantrolene related compound B.
solution 3 is 4.00 + 0.10. Test solution—Use the Assay preparation.
Determine the amount of C14H9N4NaO5 3½H2O dissolved Procedure—Inject equal volumes (about 10 mL) of the
by measuring the absorbance of the Test solution at the Standard solution and the Test solution into the chromato-
wavelength of maximum absorbance at about 395 nm in graph, record the chromatograms, and measure the peak
comparison with the appropriate Standard solution, using responses. Calculate the percentage of dantrolene related
a 0.1-cm cell and Medium as the blank. All absorbance values compound B in the portion of Capsules taken by the formula:
are obtained on solutions within 2 hours of their preparation.

100(rU / rS)(CS / CT)
Calculate the percentage of C14H9N4NaO5 3½H2O dissolved
by the formula:
Pharmacopeial Forum
in which rU is the individual peak response for dantrolene Assay preparation—Mix the combined contents of not
related compound B obtained from the Test solution; rS is the fewer than 20 Capsules, and transfer an accurately weighed
response of the corresponding peak in the Standard solution; portion, equivalent to the average weight of one Capsule, to
CS is the concentration, in mg per mL, of dantrolene related a 50-mL volumetric flask. Add 10 mL of dimethylformamide,
compound B in the Standard solution; and CT is the and sonicate for 15 minutes to dissolve. Add 5 mL of glacial
concentration, in mg per mL, of dantrolene sodium in the acetic acid, and dilute with acetone to volume. Quantitatively
Test solution: not more than 2% of dantrolene related dilute this solution with Diluent to obtain a solution having
compound B is found. 0.1 mg per mL of dantrolene sodium, and pass through
Assay— a 0.45-mm nylon filter.
Diluent—Prepare a solution of acetonitrile and water Chromatographic system (see Chromatography h621i)—
(70 : 30). The liquid chromatograph is equipped with a 365-nm detector
Buffer solution—Dissolve 3.3 g of ammonium acetate in and a 4.6-mm 615-cm column that contains 5-mm packing
1 L of water. L1. The flow rate is about 1.5 mL per minute. The
Solution A—Prepare a filtered and degassed mixture of chromatograph is programmed as follows.
Buffer solution, acetonitrile, and glacial acetic acid Time Solution A Solution B
(120 : 76 : 7). (minutes) (%) (%) Elution
acetonitrile and water (70 : 30).
8–8.1 100?0 0?100 linear gradient
8.1–13 0 100 isocratic
Solution B, as directed for Chromatographic system. Make
13–13.1 0?100 100?0 linear gradient
System suitability solution—Use the Standard solution, Separately inject the System suitability solution and the
prepared as directed in the test for Related compounds. Standard preparation into the chromatograph, record the
Standard preparation—Transfer 40 mg, accurately chromatograms, and measure the peak responses as directed
weighed, of USP Dantrolene RS to a 50-mL volumetric for Procedure: the tailing factor is not more than 1.5; and the
flask, and dissolve in 2.5 mL of dimethylformamide. Add 2.5 relative standard deviation for replicate injections for
mL of glacial acetic acid, and dilute with acetone to volume. dantrolene is not more than 1.0%. [NOTE—For the purpose
In-Process Revision
The final concentration is about 0.8 mg per mL. Quantita- of peak identification, the approximate relative retention times
tively dilute this solution with Diluent to obtain a solution are 0.68 for dantrolene related compound B and 1.0 for
having a known concentration of about 0.08 mg per mL of dantrolene.]
dantrolene.
Pharmacopeial Forum

BRIEFING
Etidronate Disodium, USP 30 page 2101. Comments were
the responses for the dantrolene peaks. Calculate the received indicating that the preparation instructions for USP
Etidronate Disodium Related Compound A RS, as provided by the
percentage of dantrolene sodium (C14H9N4NaO5 3½H2O) in Reference Standard label, are inconsistent with the preparation of the
Standard solution and the calculation equation in the test for Limit of
the portion of Capsules taken by the formula: phosphite. The moisture level of the Reference Standard is
accounted for in the preparation, as directed by the RS label, and
therefore does not need to be taken into consideration in the
monograph procedure or equation. It is proposed to revise the
100(399.29/314.25)(rU / rS)(CS / CU) Standard solution preparation and calculations to make them
consistent with the RS label.
In the absence of any adverse comments, it is proposed to
implement the inclusion of this revision in PF 33(6) [Nov.–Dec.
in which 399.29 is the molecular weight of dantrolene 2007] via the Interim Revision Announcement pertaining to USP 30–
NF 25, with an official date of December 1, 2007. Comments
sodium; 314.25 is the molecular weight of dantrolene; rU and regarding this proposal should be received by September 1, 2007.
rS are the peak responses for dantrolene obtained from the
Assay preparation and the Standard preparation, respec-
tively; CS is the concentration, in mg per mL, of dantrolene in Change to read:
the Standard preparation; and CU is the concentration, in mg Limit of phosphite—

Solution A—Prepare an aqueous solution containing 0.65 mg per
per mL, of dantrolene sodium (C14H9N4NaO5 3½H2O) in the mL of anhydrous sodium carbonate and 0.40 mg per mL of sodium
bicarbonate.
Assay preparation.&2S (USP30) Solution B—Prepare an aqueous solution containing 4.68 mg per
mL of anhydrous sodium carbonate and 2.89 mg per mL of sodium
bicarbonate.
Mobile phase—Use variable mixtures of Solution A and Solution
B as directed for Chromatographic system. Make adjustments if
BRIEFING necessary (see System Suitability under Chromatography h621i).
Standard solution—Dissolve suitable quantities of USP Etidronate
Disodium Related Compound A RS and dibasic sodium phosphate
in Solution A to obtain a solution having a known concentration of
Ethionamide, USP 30 page 2093. In the Assay, it is proposed to 0.027 mg of sodium phosphite dibasic pentahydrate
delete the requirement that the concentration of USP Ethionamide
RS in the Standard solution be calculated on the anhydrous basis. .0.016 mg of sodium phosphite dibasic on the anhydrous
The specific instruction on the Reference Standard label should be
followed. basis.6
and 0.015 mg of dibasic sodium phosphate in each mL. [NOTE—
(MD-AA: B. Davani ; H. Ramanathan) RTS—C54081 Etidronate disodium related compound A is sodium phosphite
dibasic pentahydrate.]
Suppressor regenerant solution—Use 12.5 mM sulfuric acid.
Change to read: [NOTE—This solution is needed only if the chemical suppression
option is used.]
Test solution—Transfer approximately 50 mg of Etidronate
Assay—Transfer about 100 mg of Ethionamide, accurately weighed, Disodium, accurately weighed, to a suitable flask. Dissolve in 10.0
to a 250-mL volumetric flask, dissolve in about 100 mL of methanol,
In-Process Revision
mL of Solution A.
dilute with methanol to volume, and mix. Transfer a 5-mL aliquot to Chromatographic system (see Chromatography h621i)—The
a 200-mL volumetric flask, dilute with methanol to volume, and mix liquid chromatograph is equipped with a conductivity detector,
(test solution). Dissolve a suitable quantity of USP Ethionamide RS, a 4-mm 6 25-cm column and a 4-mm 6 50-mm guard column both
accurately weighed, in methanol, and dilute quantitatively and containing packing L61, and either a 4-mm anion self-regenerating
stepwise with methanol to obtain a Standard solution having suppressor or a suitable chemical suppressor. The flow rate is about
a known concentration of about 10 mg per mL. Concomitantly 1.0 mL per minute for the Mobile phase. When a chemical
determine the absorbances of both solutions in 1-cm cells at the suppressor is used, the flow rate is 3 to 5 mL per minute for the
wavelength of maximum absorbance at about 290 nm, with a suitable Suppressor regenerant solution. The chromatograph is programmed
spectrophotometer, using methanol as the blank. Calculate the as follows.
quantity, in mg, of C8H10N2S in the portion of Ethionamide taken by
the formula: Time Solution A Solution B
10C(AU / AS) 0–6.0 100 0 isocratic
in which C is the concentration, in mg per mL, of USP Ethionamide 6.0–6.1 100?0 0?100 linear gradient
RS in the Standard solution, calculated on the anhydrous basis, 6.1–8.0 0 100 isocratic
8.0–8.1 0?100 100?0 linear gradient
&
&2S (USP31)
8.1–15 100 0 isocratic
and AU and AS are the absorbances of the test solution and the
Standard solution, respectively.
Pharmacopeial Forum
Chromatograph the Standard solution, and record the peak SPECTROPHOTOMETRIC METHOD—Determine the amount of
responses as directed for Procedure: the elution order is
C8H15N7O2S3 dissolved from UV absorption at the wavelength
phosphite, followed by phosphate; the resolution, R, between
phosphite and phosphate is not less than 2.5; and the relative of maximum absorbance at about 265 nm, using filtered
portions of the solution under test, suitably diluted with
10% for each peak.
Procedure—Separately inject equal volumes (about 20 mL) of the Medium if necessary, in comparison with a Standard solution
record the chromatograms, and measure the responses for the having a known concentration of USP Famotidine RS in the
phosphite peaks. Calculate the percentage of phosphite, determined
as sodium phosphite monobasic, in the portion of Etidronate same Medium.
Disodium taken by the formula:
CHROMATOGRAPHIC METHOD—
1000(103.98/216.06)(C/W)(rU / rS)
Buffer solution and Mobile phase—Proceed as directed in
the Assay.
.1000(103.98/125.96)(C/W)(r / rS).6
U
in which 103.98 and 216.06 tity of USP Famotidine RS in Medium to obtain a solution
.125.96
.6 having a known concentration of about 0.14 mg per mL.
are the molecular weights of sodium phosphite monobasic and
sodium phosphite dibasic pentahydrate, Dilute this solution with Medium to obtain a solution
.
.6 containing L/900 mg per mL, L being the famotidine tablet
respectively; C is the concentration, in mg per mL, of USP
Etidronate Disodium Related Compound A RS label claim, in mg.
.on the anhydrous basis.6 Test solution—Use filtered portions of the solution under
in the Standard solution; W is the weight, in mg, of Etidronate
Disodium taken to prepare the Test solution; and rU and rS are the test.
phosphite peak responses obtained from the Test solution and the
Standard solution, respectively: not more than 1.0% of phosphite, Chromatographic system—Proceed as directed in the
determined as sodium phosphite monobasic, is found.
Assay. Chromatograph the Standard solution, and record the
peak responses as directed for Procedure: the capacity factor,
BRIEFING k ’, is greater than 2.0; and the relative standard deviation for
Famotidine Tablets, USP 30 page 2112 and page 1680 of PF Procedure—Separately inject equal volumes (about 50 mL)
32(6) [Nov.–Dec. 2006]. In the Dissolution test, the definition of the
variables used to calculate the amount dissolved is corrected. Also, of the Standard solution and the Test solution into the
a Dissolution test for film-coated tablets is being proposed.
peak responses. Calculate the amount of C8 H 15N 7 O 2 S3
Change to read: dissolved by the formula:
In-Process Revision
Medium: pH 4.5, 0.1 M phosphate buffer; prepared by dissolv-
ing 13.6 g of monobasic potassium phosphate in 1 L of water; 900
mL.
Time: 30 minutes.
Procedure—Determine the amount of C8H15N7O2S3 dissolved from
UV absorption at the wavelength of maximum absorbance at about
265 nm, using filtered portions of the solution under test, suitably
diluted with Medium if necessary, in comparison with a Standard in which rU and rS are the peak responses for the Standard
solution having a known concentration of USP Famotidine RS in the
same Medium. solution and the Test solution, Test solution and the Standard
&
Determine the amount of C8H15N7O2S3 dissolved employ- solution, respectively; CS is the concentration, in mg per mL,
ing one of the following methods.
Pharmacopeial Forum
of the Standard solution; 900 is the volume, in mL, of to prevent polymerization. Formaldehyde Solution in
small containers (4 liters or less) contains not less than
Medium; 100 is the conversion factor to percentage; and LC is 36.5 percent, by weight, of formaldehyde (CH2O), with
the tablet label claim, in mg.&2S (USP31)
methanol present to prevent polymerization.
&
Tolerances—Not less than 75% (Q) of the labeled amount of &2S (USP31)
C8H15N7O2S3 is dissolved in 30 minutes.
&
FOR TABLETS LABELED AS CHEWABLE—Proceed as directed Delete the following:
for either of the methods specified above, except for the
&
Labeling—The label of bulk containers of the Solution directs the
following: drug repackager to demonstrate compliance with the USP Assay limit
for formaldehyde of not less than 37.0%, by weight, immediately
Time: 45 minutes. prior to repackaging.&2S (USP31)

Add the following:
of C8H15N7O2S3 is dissolved in 45 minutes.
&
Content of methanol—
FOR TABLETS LABELED AS FILM-COATED— Proceed as
directed for either of the methods specified above, except Internal standard solution—Dilute 10 mL of dehydrated
for the following: alcohol with water to 100 mL.
Time: 30 minutes. Test solution—To 10.0 mL of Solution add 10.0 mL of the
Tolerances—Not less than 80% (Q) of the labeled amount Internal standard solution, and dilute with water to 100.0 mL.
of C8H15N7O2S3 is dissolved in 30 minutes.&2S Standard solution—To 1.0 mL of methanol add 10.0 mL of

(USP31)
the Internal standard solution, and dilute with water to 100.0

mL.
BRIEFING
Formaldehyde Solution, USP 30 page 2192. It is proposed to detector and a 2- to 4-mm 6 1.5- to 2.0-m column containing
make the following changes:
1. Revise the Definition and eliminate two differing Assay packing S3. The carrier gas is nitrogen or helium, flowing at
requirements for bulk and small containers. The Assay limits
are also revised to reflect the quality of currently marketed a rate of 30 to 40 mL per minute. The column temperature is
products.
2. Delete the Labeling requirement. maintained at 1208. The injection port temperature and the
3. Replace the Assay procedure with a simple titration procedure
employed in the monograph for Formaldehyde Solution (35 detector temperature are maintained at 1508. Chromatograph
percent) in the European Pharmacopoeia. This proposed
revision is intended to improve the clarity of the procedure the Standard solution, and record the peak responses as
and provide consistency with the European Pharmacopoeia.
4. Add a new test for Content of methanol to ensure the correct directed for Procedure: the resolution, R, between the peaks
In-Process Revision
methanol concentration range in the Formaldehyde Solution.

The gas chromatographic procedure and the limits are adopted corresponding to methanol and alcohol is not less than 2.0.
from the European Pharmacopoeia.
Procedure—Separately inject equal volumes (1 mL) of the
(BB-VV: V. Lu) RTS—C46737 Standard solution and the Test solution into the chromato-
graph, record the chromatograms, and measure the responses
Change to read:
for the major peaks. Calculate the percentage (v/v) of
» Formaldehyde Solution in bulk containers methanol in the portion of Solution taken by the formula:
&
&2S (USP31)
contains not less than 37.0 100 6 (VM / V)(RU / RS)
&
34.5&2S (USP31)
percent, by weight, of formaldehyde (CH2O), with
methanol added
&
(9.0% to 15.0%)&2S (USP31)
Pharmacopeial Forum
in which VM is the volume, in mL, of methanol taken to 5. For each of the four Dissolution tests, it is proposed to indicate
whether the product contains micronized or nonmicronized
prepare the Standard solution; V is the volume, in mL, of glyburide.
Solution taken to prepare the Test solution; and RU and RS are (BPC: M. Marques) RTS—C50999
the peak response ratios of methanol to that of the internal
standard obtained from the Test solution and the Standard Change to read:
solution, respectively: between 9.0% and 15.0% (v/v) is &

found.&2S (USP31) TEST 1 &
(nonmicronized glyburide)&2S (USP31)—
Change to read: Medium: 0.05 M phosphate&borate&2S (USP31) buffer, pH

9.5 &(prepared by weighing about 381.5 g of sodium borate
Assay—Transfer about 3 mL of Solution to a tared flask containing
10 mL of water, insert the stopper in the flask tightly, and accurately and 19.1 g of sodium hydroxide, dissolving in water, diluting
determine the weight of the Solution taken. Slowly and quantita-
tively add a mixture of 50.0 mL of 1 N sodium hydroxide VS and 50 with water to 20 L, and adjusting with phosphoric acid to
mL of hydrogen peroxide TS that has been previously neutralized to
bromothymol blue TS with 1 N sodium hydroxide. Heat the contents a pH of 9.5 + 0.1.);&2S (USP31) 500 mL.
of the flask cautiously on a steam bath for 15 minutes, shaking it
occasionally with a rotary motion. Allow the mixture to cool, rinse Apparatus 2: 75 rpm.
the funnel and the inner wall of the flask with water, and after
allowing it to stand for 30 minutes, add 2 to 5 drops of bromothymol Time: 45 minutes.
blue TS, and titrate the excess alkali with 1 N sulfuric acid VS.
Perform a blank determination (see Residual Titrations under Determine the percentage of the labeled amount of
Titrimetry h541i). Also make a correction based upon the acidity
found in the test for Acidity. Each mL of 1 N sodium hydroxide is C23H28ClN3O5S dissolved using the following method.
equivalent to 30.03 mg of CH2O.
[NOTE—Use low-actinic volumetric flasks.]
&
Into a 100-mL volumetric flask containing 2.5 mL of water
and 1 mL of sodium hydroxide TS 2, introduce 1.0 g of the
water and acetonitrile (1 : 1), and add 4.0 mL of phosphoric
Solution to be examined, shake, and dilute with water to
acid per L of solution. Make adjustments if necessary (see
100.0 mL. To 10.0 mL of the solution add 30.0 mL of 0.1 N
iodine VS. Mix, and add 10 mL of sodium hydroxide TS 2.
Standard stock solution—Transfer about 15 mg of USP
After 15 minutes, add 25 mL of diluted sulfuric acid and
Glyburide RS, accurately weighed, to a 100-mL volumetric
4 mL of starch TS. Titrate with 0.1 N sodium thiosulphate
flask; dissolve in Medium with sonication until dissolved,
VS. Each 1 mL of 0.05 M iodine is equivalent to 1.501 mg of
about 25 minutes; and dilute with Medium to volume.
CH2O.&2S (USP31)
Standard solutions—Dilute the Standard stock solution
obtain solutions having known concentrations of 0.003 mg
In-Process Revision
BRIEFING
per mL (for Tablets labeled to contain 1.5 mg), 0.006 mg per
Glyburide Tablets, USP 30 page 2236 and page 1080 of PF mL (for Tablets labeled to contain 3.0 mg), 0.009 mg per mL
32(4) [July–Aug. 2006]. It is proposed to make the following
revisions. (for Tablets labeled to contain 4.5 mg), and 0.012 mg per mL
1. Dissolution Test 1—It is proposed to correct the composition of
the Medium and give the instructions on how to prepare it. (for Tablets labeled to contain 6.0 mg).
2. Dissolution Test 2—It is proposed to modify the Tolerances to
be in accordance with those approved by FDA and to add the Test solution—Pass a portion of the solution under test
instructions on how to prepare the Medium.
3. Dissolution Test 3—It is proposed to modify the Tolerances to through a suitable 0.45-mm filter.
be in accordance with those approved by FDA and to add the
instructions on how to prepare the Medium. Chromatographic system (see Chromatography h621i)—
4. A Dissolution Test 4 is being proposed. The chromatographic
procedure in this test was validated using a Kromasil C8 brand The liquid chromatograph is equipped with a 215-nm detector
of L7 packing. The retention time of glyburide is about
6 minutes using this column. and a 4.6-mm 6 30-cm column that contains 10-mm packing
Pharmacopeial Forum
the Standard solution, and record the peak responses as Mobile phase—Prepare a filtered and degassed mixture of
directed for Procedure: the column efficiency is not less than 520 mL of water containing 2.6 g of monobasic ammonium
4000 theoretical plates; the tailing factor is not more than 2.0; phosphate and 480 mL of acetonitrile. Make adjustments if
and the relative standard deviation for replicate injections is necessary (see System Suitability under Chromatography
not more than 3.0%. h621i).
Procedure—Separately inject equal volumes (about 50 mL) Standard stock solution—Transfer about 67 mg of USP
of the Standard solution and the Test solution into the Glyburide RS, accurately weighed, to a 500-mL volumetric
chromatograph, record the chromatograms, and measure the flask, dissolve in 40 mL of methanol with sonication for
responses for the major peaks. Determine the amount, in 5 minutes, and dilute with Medium to volume.
percentage, of C23H28ClN3O5S dissolved by the formula: Standard solutions—Dilute the Standard stock solution
obtain solutions having known concentrations of 0.0017 mg
per mL (for Tablets labeled to contain 1.5 mg), 0.0034 mg per
mL (for Tablets labeled to contain 3 mg), 0.0047 mg per mL
(for Tablets labeled to contain 4.5 mg), and 0.0067 mg per
in which rU and rS are the peak responses obtained from the mL (for Tablets labeled to contain 6 mg).
Test solution and the Standard solution, respectively; CS is the Test solution—Pass a portion of the solution under test
concentration, in mg per mL, of the Standard solution; 500 is through a suitable 0.5-mm filter.
the volume, in mL, of Medium; 100 is the conversion factor Chromatographic system—The liquid chromatograph is
to percentage; and LC is the Tablet label claim, in mg. equipped with a 215-nm detector and a 4.0-mm 6 25-cm
Tolerances—Not less than 70% (Q) of the labeled amount column that contains 10-mm packing L7. The flow rate is
of C23H28ClN3O5S is dissolved in 45 minutes. about 1.5 mL per minute. Chromatograph the Standard
TEST 2 &
(micronized glyburide)&2S (USP31)—If the product solution, and record the peak responses as directed for
complies with this test, the labeling indicates that it meets Procedure: the tailing factor is not more than 2.0; and the
USP Dissolution Test 2. relative standard deviation for replicate injections is not more
Medium: 0.05 M phosphate buffer, pH 8.5 (prepared by
&
than 2.0%.
weighing about 6.8 g of potassium phosphate monobasic and Procedure—Separately inject equal volumes (about 50 mL)
In-Process Revision
1.99 g of sodium hydroxide in 200 mL of water, diluting with of the Standard solution and the Test solution into the
water to 1 L, adjusting with diluted phosphoric acid or diluted chromatograph, record the chromatograms, and measure the
sodium hydroxide to a pH of 8.5 + 0.05.);&2S (USP31) 900 mL. responses for the major peaks. Determine the amount, in
Apparatus 2: 50 rpm. percentage, of C23H28ClN3O5S dissolved by the formula:
Time: 60 30&2S (USP31) minutes.
&
Determine the percentage of the labeled amount of

C23H28ClN3O5S dissolved using the following method.
Pharmacopeial Forum
in which rU and rS are the peak responses obtained from the Procedure—Separately inject equal volumes (about 75 mL)
Test solution and the Standard solution, respectively; CS is the of the Standard solution and the Test solution into the
concentration, in mg per mL, of the Standard solution; 900 is chromatograph, record the chromatograms, and measure the
the volume, in mL, of Medium; 100 is the conversion factor responses for the major peaks. Determine the amount, in
to percentage; and LC is the Tablet label claim, in mg. percentage, of C23H28ClN3O5S dissolved by the formula:
Tolerances—Not less than 60%&75%&2S (USP31) (Q) of the
labeled amount of C 23 H 28 ClN 3 O 5 S is dissolved in
60&30&2S (USP31) minutes.
TEST 3 &
(micronized glyburide)&2S (USP31) —If the product
complies with this test, the labeling indicates that it meets
USP Dissolution Test 3. in which rU and rS are the peak responses obtained from the
Medium: 0.05 M phosphate buffer, pH 7.5 &(prepared by Test solution and the Standard solution, respectively; CS is the
weighing about 40.8 g of potassium phosphate monobasic concentration, in mg per mL, of the Standard solution; 900 is
and 9.4 g of sodium hydroxide, dissolving in and diluting the volume, in mL, of Medium; 100 is the conversion factor
with water to 6 L, and adjusting with diluted sodium to percentage; and LC is the Tablet label claim, in mg.
hydroxide to a pH of 7.5 + 0.1);&2S (USP31) 900 mL. Tolerances—Not less than 70%&75%&2S (USP31) (Q) of the
Apparatus 2: 50 rpm. labeled amount of C23H28ClN3O5S is dissolved in 45 minutes.
Time: 45 minutes.
&
TEST 4 (nonmicronized glyburide)—If the product com-
Determine the percentage of the labeled amount of plies with this test, the labeling indicates that it meets USP
C23H28ClN3O5S dissolved using the following method. Dissolution Test 4
Mobile phase—Proceed as directed in the Assay. Medium: 0.05 M borate buffer, pH 8.0, with 0.014 M
Diluent—Prepare a mixture of acetonitrile and water (5 : 1). hexadecyltrimethylammonium bromide (prepared by dissolv-
Standard solution—Transfer about 66.6 mg of USP ing about 180.0 g of hexadecyltrimethylammonium bromide,
Glyburide RS, accurately weighed, to a 100-mL volumetric 55.6 g of boric acid, 67.1 g of potassium chloride, and 2.8 g of
flask, and dissolve in and dilute with Diluent to volume. sodium hydroxide in 1500 mL of water at 508 under vigorous
Transfer 10.0 mL of this solution to a 100-mL volumetric stirring for several hours, cooling to room temperature,
flask, and dilute with Medium to volume. Transfer 10.0 mL of diluting with water to 2000 mL, adjusting with diluted
this solution to a 100-mL volumetric flask, and dilute with hydrochloride acid or diluted sodium hydroxide to a pH of
In-Process Revision
Medium to volume. 8.00 + 0.05, and diluting 50 mL of this solution with water to
Test solution—Pass a portion of the solution under test 900 mL); 900 mL.
through a suitable 0.45-mm filter. Apparatus 1: 50 rpm.
Chromatographic system (see Chromatography h621i)— Time: 45 minutes.
The liquid chromatograph is equipped with a 254-nm detector Determine the percentage of the labeled amount of
and a 4.6-mm 6 25-cm column that contains packing L7. C23H28ClN3O5S dissolved using the following method.
The flow rate is about 2 mL per minute. Chromatograph the

for Procedure: the relative standard deviation for replicate
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of Tolerances—Not less than 75% (Q) of the labeled
acetonitrile and water (11 : 9) containing 5.2 g of ammonium amount of C 23 H 28 ClN 3 O 5 S is dissolved in 45 min-
phosphate monobasic for each 2 L. Make adjustments if utes.&2S (USP31)&2S (USP30)
necessary (see System suitability under Chromatography

h621i).
Standard solution—Transfer about 55.5 mg, accurately BRIEFING
weighed, of USP Glyburide RS to a 200-mL volumetric flask,

Hydrocodone Bitartrate and Homatropine Methylbromide
dissolve in and dilute with alcohol to volume. Transfer 1.0 Tablets, page 853 of PF 30(3) [May–June 2004]. It is proposed to
add two Dissolution tests to this monograph. The chromatographic
mL of this solution to a 100-mL volumetric flask, dilute with procedure in Dissolution Test 2 was validated using a mBondapak
C18 brand of L1 packing.
Medium to volume.
through a suitable 5 mm-filter.
Add the following:
&Hydrocodone Bitartrate and
Homatropine Methylbromide Tablets
for Procedure: the column efficiency is not less than 2000
theoretical plates; the tailing factor is not more than 2.0; and
the relative standard deviation for replicate injections is not » Hydrocodone Bitartrate and Homatropine Meth-
more than 2.0%. ylbromide Tablets contain not less than 90.0
Procedure— Separately inject equal volumes (100 mL) of percent and not more than 110.0 percent of the
the Standard solution and the Test solution into the labeled amounts of hydrocodone bitartrate dises-
chromatograph, and measure the responses for the major
quihydrate (C18H21NO3 C4H6O6 2½H2O) and ho-
peaks. Determine the amount, in percentage, of
matropine methylbromide (C17H24BrNO3).
C23H28ClN3O5S dissolved by the formula:
NOTE—Use of silanized autosampler vials such
as dimethyldichlorosilane vials* is required for the
In-Process Revision
Dissolution test, the Limit tests, and the Assay to

prevent drug degradation.

in which rU and rS are the peak responses obtained from the
containers.
Test solution and the Standard solution, respectively; CS is the
concentration, in mg per mL, of the Standard solution; 900 is Add the following:
the volume, in mL, of Medium; 100 is the conversion factor &

Labeling—When more than one Dissolution test is given,
to percentage; and LC is the Tablet label claim, in mg. the labeling states the Dissolution test used only if Test 1 is
not used.&2S (USP31)
*
A suitable grade is available from Analytical Research and Testing,
Somerville, NJ; Fax: 908-725-8848.
Pharmacopeial Forum
USP Reference standards h11i—USP Dihydrocodeine B: The retention times of the major peaks in the
Bitartrate RS. USP Homatropine Methylbromide RS. USP chromatogram of the Assay preparation correspond to those
Hydrocodone Bitartrate RS. in the chromatogram of the Standard preparation, as obtained
Identification— in the Assay.
A: Thin-Layer Chromatographic Identification Test Add the following:
h201i— &
Solution A—Dissolve 850 mg of bismuth subnitrate in TEST 1—
a mixture of 10 mL of glacial acetic acid and 40 mL of water. Medium: water; 900 mL, deaerated.
Solution B—Dissolve 8 g of potassium iodide in 20 mL of Apparatus 2: 50 rpm.
water. Time: 30 minutes.
Stock solution: a mixture of Solution A and Solution B Determine the amounts of hydrocodone bitartrate and
(1 : 1). homatropine bromide dissolved employing the following
Solvent: a mixture of methanol and water (9 : 1). method.
Spray reagent 1—[NOTE—Prepare immediately before use.] Buffer solution and Mobile phase—Proceed as directed in
Prepare a mixture of water, glacial acetic acid, and Stock the Assay.
solution (50 : 10 : 5). Standard solution—Dissolve an accurately weighed quan-
Spray reagent 2: hydrogen peroxide TS. tity of USP Hydrocodone Bitartrate RS and USP Homatro-
Standard solution 1—Transfer an accurately weighed pine Methylbromide RS in Medium, and dilute quantitatively
quantity of about 30 mg of USP Homatropine Methylbromide with Medium to obtain a solution having known concentra-
RS to a 100-mL volumetric flask, dissolve in and dilute with tions of about 0.0055 mg per mL and 0.00165 mg per mL,
Solvent to volume, and mix. respectively.
Standard solution 2—Transfer an accurately weighed Test solution—Use the solution under test passed through
quantity of about 25 mg of USP Hydrocodone Bitartrate RS a suitable 0.45-mm filter.
to a 25-mL volumetric flask, dissolve in and dilute with Chromatographic system—Proceed as directed in the
Solvent to volume, and mix. Assay, using the Standard solution: the resolution, R, between
Test solution—Transfer a portion of 20 finely powdered homatropine methylbromide and hydrocodone bitartrate is
Tablets, equivalent to the average Tablet weight, to not less than 13; and the relative standard deviation for
In-Process Revision
a centrifuge tube, add 5.0 mL of Solvent, and centrifuge. replicate injections is not more than 3.0% for each analyte.
Use the supernatant. Procedure—Separately inject equal volumes (about 250
Developing solvent system: a mixture of ethyl acetate, mL) of the Standard solution and the Test solution into the
water, and formic acid (134 : 33 : 33). chromatograph, record the chromatograms, and measure the
Procedure—Apply 50 mL of Standard solution 1, Standard areas for the major peaks. Calculate the percentage of
solution 2, and the Test solution, and proceed as directed in hydrocodone bitartrate and homatropine methylbromide
the chapter. Remove the plate, and dry at 1058. Spray the dissolved by the formula:
plate with Spray reagent 1 and then with Spray reagent 2.
The RF values for the principal spots in the chromatogram of
the Test solution correspond to those in the chromatogram of
the Standard solutions.
Pharmacopeial Forum
in which rU and rS are the peak areas of each drug substance in Chromatographic system (see Chromatography h621i)—
the Test solution and in the Standard solution, respectively; CS The liquid chromatograph is equipped with a 212-nm detector
is the concentration of each drug substance, in mg per mL, in and a 3.9-mm 6 30-cm column that contains packing L1.
the Standard solution; 900 is the volume, in mL, of Medium; The flow rate is about 2.0 mL per minute. Chromatograph the
100 is the conversion factor to percentage; and LC is the System suitability solution, and record the chromatogram as
tablet label claim for each drug substance, in mg. directed for Procedure: the tailing factor for each drug
Tolerances—Not less than 80% (Q) of hydrocodone substance is not more than 1.5; the resolution, R, between
bitartrate and homatropine methylbromide is dissolved in 30 homatropine methylbromide and hydrocodone bitartrate is
minutes. not less than 2.2; and the relative standard deviation for
TEST 2—If the product complies with this test, the labeling replicate injections is not more than 3.0% for homatropine
indicates that the product meets USP Dissolution Test 2. methylbromide and not more than 2.0% for hydrocodone
Medium: water, 500 mL. bitartrate.
Apparatus 2: 50 rpm. Procedure—Separately inject equal volumes (about 200
Time: 45 minutes. mL) of the appropriate Standard solution and the Test solution
Determine the amounts of hydrocodone bitartrate and into the chromatograph, record the chromatographs, and
homatropine bromide dissolved employing the following measure the peak responses. Calculate the percentage of each
method. drug substance dissolved by the formula:
water and acetonitrile (3 : 1) that contains 1.4 g of octane-
sulfonic acid sodium salt and 1.0 mL of phosphoric acid per
1000 mL. Make adjustments if necessary (see System
Hydrocodone bitartrate standard solution—Transfer about in which rU and rS are the peak responses of each drug
50 mg, accurately weighed, of USP Hydrocodone Bitartrate substance in the Test solution and in the correspondent
RS to a 100-mL volumetric flask, and dissolve in and dilute Standard solution, respectively; CS is the concentration of
with Mobile phase to volume. each drug substance, in mg per mL, in the correspondent
Homatropine methylbromide standard solution—Transfer Standard solution; DU is the dilution factor of the Test
In-Process Revision
about 37.5 mg, accurately weighed, of USP Homatropine

Methylbromide RS to a 250-mL volumetric flask, dissolve in conversion factor to percentage; and LC is the tablet label
and dilute with Mobile phase to volume. claim for each drug substance, in mg.
System suitability solution—Transfer 10.0 mL of Hydroco- Tolerances—Not less than 75% (Q) of hydrocodone
done bitartrate standard solution and Homatropine methyl- bitartrate and homatropine methylbromide is dissolved in 45
bromide standard solution to a 500-mL volumetric flask, add minutes.&2S (USP31)
105 mL of Mobile phase. Dilute with Medium to volume. Uniformity of dosage units h905i: meet the requirements.
Test solution—Pass a portion of 20 mL of the solution Limit of dihydrocodeine bitartrate, hydrocodone diol, and
under test through a suitable 0.45-mm filter, discarding the related substances—
first 2 to 3 mL. Mix thoroughly 15.0 mL of the filtrate with Ion-pair solution—Prepare 0.005 M sodium 1-octanesulfo-
5.0 mL of Mobile phase. nate, and adjust with glacial acetic acid to a pH of 2.5 + 0.1.
Pharmacopeial Forum
Mobile phase—Prepare a filtered and degassed mixture of the Standard solution: not more than 0.5% of hydrocodone
Ion-pair solution and methanol (6 : 4). Add 0.5 mL of diol is found, and not more than 1.0% of dihydrocodeine
triethylamine per L. Make adjustments if necessary (see bitartrate is found. Calculate the percentage of each other
System Suitability under Chromatography h621i). related substance in the portion of Tablets taken by the
System suitability solution—Dissolve about 2 mg each of formula:
hydrocodone diol and USP Dihydrocodeine Bitartrate RS in
35 mL of Mobile phase in a 100-mL volumetric flask, and 100(ri / rs)
dilute with Mobile phase to volume. Dilute this solution
quantitatively, and stepwise if necessary, with Mobile phase in which ri is the peak response for any individual related
to obtain a solution having a known concentration of each of substance with a retention time greater than 5 minutes; and rs
about 0.1 mg per mL. is the sum of the responses of all the peaks: not more than
Standard solution—Use the Standard preparation, pre- 0.5% of any individual related substance is found. The sum of
pared as directed in the Assay. all impurities is not more than 1.5%.
Test solution—Use the Assay preparation. Limit of homatropine hydrobromide and related
Chromatographic system (see Chromatography h621i)— substances—
The liquid chromatograph is equipped with a 280-nm detector Buffer solution—Prepare a solution of 0.005 M dibasic
and a 4.6-mm 6 25-cm column that contains 5-mm packing potassium phosphate, and adjust with phosphoric acid to a pH
L7. The flow rate is about 1.5 mL per minute. Chromatograph of 6.4 + 0.1.
the System suitability solution, and record the peak responses Mobile phase—Prepare a filtered and degassed mixture of
as directed for Procedure: the relative retention times are Buffer solution and acetonitrile (17 : 3). Make adjustments if
about 0.67 for hydrocodone diol, 0.75 for dihydrocodeine necessary (see System Suitability under Chromatography
bitartrate, and 1.0 for hydrocodone bitartrate; the resolution, h621i).
R, between hydrocodone diol and dihydrocodeine bitartrate is Standard solution—Dissolve an accurately weighed quan-
not less than 2.0; and the relative standard deviation for tity of homatropine hydrobromide in Mobile phase, and dilute
replicate injections of each of these compounds is not more quantitatively with Mobile phase to obtain a solution having
than 5.0%. a known concentration of about 0.6 mg per mL.
Procedure—Separately inject equal volumes (about 200 Test solution—Use the Assay preparation.
mL) of the Standard solution and Test solution into the Chromatographic system (see Chromatography h621i)—
In-Process Revision
chromatograph, record the chromatograms, and measure the The liquid chromatograph is equipped with a 210-nm detector
peak areas. Calculate the percentages of hydrocodone diol and a 4.6-mm 6 25-cm column that contains 5-mm packing
and dihydrocodeine bitartrate in the portion of Tablets taken L7. The flow rate is about 1.5 mL per minute. Chromatograph
by the formula: the Standard solution, and record the peak responses as
directed for Procedure: the relative standard deviation for
100(rD / rS) replicate injections is not more than 5.0%.
in which rD is the individual peak response of either

hydrocodone diol or dihydrocodeine in the chromatogram
obtained from the Test solution; and rS is the peak response of
hydrocodone bitartrate in the chromatogram obtained from
Pharmacopeial Forum
Procedure—Separately inject equal volumes (about 10 mL) Standard solutions A, B, C, and D having known concentra-
of the Standard solution and the Test solution into the tions of about 75 mg per mL, 37.5 mg per mL, 18.75 mg per
chromatograph, record the chromatograms, and measure the mL, and 9.38 mg per mL, respectively.
peak responses. Calculate the percentage of homatropine Spray reagent—Dissolve 300 mg of platinic acid in 3 mL
hydrobromide in the portion of Tablets taken by the formula: of diluted hydrochloric acid, add 97 mL of water and 100 mL
of 6% potassium iodide in water, and mix.
100(rH / rS) Developing solvent system: a mixture of alcohol and
ammonium hydroxide (400 : 100).
in which rH is the individual peak response for homatropine
Procedure—Apply equal volumes (about 500 mL) of the
hydrobromide in the chromatogram obtained from the Test
Standard stock solution, Standard solutions A, B, C, and D,
solution; and rS is the peak response for homatropine
and the Test solution to a thin-layer chromatographic plate
methylbromide in the chromatogram obtained from the
(see Chromatography h621i), and proceed as directed in the
Standard solution: not more than 0.5% of homatropine
chapter. After the plate has dried, position it in a chamber
hydrobromide is found. Calculate the percentage of each
saturated with iodine vapor for about 30 minutes, then place it
other related substance in the portion of Tablets taken by the
in a hood to allow the iodine to sublime from the plate, and
formula:
spray the plate with Spray reagent until spots appear. Any
spot from the Test solution occurring at an RF value
100(ri / rs)
corresponding to tropine is not greater in size or intensity
than the corresponding spot obtained from Standard solution
in which ri is the peak response for any individual related
B (0.5%): not more than 0.5% of tropine is found.
substance with a relative retention time less than 0.44 in
relation to the retention time of hydrocodone bitartrate; and rs Assay—
is the sum of the responses of all the peaks: not more than Buffer solution—Prepare a solution of 0.005 M dibasic
0.5% of any individual related substance is found. The sum of potassium phosphate, and adjust with phosphoric acid to a pH
all impurities is not more than 1.5%. of 6.4 + 0.01.

Limit of tropine—
Buffer solution and acetonitrile (17 : 3).
Adsorbent: 0.25-mm layer of chromatographic silica gel.
Diluent: diethyl ether.
In-Process Revision
quantity of USP Hydrocodone Bitartrate RS and USP

Test solution—Finely powder 25 Tablets, and add to
Homatropine Methylbromide RS in Mobile phase, and
a centrifuge tube. Pipet 5.0 mL of diethyl ether into the
dilute quantitatively with Mobile phase to obtain a solution
centrifuge tube, mix on a vortex mixer for 5 minutes, and
having known concentrations of about 0.2 mg per mL and
centrifuge. Use the supernatant.
0.06 mg per mL, respectively.
quantity of tropine in Diluent, and dilute quantitatively with
powder, equivalent to about 5 mg of hydrocodone bitartrate
about 150 mg per mL.
and about 1.5 mg of homatropine methylbromide, to a 25-mL
Stock solutions—Transfer 5.0 mL of the Standard stock
volumetric flask. Pipet 15 mL of the Mobile phase into the
solution to a 10-mL volumetric flask, and dilute with Diluent
volumetric flask, sonicate for 15 minutes, and then shake with
to volume quantitatively, and stepwise if necessary, to obtain
Pharmacopeial Forum
a wrist-action shaker for 15 additional minutes. Pipet an

additional 10 mL of Mobile phase into the volumetric flask,
(494.50/449.46)(LCS / CU)(rU / rS)
and mix well. Pass the solution through a filter having a
0.45-mm porosity prior to injection into the chromatograph. in which 494.50 and 449.46 are the molecular weights of
Chromatographic system—The liquid chromatograph is hydrocodone bitartrate disesquihydrate and anhydrous hydro-
equipped with a 230-nm detector and a 4.6-mm 6 25-cm codone bitartrate, respectively; L is the labeled amount, in
column that contains 5-mm packing L7. The flow rate is about mg, of hydrocodone bitartrate disesquihydrate in each Tablet;
1.5 mL per minute. Chromatograph the Standard preparation, CS is the concentration, in mg per mL, of USP Hydrocodone
and record the peak responses as directed for Procedure: the Bitartrate RS in the Standard preparation; CU is the
relative retention times are about 0.44 for homatropine concentration, in mg per mL, of hydrocodone bitartrate
methylbromide and 1.0 for hydrocodone bitatrate; the disesquihydrate in the Assay preparation, based on the
resolution, R, between hydrocodone bitartrate and homatro- labeled amount per Tablet and the extent of dilution; and rU
pine methylbromide is not less than 2.5; and the relative and rS are the peak responses obtained from the Assay
standard deviation for replicate injections is not more than preparation and the Standard preparation, respec-
3.0% for each analyte. tively.&1S (USP30)

the chromatograph, record the chromatograms, and measure BRIEFING
the areas for the major peaks. Calculate the amount, in mg, of
Hyoscyamine Sulfate, USP 30 page 2320 and page 382 of PF
homatropine methylbromide (C17H24BrNO3) in the portion of 33(3) [May–June 2007]. It is proposed to revise the specifications
under the test for Specific rotation by replacing the current limit with
Tablets taken by the formula: the range specified in the European Pharmacopoeia monograph.

(LCS / CU)(rU / rS)
Change to read:
in which L is the labeled quantity, in mg, of homatropine
Specific rotation h781Si: not less than
methylbromide in each Tablet; CS is the concentration, in mg
&
between&2S (USP31)
per mL, of USP Homatropine Methylbromide RS in the –248
Standard preparation; CU is the concentration, in mg per mL, &

and –298, measured at 208.&2S (USP31)
Test solution: 50 mg per mL, in water.
In-Process Revision
of homatropine methylbromide in the Assay preparation,
based on the labeled amount per Tablet and the extent of
dilution; and rU and rS are the homatropine methylbromide
BRIEFING
peak responses obtained from the Assay preparation and the
Standard preparation, respectively. Calculate the amount, in Isosorbide Mononitrate Extended-Release Tablets, page 1703
of PF 32(6) [Nov.–Dec. 2006]. It is proposed to revise the injection
mg, of hydrocodone bitartrate disesquihydrate (C18H21NO3 volume in Dissolution Test 1 to be in accordance with the validation
report. It is also proposed to revise the Tolerances in Dissolution Test
C4H6O6 2½H2O) in the portion of Tablets taken by the 2 to be in accordance with those approved by FDA. In addition,
minor editorial style changes have been made.
formula:
Pharmacopeial Forum
Add the following: Apparatus 2: 50 rpm. The Tablets are placed in a metal
~
Isosorbide Mononitrate Extended- helix, prepared by winding 10 inches of a 0.8-mm stainless
Release Tablets steel wire around a 9/32-inch shaft and pulling the coils to
form a helix 1 inch long.
Times: 1, 2, 4, 8, and 12 hours.
» Isosorbide Mononitrate Extended-Release Tablets Determine the amount of C6H9NO6 dissolved by employing
contain not less than 90.0 percent and not more the following method.
than 110.0 percent of the labeled amount of Mobile phase—Prepare a filtered and degassed mixture of
water and methanol (7 : 3). Make adjustments if necessary
isosorbide mononitrate (C6H9NO6).
Packaging and storage—Preserve in tight containers. Store Standard solution—Dissolve an accurately weighed quan-
at a temperature between 208 and 308. tity of USP Diluted Isosorbide Mononitrate RS in Medium,
Labeling—[To come.] When more than one Dissolution test and dilute quantitatively, and stepwise if necessary, with
is given, the labeling states the test used only if Test 1 is not Medium to obtain a solution having a known concentration of
used. about 0.06 mg of isosorbide mononitrate per mL&LC/1000

where LC is the tablet label claim in mg.&2S (USP31)
USP Reference standards h11i—USP Isosorbide RS.
[NOTE—The following Reference Standards are dry mixtures
passed through a 0.45-mm nylon filter, discarding the first 4 to
of an active component and suitable excipients to permit safe
6 mL of the filtrate.
handling. For quantitative applications, calculate the concen-
tration of the active component based on the content stated on
the label.] USP Diluted Isosorbide Dinitrate RS. USP Diluted
Isosorbide Mononitrate RS. USP Diluted Isosorbide Mono-
nitrate Related Compound A RS.
Standard solution, and record the chromatogram as directed
Identification—
for Procedure: the relative standard deviation for replicate
A: Thin-Layer Chromatographic Identification Test
h201i— Proceed as directed for Identification test A under
Isosorbide Mononitrate Tablets.
In-Process Revision
&
25&2S (USP31) mL) of the Standard solution and the Test
solution into the chromatograph, record the chromatograms,
and measure the peak responses. Determine the amount, in
mg, of isosorbide mononitrate dissolved at each interval by
in the Assay.
the formula:
Drug release h724i—[To come.]
Change to read:
TEST 1—
Pharmacopeial Forum
in which rU and rS are the peak responses obtained from the

Test solution and the Standard solution, respectively; CS is the Time
concentration, in mg per mL, of the Standard solution; and V (hours) Amount dissolved
is the volume, in mL, of Medium in the vessel at each time 1 between 12% and 32% 15% and 35%
point. 2 between 23% and 43% 28% and 48%
Calculate the amount, in mg, of isosorbide mononitrate 4 between 39% and 59% 43% and 68%
removed by sampling at the previous time points by the 8 between 65% and 85% 90%
formula: 12 not less than 80%
Medium: Simulated gastric fluid (without enzymes); 500
mL.
in which AD is the amount, in mg, of isosorbide mononitrate
dissolved at each time point; VS is the volume, in mL, of the
sample taken; and V is the volume, in mL, of Medium in the
vessel at each time point.
Calculate the percentage of isosorbide mononitrate dis-
solved at each time point by the formula:
(see System suitability under Chromatography h621i).
quantity of USP Diluted Isosorbide Mononitrate RS in
Medium, and dilute quantitatively, and stepwise if necessary,
in which AD is the amount, in mg, of isosorbide mononitrate with Medium to obtain a solution having a known concen-
dissolved at a given time point; AR is the amount, in mg, of tration of about 1.2 mg of isosorbide mononitrate per mL.
isosorbide mononitrate removed at the previous time point; Working standard solution—Dilute the Standard stock
100 is the conversion factor to percentage; and LC is the solution with Medium to obtain a final concentration of 60
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Tablet label claim, in mg. mg per mL for Tablets labeled to contain 30 mg and a final
Tolerances—The percentages of the labeled amount of concentration of 120 mg per mL for Tablets labeled to contain
C6H9NO6 dissolved at the times specified conform to 60 mg.
Acceptance Table 2. Test solution—Use portions of the solution under test
the Working standard solution, and record the chromatogram
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as directed for Procedure: the tailing factor is not more than

2.0; and the relative standard deviation for replicate injections 30-mg Tablet, 60-mg Tablet,
is not more than 2.0%. Time Amount dis- &
&2S (USP31) Amount dis-
Procedure—Separately inject equal volumes (about 20 mL) (hours) solved&&2S (USP31) solved
of the appropriate Working standard solution and the Test 1 between 25% and 40% between 25% and 45%
solution into the chromatograph, record the chromatograms, &
&2S (USP31)
and measure the peak responses. Calculate the concentration 2 between 35% and 60% between 35% and 60%
(Ci), in mg per mL, of isosorbide mononitrate removed at &
&2S (USP31)
each time point by the formula: 6 between 72% and 90% between 72% and 90%
&
&2S (USP31)
12 not less than 80% not less than 80%

&
&2S (USP31)
in which rU(i) is the peak response obtained from the Test
solution at time point i; rS is the peak response obtained from
Medium: Simulated gastric fluid (without enzymes); 500
the Working standard solution; and CS is the concentration, in
mL.
mg per mL, of the Working standard solution. Calculate the
total amount, in percentage, of isosorbide mononitrate
dissolved at each time point i by the formula:
Buffer solution—Transfer 15.4 g of ammonium acetate and
11.5 mL of acetic acid to a 1-L volumetric flask containing
about 500 mL of water. Adjust with acetic acid to a pH of 4.7.
in which Ci is the concentration, in mg per mL, of drug Dilute with water to volume.
removed at time point i; V0 is the initial volume, in mL, of Standard stock solution—Dissolve an accurately weighed
Medium; Vt is the volume, in mL, of sample removed at each quantity of USP Diluted Isosorbide Mononitrate RS in
In-Process Revision
sampling time; Cj is the concentration, in mg per mL, of Medium, and dilute quantitatively, and stepwise if necessary,
isosorbide mononitrate released at time j; Vt is the volume, in with Medium to obtain a solution having a known concen-
mL, removed at each sampling time t;&&2S 100 is the tration of about 0.12 mg of isosorbide mononitrate per mL.
(USP31)
conversion factor to percentage; and LC is the Tablet label Working standard solution—For Tablets labeled to contain
claim, in mg. 60 mg, use the Standard stock solution with no further
Tolerances—The percentages of the labeled amount of dilution. For Tablets labeled to contain 30 mg, transfer 25.0
C6H9NO6 dissolved at the times specified conform to mL of the Standard stock solution to a 50-mL volumetric
Acceptance Table 2. flask, dilute with Medium to volume, and mix.

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Mobile phase—Prepare a filtered and degassed mixture of released at time j; Vt is the volume, in mL, removed at each
water, methanol, and Buffer solution (6 : 3 : 1). Make adjust- sampling time t;&&2S (USP31) 100 is the conversion factor to
ments if necessary (see System Suitability under Chromatog- percentage; and LC is the Tablet label claim, in mg.
raphy h621i). Tolerances—The percentages of the labeled amount of
Chromatographic system (see Chromatography h621i)— isosorbide mononitrate dissolved at the times specified
The liquid chromatograph is equipped with a 220-nm detector conform to Acceptance Table 2.
the Working standard solution, and record the chromatogram
as directed for Procedure: the relative standard deviation for
mL) of the appropriate Working standard solution and Test
solution into the chromatograph, record the chromatograms, Uniformity of dosage units h905i: meet the requirements
and measure the peak responses. Calculate the concentration for Content Uniformity. Proceed as directed in the Assay,
(Ci), in mg per mL, of isosorbide mononitrate removed at except to use 1 Tablet instead of the portion of powdered
each time point by the formula: Tablets used in the Assay preparation.

Test solution—Weigh and finely powder 20 Tablets.
Transfer an accurately weighed portion of the powder,
equivalent to one Tablet, accurately weighed, to a suitable
container. Add 5.0 mL of methanol, shake for 45 minutes, and
in which rU(i) is the peak response obtained from the Test then centrifuge at about 4000 rpm for 10 minutes. Use 0.25
solution at time point i; rS is the peak response obtained from mL of the resulting supernatant, correcting for the blank.
the Working standard solution; and CS is the concentration, in Related compounds—
mg per mL, of the Working standard solution. Calculate the TEST 1—
total amount, in percentage, of isosorbide mononitrate Adsorbent: 0.25-mm layer of chromatographic silica gel
dissolved at each time point i by the formula: mixture.
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Standard solution 1—Weigh accurately a quantity of USP
Isosorbide RS, and dilute quantitatively, and stepwise if
a known concentration of about 0.0125 mg of isosorbide
per mL.
in which Ci is the concentration, in mg per mL, of drug
Standard solution 2—Weigh accurately a quantity of USP
removed at time point i; V0 is the initial volume, in mL, of
Isosorbide RS, and dilute quantitatively, and stepwise if
Medium; Vt is the volume, in mL, of sample removed at each
sampling time; Cj is the concentration, in mg per mL, of drug
a known concentration of about 0.025 mg of isosorbide per
mL.
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Standard solution 3—Weigh accurately a quantity of USP Isosorbide mononitrate related compound A standard stock
Isosorbide RS, and dilute quantitatively, and stepwise if solution—Dissolve an accurately weighed quantity of USP
necessary, with acetonitrile to obtain a solution having Diluted Isosorbide Mononitrate Related Compound A RS in
a known concentration of about 0.05 mg of isosorbide per water, and dilute quantitatively, and stepwise if necessary,
mL. with water to obtain a solution having a known concentration
Test solution—Weigh and finely powder not fewer than 20 of about 0.3 mg of isosorbide mononitrate related compound
Tablets. Transfer an accurately weighed portion of the A per mL.
powder, equivalent to about 100 mg of isosorbide mononi- Isosorbide dinitrate standard stock solution—Dissolve an
trate, to a suitable flask containing 20.0 mL of acetonitrile. accurately weighed quantity of USP Diluted Isosorbide
Sonicate for 10 minutes, and then centrifuge. Use the Dinitrate RS in methanol, and dilute quantitatively, and
supernatant. stepwise if necessary, with methanol to obtain a solution
Application volume: 20 mL. having a known concentration of about 0.15 mg of isosorbide
Developing solvent system: a mixture of toluene, ethyl dinitrate per mL.
acetate, and isopropyl alcohol (53 : 32 : 15). Standard stock solution—Transfer 2.0 mL of Isosorbide
Procedure—Proceed as directed for Thin-Layer Chroma- mononitrate related compound A standard stock solution and
tography under Chromatography h621i. After developing, 4.0 mL of Isosorbide dinitrate standard stock solution to
dry the plate with warm air for about 10 minutes, dip the plate a 100-mL volumetric flask. Dilute with water to volume, and
in a solution prepared by dissolving 1.25 g of potassium mix.
permanganate and 10.0 g of sodium hydroxide in 500 mL of Standard Resolution solution—Transfer about 24 mg
water (prepared fresh for each plate), and heat at 1058 for a quantity of USP Diluted Isosorbide Mononitrate RS,
5 minutes. Any spot in the chromatogram obtained from the accurately weighed equivalent to about 24 mg of isosorbide
Test solution and corresponding to the RF value of the spots mononitrate, to a 100-mL volumetric flask, add 10.0 mL of
obtained from the Standard solutions is not more intense than Standard stock solution, add 20 mL of methanol, and dilute
the spot in the chromatogram obtained from Standard with water to volume.
solution 3: not more than 1% of any individual impurity is Resolution Standard solution—Transfer 10.0 mL of
found. [NOTE—The RF values of isosorbide and isosorbide Standard stock solution and 20 mL of methanol to a
mononitrate are about 0.2 and 0.6, respectively.] If the spot in 100-mL volumetric flask. Dilute with water to volume, and
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the chromatogram obtained from the Test solution is nearly as mix.

intense as the spot obtained from Standard solution 3, further Test solution—Weigh and finely powder not fewer than 20
dilute the Test solution with acetonitrile (1 : 1), repeat the test, Tablets. Transfer an accurately weighed portion of the
and compare the intensity of the isosorbide spot in the diluted powder, equivalent to about 60 mg of isosorbide mononitrate,
Test solution with the intensity of the spots obtained from the to a 50-mL volumetric flask, add 40 mL of methanol, and
Standard solutions, correcting the percentage level for the sonicate for about 30 minutes with cooling. Warm to ambient
additional dilution of the Test solution. temperature, dilute with methanol to volume, and mix.
TEST 2— Centrifuge at about 3000 rpm for 10 minutes. Quantitatively
Mobile phase—Prepare a filtered and degassed mixture of dilute the supernatant with water (10 in 50). Pass a portion of
water and methanol (75 : 25). Make adjustments if necessary this solution through a filter having a 0.45-mm or finer
(see System Suitability under Chromatography h621i). porosity, and use the filtrate.
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100(ri / rs)
The flow rate is about 1.0 mL per minute. Chromatograph the in which ri is the peak area for each other impurity obtained
Resolution solution, and record the peak responses as directed from the Test solution; and rs is the sum of the areas of all the
for Procedure: the resolution, R, between isosorbide peaks: not more than 0.25% of total other impurities is found,
mononitrate related compound A and isosorbide mononitrate and not more than 0.5% of total impurities is found, including
is not less than 1.0. [NOTE—The relative retention times are isosorbide mononitrate related compound A and isosorbide
about 0.9 for isosorbide mononitrate related compound A, 1.0 dinitrate.
for isosorbide mononitrate, and 5.6 for isosorbide dinitrate.]
Assay—
deviation for replicate injections is not more than 10% for the
isosorbide mononitrate related compound A and isosorbide
Isosorbide mononitrate related compound A standard
dinitrate peaks.
preparation—Dissolve an accurately weighed quantity of
USP Diluted Isosorbide Mononitrate Related Compound A
RS in water, and dilute quantitatively, and stepwise if
necessary, with water to obtain a solution having a known
areas for the major peaks. Calculate the percentage of
concentration of about 0.15 mg of isosorbide mononitrate
isosorbide mononitrate related compound A and isosorbide
related compound A per mL.
dinitrate in the portion of Tablets taken by the formula:
Resolution solution—Transfer a quantity of USP Diluted
Isosorbide Mononitrate RS, accurately weighed and equiva-
25(C/W)(rU / rS)
lent to about 30 mg of isosorbide mononitrate, to a 250-mL
volumetric flask. Dissolve in water, add 10.0 mL of
in which C is the concentration, in mg per mL, of the
Isosorbide mononitrate related compound A standard
appropriate Standard, USP Diluted Isosorbide Mononitrate
Related Compound A RS or USP Diluted Isosorbide Dinitrate preparation, add 50 mL of methanol, and dilute quantita-
tively, and stepwise if necessary, with water to obtain
RS, in the Standard solution; W is the weight, in mg, of
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a solution having a concentration of about 0.12 mg of
isosorbide mononitrate in the sample used to prepare the Test
isosorbide mononitrate per mL and about 0.006 mg of
solution; and rU and rS are the peak areas of the corresponding
isosorbide mononitrate related compound A per mL.
component obtained from the Test solution and the Standard
Standard preparation—Transfer a quantity of USP Diluted
solution, respectively: not more than 0.25% of isosorbide
Isosorbide Mononitrate RS, accurately weighed, to a suitable
mononitrate related compound A is found, and not more than
volumetric flask. Dissolve in water, add a portion of methanol
0.25% of isosorbide dinitrate is found. Calculate the
equivalent to about 20% of the flask volume, and dilute with
percentage of each other impurity (other than isosorbide
water to volume to obtain a solution having a known
mononitrate related compound A or isosorbide dinitrate) in
concentration of about 0.12 mg of isosorbide mononitrate per
the portion of Tablets taken by the formula:
mL.
Pharmacopeial Forum

BRIEFING
powder, equivalent to about 60 mg of isosorbide mononitrate, Isotretinoin Capsules, USP 30 page 2428. It is proposed to add
to a 100-mL volumetric flask, add 50 mL of methanol, and a Dissolution test to this monograph.
sonicate for about 30 minutes with cooling. Warm to ambient (BPC: M. Marques) RTS—C55248
temperature, dilute with methanol to volume, and mix.

Add the following:
Centrifuge at about 3000 rpm for 10 minutes. Quantitatively
dilute the supernatant with water (10 in 50). Pass a portion of
&
this solution through a filter having a 0.45-mm or finer Medium—

porosity, and use the filtrate. STAGE 1: simulated gastric fluid with pepsin, prepared
Chromatographic system (see Chromatography h621i)— freshly and purged with nitrogen.
The liquid chromatograph is equipped with a 220-nm detector STAGE 2: 0.13 N sodium hydroxide, prepared by transfer-
and a 4-mm 6 12.5-cm column that contains packing L1. ring 5 g of sodium hydroxide to a 1-L volumetric flask and
The flow rate is about 1.5 mL per minute. Chromatograph the dissolving in and diluting with water to volume. Prepare
Resolution solution, and record the peak responses as directed fresh, and purge with nitrogen.
for Procedure: the resolution, R, between isosorbide Apparatus (see Disintegration h701i)—No disks; the
mononitrate related compound A and isosorbide mononitrate apparatus is adjusted so that the bottom of the basket-rack
is not less than 1.5. Chromatograph the Standard preparation, assembly descends to 1.0 + 0.1 cm from the inside bottom
and record the peak responses as directed for Procedure: the surface of the vessel on the downward stroke; the 10-mesh
tailing factor is not more than 1.5, and the relative standard stainless steel cloth in the basket-rack assembly is replaced
deviation for replicate injections is not more than 1.5%. with a 40-mesh stainless steel cloth; a 10-mesh stainless-steel
Procedure—Separately inject equal volumes (about 50 mL) cloth is fitted to the top of the basket-rack assembly.
20 mL) of the Standard preparation and the Assay Time: 60 minutes.
preparation into the chromatograph, record the chromato- Standard solution—Transfer about 10 mg of USP Isotret-
grams, and measure the responses for the major peaks. inoin RS, accurately weighed, to a 200-mL low-actinic
Calculate the quantity, in mg, of isosorbide mononitrate volumetric flask; add 25.0 mL of Stage 1 Medium and about
(C6H9NO6) in the portion of Tablets taken by the formula: 150 mL of Stage 2 Medium; sonicate until completely
In-Process Revision
dissolved (about 20 minutes); and dilute with Stage

500C(rU / rS) 2 Medium to volume. Pass 20 mL of this solution through
a suitable filter, discarding the first 5 mL. Dilute 5.0 mL of the
in which C is the concentration, in mg per mL, of isosorbide filtrate with Stage 2 Medium to 50 mL.
mononitrate in the Standard preparation; and rU and rS are the Sample solution—Perform a dissolution test on each of
peak responses obtained from the Assay preparation and the 6 Capsules: place 1 Capsule in one of the tubes in each of six
Standard preparation, respectively.~USP31 basket-rack assemblies. Place each basket in a 1-L beaker
containing 100 mL of Stage 1 Medium in a bath having
a temperature of 37.0 + 0.58. Allow to stand for 30 minutes.
Carefully add 800 mL of Stage 2 Medium to each beaker.
With the disintegration apparatus operating, connect each
Pharmacopeial Forum
basket-rack assembly to the drive rod in a timed sequence.

BRIEFING
After 60 minutes, withdraw 20 mL of Medium (Stage 1 and
Stage 2), immediately pass the solution through a suitable Mefloquine Hydrochloride, USP 30 page 2561. It is proposed to
use additional steps in the titration procedure for the Assay to
0.45-mm filter, discard the first 5 mL, and collect the solution increase the precision of the method. The addition of acetic
anhydride to the sample in formic acid is exothermic and is believed
in argon-charged, low-actinic glassware. Dilute, if necessary, to cause acylation of the analyte at an elevated temperature, thus
leading to lower results. Therefore, it is proposed to perform the
using low-actinic glassware, with Stage 2 Medium, to obtain titration assay thermostatically and more rapidly.
a theoretical concentration of about 0.0055 mg per mL of (MD-AA: B. Davani) RTS—C43415
isotretinoin, assuming complete dissolution, based on the
label claim.
Change to read:
Capsule shell correction—Empty the contents of 3 Cap-
Assay—Dissolve about 0.35 g, accurately weighed, in 15 mL of
sules. Wash the capsule shells in several 20-mL aliquots of anhydrous formic acid, and add 40 mL of acetic anhydride.
chloroform. Allow the capsule shells to air dry. Place the &
Place the sample solution in a glass container thermostated
capsule shells in a 1-L flask containing 100 mL of Stage
at 208.&2S (USP31)
1 Medium and 800 mL of Stage 2 Medium. Allow the flask to Titrate with 0.1 N perchloric acid VS, and determine the endpoint
potentiometrically.
stand for about 1 hour in a bath having a temperature of &
[NOTE—Perform the titration rapidly after the addition of
37.0 + 0.58, stirring occasionally. Filter, and dilute as
acetic anhydride by predosing with about 60% of the
described for Sample solution.
expected titrant, and then slowly titrate to a potentiometric
Procedure—Determine the amount of C20H28O2 dissolved
endpoint.]&2S (USP31)
by employing UV absorption at the wavelength of maximum Perform a blank determination, and make any necessary correction.
Each mL of 0.1 N perchloric acid is equivalent to 41.48 mg of
absorbance at about 343 nm, in portions of the Sample C17H16F6N2O HCl.
solution in comparison with the Standard solution, correcting

for the capsule shell absorbance, and using Medium (Stage
BRIEFING
1 and Stage 2) as the blank. Calculate the percentage of
C20H28O2 dissolved by the formula: Methylphenidate Hydrochloride Extended-Release Tablets,
USP 30 page 2635. It is proposed to add Dissolution Test 2 to this
monograph. The chromatographic procedure in this test was
validated with the HAISIL HL C18 brand of packing L1. Using
this column, the retention time of methylphenidate is approximately
2.2 minutes. In the absence of any negative comments, it is proposed
to implement the inclusion of Dissolution Test 2 via the Interim
Revision Announcement pertaining to USP 30–NF 25 in PF 33(5)
In-Process Revision
[Sept.–Oct. 2007] with an official date of October 1, 2007.

in which AU, ACS, and AS are the absorbances obtained from the
Sample solution, the Capsule shell correction, and the Add the following:
Standard solution, respectively; CS is the concentration, in .Labeling—When more than one Dissolution Test is given,
mg per mL, of the Standard solution; DU is the dilution factor the labeling states the Dissolution Test used only if Test 1 is
of the Sample solution; 100 is the conversion factor to not used..5
percentage; and LC is the Capsule label claim, in mg.
of C20H28O2 is dissolved in 60 minutes.&2S (USP31)
Pharmacopeial Forum
Change to read:
Standard solution—Prepare at least six solutions by making
serial dilutions of the Standard stock solution in Dilution
.TEST 1—
.5 medium to bracket the expected drug concentration range.
Apparatus 2: 50 rpm. Solution A—Dissolve 2.0 g of 1-octanesulfonic acid sodium
Times: 1, 2, 3.5, 5, and 7 hours.
Test solution—Use portions of the solution under test passed salt in 700 mL of water, mix well, and adjust with phosphoric
through a
.suitable acid to a pH of 3.0.
.5
0.45-mm polypropylene Mobile phase—Prepare a filtered and degassed mixture of
.
.5 Solution A and acetonitrile (70 : 30). Make adjustments if
filter. [NOTE—Do not use glass fiber filters.]
Procedure—Determine the amount of C14H19NO2 HCl dissolved, necessary (see System Suitability under Chromatography
employing the procedure set forth in the Assay, making any
necessary volumetric adjustments. h621i).
C14H19NO2 HCl dissolved at the times specified conform to Chromatographic system (see Chromatography h621i)—
Acceptance Table 2.
Time (hours) Amount dissolved The liquid chromatograph is equipped with a 220-nm detector
1 between 25% and 45% and a 3.2-mm 6 5-cm column that contains 5-mm packing
3.5 between 55% and 80% L1. The flow rate is about 1.0 mL per minute. The column
7 not less than 80% temperature is maintained at 308. Chromatograph the
Standard solution, and record the chromatogram as directed
.TEST 2 (for products labeled for dosing every 24 hours)—If for Procedure: the tailing factor is not more than 2; the
the product complies with this test, the labeling indicates that capacity factor is not less than 2; the relative standard
it meets USP Dissolution Test 2. deviation of the response is not more than 2%; and the
Medium: acidified water (adjust the pH to 3 with relative standard deviation of the retention time is not more
phosphoric acid); 50 mL, at 37 + 0.58. than 2%.
Apparatus 7 (see Drug Release h724i): 30 cycles per Procedure—Separately inject equal volumes (about 25 mL)
minute; 2–3 cm amplitude. Use Sample Preparation A using of the Standard solutions and the solution under test into the
a metal coil sample holder (Figure 4d). Place 1 Tablet in the chromatograph. Record the chromatograms and measure the
holder with the Tablet orifice facing down, and cover the top peak responses. Construct a calibration curve by plotting the
of the holder with Parafilm2. At the end of each specified test peak response versus the concentration of the Standard
interval, the systems are transferred to the next row of new solutions. Determine the amount of C14H19NO2 HCl in each
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test tubes containing 50 mL of fresh Medium. interval by linear regression analysis of the standard curve.
Times: 1-hour intervals for a duration of 10 hours. Tolerances—The percentages of the labeled amount of
Determine the percentages of the labeled amount of C14H19NO2 HCl dissolved at the times specified conform to
C14H19NO2 HCl dissolved by employing the following Acceptance Table 2.
method.
Dilution medium—Prepare a mixture of Medium and
acetonitrile (75 : 25).
quantity of USP Methylphenidate Hydrochloride RS in
average from 3 to 6 hours between 9% and 15% per hour
Dilution medium to obtain a solution having a concentration
Pharmacopeial Forum
Calculate the average percentage released from 3 to 6 hours Apparatus 2: 100 rpm, with sinkers made of teflon-coated steel
wire prepared by forming a coil approximately 22 mm long from
using the formula: a 13-cm length of 20-gauge wire (see Figure 1).
in which Y is the cumulative drug released, in percentage,

from 0 to 6 hours; and X is the cumulative drug released, in
percentage, from 0 to 3 hours..5
Figure 1. Sinker.

Acid-stage standard solution—Prepare a solution of USP
BRIEFING Nitrofurantoin RS in Acid medium to obtain a solution having
Buffer-stage standard solution—Prepare a solution of USP
Nitrofurantoin Capsules, USP 30 page 2759, and the Interim Nitrofurantoin RS in pH 7.5 Buffer medium to obtain a solution
Revision Announcement on page 1428 of PF 32(5) [Sept.–Oct. having a known concentration of about 0.075 mg per mL.
2006]. It is proposed to add Dissolution Test 4 to this monograph. In Procedure—Determine the amount of C8H6N4O5 dissolved from
the absence of any negative comments, it is proposed to implement UV absorbances at the isosbestic wavelength at about 375 nm on
this revision through the Interim Revision Announcement pertaining filtered portions of each solution under test, suitably diluted, if
to USP 30–NF 25 with an official date of December 1, 2007. necessary, with Acid medium or pH 7.5 Buffer medium when
appropriate in comparison with the appropriate Standard solution.
(BPC: M. Marques) RTS—C53608 Tolerances—The percentages of the labeled amount of C8H6N4O5
dissolved at the specified times conform to the accompanying
Acceptance Table.
Change to read: Time Amount dissolved Amount dissolved
(hours) (individual) (mean)
Dissolution h711i— 1 between 2% and 16% between 5% and 13%
TEST 1 (where it is labeled as containing nitrofurantoin macro- 3 between 27% and 69% between 39% and 56%
crystals)— 7 not less than 68% not less than 81%
Medium: pH 7.2 (+0.05) phosphate buffer; 900 mL.
Procedure—Determine the amount of C8H6N4O5 dissolved by Acceptance Table
employing UV absorption at the wavelength of maximum absor-
bance at about 375 nm on filtered portions of the solution under test, Number
suitably diluted with Medium, if necessary, in comparison with Level Tested Criteria
a Standard solution having a known concentration of USP L1 12 The mean percentage of dissolved label claim
Nitrofurantoin RS in the same Medium. lies within the range for the means at each
Tolerances—The percentage of the labeled amount of C8H6N4O5 interval and is not less than the stated amount at
In-Process Revision
dissolved at the 1-hour point conforms to Acceptance Table 2, and the final test time. All individual values lie
the percentages dissolved at the 3- and 8-hour points conform to the within the ranges for the individuals at each
criteria for the final test time in Acceptance Table 2. interval and are not less than the stated amount
Time (hours) Amount dissolved at the final test time.
L2 12 The mean percentage of dissolved label claim
1 between 20% and 60% lies within the range for the means at each
3 not less than 45% interval and is not less than the stated amount at
8 not less than 60% the final test time. Not more than 2 of the 24
individual values lie outside the stated range for
individuals at each interval, and not more than
TEST 2 (where it is labeled as containing both nitrofurantoin 2 of 24 are less than the stated amount at the
macrocrystalline and monohydrate forms)—If the product complies final test time.
with this test, the labeling indicates that it meets USP Dissolution
Test 2.
Acid medium: 0.01 N hydrochloric acid for 1 hour; 900 mL. .TEST 3 (where it is labeled as containing both nitrofurantoin
pH 7.5 Buffer medium—Prepare a pH 7.5 buffer concentrate by macrocrystalline and monohydrate forms)—If the product complies
dissolving 62.2 g of potassium hydroxide and 129.3 g of monobasic with this test, the labeling indicates that it meets USP Dissolution
potassium phosphate in water, dilute with water to 1 L, and mix. Test 3.
After 1 hour change the Acid medium to pH 7.5 Buffer medium by Acid medium, pH 7.5 Buffer medium, Apparatus 2, Times, Acid-
adding 50 mL of pH 7.5 buffer concentrate, for an additional stage standard solution, Buffer stage standard solution, and
6 hours. Procedure—Proceed as directed for Test 2.
Pharmacopeial Forum
Tolerances—The percentages of the labeled amount of C8H6N4O5 Acid-stage capsule shell blank—Transfer 100.0 mL of the
dissolved at the specified times conform to Acceptance Table 2.
Stock capsule shell blank to a 1000-mL volumetric flask,
Time Amount dissolved Amount dissolved
(hours) (individual) (mean) dilute with Acid medium to volume, and mix. Filter using the
1 between 2% and 16% between 5% and 13%
3 between 50% and 80% between 55% and 75% same filter as for the Test solution.
7 not less than 85% not less than 90%
Buffer-stage capsule shell blank—Transfer 100.0 mL of the
.5
Stock capsule shell blank to a 1000-mL volumetric flask. Add
.TEST 4 (where it is labeled as containing both nitrofuran-
56 mL of pH 7.5 buffer concentrate, dilute with Acid medium
toin macrocrystalline and monohydrate forms)—If the
to volume, and mix. Filter using the same filter as for the Test
product complies with this test, the labeling indicates that it
solution.
meets USP Dissolution Test 4.
Test solution—Pass portions of the solution under test
Acid medium: 0.01 N hydrochloric acid for 1 hour; 900
through a 1.2-mm glass/0.45-mm polyethersulfone combina-
mL, deaerated.
tion filter, discarding the first few mL.
pH 7.5 Buffer medium—Prepare a pH 7.5 buffer concen-
Procedure—Determine the amount of C8H6N4O5 dissolved
trate by dissolving 62.2 g of potassium hydroxide and 129.3 g
by UV/Vis absorption at the wavelength of maximum
of monobasic potassium phosphate in water, dilute with water
absorbance at about 375 nm on portions of the Test solution
to 1 L, and mix. After 1 hour change the Acid medium to pH
in comparison with the appropriate Acid- or buffer-stage
7.5 Buffer medium by adding 50 mL of pH 7.5 buffer
standard solution. Correct for the appropriate capsule shell
concentrate, and run for an additional 9 hours.
blank absorbance, using a 0.1 cm cell, and the appropriate
Apparatus 2: 100 rpm, with helix sinkers.
medium as blank.
Stock standard solution—Transfer about 25 mg, accurately
C8H6N4O5 dissolved at specified times conform to Acceptance
weighed, of USP Nitrofurantoin RS to a 10-mL volumetric
Table 2.
flask. Add 7.5 mL of dimethylformamide, and sonicate until
dissolved. Allow to cool to room temperature, dilute with Time (hours) Amount dissolved
dimethylformamide to volume, and mix. 1 not more than 25%

Acid-stage standard solution—Transfer 2.0 mL of the Stock 3 between 25% and 50%
standard solution to a 200-mL volumetric flask. Dilute with 10 not less than 80%
Acid medium to volume, and mix. .6
In-Process Revision
Buffer-stage standard solution—Transfer 3.0 mL of the

Stock standard solution to a 100-mL volumetric flask. Add
5.6 mL of pH 7.5 buffer concentrate, dilute with Acid medium
to volume, and mix.
Stock capsule shell blank—Place 10 empty, clean capsules
into a 900-mL volumetric flask. Add approximately 800 mL
of Acid medium. Gently heat to 378 + 0.58, and stir until all
the capsules are dissolved. Allow to cool to room
temperature, dilute with Acid medium to volume, and mix.
Pharmacopeial Forum

BRIEFING Standard solutions and the Test solution into the chromatograph,
Construct a calibration curve by plotting the peak response versus
concentration of the Standard solutions. A weighing factor, 1/x, is
Oxybutynin Chloride Extended-Release Tablets, USP 30 page applied to the regression line of the calibration curve to enhance the
2822 and page 1742 of PF 32(6) [Nov.–Dec. 2006]. It is proposed to accuracy of the low standard concentrations. Determine the amount
add a Dissolution Test 2 to this monograph, because FDA recently of C22H31NO3 HCl dissolved in each interval from a linear
approved a new generic version of this product; and to add regression analysis of the calibration curve.
a Labeling section. The chromatographic procedure in the new Tolerances—The percentages of the labeled amount of
dissolution test was validated using the Spherisorb C8 brand of C22H31NO3 HCl dissolved at the times specified conform to
packing L7. In the absence of negative comments, it is proposed to Acceptance Table 2.
implement the inclusion of this test in PF 33(6) [Nov.–Dec. 2007] FOR TABLETS LABELED TO CONTAIN 5 MG OR 10 MG OF OXYBUTYNIN
via the Interim Revision Announcement pertaining to USP 30–NF CHLORIDE:
25, with an official date of December 1, 2007.
(BPC: M. Marques) RTS—C54582 4 not more than 20%
10 between 34.5% and 59.5%
Add the following:
.Labeling—when more than one Dissolution test is given, FOR TABLETS LABELED TO CONTAIN 15 MG OF OXYBUTYNIN
CHLORIDE:
the labeling states the Dissolution test used only if Test 1 is Time (hours) Amount dissolved
not used..6 4 not more than 20%
10 between 34.5% and 59.5%
Change to read:
Drug release h724i— .TEST 2—If the product complies with this test, the labeling
.Dissolution h711i— indicates that the product meets USP Dissolution Test 2.
TEST 1—.6
Medium: simulated gastric fluid without enzymes; 50 mL. Medium—
Apparatus 7:
ACID STAGE: simulated gastric fluid, without enzymes, pH
.Drug Release h724i,.6
30 cycles per minute; 2- to 3-cm amplitude, 1.2 + 0.05; 250 mL (first row).
~
at 37.0 + 0.58.~USP31 BUFFER STAGE: simulated intestinal fluid, without en-
Determine the amount of C22H31NO3 HCl dissolved by employing zymes, pH 6.8 + 0.1; 250 mL (rows 2 to 4).
0.035 M Phosphate buffer, pH 2.2—Dissolve about 4.83 g of Apparatus 3: 25 dips per minute; 20-mesh polypropylene
monobasic sodium phosphate in 1000 mL of water, add 2.3 mL of
triethylamine, and adjust with phosphoric acid to a pH of 2.2 + 0.2. screen on top and bottom; 30 seconds drip time.
Acidified water—To 1 L of water add phosphoric acid dropwise to
a pH of 3.5, and mix well. Times: 2 hours in the Acid stage (first row); 4, 8, and 16
Standard stock solutions—Dissolve accurately weighed quantities
of USP Oxybutynin RS in acetonitrile, and dilute quantitatively, and hours in the Buffer stage (rows 2 to 4).
stepwise if necessary, with acetonitrile to obtain solutions having
known concentrations of about 250, 300, and 350 mg per mL. Determine the amount of C22H31NO3 HCl dissolved by
Standard solutions—Prepare a series of dilutions of the Standard
In-Process Revision
stock solutions in acidified water having final concentrations similar employing the following method.
to those expected in the Test solution.
Test solution—Use portions of the solution under test. If the Buffer solution—Transfer 1 mL of triethylamine to 1000
solution is cloudy, centrifuge at 2000 rpm for 10 minutes, and use
the supernatant. mL of water. Adjust with phosphoric acid to a pH of
Mobile phase—Prepare a suitable filtered and degassed mixture of
0.035 M Phosphate buffer, pH 2.2 and acetonitrile (65 : 35). Make 3.50 + 0.05.
adjustments if necessary (see System Suitability under Chromatog-
raphy h621i). Mobile phase—Prepare a filtered and degassed mixture of
System suitability solution—Use a medium range Standard
solution of USP Oxybutynin Chloride RS. acetonitrile and Buffer solution (4 : 1). Make adjustments if
liquid chromatograph is equipped with a 230-nm detector and necessary (see System Suitability under Chromatography
is about 1.5 mL per minute. The column temperature is maintained at h621i).
about 358. Chromatograph the System suitability solution, and record
the peak responses as directed for Procedure: the tailing factor is
greater than 0.5 and less than 2.5; and the relative standard deviation
for replicate injections is not more than 2.0%.
Pharmacopeial Forum
Standard stock solution—Transfer 20 mg, accurately

weighed, of USP Oxybutynin Chloride RS to a 100-mL
C2 + C4
volumetric flask, dissolve in and dilute with Acid stage
Percentage dissolved at 8 hours:
Working standard solution—Transfer 5.0 mL of the
Standard stock solution, for Tablets labeled to contain
C2 + C4 + C8
5 mg, or 10 mL, for Tablets labeled to contain 10 mg, to
a 100-mL volumetric flask; dilute with Buffer stage Medium
to volume; and mix. Percentage dissolved at 16 hours:
Test solution—Centrifuge a portion of the solution under
test at approximately 3000 rpm for 10 minutes. Use the C2 + C4 + C8 + C16
supernatant.
C22H31NO3 HCl dissolved at the times specified conform to
Acceptance Table 2.
The flow rate is about 1.5 mL per minute. Chromatograph the Time (hours) Amount dissolved
Working standard solution, and record the peak responses as 2 between 0% and 10%
directed for Procedure: the tailing factor is not more than 2.0, 4 between 10% and 30%
and the relative standard deviation for replicate injections is 8 between 40% and 65%
not more than 3.0%. 16 not less than 80%
Procedure—Separately inject equal volumes (about 25 mL) .6
of the Working standard solution and the Test solution into

the peak responses. Calculate the amount of C22H31NO3 HCl
BRIEFING
dissolved by the following formulas:
Percentage dissolved at each time point (Ct): Paroxetine Tablets, USP 30 page 2868. On the basis of
comments received, it is proposed to delete Identification test C
because the specific rotation test is not needed in the monograph. In
addition, it is proposed to revise the test for Uniformity of dosage
In-Process Revision
units and the Assay to clarify the calculation formulas based on the
Stimuli article ‘‘Common Pharmacopeial Calculations in USP
Monographs’’ (see page 626 of PF 31(2) [Mar.–Apr. 2005]).
in which rU and rS are the peak responses for the Test solution Change to read:
and the Working standard solution, respectively; CS is the Identification—

concentration, in mg per mL, of the Working standard A: Infrared Absorption h197Ki—
Test specimen—Transfer a quantity of finely powdered Tablets,
solution; 250 is the volume, in mL, of Medium; 100 is the equivalent to about 90 mg of paroxetine, to a suitable flask, add 100
mL of 0.1 N hydrochloric acid, and stir for 1 hour. Transfer the
conversion factor to percentage; and LC is the Tablet label mixture to a separatory funnel, and add 1.5 mL of ammonium
hydroxide to make the solution alkaline. Add 100 mL of ethyl ether
claim, in mg. to the funnel, and shake for 2 minutes. Transfer the organic layer into
the necessary number of centrifuge tubes, and centrifuge for 10
Percentage dissolved at 4 hours: minutes. Recombine the clarified extracts, add 1 drop of water and
0.5 mL of hydrochloric acid, stir, and evaporate to dryness under
a stream of nitrogen. Dry the residue in an oven at 908 for 1 hour.
Pharmacopeial Forum
B: The retention time of the major peak in the chromatogram of preparation, and record the peak responses as directed for
the Assay preparation corresponds to that in the chromatogram of Procedure: the column efficiency is not less than 750 theoretical
the Standard preparation, as obtained in the Assay. plates; the tailing factor is not more than 4; and the relative standard
C: Place a quantity of finely powdered Tablets, equivalent to deviation for replicate injections is not more than 2.0%.
about 450 mg of paroxetine, in a stoppered flask. Add 100 mL of Procedure—Separately inject equal volumes (about 5 mL) of the
alcohol, and shake for 1 hour. Centrifuge about 20 mL of the Standard preparation and the Assay preparation into the chromat-
mixture, and measure the specific rotation of the supernatant at 208 ograph, record the chromatograms, and measure the responses for
(see Optical Rotation h781i): the specific rotation is between –758 the major peaks. Calculate the quantity, in mg of paroxetine
and –1158. (C19H20FNO3) in the portion of Tablets taken by the formula:
&
&2S (USP31)
1000C(329.37/365.83)(rU / rS)
in which C is the concentration, in mg per mL, of USP Paroxetine
Change to read: Hydrochloride RS in the Standard preparation;

&
percent of tablet label claim, of paroxetine (C19H20FNO3) in
Buffer solution, Mobile phase, and Chromatographic system—
the portion of Tablets taken by the formula:
Standard solution—Use the Standard preparation, prepared as
directed in the Assay. 100(CS / CU)(329.37/365.83)(rU / rS)
Test solution—Place 1 Tablet in a suitable volumetric flask, and
add a volume of a hydrochloric acid solution (7 in 1000), equivalent
to about 25% of the flask volume. Allow the Tablet to disintegrate,
dilute with methanol to volume, and mix to obtain a solution in which CS is the concentration, in mg per mL, of USP
containing about 0.1 mg of paroxetine per mL. Centrifuge a portion
of the solution. Paroxetine Hydrochloride RS in the Standard preparation; CU
Procedure—Proceed as directed in the Assay. Calculate the
quantity, in mg, of C19H20FNO3 in the Tablet taken by the formula: is the nominal concentration of paroxetine, in mg per mL,
VC(329.37/365.83)(rU / rS) based on the tablet label claim, in the Assay prepara-
tion;&2S (USP31)
329.37 and 365.83 are the molecular weights for paroxetine and
&
VCS (329.37/365.83)(rU / rS)&2S (USP31)
paroxetine hydrochloride, respectively; and rU and rS are the peak
responses obtained from the Assay preparation and the Standard
preparation, respectively.
in which V is the volume of the flask used;
&
CS is the concentration, in mg per mL, of USP Paroxetine
Hydrochloride RS in the Standard solution; 329.37 and
BRIEFING
365.83 are the molecular weights for paroxetine and
paroxetine hydrochloride, respectively; and&2S (USP31) Raloxifene Hydrochloride. Because there is no existing USP
rU and rS are the peak responses obtained from the Test solution and monograph for this drug substance, a new monograph is being
the Standard solution, respectively. and the other terms are as proposed. The HPLC procedure used in the test for Related
defined therein. compounds was validated using an Inertsil C8 brand of L7
column. Raloxifene elutes at approximately 18 minutes. The
&
&2S (USP31) HPLC procedure used in the Assay was validated using a Zorbax
Rx-C8 or SB-C8 brand of L7 column. Raloxifene elutes at
approximately 3 minutes.
Change to read:
(MD-PS: D. Bempong) RTS—C47067
In-Process Revision
Assay—
Buffer solution—Prepare a mixture of water, phosphoric acid, and
triethylamine (100 : 0.6 : 0.3).
solution and acetonitrile (7 : 3). Make adjustments if necessary (see
System Suitability under Chromatography h621i). Add the following:
Standard preparation—Dissolve an accurately weighed quantity
of USP Paroxetine Hydrochloride RS in methanol, and dilute &Raloxifene Hydrochloride
quantitatively, and stepwise if necessary, with methanol to obtain
equivalent to about 100 mg of paroxetine, to a 200-mL volumetric
flask, dissolve in and dilute with methanol to volume, and mix.
Centrifuge a portion of this solution for 6 minutes. Transfer 20 mL of
the supernatant to a 100-mL volumetric flask, dilute with methanol
to volume, and mix.
a 4.6-mm 6 3.3-cm column that contains 3-mm packing L7. The C28H27NO4S HCl 510.04
flow rate is about 2.0 mL per minute. Chromatograph the Standard
Pharmacopeial Forum
Methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien- 5.0 mL of hydrogen peroxide 30 percent. Let it stand at 308

3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. for at least 6 hours. Dilute with Solution A to 50.0 mL.
[NOTE—Raloxifene hydrochloride is partly converted to
6-Hydroxy-2-(p-hydroxyphenyl)benzo[b]thien-3-yl-p-(2-
raloxifene N-oxide under these conditions.]
piperidinoethoxy)phenyl ketone, hydrochloride
System suitability solution—Transfer about 15 mg of USP
[82640-04-8].
Raloxifene Hydrochloride RS to a 50-mL volumetric flask,
add 5.0 mL of System suitability stock solution, dilute with
» Raloxifene Hydrochloride contains not less than Diluent to volume, and mix.
97.0 percent and not more than 102.0 percent of Standard solution—Dissolve an accurately weighed quan-
C28H27NO4S HCl, calculated on the as-is basis. tity of USP Raloxifene Hydrochloride RS in Diluent, and
dilute quantitatively with Diluent to obtain a solution having
and store at room temperature.
Test solution—Transfer about 30 mg of Raloxifene
USP Reference standards h11i—USP Raloxifene Hydro- Hydrochloride, accurately weighed, to a 10-mL volumetric
chloride RS. flask, dissolve in and dilute with Diluent to volume, and mix.
Identification— Chromatographic system (see Chromatography h621i)—
A: Infrared Absorption h197Ki. The liquid chromatograph is equipped with a 280-nm detector
B: It responds to the test for Chloride h191i, the sample and a 4.6-mm 6 25-cm column that contains 5-mm base
being dissolved in methanol. deactivated L7 packing. The temperature is maintained at 358.
Loss on drying h731i—Dry it at 1058 for 3 hours: it loses not The flow rate is about 1 mL per minute. The chromatograph is
more than 0.5% of its weight. programmed as follows:
Residue on ignition h281i: not more than 0.1%. Time Solution A Solution B
Heavy metals, Method II h231i: 10 ppm. (minutes) (%) (%) Elution
Related compounds— 0.00–9.00 75 25 isocratic
Solution A—Dissolve 9.0 g of monobasic potassium 9.00–40.25 75?50 25?50 linear gradient
phosphate in 1000 mL of water, and mix. Add 0.6 mL of 40.25–42.25 50?75 50?25 linear gradient
phosphoric acid, further adjust with phosphoric acid or 42.25–49.00 75 25 equilibration

In-Process Revision
potassium hydroxide solution to a pH of 3.0 + 0.1, and mix. [NOTE—Adjust the start time of the gradient step based on the
Solution B—Use acetonitrile. instrument’s dwell volume.] Chromatograph the System
Mobile phase—Use variable mixtures of Solution A and suitability solution, and record the peak responses as directed
Solution B as directed for Chromatographic system. Make for Procedure: the resolution, R, between the raloxifene and
adjustments if necessary (see System Suitability under raloxifene N-oxide peaks is not less than 3.0; and the tailing
Chromatography h621i). factor for the raloxifene peak is not more than 2.0.
Diluent—Prepare a mixture of Solution A and acetonitrile Procedure—Separately inject equal volumes (about 10 mL)
(70 : 30). of the Standard solution and the Test solution into the
System suitability stock solution—Transfer about 6 mg of chromatograph, record the chromatograms for not less than
USP Raloxifene Hydrochloride RS to a 50-mL volumetric two times the retention time of the raloxifene peak, and
flask, and add 15.0 mL of acetonitrile, 3.0 mL of water, and
Pharmacopeial Forum
measure all of the peak responses. Calculate the percentage of

System suitability stock solution—Prepare as directed under
each impurity in the portion of Raloxifene Hydrochloride
Related compounds.
quantity of USP Raloxifene Hydrochloride RS in Mobile
100(CS / CU)(ri / rS)
phase, and dilute quantitatively to obtain a solution having
in which CS is the concentration, in mg per mL, of USP a known concentration of about 0.05 mg per mL.
Raloxifene Hydrochloride RS in the Standard solution; CU is Assay preparation—Transfer about 5 mg of Raloxifene
the concentration, in mg per mL, of Raloxifene Hydrochlo- Hydrochloride, accurately weighed, to a 100-mL volumetric
ride in the Test solution; ri is the peak response of each flask, dissolve in and dilute with Mobile phase to volume, and
impurity in the Test solution; and rS is the response of the mix.
raloxifene peak in the Standard solution. The limits are as Chromatographic system (see Chromatography h621i)—
shown in the accompanying table. Disregard any peak that is The liquid chromatograph is equipped with a 280-nm detector
less than 0.05%. and a 4.6-mm 6 15-cm column that contains 3.5-mm base
deactivated L7 packing. The temperature is maintained at 358.
Relative
Retention
System suitability stock solution, and record the peak
Related Compound Time Limit (%)
responses as directed for Procedure: the tailing factor for
Raloxifene diacylated I 1 0.74 NMT 0.20 the raloxifene peak is not more than 2.0; the resolution, R,
Raloxifene 1.00 — between raloxifene and raloxifene N-oxide is not less than
Raloxifene N-oxide 2 1.17 NMT 0.10 2.0; and the relative standard deviation for replicate injections
Raloxifene 7-isomer3 1.22 NMT 0.15 calculated for the raloxifene peak is not more than 0.7%.
Any unspecified individual — NMT 0.10 Procedure—Separately inject equal volumes (about 10 mL)
impurity of the Standard preparation and the Assay preparation into
Total impurities NMT 0.5 the chromatograph, record the chromatograms, and measure
1
{6-Hydroxy-2-(4-hydroxyphenyl)-7-[4-(2-piperdin-1-yl-ethoxy)- the responses for the raloxifene peaks. Calculate the
benzoyl]benzo[b]thiophen-3-yl}-[4-(2-piperdin-1-yl-ethoxy)phen-
yl]-methanone. percentage of C28H27NO4S HCl in the portion of Raloxifene
2
[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]-{4-(2-(1-
oxo-piperdin-1-yl)ethoxy]phenyl}-methanone. Hydrochloride taken by the formula:
3
[6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-7-yl]-[4-(2-
In-Process Revision
piperdin-1-yl-ethoxy)phenyl]-methanone.
100(CS / CU)(rU / rS)
Assay—
Raloxifene Hydrochloride RS in the Standard preparation;
phosphate in 1000 mL of water, and mix. Add 1.5 mL of
CU is the concentration, in mg per mL, of Raloxifene
phosphoric acid, further adjust with phosphoric acid or
Hydrochloride in the Assay preparation; and rU and rS are the
potassium hydroxide solution to a pH of 2.5 + 0.1, and mix.
peak responses obtained from the Assay preparation and the
Buffer solution and acetonitrile (67 : 33). Make adjustments if
h621i).
Pharmacopeial Forum

BRIEFING
Raloxifene Hydrochloride Tablets. Because there is no existing
USP monograph for this drug product, a new monograph, based on in the Assay.
validated methods of analysis, is being proposed. The HPLC
procedure used in the test for Related compounds was validated
using an Inertsil C8 brand of L7 column. Raloxifene elutes at Dissolution h711i—
approximately 18 minutes. The HPLC procedure used in the Assay
was validated using a Zorbax Rx-C8 or SB-C8 brand of L7 column. Medium: 0.1% polysorbate 80; 1000 mL.
Raloxifene elutes at approximately 3 minutes. The HPLC procedure
used in the Dissolution test was validated using a Zorbax CN brand Apparatus 2: 50 rpm.
of L10 column.
Time: 30 minutes.
(MD-PS: D. Bempong; BPC: M. Marques) RTS—C47067 Determine the amount of C28H27NO4S HCl dissolved
acetonitrile, water, and triethylamine (500 : 500 : 2). Adjust
Add the following: with phosphoric acid to a pH of 4.0, filter, and degas. Make
&Raloxifene Hydrochloride Tablets adjustments if necessary (see System Suitability under
Triethylamine phosphate suspension—Add 2.0 mL of
» Raloxifene Hydrochloride Tablets contain not triethylamine to 500 mL of acetonitrile, mix, and adjust
with phosphoric acid to a pH of 4.0. [NOTE—Triethylamine
less than 93.0 percent and not more than 107.0
phosphate will precipitate; keep the suspension well mixed.]
percent of the labeled amount of raloxifene
hydrochloride (C28H27NO4S HCl).
tity of USP Raloxifene Hydrochloride RS in methanol, and
Packaging and storage—Preserve in tight containers, and dilute quantitatively, and stepwise if necessary, with methanol
store at controlled room temperature. to obtain a solution having a known concentration equivalent
USP Reference standards h11i—USP Raloxifene Hydro- to the expected concentration of the solution under test.
chloride RS. Transfer 5.0 mL of this solution to a suitable container, add

5.0 mL of Triethylamine phosphate suspension, and mix.
Identification—
A: Infrared Absorption h197Ki— Obtain the test speci-
In-Process Revision
through an appropriate filter having a porosity of 0.45 mm.

men as follows. Transfer a quantity of powdered Tablets,
Transfer 5.0 mL of the filtrate to a suitable container, add 5.0
equivalent to about 120 mg of raloxifene hydrochloride, to
mL of Triethylamine phosphate suspension, and mix.
a suitable container, add 20 mL of water, and shake to form
a uniform slurry. Centrifuge, and discard the supernatant. Add
5 mL of isopropyl alcohol, shake to form a slurry, filter, and
and a 4.6-mm 6 15-cm column that contains 3.5-mm base-
rinse the residue with isopropyl alcohol. Dry the residue at
deactivated packing L10. If the analyte peak splits, use
1058 for 30 minutes. Prepare a potassium bromide dispersion.
a guard column containing packing L3. The flow rate is about
Similarly prepare the standard specimen, starting with a slurry
2 mL per minute. Chromatograph the Standard solution, and
containing 12 mg of USP Raloxifene Hydrochloride RS per
mL of water.
Pharmacopeial Forum
record the peak responses as directed for Procedure: the System suitability stock solution—Transfer about 6 mg of
relative standard deviation for replicate injections is not more USP Raloxifene Hydrochloride RS to a 50-mL volumetric
than 2.0%. flask. Add 15.0 mL of acetonitrile, 3.0 mL of water, and 5.0
Procedure—Separately inject equal volumes (about 10 mL) mL of 30 percent hydrogen peroxide. Keep at 308 for at least
of the Standard solution and the Test solution into the 6 hours. Dilute with Diluent to 50.0 mL. [NOTE—Raloxifene
chromatograph, record the chromatograms, and measure the hydrochloride is partly converted to raloxifene N-oxide under
peak responses. Determine the percentage of these conditions.]
C28H27NO4S HCl dissolved by the formula: System suitability solution—Transfer about 15 mg of USP
Raloxifene Hydrochloride RS to a 50-mL volumetric flask,
and add 5.0 mL of System suitability stock solution and 20
mL of Diluent. Dilute with Solution A to volume, and mix.
tity of USP Raloxifene Hydrochloride RS in Diluent, and
in which rU and rS are the peak responses obtained from the dilute quantitatively, and stepwise if necessary, with Diluent
Test solution and the Standard solution, respectively; CS is the to obtain a solution having a known concentration of about
concentration, in mg per mL, of raloxifene hydrochloride in 0.06 mg per mL. Transfer 5 mL of this solution to a 100-mL
the Standard solution; 1000 is the volume, in mL, of volumetric flask, and add 45 mL of Diluent. Dilute with
Medium; 100 is the conversion factor to percentage; and L is Solution A to volume to obtain a solution having a known
the Tablet label claim, in mg. concentration of about 0.003 mg per mL.
Tolerances—Not less than 80% (Q) of the labeled amount Test solution—Transfer a sufficient quantity of Tablets to
of C28H27NO4S HCl is dissolved in 30 minutes. a volumetric flask of suitable size to obtain a solution of
Uniformity of dosage units h905i: meet the requirements. raloxifene hydrochloride having a concentration of 6 mg per
mL, based on the label claim. Add Diluent, and shake to
disintegrate the Tablets. Sonicate, if necessary, and add
Diluent to volume. Transfer 5 mL of this solution to a 10-mL
phosphate in 1000 mL of water, and mix. Add 0.5 mL of
volumetric flask, and dilute with Solution A to volume to
phosphoric acid, adjust with phosphoric acid or potassium
obtain a solution having a concentration of about 3 mg of
hydroxide solution to a pH of 3.0 + 0.1, and mix.
raloxifene hydrochloride per mL, based on the label claim.
In-Process Revision
Filter, and use the clear solution.
and a 4.6-mm 6 25-cm column that contains 5-mm base-
Diluent—Prepare a mixture of acetonitrile and Buffer
solution (60 : 40).
Pharmacopeial Forum
deactivated L7 packing. The column temperature is main- Assay—

tained at 358. The flow rate is about 1 mL per minute. The Buffer solution—Dissolve 7.2 g of monobasic potassium
chromatograph is programmed as follows. phosphate in 1000 mL of water, and mix. Add 1.3 mL of
phosphoric acid, adjust with phosphoric acid or potassium
hydroxide solution to a pH of 2.5 + 0.1, and mix.
0.00–5.00 100 0 isocratic
the Buffer solution and acetonitrile (67 : 33). Make adjust-
5.00–36.25 100?0 0?100 linear gradient
ments if necessary (see System Suitability under Chromatog-
36.25–38.25 0?100 100?0 linear gradient
raphy h621i).
38.25–48.00 100 0 equilibration
Diluent—Prepare a mixture of acetonitrile and Buffer
[NOTE—Adjust the start time of the gradient step on the basis
solution (60 : 40).
of the instrument’s dwell volume.] Chromatograph the System
System suitability stock solution—Prepare as directed in the
suitability solution, and record the peak responses as directed
test for Related compounds.
for Procedure: the resolution, R, between raloxifene and
raloxifene N-oxide is not less than 3.0; and the tailing factor
quantity of USP Raloxifene Hydrochloride RS in Diluent, and
for the raloxifene peak is not more than 2.0.
dilute quantitatively, and stepwise if necessary, with Diluent
of the Standard solution and Test solution into the
0.06 mg per mL.
chromatograph, record the chromatograms for not less than
Assay preparation—Transfer a sufficient quantity of Tablets
two times the retention time of the raloxifene peak, and
to a volumetric flask of suitable size, add Diluent, and shake
measure all the peak responses. Calculate the percentage of
to disintegrate the Tablets. Sonicate if necessary. Dilute
each impurity in the portion of Tablets taken by the formula:
quantitatively with Diluent to obtain a solution having
a concentration of about 0.06 mg of raloxifene hydrochloride
100(CS / CU)(ri / rS)
per mL, based on the label claim. Filter, and use the clear
in which CS is the concentration, in mg per mL, of raloxifene solution.
hydrochloride in the Standard solution; CU is the concentra- Chromatographic system (see Chromatography h621i)—
tion, in mg per mL, of raloxifene hydrochloride in the Test The liquid chromatograph is equipped with a 280-nm detector
In-Process Revision
solution; ri is the response for each impurity in the Test and a 4.6-mm 6 15-cm column that contains 3.5-mm base-
solution; and rS is the response of the raloxifene peak deactivated L7 packing. The column temperature is main-
obtained from the Standard solution: the limits are as shown tained at 358. The flow rate is about 1.5 mL per minute.
in the table below. Disregard any peak that is less than 0.05%. Chromatograph the System suitability stock solution, and
Related compound Relative retention time Limit (%)

Raloxifene 1.00 —
Raloxifene N-oxide 1 1.17 NMT 0.3
Any unspecified individual impurity — NMT 0.2
Total impurities — NMT 1.0
1
6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-7-yl]-[4-(2-piperdin-1-yl-ethoxy)phenyl]methanone.
Pharmacopeial Forum
record the peak responses as directed for Procedure: the

&
h197i—&1S (USP30)
Test specimen—Dissolve 50 mg of Ritonavir in 1.0 mL of
resolution, R, between raloxifene and raloxifene N-oxide is chloroform. Add 1 drop of this solution to the surface of a potassium
bromide or a sodium chloride disk, and evaporate to dryness.
not less than 2.0; and the tailing factor for the raloxifene peak B: The retention time of the major peak in the chromatogram of
the Assay preparation is within 2% of the retention time of the major
is not more than 2.0. Chromatograph the Standard prepara- peak in the chromatogram of the Standard preparation, as obtained
in the Assay.
tion, and record the peak responses as directed for Procedure: C: X-Ray diffraction h941i—The X-ray diffraction pattern
conforms to that of USP Ritonavir RS.
the relative standard deviation for replicate injections is not &
&2S (USP30)
more than 1.0%.
Add the following:
&
X-ray diffraction h941i—The X-ray diffraction pattern
the chromatograph, record the chromatograms, and measure conforms to that of USP Ritonavir RS if the drug substance is
the responses for the raloxifene peaks. Calculate the used for the solid dosage forms.&2S (USP30)
percentage of raloxifene hydrochloride (C28H27NO4S HCl), Change to read:

based on the label claim, in the portion of Tablets taken by the
Related compounds—[NOTE—Ritonavir is alkaline
formula: &
alkali&1S (USP30)
sensitive. All glassware should be prerinsed with distilled water prior
to use to remove residual detergent contamination.]
100(CS / CU)(rU / rS) Monobasic potassium phosphate solution (0.03M), Diluent,
Solution A, Solution B, and Mobile phase—Prepare as directed in
the Assay.
Standard stock solution and Intermediate stock solution—Prepare
in which CS is the concentration, in mg per mL, of raloxifene as directed for Standard stock preparation and Intermediate
standard preparation in the Assay.
hydrochloride in the Standard preparation; CU is the Ritonavir identity standard solution—Transfer about 50 mg of
USP Ritonavir Related Compounds Mixture RS, accurately
concentration, in mg per mL, of raloxifene hydrochloride in weighed, to a 50-mL volumetric flask. Dissolve in and dilute with
Diluent to volume, and mix.
the Assay preparation, based on the label claim; and rU and rS
&
Dissolve an accurately weighed quantity of USP Ritonavir
are the peak responses obtained from the Assay preparation
Related Compounds Mixture RS, and dilute quantitatively
and the Standard preparation, respectively.&2S (USP31)
with Diluent to obtain a solution having a concentration of
about 1 mg per mL.&2S (USP31)
Standard solution—Transfer 5.0 mL of the Intermediate standard
BRIEFING solution to a 100-mL volumetric flask, dilute with Diluent to volume,
and mix. [NOTE—This solution may be used for 48 hours if stored at
room temperature.]
Test solution—Transfer about 50 mg of Ritonavir, accurately
Ritonavir, USP 30 page 3143 and page 1113 of PF 32(4) [July.– weighed, to a 50-mL volumetric flask. Dissolve in and dilute with
Aug. 2006]. It is proposed to remove the specified amount of USP Diluent to volume, and mix.
Ritonavir Compounds Mixture RS used in the preparation of the
In-Process Revision
Ritonavir identity standard solution. This will provide the flexibility liquid chromatograph is equipped with a 240-nm detector and
to use proportionally smaller quantities/volumes and to prepare a 4.6-mm 6 15-cm column that contains 3-mm packing L26 and is
a solution with a final known concentration of about 1 mg per mL for maintained at a constant temperature of about 608. The flow rate is
the Related compounds test. about 1.0 mL per minute. The chromatograph is programmed as
It is also proposed to reformat the formula in the Related follows.
compounds test to be consistent with the recommendations in the
Stimuli article, Common Pharmacopeial Calculations in USP Time Solution A Solution B
Monographs, published on page 626 of PF 31(2) [Mar.–Apr. 2005]. (minutes) (%) (%) Elution
0 100 0 equilibrium
(MD-AA: B. Davani; H. Ramanathan) RTS—C49018 0–60 100 0 isocratic
60–120 100?0 0?100 gradient
120.1 0?100 100?0 step gradient
Change to read: 120.1–155 100 0 isocratic
The run time for the Standard solution is 40 minutes, and the run
Identification— time for the Test solution is 155 minutes. Chromatograph the
A: Infrared Absorption h197Si Ritonavir identity standard solution and the Standard solution, and
record the responses as directed for Procedure: the retention time of
ritonavir is between 30 and 35 minutes; the resolution, R, between
Pharmacopeial Forum
impurity E and impurity F (see Table 1) in the Ritonavir identity relative to ritonavir, as presented in Table 1; and P is the
standard solution is not less than 1.0; the ratio of peak (Hp) to valley
(Hv) of purity, in percentage, of USP Ritonavir RS taken to prepare
&
ritonavir and&1S (USP30) the Standard solution:&2S (USP31)
impurity N (regioisomer) is not less than 1; the capacity factor, k ’, not more than 0.3% of impurity E and O is found; not more than
using the main component peak of the first Standard solution 0.2% of impurity T is found; not more than 0.1% of any other
injection, is not less than 13; the column efficiency, using the main impurity is found; and not more than 1.0% of total impurities is
component peak of the first Standard solution injection, is not less found.
than 5000 theoretical plates; the tailing factor, using the main
component peak of the first Standard solution injection, is between
0.8 and 1.2; and the relative standard deviation of the peak area
response of the main component peak, for replicate injections of the
Standard solution, is not more than 3.0%.
Procedure—Separately inject equal volumes (about 50 mL) of the BRIEFING
Diluent, Ritonavir identity standard solution, Standard solution, and
Test solution into the chromatograph, record the chromatograms, and
measure the peak area responses. Calculate the percentage of each Tizanidine Tablets, USP 30 page 3366. It is proposed to update
impurity in the portion of Ritonavir taken by the formula: the Tolerances in the Dissolution test to be in accordance with those
approved by FDA. In the absence of any negative comments, it is
0.0025(WS / WT) (RT / RS)(1/F)P proposed to implement this revision via the Interim Revision
in which WS is the the weight, in mg, of USP Ritonavir RS taken to Announcement pertaining to USP 30–NF 25 in PF 33(6) [Nov.–
prepare the Standard solution; WT is the weight, in mg, of Ritonavir Dec. 2007], with an official date of December 1, 2007.
taken to prepare the Test solution; RT is the area of the impurity peak
obtained from the Test solution; RS is the average peak area of (BPC: M. Marques) RTS—C55251
ritonavir obtained from the the six injections of the Standard
solution; F is the response factor for the impurity (see values in
Table 1); and P is the purity, in percentage, of USP Ritonavir RS
taken to prepare the Standard solution.
&
Tizanidine Tablets
100(CS / CT)(ri / rS)(1/F)P Change to read:
in which CS and CT are the concentrations, in mg per mL, of Medium: 0.1 N hydrochloric acid; 500 mL, degassed.
ritonavir in the Standard solution and in the Test solution, Time: 45 minutes .15 minutes..6
Determine the amount of tizanidine hydrochloride
respectively; ri is the peak response for each impurity (C9H8ClN5S HCl) dissolved by employing the following method.
Phosphoric acid solution, Buffer solution, and Mobile phase—
obtained from the Test solution; rS is the average peak Proceed as directed in the Assay.
Standard stock solution—Dissolve an accurately weighed quantity
response of ritonavir obtained from the six injections of of USP Tizanidine Hydrochloride RS, and dilute quantitatively, and
Standard solution; F is the response factor for each impurity, a concentration of about 201 mg per mL.
Table 1. Approximate Relative Retention Time (RRT) for Known Related Impurities
In-Process Revision
Impurity Identity Common Name Response Factor RRT

A+B Mixture of 2,4-Wing acid and monoacyl valine — 0.07
C Monoacylacetamide — 0.15
D 5-Wing diacyl 1.37 0.24
E Oxidation impurity — 0.36
F Acid hydrolysis product 0.73 0.39
G Ritonavir hydroperoxide — 0.45
H Acid/base by-product 0.76 0.47
I Ethyl analog — 0.64
J+K Mixture of Boc-monoacyl and monoacyl isobutyl carbamate 0.74 0.81
L Base cyclization product 0.53 0.87
M 2,4-Wing isobutyl ester — 0.94
N Regioisomer — 1.05
O Isomer #2 — 1.11
P Di-monoacyl urea — 1.14
Q Isomer #4 — 1.23
R Isomer #1 — 1.32
S Di-monoacyl valine urea — 1.62
T 2,4-Wing diacyl 0.73 2.87
U Triacyl impurity — 3.20
Pharmacopeial Forum
Working standard solution—For Tablets labeled to contain 2 mg, Add the following:
transfer 4.0 mL of the Standard stock solution to a 200-mL
volumetric flask, dilute with Medium to volume, and mix. For &
Completeness of solution h641i—A solution of 1.40 g of
Tablets labeled to contain 4 mg, transfer 4.0 mL of the Standard
stock solution to a 100-mL volumetric flask, dilute with Medium to Triclosan in 10 mL of acetone is clear.&2S (USP31)
volume, and mix.
Test solution—Withdraw 10 mL of the solution under test. Pass
through a suitable 0.45-mm filter, discarding the first 5 mL of the Change to read:
filtrate.
Chromatographic system (see Chromatography h621i)—The Assay—
a 4.6-mm 6 25-cm column that contains packing L1. The flow rate Standard preparation—Dissolve an accurately weighed quantity
is about 1.0 mL per minute. The column temperature is maintained at of USP Triclosan RS in dichloromethane
508. Chromatograph the Working standard solution, and record the
peak responses as directed for Procedure: the column efficiency is
&
ethyl acetate,&1S (USP30)
not less than 2000 theoretical plates; the tailing factor is not more and dilute quantitatively, and stepwise if necessary, with dichloro-
than 2.0; and the relative standard deviation for replicate injections is methane
not more than 2.0%.
&
ethyl acetate&1S (USP30)
Working standard solution and the Test solution into the chromat- to obtain a solution having a known concentration of about 4.0
the major peaks. Calculate the quantity, in percentage, of
&
0.4&1S (USP30)
C9H8ClN5S HCl dissolved by the formula: mg per mL.
Assay preparation—Transfer about 40 mg of Triclosan, accurately
weighed, to a 10-mL
&
100-mL&1S (USP30)
volumetric flask, dissolve in and dilute with dichloromethane
&
ethyl acetate&1S (USP30)
in which rU and rS are the peak responses for the Test solution and the to volume, and mix.
Working standard solution, respectively; CS is the concentration, in Chromatographic system (see Chromatography h621i)—The gas
mg per mL, of the Working standard solution; 500 is the volume, in chromatograph is equipped with a flame-ionization detector and
mL, of Medium; 100 is the conversion factor to percentage; LC is the a 0.53-mm 6 15-m capillary column with G3. The carrier gas is
Tablet label claim, in mg; 253.71 is the molecular weight of helium maintained at about 6 psi. The injector temperature is
tizanidine; and 290.17 is the molecular weight of tizanidine maintained at 348 and is increased rapidly to 2008 immediately after
hydrochloride. the injection, the column temperature is maintained at 348, and the
Tolerances—Not less than 80% (Q) of the labeled amount of detector temperature is maintained at 2608. Chromatograph the
C9H8ClN5S HCl is dissolved in 45 minutes Standard preparation, and record the peak responses as directed for
Procedure: the relative standard deviation for replicate injections is
.15 minutes..6 not more than 2.0%.
Procedure—Separately inject equal volumes (about 0.5
&
2.0&1S (USP30)
mL) of the Standard preparation and the Assay preparation into the
chromatograph, increase the column temperature by 208 per minute
to 1408, then increase the column temperature by 48 per minute to
BRIEFING 2408, maintain this temperature for not less than 5 minutes, record
the chromatograms, and measure the responses for the major peaks.
Calculate the quantity, in mg, of C12H7Cl3O2 in the portion of
Triclosan, USP 30 page 3404 and page 377 of PF 32(2) [Mar.– Triclosan taken by the formula:
Apr. 2006]. On the basis of supporting data received, it is proposed
to replace the test for Residue on ignition with a test for 10C(rU / rS)
Completeness of solution. The rationale for this proposal is to
avoid potential exposure to dioxin, a toxic substance that can be
In-Process Revision
released in the test for Residue on ignition.
(MD-AA: B. Davani) RTS—C46453 &

100C(rU / rS)&1S (USP30)
Delete the following: in which C is the concentration, in mg per mL, of USP Triclosan RS
in the Standard preparation; and rU and rS are the peak responses
&
Residue on ignition h281i: not more than 0.1%.&2S (USP31) respectively.
Pharmacopeial Forum
Related Compound F RS in 0.0025 N hydrochloric acid, and dilute

BRIEFING quantitatively, and stepwise if necessary, with 0.0025 N hydrochloric
acid to obtain a solution having a known concentration of
Vecuronium Bromide, USP 30 page 3453. The currently official

&
containing&2S (USP31)
about 0.005 mg of each compound per mL.
test for Related compounds requires the use of quantitative reference
standards. During the reference standard development collaborative &
Standard solution—Dissolve an accurately weighed
study, comments were received from the collaborators about the
hygroscopic nature of the related compounds, which makes their use quantity of USP Vecuronium Bromide RS in 0.0025 N
as quantitative references rather difficult. On the basis of these
comments, it is proposed to revise the test for Related compounds to hydrochloric acid to obtain a solution having a known
use a solution containing the related compounds for peak
identification and system suitability purposes only, and to quantify concentration of about 0.005 mg per mL.&2S (USP31)
the related compounds using relative response factors. The specific Test solution—Transfer about 25 mg of Vecuronium Bromide,
proposed changes are as follows: accurately weighed, to a 25-mL volumetric flask. Add 0.5 mL of
1. A System suitability solution containing a mixture of all the acetonitrile, dilute with 0.0025 N hydrochloric acid to volume, and
related compounds has been included. mix.
2. The Standard solution now contains only vecuronium bromide.
3. The calculation in the test for Related compounds has been &
Add 0.5 mL of acetonitrile, sonicate to aid dissolution,
revised using the relative response factors.
In addition, the sequence of addition of Mobile phase components rapidly add 0.0025 N hydrochloric acid to volume, and mix
has been modified to minimize the loss of tetrahydrofuran. A note
indicating the possible need for longer than 4 hours of system promptly.&2S (USP31)
equilibration has been included. Chromatographic system (see Chromatography h621i)—The
liquid ion
&
&2S (USP31)
chromatograph is equipped with a conductivity detector, a 4-mm
Change to read: cation suppressor, and a 4.6-mm 6 25-cm column that contains
&
5-mm&2S (USP31)
Related compounds— packing L1. The flow rate is about 1.5 mL per minute. The flow rate
for the cation suppressor is about 2 mL per minute. Chromatograph
&
[NOTE—This note applies to all of the solution prepara- the Standard solution,
tions. The addition, with sonication, of a small amount of &
System suitability solution,&2S (USP31)
and record the peak responses as directed for Procedure: the relative
acetonitrile (a maximum of 0.5 mL per 25 mg) to the weighed retention times are given in Table 1; and the ratio of the height of the
peak for vecuronium bromide related compound F to the height of
quantity of the related compounds, as well as to vecuronium the valley
bromide, may be used to aid in dissolution. Shaking and &
trough&2S (USP31)
between the peak for vecuronium bromide related compound F and
sonication may also be used after the addition of the required the peak for pancuronium bromide is not less than 2.0. and the
amount of 0.0025 N hydrochloric acid.]&2S (USP31) 10.0% for each compound. [NOTE—The system may need equilibra-
Cation suppressor regeneration solution: 0.02 M tetrabutylam- tion for 4 hours.]
monium hydroxide.
Mobile phase—Mix 1500 mL of filtered water, 250 mL of filtered &
methanol, 45 mL of filtered tetrahydrofuran, and 1 mL of
hydrochloric acid in a 2000-mL volumetric flask. Leave at room responses as directed for Procedure: the relative standard
temperature for few minutes, and dilute with water to volume. Mix,
and degas. deviation for three replicate injections of vecuronium bromide
In-Process Revision
&
Mix 1500 mL of filtered water, 250 mL of filtered methanol, is not more than 10.0%. [NOTE—The system may need
and 1 mL of hydrochloric acid in a 2000-mL volumetric flask. equilibration for 4 hours or longer. It is recommended that the
Leave at room temperature for a few minutes, add 45 mL of column be rinsed with a mixture of acetonitrile and water
filtered tetrahydrofuran, and dilute with water to volume. Mix (1 : 1) and stored in the same mixture when not in
and degas.&2S (USP31) use.]&2S (USP31)
[NOTE—Avoid evaporation of tetrahydrofuran during degassing.] Procedure—Separately inject equal volumes (about 25 mL) of the
Standard solution Standard solution and the Test solution into the chromatograph,
&
System suitability solution—&2S (USP31) Calculate the percentage of each vecuronium bromide related
Dissolve an accurately weighed quantity compound in the portion of Vecuronium Bromide taken by the
formula:
&
suitable quantities&2S (USP31)
of USP Vecuronium Bromide RS, USP Pancuronium Bromide RS, 2500(C/W)(rU / rS)
USP Vecuronium Bromide Related Compound A RS, USP
Vecuronium Bromide Related Compound B RS, USP Vecuronium in which C is the concentration, in mg per mL, of the relevant USP
Bromide Related Compound C RS, and USP Vecuronium Bromide Reference Standard in the Standard solution; W is the weight, in mg,
of Vecuronium Bromide taken to prepare the Test solution;and rU and
rS are the peak areas for the correspondent vecuronium bromide
Pharmacopeial Forum
related compound obtained from the Test solution and Standard in which F is the relative response factor of the specific
solution, respectively: the limits of impurities are specified in Table
1. [NOTE—Use the peak area of vecuronium bromide in the Standard related compound obtained from Table 1; CS is the
solution as rS to calculate any unknown impurity.]
concentration, in mg per mL, of USP Vecuronium Bromide
Table 1
RS in the Standard solution; CT is the concentration, in mg
Relative
Retention Limit per mL, of vecuronium bromide in the Test solution; rU is the
Compound Name Time %
Pancuronium bromide about 0.5 0.5 peak area of each related compound in the Test solution; and
Vecuronium bromide related about 0.6 0.5
compound F1 rS is the peak area for vecuronium bromide in the Standard
compound C2 solution: the limits of impurities are specified in Table 1.
Vecuronium bromide 1.0 —
compound A3
compound B4 BRIEFING
Unknown — 0.1
Total — 1.0
1
3-deacetyl vecuronium bromide, (Piperidinium, 1-[(2b,3a,5a,16b,17b)-17- Verapamil Hydrochloride Extended-Release Tablets, USP 30
acetyloxy-3-hydroxy-2-(1-piperidinyl)androstan-16-yl]-1-methyl bromide) page 3456. It is proposed to include the 120-mg strength tablet in
2
3,17-Bis deacetyl vecuronium bromide; (Piperidinium, 1- Dissolution Test 2. Also, it is proposed to update the Medium in
[(2b,3a,5a,16b,17b)-3,17-dihydroxy-2-(1-piperidinyl)androstan-16-yl]-1- Dissolution Test 4 in accordance with the FDA approval. In the
methyl bromide)
3
absence of any adverse comment, it is proposed to implement this
Dipiperidino diol diacetate; (3a,17b-diacetyl-oxy-2b,16b-bispiperidinyl- revision in PF 33(6) [Nov.–Dec. 2007] via the Interim Revision
5a-androstan) Announcement pertaining to USP 30–NF 25, with an official date of
4
17-deacetyl vecuronium bromide; (Piperidinium, 1-[(2b,3a,5a,16b,17b)-3- December 1, 2007.
acetyloxy-17-hydroxy-2-(1-piperidinyl)androstan-16-yl]-1-methyl bromide)
&
100(1/F)(CS / CT)(rU / rS)
Table 1
Relative Relative
Compound Name Time Factor (RRF) (%)
Pancuronium bromide about 0.5 1.1 0.5
1
Vecuronium bromide related compound F about 0.6 1.3 0.5
Vecuronium bromide related compound C2 about 0.9 1.4 0.5
In-Process Revision
Vecuronium bromide 1.0 — —
Vecuronium bromide related compound A3 about 1.8 0.4 0.3
4
Vecuronium bromide related compound B about 2.2 1.0 0.5
Any individual unspecified impurity — 1.0 0.1
Total — — 1.0
1
3-Deacetyl vecuronium bromide, (Piperidinium, 1-[(2b,3a,5a,16b,17b)-17-acetyloxy-3-hydroxy-2-(1-piperidinyl)androstan-16-yl]-1-methyl
bromide)
2
3,17-Bis deacetyl vecuronium bromide; (Piperidinium, 1-[(2b,3a,5a,16b,17b)-3,17-dihydroxy-2-(1-piperidinyl)androstan-16-yl]-1-methyl
bromide)
3
Dipiperidino diol diacetate; (3a,17b-diacetyl-oxy-2b,16b-bispiperidinyl-5a-androstan)
4
17-Deacetyl vecuronium bromide; (Piperidinium, 1-[(2b,3a,5a,16b,17b)-3-acetyloxy-17-hydroxy-2-(1-piperidinyl)androstan-16-yl]-1-
methyl bromide)
&2S (USP31)
Pharmacopeial Forum
Change to read: FOR PRODUCTS LABELED TO CONTAIN 180 MG:

TEST 1—If the product complies with this test, the labeling 1 between 10% and 25%
indicates that it meets USP Dissolution Test 1. Proceed as directed 2 between 20% and 40%
for Procedure for Method B under Apparatus 1 and Apparatus 2, 3.5 between 40% and 75%
Delayed-Release Dosage Forms. 8 not less than 80%
Acid stage—Using 900 mL of simulated gastric fluid TS (without
enzyme), conduct this stage of the test for 1 hour.
Buffer stage—Using 900 mL of simulated intestinal fluid TS TEST 3—If the product complies with this test, the labeling
(without enzyme), conduct this stage of the test for 7 hours. indicates that it meets USP Dissolution Test 3. Proceed as directed
Apparatus 2: 50 rpm. for Test 1.
Times: Acid stage—1 hour; Buffer stage—2, 3.5, 5, and 8 hours. Times and Tolerances—The percentage of the labeled amount of
Procedure—Wrap each Tablet in a wire helix to prevent the C27H38N2O4 HCl dissolved at the times specified conforms to
Tablets from floating. After 1 hour in the Acid stage, withdraw Acceptance Table 2.
a specimen for analysis, and carefully transfer the dosage form,
including the wire helix, to a vessel containing the Buffer stage Time (hours) Amount dissolved
medium, which has been previously warmed to 37 + 0.58. Filter 1 between 8% and 20%
a portion of the solution under test at each time interval, using 2 between 15% and 35%
a suitable glass microfiber filter paper. [NOTE—Use only filters that 3.5 between 27% and 57%
have been shown not to absorb verapamil.] Dilute, if necessary, the 5 between 45% and 75%
filtered portions of the solutions under test with water at the 1-hour 8 not less than 80%
interval and with 0.1 N hydrochloric acid at the 2-, 3.5-, 5-, and
8-hour intervals. Determine the amounts of C27H38N2O4 HCl
dissolved by employing UV absorption at the wavelength of TEST 4—If the product complies with this test, the labeling
maximum absorbance at about 278 nm, using 0.01 N hydrochloric indicates that it meets USP Dissolution Test 4.
acid as the blank, by comparison with a Standard solution having Phosphate buffer solution—Dissolve 6.8 g of monobasic potassi-
a known concentration of USP Verapamil Hydrochloride RS in um phosphate in 250 mL of water. Add 190 mL of 0.2 N sodium
0.01 N hydrochloric acid. hydroxide in 400 mL of water, adjust with 0.2 N sodium hydroxide
Tolerances—The percentage of the labeled amount of to a pH of 7.5 + 0.1, dilute with water to 1000 mL, and mix.
C27H38N2O4 HCl dissolved at the times specified conforms to
Acceptance Table 2. .
.6
Medium: Phosphate buffer solution
.simulated intestinal fluid TS (without enzyme);.6
FOR PRODUCTS LABELED TO CONTAIN 180 MG OR 240 MG:
50 mL.
Time (hours) Amount dissolved Apparatus 7 (see Drug Release h724i): 20 cycles per minute.
Procedure—Scrape about 2 mm 6 2 mm of the coating from the
1 between 7% and 15% side edge of the Tablet under test. Glue the system to a plastic rod
2 between 16% and 30% sample holder at the area where the color has been removed. Attach
3.5 between 31% and 50% each plastic sample holder to an arm of the apparatus, which
5 between 51% and 75% reciprocates at an amplitude of about 2 cm and 15 to 30 cycles per
8 not less than 85% minute. The Tablet is continuously immersed in tubes containing 50
mL of Medium at 378. At the end of each specified test interval, the
systems are transferred to the next row of new test tubes containing
50 mL of fresh Medium. Remove the tubes after the last test interval,
FOR PRODUCTS LABELED TO CONTAIN 120 MG: and allow them to cool to room temperature. Add 2.0 mL of 1.0 M
phosphoric acid to each tube, and dilute with water to 50 mL. Stir
Time (hours) Amount dissolved and mix each tube thoroughly. Determine the amount of
1 between 10% and 21% C27H38N2O4 HCl dissolved by employing UV absorption at the
2 between 18% and 33% wavelength of maximum absorbance at about 278 nm on filtered
3.5 between 35% and 60% portions of the solution under test, suitably diluted with Medium, if
5 between 50% and 82% necessary, in comparison with a Standard solution having a known
8 not less than 85% concentration of USP Verapamil Hydrochloride RS in the same
Medium.
In-Process Revision
Times and Tolerances—The percentages of the labeled amount of

TEST 2—If the product complies with this test, the labeling C27H38N2O4 HCl dissolved at the times specified conform to
indicates that it meets USP Dissolution Test 2. Proceed as directed Acceptance Table 2.
for Test 1, except that for Procedure, the Tablet is not required to be
wrapped in a wire helix. Time (hours) Amount dissolved
Times and Tolerances—The percentage of the labeled amount of 3 not more than 10%
C27H38N2O4 HCl dissolved at the times specified conforms to 6 between 20% and 50%
Acceptance Table 2. 9 between 52.5% and 82.5%
FOR PRODUCTS LABELED TO CONTAIN
.120 MG OR
.6
240 MG: TEST 5—If the product complies with this test, the labeling
Time (hours) Amount dissolved Phosphate buffer solution—Dissolve 6.8 g of monobasic potassi-
um phosphate in 250 mL of water. Add 190 mL of 0.2 N sodium
1 between 8% and 20% hydroxide in 400 mL of water, adjust with 0.2 N sodium hydroxide
2 between 15% and 35% to a pH of 7.5 + 0.1, dilute with water to 1000 mL, and mix.
3.5 between 35% and 65% Medium: Phosphate buffer solution; 900 mL.
5 between 55% and 85% Apparatus 2: 50 rpm.
8 not less than 80%
Pharmacopeial Forum
Procedure—Determine the amount of C27H38N2O4 HCl dissolved Extract is between 153 : 1 and 76 : 1. It contains not
absorbance at about 278 nm on filtered portions of the solution under less than 36.0 percent of anthocyanosides, calcu-
test, suitably diluted with Medium, if necessary, in comparison with
a Standard solution having a known concentration of USP Verapamil
Hydrochloride RS in the same Medium. lated as cyanidin-3-O-glucoside chloride, and not
Times and Tolerances—The percentages of the labeled amount of
C27H38N2O4 HCl dissolved at the times specified conform to more than 1.0 percent of anthocyanidins, calculated
Acceptance Table 2.
as cyanidin chloride; both are calculated on the
1 between 2% and 12% anhydrous basis.
8 not less than 80% Packaging and storage—Preserve in well-closed containers,
protected from light and moisture, and store at controlled
room temperature.
Labeling—The label states the Latin binomial and, following

DIETARY SUPPLEMENTS— the official name, the part of the plant contained in the article.
MONOGRAPHS It meets other labeling requirements under Botanical Extracts
h565i.
USP Reference standards h11i—USP Powdered Bilberry

BRIEFING
Extract RS. USP Cyanidin Chloride RS. USP Cyanidin-3-O-
Powdered Bilberry Extract. A new monograph is being glucoside Chloride RS.

proposed. The liquid chromatographic procedure in the test for
Content of anthocyanosides and anthocyanidins is based on analyses Identification—
performed with the Zorbax Extend brand of L1 column. The typical
retention times observed are about 11.9, 14.2, 16.3, 16.7, 19.5, 21.0, A: Thin-Layer Chromatographic Identification Test
21.6, 24.2, 25.0, 26.4, 26.9, 30.2, 30.8, 32.5, 34.2, 35.4, 37.1, 40.5,
44.1, and 44.8 minutes for delphinidin-3-O-galactoside chloride, h201i—
delphinidin-3-O-glucoside chloride, cyanidin-3-O-galactoside chlo-
ride, delphinidin-3-O-arabinoside chloride, cyanidin-3-O-glucoside Standard solution—Dissolve about 100 mg of USP
chloride, petunidin-3-O-galactoside chloride, cyanidin-3-O-arabino-
side chloride, petunidin-3-O-glucoside chloride, delphinidin chlo- Powdered Bilberry Extract RS in 25 mL of methanol,
ride, peonidin-3-O-galactoside chloride, petunidin-3-O-arabinoside
chloride, peonidin-3-O-glucoside chloride, malvidin-3-O-galactoside centrifuge, and use the clear supernatant.
chloride, peonidin-3-O-arabinoside chloride, malvidin-3-O-gluco-
side chloride, cyanidin chloride, malvidin-3-O-arabinoside chloride, Test solution—Proceed as directed for the Standard
petunidin chloride, peonidin chloride, and malvidin chloride,
respectively. solution, except to use Powdered Extract.
(DSB: M. Sharaf) RTS—C50934 Adsorbent—Use suitable thin-layer chromatographic plates
coated with a layer of cellulose.
In-Process Revision
Add the following: Developing solvent system A—Use a mixture of water,
&Powdered glacial acetic acid, and hydrochloric acid (82 : 15 : 3).

Bilberry Extract
Developing solvent system B—Use a mixture of glacial
acetic acid and water (6 : 4).
Procedure—Use a saturated chamber. Develop the chro-
» Powdered Bilberry Extract is prepared from the
matograms using Developing solvent system A until the
ripe fruits of Vaccinium myrtillus L. (Fam. solvent front has moved about three-fourths of the plate, and
Ericaceae) using suitable solvents such as alcohol, dry the plate with the aid of a current of warm air. Develop
methanol, or water or mixtures of these solvents. the chromatograms in the same direction using Developing
The ratio of the starting plant material to Powdered solvent system B until the solvent front has moved about
Pharmacopeial Forum
three-fourths of the plate, and dry the plate with the aid of filter, wash the flask with 30 mL of 0.1 N hydrochloric acid,
a current of warm air. Examine the plate under visible light: and transfer the washings to the filter. Wash the filter with 30
the chromatogram of the Test solution exhibits three main red mL of 0.1 N hydrochloric acid in 5-mL portions. Dry the filter
bands with RF values of approximately 0.55, 0.65, and 0.70 for three hours at 1058, cool in a desiccator, and weigh.
that are similar in position and color to the corresponding Calculate the percentage of the 0.1 N hydrochloric acid
main bands in the chromatogram of the Standard solution. insoluble fraction: not more than 5% is found.
B: The retention times of the anthocyanoside peaks in the Content of anthocyanosides and anthocyanidins—
chromatogram of the Test solution correspond to those in the Solvent: a mixture of methanol and hydrochloric acid
chromatogram of Standard solution 3, as obtained in the test (98 : 2).
for Content of anthocyanosides and anthocyanidins; the Diluent: a mixture of water and 85% phosphoric acid
peaks due to delphinidin-3-O-galactoside chloride and (9 : 1).
delphinidin-3-O-glucoside chloride are the most intense Solution A—Prepare a filtered and degassed mixture of
peaks in the chromatogram and are of similar intensity, and water and formic acid (9 : 1).
each is more intense than the peak due to cyanidin-3-O- Solution B—Prepare a filtered and degassed mixture of
glucoside chloride; the peaks due to cyanidin-3-O-galactoside w a t e r, a ce t o n i t r i l e , m e t h a no l , a n d fo r m i c a c i d
chloride, delphinidin-3-O-arabinoside chloride, and cyanidin- (40 : 22.5 : 22.5 : 10).
3-O-glucoside chloride are of similar intensity; and each of Mobile phase—Use variable mixtures of Solution A and
the remaining anthocyanoside peaks in the chromtogram is of Solution B as directed for Chromatographic system. Make
lower intensity than the peak due to cyanidin-3-O-glucoside adjustments if necessary (see System Suitability under
chloride. Chromatography h621i).
Microbial enumeration h2021i—The total aerobic microbial Standard solution 1—Dissolve, using sonication, an
count does not exceed 104 cfu per g. The total combined yeast accurately weighed quantity of USP Cyanidin-3-O-glucoside
and mold count does not exceed 103 cfu per g. Chloride RS in Solvent to obtain a solution having a known
Absence of specified microorganisms h2022i—It meets the concentration of about 0.4 mg per mL. Transfer 2.0 mL of
requirements of the tests for absence of Salmonella species this solution to a 10-mL volumetric flask, dilute with Diluent
and Escherichia coli. to volume, and mix. [NOTE—This solution is stable for 48
hours at 48.]
Water, Method Ia h921i: not more than 4.5%, determined
In-Process Revision
Standard solution 2—Dissolve, using sonication, an

on 0.5 g.
accurately weighed quantity of USP Cyanidin Chloride RS
in Solvent to obtain a solution having a known concentration
mined on 1.0 g.
of about 0.5 mg per mL. Transfer 2.0 mL of this solution to
Pesticide residues h561i: meets the requirements. a 100-mL volumetric flask, dilute with Diluent to volume,
Heavy metals, Method II h231i: not more than 20 mg per g. and mix. [NOTE—This solution is stable for 36 hours at 48.]
Standard solution 3—Transfer about 125 mg of USP
0.1 N Hydrochloric acid insoluble fraction—Finely grind
Powdered Bilberry Extract RS, accurately weighed, to a
about 5 g of Powdered Extract. Transfer about 1 g, accurately
100-mL volumetric flask, add 25 mL of Solvent, sonicate to
weighed, to a 500-mL flask, add 200 mL of 0.1 N
dissolve, dilute with Diluent to volume, and mix. [NOTE—
hydrochloric acid, and shake vigorously for two hours.
This solution is stable for 48 hours at 48.]
Filter the solution through a previously tared sintered-glass
Pharmacopeial Forum
Test solution—Proceed as directed for Standard solution 3, USP Powdered Bilberry Extract RS being used, identify the
except to use Powdered Extract. retention times of the peaks corresponding to the different
Chromatographic system (see Chromatography h621i)— anthocyanosides and anthocyanidins. The approximate rela-
[NOTE—Use deactivated silanized HPLC vials.] The liquid tive retention times of the anthocyanosides and anthocyani-
chromatograph is equipped with a refrigerated autosampler dins are provided in the following table:
maintained at 48, a 535-nm detector, and a 4.6-mm 6 25-cm
Relative Retention
column that contains 5-mm L1 packing. The flow rate is about
Analyte Time
1.0 mL per minute. The column temperature is maintained at
Delphinidin-3-O-galactoside chloride 0.61
30+18. The chromatograph is programmed as follows:
Delphinidin-3-O-glucoside chloride 0.73
Cyanidin-3-O-galactoside chloride 0.84
Delphinidin-3-O-arabinoside chloride 0.86
0–35 93?75 7?25 linear gradient Cyanidin-3-O-glucoside chloride 1.00
35–45 75?35 25?65 linear gradient Petunidin-3-O-galactoside chloride 1.08
45–46 35?0 65?100 linear gradient Cyanidin-3-O-arabinoside chloride 1.11
46–50 0 100 isocratic Petunidin-3-O-glucoside chloride 1.24
50–51 0?93 100?7 linear gradient Delphinidin chloride 1.28
51–60 93 7 isocratic Peonidin-3-O-galactoside chloride 1.36
Chromatograph Standard solution 1, and record the peak Petunidin-3-O-arabinoside chloride 1.39
responses as directed for Procedure: the tailing factor for the Peonidin-3-O-glucoside chloride 1.55
cyanidin-3-O-glucoside chloride peak is not less than 0.8 and Malvidin-3-O-galactoside chloride 1.58
not more than 2.0; and the relative standard deviation Peonidin-3-O-arabinoside chloride 1.67
determined from the cyanidin-3-O-glucoside chloride peak Malvidin-3-O-glucoside chloride 1.76
for replicate injections is not more than 2.0%. Chromatograph Cyanidin chloride 1.82
Standard solution 3, and record the peak responses as Malvidin-3-O-arabinoside chloride 1.91
directed for Procedure: the chromatogram obtained is similar Petunidin chloride 2.08
to the Reference chromatogram provided with the lot of USP Peonidin chloride 2.27
Powdered Bilberry Extract RS being used; the resolution, R, Malvidin chloride 2.30
In-Process Revision
for the delphinidin-3-O-arabinoside, malvidin-3-O-galacto- Separately calculate the percentages of delphinidin-3-O-
side, and petunidin-3-O-arabinose peaks is not less than 0.8; galactoside chloride, delphinidin-3-O-glucoside chloride,
and the resolution, R, for other components is not less than cyanidin-3-O-galactoside chloride, delphinidin-3-O-arabino-
1.0. side chloride, cyanidin-3-O-glucoside chloride, petunidin-3-
Procedure—Separately inject equal volumes (about 10 mL) O-galactoside chloride, cyanidin-3-O-arabinoside chloride,
of Standard solution 1, Standard solution 2, Standard petunidin-3-O-glucoside chloride, peonidin-3-O-galactoside
solution 3, and the Test solution into the chromatograph; chloride, petunidin-3-O-arabinoside chloride, peonidin-3-O-
record the chromatograms; and measure the areas of the glucoside chloride, malvidin-3-O-galactoside chloride, peo-
analyte peaks. Using the chromatogram of Standard solution
3 and the Reference chromatogram provided with the lot of
Pharmacopeial Forum
nidin-3-O-arabinoside chloride, malvidin-3-O-glucoside chlo-

BRIEFING
ride, and malvidin-3-O-arabinoside chloride in the portion of
the Powdered Extract using the formula: Chamomile, USP 30 page 901. In the test for Content of
apigenin-7-glucoside changes are proposed to use a different solvent
for the Standard solution, to clarify the system suitability
10,000(C/W)(rU / rS) requirements, and to add the relative retention times of different
components of interest with reference to the Standard. In the test for
Content of bisabolane derivatives it is proposed to add the relative
retention times of different components of interest with reference to
in which C is the concentration, in mg per mL, of USP the Standard, and to revise the calculation formula. Changes in the
tests for Microbial enumeration are proposed to comply with the
Cyanidin-3-O-glucoside Chloride RS in the Standard solution general information chapter Microbiological Attributes of Nonsterile
Nutritional and Dietary Supplements h2023i. In addition, editorial
1; W is the weight, in mg, of Powdered Extract taken to changes have been proposed.
prepare the Test solution; rU is the peak response obtained for (DSB; MSA: M. Sharaf) RTS—C55236
each of the anthocyanosides in the Test solution; and rS is the
peak response obtained for cyanidin-3-O-glucoside chloride
Change to read:
in Standard solution 1. Add the percentages calculated for all
the anthocyanosides: not less than 36.0% is found. Separately
calculate the percentages of delphinidin chloride, cyanidin Chamomile
chloride, petunidin chloride, peonidin chloride, and malvidin
chloride in the portion of the Powdered Extract using the » Chamomile consists of the dried flower heads of
formula: Matricaria recutita Linné (Matricaria chamomilla
Linné, Matricaria chamomilla Linné var. courrantiana,
Chamomilla recutita Linné) Rauschert (Fam. Asteraceae
10,000(C/W)(rU / rS) alt. Compositae). It contains not less than 0.4 percent of
blue volatile oil, not less than 0.3 percent of apigenin-7-
glucoside, and not less than 0.15 percent of bisabolan
in which C is the concentration, in mg per mL, of USP &
bisabolane&2S (USP31)
Cyanidin Chloride RS in the Standard solution 2; W is the derivatives, calculated as levomenol.
weight, in mg, of Powdered Extract taken to prepare the Test Change to read:
solution; rU is the peak response obtained for each of the Identification—
anthocyanidins in the Test solution; and rS is the peak A: Thin-Layer Chromatographic Identification Test h201i—
Adsorbent: 0.25-mm layer of chromatographic silica gel.
response obtained for cyanidin chloride in Standard solution Test solution—Reduce about 1.0 g of Chamomile to a coarse
powder, using a porcelain pestle and mortar. Transfer to a 1.5-cm
2. Add the percentages calculated for all the anthocyanidins: 6 15-cm chromatographic column, and tamp lightly with a short
length of rubber hose. Rinse the pestle and mortar twice, each time
In-Process Revision
not more than 1.0% is found. with 10 mL of methylene chloride. Pour the rinsings into the column.
Collect the percolate in a flask with a long, narrow neck, and remove
the solvent by evaporation on a water bath.
Other requirements—It meets the requirements of the test
for Residual solvents under Botanical Extracts
&
and evaporate the extract to dryness.&2S (USP31)
Dissolve the residue in 0.5 mL of toluene.
Standard solution—Prepare a solution of borneol, bornyl acetate,
h565i.&2S (USP31) and guaiazulene in toluene containing 1.0 mg per mL, 2.0 mg per
mL, and 0.4 mg per mL, respectively.
Developing solvent: chloroform.
Spray reagent—Mix 0.5 mL of anisaldehyde and 10 mL of glacial
acetic acid, add 85 mL of methanol, and mix. Then carefully add
5 mL of sulfuric acid to this solution, and mix.
Procedure—Separately apply, as 3-mm 6 20-mm bands, equal
volumes (about 10 mL) of the Test solution and the Standard
solution, and proceed as directed in the chapter. Examine the plate
under short-wavelength UV light: the chromatogram of the Test
solution exhibits a number of quenching areas, the largest of which is
due to en-yne-dicycloether and has the same RF value as the band
due to bornyl acetate in the chromatogram of the Standard solution;
there is also a band due to matricin near the line of application. Spray
the plate evenly with the Spray reagent. Examine the plate in
Pharmacopeial Forum
daylight while heating at 1008 to 1058 for 5 to 10 minutes. The Mobile phase—Use variable mixtures of Solution A and Solution
chromatogram obtained from the Standard solution shows in the B as directed for Chromatographic system (see System Suitability
lower third a brownish yellow zone that becomes violet-gray after under Chromatography h621i).
a few hours and is due to borneol; in the middle a yellowish-brown Standard solution—Dissolve accurately weighed quantities of
to gray zone due to bornyl acetate; and in the upper third a deep red USP Apigenin-7-glucoside RS and 7-methoxycoumarin in methanol,
zone with a blue edge due to guaiazulene. The chromatogram of the and dilute quantitatively, and stepwise if necessary, with methanol to
Test solution exhibits a blue zone due to matricin near the starting obtain a solution having known concentrations of about 25.0 mg of
point; several violet-red zones, one of which is due to bisabolol, at RF USP Apigenin-7-glucoside RS and 10.0 mg of 7-methoxycoumarin
values between those of borneol and bornyl acetate; a brownish per mL.
zone, due to en-yne-dicycloether, at an RF value corresponding to
that of bornyl acetate; red zones, due to terpenes, at RF values similar &
Dissolve accurately weighed quantities of USP Apigenin-7-
to that of guaiazulene; and other zones that appear in the middle and
lower parts of the chromatogram. glucoside RS and 7-methoxycoumarin in methanol and water
B: Dissolve 0.25 g of dimethylaminobenzaldehyde in a mixture
of 5 mL of phosphoric acid, 45 mL of acetic acid, and 45 mL of (1 : 1) to obtain a solution having known concentrations of
water. Transfer 2.5 mL of this solution and 0.1 mL of the test
solution, prepared as directed for Identification test A, to a test tube. about 25.0 mg per mL of USP Apigenin-7-glucoside RS and
Heat on a water bath for 2 minutes, and allow to cool. Add 5 mL of
solvent hexane, and shake. The aqueous layer has a distinct greenish 10.0 mg per mL of 7-methoxycoumarin.&2S (USP31)
blue or blue color. Test solution—Transfer about 1.0 g of Chamomile, accurately
weighed, to a suitable flask fitted with a reflux condenser and
a stirrer, add 80.0 mL of methanol, and heat and reflux the mixture
Change to read: with stirring for 1 hour. Cool the flask to room temperature, pass the
methanolic distillate through a folded filter paper, and collect the
Microbial enumeration h2021i—The total bacterial count does not filtrate in a 100-mL volumetric flask. Rinse the flask with 3 mL of
exceed 104 cfu per g, the total combined molds and yeasts count does methanol, pour the methanolic rinsings through the filter paper, and
not exceed 100 cfu per g, and it meets the requirements of the tests add the filtrate to the volumetric flask. Dilute with methanol to
for absence of Salmonella species and Escherichia coli and for volume, mix, and filter. Transfer 25.0 mL of the filtered solution to
absence of Staphylococcus aureus. a round-bottom flask fitted with a reflux condenser and a stirrer, add
5.0 mL of sodium hydroxide solution, prepared by dissolving 0.4 g
&
The total bacterial count does not exceed 105 cfu per g, the of sodium hydroxide in 5.0 mL of water, and heat and reflux the
mixture for 25 minutes. Cool the flask, and adjust the solution with
total combined mold and yeast count does not exceed 103 cfu hydrochloric acid to a pH of 5.0 to 6.2. Quantitatively transfer the
solution to a 50-mL volumetric flask, dilute with methanol to
per g, and the bile-tolerant Gram-negative bacterial count volume, mix, and filter, discarding the first 10 mL of the filtrate.
does not exceed 103 cfu per g.&2S (USP31) &

Transfer about 1.0 g of Chamomile, accurately weighed, to
a suitable flask fitted with a reflux condenser and a stirrer, add
Add the following:
80.0 mL of methanol, and reflux the mixture with stirring for
&
Absence of specified microorganisms h2022i—It meets
1 hour. Cool the flask to room temperature, pass the extract
the requirements of the tests for absence of Salmonella
through filter paper, and collect the filtrate in a 100-mL
species and Escherichia coli.&2S (USP31)
volumetric flask. Rinse the extraction flask with 3 mL of
Change to read: methanol, pour the methanolic rinsings through the filter
Volatile oil content h561i—Proceed as directed, except to use 60 g paper, and add the filtrate to the volumetric flask. Dilute with
of coarsely powdered Chamomile as the test specimen, a 2-L round-
bottom flask, 300 mL of water as distillation liquid, and 0.5 mL of methanol to volume, and mix. Transfer 25.0 mL of the
xylene in the graduated tube. Distill for 4 hours at a rate of 3 to 4 mL
per minute: not less than 0.4% of blue volatile oil is found. solution to a suitable flask fitted with a reflux condenser and
In-Process Revision
NOTE—Retain the volatile oils for use in the test for Content of
bisabolan derivatives. a stirrer, add 5.0 mL of sodium hydroxide solution, prepared
&
Content of bisabolane derivatives.&2S (USP31) by dissolving 0.4 g of sodium hydroxide in 5.0 mL of water,
and reflux the mixture for 25 minutes. Cool the flask, and
Change to read: adjust the solution with hydrochloric acid to a pH of 5.0 to
Content of apigenin-7-glucoside— 6.2. Quantitatively transfer the solution to a 50-mL

Dilute phosphoric acid—Transfer 5.0 mL of phosphoric acid to
a 100-mL volumetric flask containing about 50 mL of water, dilute volumetric flask, dilute with methanol to volume, mix, and
with water to volume, and mix.
Solution A—Prepare a 0.005 M solution of monobasic potassium filter, discarding the first 10 mL of the filtrate.&2S (USP31)
phosphate. Adjust with Dilute phosphoric acid to a pH of Chromatographic system (see Chromatography h621i)—The
2.55 + 0.05. liquid chromatograph is equipped with a 335-nm detector and a 4-
Solution B—Prepare a mixture of acetonitrile and methanol mm 6 12.5-cm column that contains packing L1. The flow rate is
(65 : 35). about 1 mL per minute. The chromatograph is programmed as
follows:
Pharmacopeial Forum
follows. Initially the column temperature is maintained at 708, then it

Time Solution A Solution B is increased at a rate of 48 per minute to 2308, and maintained at 2308
(minutes) (%) (%) Elution for 10 minutes. The detector is maintained at a temperature of 2508,
0–3 74 26 isocratic and the injection port is maintained at 2208. Chromatograph the
3–22 74?15 26?85 linear gradient Standard solution, and record the peak areas as directed for
22–27 15?74 85?26 linear gradient Procedure: the tailing factor for levomenol is not more than 1.8;
27–30 74 26 isocratic and the relative standard deviation for replicate injections is not more
than 2.0%.
Make adjustments, if necessary, to obtain relative retention times of Procedure—Separately inject equal volumes (about 1 mL) of the
about 0.63 and 1.0 for apigenin-7-glucoside and 7-methoxycou- Standard solution and the Test solution into the chromatograph,
marin, respectively. Chromatograph the Standard solution, and record the chromatograms, and measure the peak areas. Identify
record the peak responses as directed for Procedure: the relative levomenol, bisabol oxide B, bisabol oxide, and bisabol oxide A in
retention times are about 0.30, 0.47, 0.66, 0.89, and 1.0 for apigenin- the Test solution using the retention time of levomenol in the
7-glucoside, 7-methoxycoumarin, apigenin, trans-spiroether, and Standard solution and the chromatogram that is provided with USP
cis-spiroether, respectively; the resolution, R, between apigenin-7- Levomenol RS. Calculate the percentage of levomenol in the portion
glucoside and 7-methoxycoumarin is not less than 3.5; and the of Chamomile taken by the formula:
2.0%. 100(rU / rS)(CS/CU),
&
Make adjustments, if necessary, to obtain relative retention in which rU is the sum of the peak areas for bisabol oxide B, bisabol
oxide, levomenol, and bisabol oxide A obtained from the Test
times of about 0.63 and 1.0 for apigenin-7-glucoside and 7- solution; rS is the levomenol peak area obtained from the Standard
solution; CS is the concentration, in mg per mL, of USP Levomenol
methoxycoumarin, respectively. Chromatograph the Standard RS in the Standard solution; and CU is the concentration, in mg per
mL, of chamomile in the Test solution: not less than 0.15% of
solution, and record the peak responses as directed for bisabolan derivatives is found.
Procedure: the resolution, R, between apigenin-7-glucoside

&
Separately inject equal volumes (about 1 mL) of the
and 7-methoxycoumarin is not less than 3.5; and the relative Standard solution and the Test solution into the chromato-
standard deviation for the apigenin-7-glucoside peak for graph, record the chromatograms, and measure the peak
replicate injections is not more than 2.0%.&2S (USP31)

areas. Identify the peaks due to levomenol, bisabol oxide B,
Standard solution and the Test solution into the chromatograph, and bisabol oxide, and bisabol oxide A in the Test solution using
allow the Test solution to elute for not less than six times the
retention time of apigenin-7-glucoside. Record the chromatograms, the retention time of levomenol in the Standard solution and
and measure the responses for all the peaks observed in the
chromatogram of the Test solution: the approximate relative retention times of 0.89, 0.97, and 1.1
&
the approximate relative retention times are about 0.63, 1.0, for bisabol oxide B, bisabol oxide, and bisabol oxide A,
1.2, 1.4, and 1.5 for apigenin-7-glucoside, 7-methoxycou- respectively, with reference to the levomenol peak. Calculate
marin, apigenin, trans-spiroether, and cis-spiroether, respec- the percentage of the bisabolane derivatives in the portion of
tively.&2S (USP31)
Chamomile taken by the formula:
Calculate the percentage of apigenin-7-glucoside in the portion of
Chamomile taken by the formula:
20(C/W)(rU / rS) 2500 (rU / rS)(CS / W)
in which C is the concentration, in mg per mL, of USP Apigenin-7-
glucoside RS in the Standard solution; W is the weight, in g, of
In-Process Revision
Chamomile taken for the Test solution; and rU and rS are the in which rU is the sum of the peak areas for bisabol oxide B,
apigenin-7-glucoside peak responses obtained from the Test solution
and the Standard solution, respectively: not less than 0.3% is found. bisabol oxide, levomenol, and bisabol oxide A obtained from
the Test solution; rS is the levomenol peak area obtained from
Change to read:
the Standard solution; CS is the concentration, in mg per mL,
Content of bisabolan derivatives—
of USP Levomenol RS in the Standard solution; and W is the
&
Content of bisabolane derivatives—&2S (USP31)
Standard solution—Prepare a solution of USP Levomenol RS in weight, in mg, of Chamomile used in the test for Volatile oil
cyclohexane having a known concentration of about 1 mg per mL.
Test solution—Transfer the volatile oils obtained in the test for content: not less than 0.15% of bisabolane derivatives is
Volatile oil content to a 25-mL volumetric flask, rinse the graduated
tube of the apparatus with a small portion of cyclohexane, transfer found.&2S (USP31)
the rinsing to the 25-mL volumetric flask, add cyclohexane to
volume, and mix.
chromatograph is equipped with a flame-ionization detector and
a 0.32-mm 6 30-m fused-silica capillary column coated with a 0.25-
mm film of phase G16. The carrier gas is helium, flowing at a rate of
about 1.0 mL per minute. The chromatograph is programmed as
Pharmacopeial Forum
BRIEFING Phosphate buffer—In a 2-L volumetric flask, dissolve 7.0 g

of dibasic potassium phosphate in water, add 0.5 mL of
Glucosamine Hydrochloride, USP 30 page 946. It is proposed to
add a statement in the test for Specific rotation to indicate that the ammonium hydroxide, dilute with water to volume, and mix.
measurement should be made 3 hours after sample preparation.
Because glucosamine undergoes mutarotation, the change in specific Adjust with phosphoric acid to a pH of 7.5.
rotation that occurs between the alpha and beta forms, the additional
time is needed so that a steady-state can be achieved. Additional text Mobile phase—Prepare a mixture of acetonitrile and
is also included to indicate that water is the solvent used in the Test
solution. On the basis of comments received, it is also proposed to Phosphate buffer (75 : 25). Make adjustments if necessary
replace the current Assay procedure because the peak for
glucosamine is not adequately retained using the conditions and (see System Suitability under Chromatography h621i).
C8 column prescribed. The proposed liquid chromatographic
procedure is based on analysis using the Luna Amino brand of L8 Standard preparation—Dissolve an accurately weighed
column. The typical retention time for glucosamine is about 10.5
minutes. quantity of USP Glucosamine Hydrochloride RS in Diluent to
mg per mL. Shake for 5 minutes by mechanical means to
Change to read: allow for complete dissolution.
Specific rotation h781Si: between +70.08 and +73.08. Assay preparation—Transfer about 187.5 mg of Glucosa-
Test solution: 25 mg per mL, mine Hydrochloride, accurately weighed, to a 50-mL
&
in water. volumetric flask. Dissolve in 25 mL of Diluent, and shake
Measure the specific rotation 3 hours after sample by mechanical means. Dilute with Diluent to volume, and
preparation.&2S (USP31) mix.
Change to read: Chromatographic system (see Chromatography h621i)—

Assay—
Phosphate buffer—Mix 1.0 mL of phosphoric acid with 2 L of and a 4.6-mm 6 15-cm column that contains 5-mm packing
water, and adjust with potassium hydroxide to a pH of 3.0.
Mobile phase—Prepare a mixture of Phosphate buffer and L8. The flow rate is about 1.5 mL per minute. The column is
acetonitrile (3 : 2). Sonicate for 15 minutes, and pass through
a filter having a 0.5-mm or finer porosity. Make adjustments if maintained at a temperature of 358. Chromatograph the
necessary (see System Suitability under Chromatography h621i).
Standard preparation—Dissolve an accurately weighed quantity Standard preparation, and record the peak responses as
of USP Glucosamine Hydrochloride RS in water to obtain a solution
having a known concentration of about 1.0 mg per mL. directed for Procedure: the tailing factor for the glucosamine
Assay preparation—Transfer about 100 mg of Glucosamine
Hydrochloride, accurately weighed, to a 100-mL volumetric flask. peak is not more than 2.0; the column efficiency is not less
Dissolve in 30 mL of water, shake by mechanical means, dilute with
water to volume, and mix. than 1500 theoretical plates; and the relative standard
liquid chromatograph is equipped with a 195-nm detector and deviation for replicate injections is not more than 2.0%.
In-Process Revision
is about 0.6 mL per minute. Chromatograph the Standard Procedure—Separately inject equal volumes (about 10 mL)
preparation, and record the responses as directed for Procedure:
the tailing factor for the glucosamine peak is not more than 2.0; and of the Standard preparation and the Assay preparation into
the relative standard deviation for replicate injections is not more
than 2.0%. the chromatograph, record the chromatograms, and measure
Standard preparation and the Assay preparation into the chromat- the areas for the glucosamine peaks. Calculate the percentage
ograph, record the chromatograms, and measure the areas for the
glucosamine peaks. Calculate the percentage of C6H13NO5 HCl in of C6H13NO5 HCl in the portion of Glucosamine Hydrochlo-
the portion of Glucosamine Hydrochloride taken by the formula:
10,000(C/W)(rU / rS)
ride taken by the formula:
in which C is the concentration, in mg per mL, of USP Glucosamine
Hydrochloride RS in the Standard preparation; W is the weight, in
mg, of Glucosamine Hydrochloride used to prepare the Assay 5,000(C/W)(rU / rS)
preparation; and rU and rS are the peak responses obtained from the
Assay preparation and the Standard preparation, respectively.
&
Diluent—Prepare a mixture of acetonitrile and water
(50 : 50).
Pharmacopeial Forum
in which C is the concentration, in mg per mL, of USP Test solution: 35 mg per mL.
Glucosamine Hydrochloride RS in the Standard preparation; &

Measure the specific rotation 3 hours after sample
W is the weight, in mg, of Glucosamine Hydrochloride used preparation.&2S (USP31)
to prepare the Assay preparation; and rU and rS are the peak
responses obtained from the Assay preparation and the Change to read:
Standard preparation, respectively.&2S (USP31) Residue on ignition h281i: between 27.0% and 29.0%
&
26.5% and 31.0%.&2S (USP31)
Change to read:
BRIEFING
Assay—
Glucosamine Sulfate Potassium Chloride, USP 30 page 946. On &

Diluent,&2S (USP31)
the basis of comments received, the following changes are proposed: Phosphate buffer, Mobile phase, Standard preparation, and
1. In Identification test B, to delete the reference to the test for Chromatographic system—Proceed as directed in the Assay under
Sulfate under general chapter h191i. Instead, it is proposed to Glucosamine Hydrochloride.
identify sulfate by adding an Identification test D that refers to Assay preparation—Transfer about 125
the test for Content of sulfate in this monograph.
2. To revise the tests for Specific rotation and Residue on ignition &
187.5&2S (USP31)
in order to center the ranges of each on their associated mg of Glucosamine Sulfate Potassium Chloride, accurately weighed,
theoretical values, which are also consistent with the values to a 100-mL
obtained experimentally from historical batch data.
3. In the test for Specific rotation, to add a requirement that the &
50-mL&2S (USP31)
measurement should be obtained 3 hours after sample volumetric flask. Dissolve in 30 mL of water,
preparation to allow for mutarotation.
4. In the Assay, to make changes to the first subsection and to the &
Diluent,&2S (USP31)
Assay preparation. These changes are proposed because the shake by mechanical means, dilute with water
monograph Glucosamine Hydrochloride, appearing elsewhere
in this issue of PF, includes changes in the Assay, and the Assay &
Diluent&2S (USP31)
here references Glucosamine Hydrochloride. to volume, and mix.
In addition, minor editorial style changes have been made. Procedure—Proceed as directed in the Assay under Glucosamine
Hydrochloride. Calculate the percentage of (C6H14NO5)2SO4 2KCl
(DSN: L. Evans) RTS—C41981 in the portion of Glucosamine Sulfate Potassium Chloride taken by
the formula:
(605.52/431.26)(10,000C / W)(rU / rS)
Change to read:
in which 605.52 is the molecular weight of glucosamine sulfate
Identification— potassium chloride and 431.26 is twice the molecular weight of
glucosamine HCl; W is the weight, in mg, of Glucosamine Sulfate
A: Infrared Absorption h197Ki. Potassium Chloride used to prepare the Assay preparation; and the
Test solution—Transfer about 50 mg of Glucosamine Sulfate other terms are as defined therein.
Potassium Chloride to a centrifuge tube, and dissolve in 2 mL of
water. Add about 0.5 mL of barium chloride TS, and centrifuge.
Evaporate the supernatant, and dry the residue at 1058 for 2 hours.
The IR spectrum corresponds to that of a similar preparation of USP
Glucosamine Hydrochloride RS, except that the addition of barium
In-Process Revision
chloride TS is omitted. BRIEFING

B: It meets the requirements of the tests for Chloride h191i
&
and&2S (USP31) Glucosamine Sulfate Sodium Chloride, USP 30 page 947. On
Potassium h191i. and Sulfate h191i. the basis of comments received, the following changes are proposed:
& 1. In Identification test B, to delete the reference to the test for
&2S (USP31) Sulfate under general chapter h191i. Instead, it is proposed to
C: The retention time of the major peak in the chromatogram of identify sulfate by adding an Identification test D that refers to
the Assay preparation corresponds to that in the chromatogram of the test for Content of sulfate in this monograph.
the Standard preparation, as obtained in the Assay. 2. To revise the tests for Specific rotation and Residue on ignition
in order to center the ranges of each on their associated
&
D: In the test for Content of sulfate, after the addition of theoretical values, which are consistent with the values obtained
experimentally from historical batch data.
barium chloride TS a white precipitate is formed.&2S (USP31) 3. In the test for Specific rotation, to add a requirement that the
measurement should be obtained 3 hours after sample
Change to read: preparation to allow for mutarotation.
Specific rotation h781Si: between +50.08 and +52.08

&
+478 and + 538.&2S (USP31)
Pharmacopeial Forum
4. In the Assay, to make changes to the first subsection and to the

&
Diluent,&2S (USP31)
Assay preparation. These changes are proposed because the shake by mechanical means, dilute with water
monograph Glucosamine Hydrochloride, appearing elsewhere
in this issue of PF, includes changes in the Assay, and the Assay
&
Diluent&2S (USP31)
here references Glucosamine Hydrochloride. to volume, and mix.
In addition, minor editorial style changes have been made. Procedure—Proceed as directed in the Assay under Glucosamine
Hydrochloride. Calculate the percentage of (C6H14NO5)2SO4 2NaCl
in the portion of Glucosamine Sulfate Sodium Chloride taken by the
(DSN: L. Evans) RTS—C45824 formula:
10,000(573.31/431.26)(C / W)(rU / rS)
Change to read: in which 573.31 is the molecular weight of the glucosamine sulfate
sodium chloride and 431.26 is twice the molecular weight of
Identification— glucosamine HCl; W is the weight, in mg, of Glucosamine Sulfate
A: Infrared Absorption h197Ki. Sodium Chloride used to prepare the Assay preparation; and the
Test solution—Transfer about 50 mg of Glucosamine Sulfate others terms are as defined therein.
Sodium Chloride to a centrifuge tube, and dissolve in 2 mL of water.
Add about 0.5 mL of barium chloride TS, and centrifuge. Evaporate
the supernatant, and dry the residue at 1058 for 2 hours. The IR
spectrum corresponds to that of a similar preparation of USP
Glucosamine Hydrochloride RS, except that the addition of barium BRIEFING
chloride TS is omitted.
B: It meets the requirements of the tests for Chloride h191i
&
and&2S (USP31)
Powdered Decaffeinated Green Tea Extract. A new monograph
Sodium h191i. , and Sulfate h191i. is being proposed. The liquid chromatographic procedure in the tests
for Content of polyphenols and Limit of gallic acid is based on
&
&2S (USP31)
analyses performed with the Zorbax SB brand of L1 column. The
C: The retention time of the major peak in the chromatogram of typical retention times observed are about 22 minutes for
the Assay preparation corresponds to that in the chromatogram of (–)-epigallocatechin, 26 minutes for (+)-catechin, 38 minutes for
the Standard preparation, as obtained in the Assay. (–)-epicatechin, 39 minutes for (–)-epigallocatechin-3-O-gallate, 42
minutes for gallocatechin-3-O-gallate, 46 minutes for (–)-epigallo-
&
D: In the test for the Content of sulfate, after the catechin-3-O-(3’-O-methyl)-gallate, and 49 minutes for (–)-epicate-
chin-3-O-gallate. The typical retention time observed for the gallic
addition of barium chloride TS a white precipitate is acid peak is about 6 minutes. The liquid chromatographic procedure
in the test for Limit of caffeine is based on analyses performed with
formed.&2S (USP31)
the Supelcosil LC-ABZ brand of L60 column. The typical retention
time observed for the caffeine peak is about 25 minutes.
Change to read: (DSB; MSA: M. Sharaf) RTS—C50926
Specific rotation h781Si: between +52.08 and +54.08
&
+50.08 and +55.08.&2S (USP31)
Test solution: 35 mg per mL.
&
Measure the specific rotation 3 hours after sample
Add the following:
preparation.&2S (USP31)
&Powdered Decaffeinated Green Tea
Extract
Change to read:
Residue on ignition h281i: between 23.5% and 25.0%
In-Process Revision
&
22.5% and 26.0%.&2S (USP31)
» Powdered Decaffeinated Green Tea Extract is
Change to read:
prepared from the young, unfermented leaf and leaf
Assay—
buds of Camellia sinensis (L.) Kuntze (Fam.
&
Diluent,&2S (USP31) Theaceae), also known as Thea sinensis L., using
Phosphate buffer, Mobile phase, Standard preparation, and
Chromatographic system—Proceed as directed in the Assay under suitable solvents such as alcohol, methanol,
Glucosamine Hydrochloride.
Assay preparation—Transfer about 100 acetone, or water or mixtures of these solvents;
&
187.5&2S (USP31)
mg of Glucosamine Sulfate Sodium Chloride, accurately weighed, to the caffeine has been removed. The ratio of the
a 100-mL
starting crude plant material to Powdered Extract is
&
50-mL&2S (USP31)
volumetric flask. Dissolve in 30 mL of water, between 6 : 1 and 10 : 1. It contains not less than
Pharmacopeial Forum
60.0 percent of polyphenols, calculated as Developing solvent system until the solvent front has moved
(–)-epigallocatechin-3-O-gallate, not less than about three-fourths of the plate, dry the plate at 1008, dip in
the Immersion reagent, dry, and immediately examine the
40.0 percent of (–)-epigallocatechin-3-O-gallate,
plate under visible light [NOTE—The chromatogram is stable
and not more than 0.1 percent of caffeine,
up to 30 minutes; afterward, the plate’s background darkens
calculated on the anhydrous basis.
significantly.]: the chromatogram of the Test solution exhibits
Packaging and storage—Preserve in well-closed containers, main bands similar in position and color to the main bands in
protected from light and moisture, and store at controlled the chromatogram of the Standard solution. The chromato-
room temperature. gram of the Test solution exhibits four main brownish-orange
bands with RF values of approximately 0.38, 0.48, 0.52, and
Labeling—The label states the Latin binomial and, following
0.62 corresponding to (–)-epigallocatechin-3-O-gallate,
the official name, the part of the plant contained in the article.
(–)-epigallocatechin, (–)-epicatechin-3-O-gallate, and
It meets other labeling requirements under Botanical Extracts
(–)-epicatechin, respectively. The most intense band is the
h565i.
one for (–)-epigallocatechin-3-O-gallate. The least intense
USP Reference standards h11i—USP Caffeine RS. USP
band is the one for (–)-epicatechin.
(–)-Epigallocatechin-3-O-gallate. USP Powdered Decaf-
B: The retention times of the peaks for (–)-epigallo-
feinated Green Tea Extract RS.
catechin, (+)-catechin, (–)-epicatechin, (–)-epigallocatechin-
Identification—
3-O-gallate, (–)-gallocatechin-3-O-gallate, (–)-epigallocate-
A: Thin-Layer Chromatographic Identification Test
chin-3-O-(3’-O-methyl)-gallate, and (–)-epicatechin-3-O-gal-
h201i—
late in the chromatogram of the Test solution correspond to
Standard solution—Dissolve about 40 mg of USP Pow-
those in the chromatogram of Standard solution 2, as
dered Decaffeinated Green Tea Extract RS in 10 mL of
obtained in the test for Content of polyphenols.
a mixture of alcohol and water (8 : 2) by sonication for 10
Microbial enumeration h2021i—The total aerobic microbial
minutes, and centrifuge. Use the clear supernatant. [NOTE—
count does not exceed 104 cfu per g. The total combined
Prepare fresh. Store below –208, if storage is needed.]
yeasts and molds count does not exceed 103 cfu per g.
Test solution—Proceed as directed for Standard solution,
except to use Powdered Extract. Absence of specified microorganisms h2022i—It meets the
Adsorbent—Use a chromatographic silica gel mixture with requirements of the tests for absence of Salmonella species
In-Process Revision
an average particle size of 5 mm. and Escherichia coli.
Application volume: 1 mL. Water, Method Ia h921i: not more than 6.0%, determined
Developing solvent system—Use a mixture of toluene, on 0.5 g.
acetone, and formic acid (9 : 9 : 2). Residue on ignition h281i: not more than 0.5%, deter-
Immersion reagent—Dissolve 140 mg of fast blue B salt in mined on 1.0 g.
10 mL of water, add 140 mL of methanol and 50 mL of
Heavy metals, Method II h231i: not more than 20 mg per g.
dichloromethane, and mix. [NOTE—Prepare weekly and store
Pesticide residues h561i: meets the requirements.
at 48 in the dark.]
Procedure—[NOTE—Use an unsaturated chamber, and
condition the plate to a relative humidity of about 30%
using a suitable device.] Develop the chromatograms using
Pharmacopeial Forum
Limit of gallic acid—

Solution A, Solution B, Mobile phase, and
Chromatographic system—Proceed as directed in the test
for Content of polyphenols.
tity of gallic acid in Solution A to obtain a solution having
tity of USP Caffeine RS in methanol to obtain a solution
having known concentration of about 0.1 mg per mL.
Test solution—Transfer about 500 mg of Powdered Extract,
accurately weighed, to a 25-mL volumetric flask, dissolve,
dilute with methanol to volume, and mix.
dilute with Solution A to volume, mix, and centrifuge.
Test solution—Transfer about 10 mg of Powdered Extract,
accurately weighed, to a 10-mL volumetric flask, add 5 mL of
methanol, dissolve, dilute with methanol to volume, mix, and
centrifuge.
areas of the gallic acid peaks. Separately calculate the
percentages of gallic acid in the portion of Powdered Extract
taken using the formula:
L60.* The flow rate is about 1.0 mL per minute. The column
2,500(C / W)(rU / rS)
temperature is maintained at 25 + 18. The chromatograph is
in which C is the concentration, in mg per mL, of gallic acid programmed as follows.
in the Standard solution; W is the weight, in mg, of Powdered Time Solution A Solution B
Extract taken to prepare the Test solution; and rU and rS are the (minutes) (%) (%) Elution
peak responses obtained for gallic acid in the Test solution
and the Standard solution, respectively: not more than 1.0%
is found.
Limit of caffeine— 40–45 0?100 100?0 linear gradient
Solution A—Prepare a filtered and degassed mixture of 45–55 100 0 isocratic
water, methanol, tetrahydrofuran, and phosphoric acid 85%
In-Process Revision
(936.5 : 50 : 10 : 3.5).
deviation determined from the caffeine peak for replicate
acetonitrile, methanol, and phosphoric acid 85%
(946.5 : 50 : 3.5).
Pharmacopeial Forum
A, dissolve, dilute with the same solvent to volume, and mix.

dilute with Solution A to volume, mix, and centrifuge.
Test solution—Proceed as directed for Standard solution 2,
areas of the caffeine peaks. Separately calculate the
except to use Powdered Extract.
percentages of caffeine in the portion of Powdered Extract
taken using the formula:
1,000(C/W)(rU / rS)
in which C is the concentration, in mg per mL, of USP temperature is maintained at 25 + 18. The chromatograph is
Caffeine RS in the Standard solution; W is the weight, in mg, programmed as follows.
of Powdered Extract taken to prepare the Test solution; and rU

and rS are the peak responses obtained for caffeine in the Test
solution and the Standard solution, respectively: not more
than 0.1% is found.
Content of polyphenols—
70–75 38?94 62?6 isocratic
water, methanol, and phosphoric acid 85% (946.5 : 50 : 3.5).
Chromatograph Standard solution 1, and record the peak
acetonitrile and methanol (95 : 5).
responses as directed for Procedure: the tailing factor for the
(–)-epigallocatechin-3-O-gallate peak is not less than 0.8 and
not more than 2.0; and the relative standard deviation
determined from the (–)-epigallocatechin-3-O-gallate peak
for replicate injections is not more than 2.0%. Chromatograph
Standard solution 1—Dissolve an accurately weighed
Standard solution 2, and record the peak responses as
quantity of USP (–)-Epigallocatechin-3-O-gallate RS in
directed for Procedure: the chromatogram obtained is similar
Solution A to obtain a solution having a known concentration
In-Process Revision
to the Reference chromatogram provided with the lot of USP

of about 1.0 mg per mL. Transfer 1.0 mL of this solution to
Powdered Decaffeinated Green Tea Extract RS being used;
a 10-mL volumetric flask, dilute with Solution A to volume,
and the resolution, R, between the (–)-epigallocatechin-3-O-
and mix.
gallate peak and the preceding peak is not less than 1.
Standard solution 2—Transfer about 20 mg of USP
Powdered Decaffeinated Green Tea Extract RS, accurately
weighed, to a 10-mL volumetric flask, add 5 mL of Solution
Pharmacopeial Forum
Separately calculate the percentages of (–)-epigallocatechin,

(+)-catechin, (–)-epicatechin, (–)-epigallocatechin-3-O-gal-
of Standard solution 1, Standard solution 2, and the Test
late, (–)-gallocatechin-3-O-gallate, (–)-epigallocatechin-3-O-
solution into the chromatograph; record the chromatograms;
(3’-O-methyl)-gallate, and (–)-epicatechin-3-O-gallate as
and measure the areas of the analyte peaks. Using the
(–)-epigallocatechin-3-O-gallate in the portion of the Pow-
chromatogram of Standard solution 2 and the Reference
dered Extract taken using the formula:
chromatogram provided with the lot of USP Powdered
Decaffeinated Green Tea Extract RS, identify the retention
5,000(C/W)(rU / rS)
times of the peaks corresponding to the different polyphenols.
The approximate relative retention times of the polyphenols in which C is the concentration, in mg per mL, of USP
are provided in the following table: (–)-Epigallocatechin-3-O-gallate RS in the Standard solution
1; W is the weight, in mg, of Powdered Extract taken to
Relative
prepare the Test solution; rU is the peak response obtained for
Analyte Retention Time
each of the polyphenols in the Test solution; and rS is the peak
(–)-Epigallocatechin 0.56
response obtained for (–)-epigallocatechin-3-O-gallate in
(+)-Catechin 0.68
Standard solution 1: not less than 40.0% of (–)-epigallo-
(–)-Epicatechin 0.98
catechin-3-O-gallate is found. Add the percentages calculated
(–)-Epigallocatechin-3-O-gallate 1.00
for the individual analytes: not less than 60.0% of
(–)-Gallocatechin-3-O-gallate 1.09
polyphenols, calculated as (–)-epigallocatechin-3-O-gallate,
(–)-Epigallocatechin-3-O-(3’-O-methyl)- 1.19
is found.
gallate
Other requirements—It meets the requirements of the test
(–)-Epicatechin-3-O-gallate 1.27
for Residual solvents under Botanical Extracts
h565i.&2S (USP31)
In-Process Revision
Pharmacopeial Forum
~
BRIEFING Shellac
Sucrose
Excipients, USP and NF Excipients, Listed by Category, NF 25 Titanium Dioxide
page 1045 and page 480 of PF 33(3) [May–June 2007]. It is proposed Wax, Carnauba
to add Gamma Cyclodextrin to the Emulsifying and/or Solubilizing Wax, Microcrystalline
Agent category and Inositol to the Humectant category to comple- Zein
ment the proposed new monographs for Gamma Cyclodextrin and
Inositol, respectively, which appear elsewhere in this issue of PF.
Change to read:
(EM1; EM2) RTS—C43218; C51303
Desiccant
Calcium Chloride
Calcium Sulfate
~
Polyvinyl Acetate~NF26
Change to read: Silicon Dioxide
Bulking Agent for Freeze-Drying

Creatinine Change to read:
Mannitol
~ Emollient
Polydextrose~NF26 Alkyl (C12-15) Benzoate
&
Trehalose&1S (NF26)
&
~
Change to read: Oleyl Oleate~NF26
Coating Agent
Change to read:
&
Ammonio Methacrylate Copolymer Emulsifying and/or Solubilizing Agent
Ammonio Methacrylate Copolymer Dispersion Acacia
Carboxymethylcellulose, Sodium Carbomer Copolymer
Cellaburate Carbomer Interpolymer
Cellacefate (formerly Cellulose Acetate Phthalate) Cholesterol
Cellulose Acetate
Cellulose Acetate Phthalate (see Cellacefate) &
Diethanolamine (Adjunct)
&
Coconut Oil&1S (NF25) Diethylene Glycol Stearates
Copovidone Ethylene Glycol Stearates
&
Glyceryl Distearate
&
Ethyl Acrylate and Methyl Methacrylate Copolymer Glyceryl Monolinoleate
Glyceryl Monooleate
Dispersion&1S (NF25) Glyceryl Monostearate
Ethylcellulose Lanolin Alcohols
Ethylcellulose Aqueous Dispersion Lecithin
Gelatin Mono- and Di-glycerides
In-Process Revision
Glaze, Pharmaceutical Monoethanolamine (Adjunct)

Hydroxypropyl Cellulose Oleic Acid (Adjunct)
Hydroxypropyl Methylcellulose (see Hypromellose) Oleyl Alcohol (Stabilizer)
Hydroxypropyl Methylcellulose Phthalate (see Hypromellose
Phthalate) ~
Oleyl Oleate~NF26
Hypromellose Acetate Succinate &
Hypromellose Phthalate (formerly Hydroxypropyl Poloxamer
Methylcellulose Phthalate) Polyoxyethylene 50 Stearate
Maltodextrin Polyoxyl 10 Oleyl Ether
Methacrylic Acid Copolymer Polyoxyl 20 Cetostearyl Ether
Methacrylic Acid Copolymer Dispersion Polyoxyl 35 Castor Oil
Methylcellulose Polyoxyl 40 Hydrogenated Castor Oil
Polyoxyl 40 Stearate
&
Palm Kernel Oil&2S (NF25) Polyoxyl Lauryl Ether
Polyethylene Glycol Polyoxyl Stearyl Ether
~ Polysorbate 20
Polyvinyl Acetate~NF26 Polysorbate 40
Polyvinyl Acetate Phthalate Polysorbate 60
~ Polysorbate 80
Fully Hydrogenated Rapeseed Oil~NF26
Pharmacopeial Forum
&
&
Propylene Glycol Monostearate
~
persion&1S (NF25)
Sodium Cetostearyl Sulfate
Sodium Lauryl Sulfate
Sodium Stearate Change to read:
Sorbitan Monolaurate
Sorbitan Monooleate Sequestering Agent
Sorbitan Monopalmitate Beta Cyclodextrin (see Betadex)
Sorbitan Monostearate Betadex (formerly Beta Cyclodextrin)
Sorbitan Sesquioleate
Sorbitan Trioleate
&
Stearic Acid
Trolamine
&
Wax, Emulsifying Sodium Tartrate
Humectant Solvent
Acetone
&
Corn Syrup Solids&2S (NF25) Alcohol
Alcohol, Diluted
&
Erythritol&1S (NF25) Amylene Hydrate
Glycerin Benzyl Benzoate
Hexylene Glycol Butyl
~
Alcohol
Canola Oil~NF25
&
Caprylocaproyl Polyoxylglycerides
Corn Oil
&
Inositol&2S (NF26) Cottonseed Oil
Maltitol Diethylene Glycol Monoethyl Ether
Ethyl Acetate
~
Polydextrose~NF26 Glycerin
Propylene Glycol Hexylene Glycol
Sorbitol
Sorbitol Sorbitan Solution
&
Tagatose Isopropyl Alcohol
Lauroyl Polyoxylglycerides
Methyl Alcohol
Change to read: Methylene Chloride
Methyl Isobutyl Ketone
Ointment Base Mineral Oil
Caprylocaproyl Polyoxylglycerides Oleoyl Polyoxylglycerides
Diethylene Glycol Monoethyl Ether Peanut Oil
Polyethylene Glycol
&
Hydrogenated Polydecene&1S (NF26) Polyethylene Glycol Monomethyl Ether
Lanolin Propylene Glycol
Lauroyl Polyoxylglycerides Sesame Oil
Linoleoyl Polyoxylglycerides Stearoyl Polyoxylglycerides
Ointment, Hydrophilic Water for Injection
Ointment, White Water for Injection, Sterile
Ointment, Yellow Water for Irrigation, Sterile
Oleoyl Polyoxylglycerides Water, Purified
In-Process Revision
Polyethylene Glycol Monomethyl Ether
Petrolatum
Petrolatum, Hydrophilic
Petrolatum, White Change to read:
Rose Water Ointment
Squalane Stiffening Agent
Stearoyl Polyoxylglycerides Castor Oil, Hydrogenated
Vegetable Oil, Hydrogenated, Type II Cetostearyl Alcohol
Cetyl Alcohol
Cetyl Esters Wax
Cetyl Palmitate
Change to read: Hard Fat
Paraffin
Polymer Membrane Synthetic Paraffin
~
&
Amino Methacrylate Copolymer&1S (NF25) Fully Hydrogenated Rapeseed Oil~NF26
Ammonio Methacrylate Copolymer ~
Ammonio Methacrylate Copolymer Dispersion Superglycerinated Fully Hydrogenated Rapeseed Oil~NF26
Cellaburate
Cellulose Acetate
Pharmacopeial Forum
Stearyl Alcohol &

Wax, Emulsifying Fructose
Wax, White Galactose
Wax, Yellow
&
Maltitol
Maltose
Saccharin
Agar Sorbitol
Bentonite Syrup
Bentonite, Purified Tagatose
Bentonite Magma
Carbomer 910 &
Trehalose&1S (NF26)
Carbomer 934
Carbomer 934P
Carbomer 940
Carbomer 1342
Carbomer Copolymer Tablet Binder
Carbomer Homopolymer Acacia
Carrageenan Ammonio Methacrylate Copolymer Dispersion
Cellulose, Microcrystalline, and Carboxymethylcellulose Carbomer Copolymer
Sodium Carbomer Homopolymer
Carbomer Interpolymer
&
Corn Syrup Solids&2S (NF25) Carboxymethylcellulose Sodium
Dextrin Cellulose, Microcrystalline
Gelatin Copovidone
Gellan Gum
Guar Gum &
Hydroxyethyl Cellulose Dextrin
Hydroxypropyl Cellulose
Hydroxypropyl Methylcellulose (see Hypromellose) &
Magnesium Aluminum Silicate Dispersion&1S (NF25)
Maltodextrin Ethylcellulose
Methylcellulose Gelatin
Pectin Glucose, Liquid
Polyethylene Oxide Guar Gum
Polyvinyl Alcohol
Povidone &
Propylene Glycol Alginate Low-Substituted Hydroxypropyl Cellulose
Silicon Dioxide Hydroxypropyl Methylcellulose (see Hypromellose)
Silicon Dioxide, Colloidal Hypromellose (formerly Hydroxypropyl Methylcellulose)
In-Process Revision
Sodium Alginate Hypromellose Acetate Succinate

Starch, Corn Maltodextrin
Starch, Potato Maltose
Starch, Tapioca Methylcellulose
Starch, Wheat Polyethylene Oxide
Tragacanth ~
Xanthan Gum Polyvinyl Acetate~NF26
Povidone
Starch, Corn
Starch, Potato
Change to read: Starch, Pregelatinized
Sweetening Agent Starch, Tapioca
Acesulfame Potassium Starch, Wheat
Aspartame Syrup
Aspartame Acesulfame
&
Trehalose&1S (NF26)
Dextrates
Dextrose
Dextrose Excipient
Pharmacopeial Forum
Change to read: Starch, Tapioca

Starch, Wheat
Tablet and/or Capsule Diluent
Calcium Carbonate &
Trehalose&1S (NF26)
Calcium Phosphate, Dibasic
Calcium Phosphate, Tribasic
Calcium Sulfate Change to read:
Cellulose, Powdered Tonicity Agent
&
&
Dextrates Dextrose
Dextrin Glycerin
Dextrose Excipient Mannitol
Fructose Potassium Chloride
Sodium Chloride
&
Kaolin
Lactitol Change to read:
Lactose, Anhydrous
Lactose, Monohydrate Vehicle
Maltitol
FLAVORED AND/OR SWEETENED
Maltodextrin
Maltose Aromatic Elixir
Mannitol Benzaldehyde Elixir, Compound
&
Propylene Glycol Monocaprylate&1S
&
(NF26)
Sorbitol Dextrose
Starch Peppermint Water
Starch, Corn Sorbitol Solution
Starch, Potato Syrup
&
Trehalose&1S (NF26)
Starch, Tapioca OLEAGINOUS
Starch, Wheat Alkyl (C12-15) Benzoate
Sucrose Almond
~
Oil
Sugar, Compressible Canola Oil~NF25
Sugar, Confectioner’s Corn Oil
Cottonseed Oil
&
Trehalose&1S (NF26) Ethyl Oleate
&
Isopropyl Myristate
Change to read: Isopropyl Palmitate
Mineral Oil
Tablet Disintegrant Mineral Oil, Light
Alginic Acid Octyldodecanol
Cellulose, Microcrystalline Olive Oil
Croscarmellose Sodium Peanut Oil
Crospovidone Safflower Oil
Low-Substituted Hydroxypropyl Cellulose Sesame Oil
Maltose Soybean Oil
Polacrilin Potassium Squalane
Sodium Starch Glycolate SOLID CARRIER
Starch
In-Process Revision
Starch, Corn &
Starch, Potato Sugar Spheres
STERILE
Sodium Chloride Injection, Bacteriostatic
Water for Injection, Bacteriostatic
Pharmacopeial Forum
MONOGRAPHS (NF) Add the following:
&
Packaging and storage—Preserve in well-closed contain-
ers. No storage requirements are specified.&2S (NF26)
BRIEFING
Add the following:
Agar, NF 25 page 1055. On the basis of data and comments &
USP Reference standards h11i—USP Agar RS.&2S (NF26)
received, it is proposed to make the following revisions:
1. Add an Infrared Absorption test under Identification and insert
a USP Reference standards section to include USP Agar RS. Change to read:
2. Revise the specification for the Microbial limits test to be in line
with the general requirements for excipients.
On the basis of text in the Agar monographs in (1) the Food Identification—
Chemicals Codex, Fifth Edition, page 17, (2) the European
Pharmacopoeia, Fifth Edition, page 928, and (3) the Japanese
Pharmacopoeia, Fourteenth Edition [English version], page 859, it
&
A: Infrared absorption h197Ki.&2S (NF26)
is proposed to make the following revisions:
1. Assign a CAS number and clarify the definition. A:
2. Add a Packaging and storage section. &
3. Make some revisions to the existing Identification tests. B: &2S (NF26)
In addition, some editorial changes are proposed. Iodine TS colors some of the fragments of Agar bluish black, with
some areas reddish to violet.
B
(EM2: H. Wang; MSA: R. Tirumalai) RTS—C49043
&
C: &2S (NF26)
When boiled with 65 times its weight of water for 10 minutes,
with constant stirring, and

subsequently&2S (NF26)
adjusted to a concentration of 1.5%, by weight, with hot water, Agar
&
[9002-18-0 ].&2S (NF26) forms a clear liquid which congeals at 328
Change to read:
&
308&2S (NF26)
to 398 to form a firm resilient gel, which does not melt
» Agar is the dried, hydrophilic, colloidal substance &
liquefy&2S (NF26)
below 858
&
consisting of the polysaccharides&2S (NF26)
extracted from Gelidium cartilagineum (Linné) Gaillon
&
808.&2S (NF26)
(Fam. Gelidiaceae), Gracilaria confervoides (Linné)
Greville (Fam. Sphaerococcaceae), and related red algae
(Class Rhodophyceae). Change to read:
Change to read: Microbial limits h61i—It meets the requirements of the test for
absence of Salmonella species.
Botanic characteristics— &
The total aerobic microbial count does not exceed 1000 cfu
Agar—Usually
per g, and the total combined molds and yeasts count does not
&
occurs&2S (NF26)
In-Process Revision
in bundles consisting of thin, membranous, agglutinated strips or in exceed 100 cfu per g. It meets the requirements of the tests for
cut, flaked, or granulated forms. May be
absence of Salmonella species and Escherichia coli.&2S (NF26)
&
It may be colored&2S (NF26)
weak yellowish orange, yellowish gray to pale yellow, or colorless.
Is Change to read:
&
It is&2S (NF26) Limit of foreign insoluble matter—To 7.5 g add sufficient water to
tough when damp, brittle when dry. make 500 g, boil for 15 minutes, and readjust to the original 500 g.
Histology—In water mounts To 100 g of the uniformly mixed material
&
When mounted in water,&2S (NF26) &
this uniformly mixed dispersion&2S (NF26)
Agar appears granular and somewhat filamentous; a few fragments add hot water to make 200 mL, heat almost to boiling, filter while
of the spicules of sponges and a few frustules of diatoms may be hot through a tared filtering crucible, rinse the container with several
present; in Japanese Agar, the frustules of Arachnoidiscus portions of hot water, and pass these rinsings through the crucible.
ehrenbergii Baillon often occur, being disk-shaped and from 100 Dry the crucible and its contents at 1058 to constant weight: not more
mm to 300 mm in diameter. than 15 mg (1.0%) remains.
Powdered Agar—White to yellowish white or pale yellow; in
chloral hydrate TS its fragments are transparent, more or less
granular, striated, and angular, and occasionally they contain
frustules of diatoms.
Pharmacopeial Forum
Melting range, Class I h741i: between 1098 and 1118.

BRIEFING
Dehydroacetic Acid. It is proposed to reinstate this NF
monograph, which was omitted from USP 23–NF 18 in 1995, Assay—Transfer about 500 mg of Dehydroacetic Acid,
with several changes. To be consistent with the entry in the USAN
dictionary, only the structure for predominant keto form is included, accurately weighed, into a 250-mL conical flask, dissolve it
and the test for Arsenic is deleted.
in 75 mL of neutralized alcohol, add phenolphthalein TS, and
(EM1: R. Lafaver; NOM: W. Paul) RTS—C51226 titrate with 0.1 N sodium hydroxide VS to a pink endpoint
that persists for not less than 30 seconds. Each mL of 0.1 N
sodium hydroxide is equivalent to 16.82 mg of
C8H8O4.&2S (NF26)
Add the following:

&Dehydroacetic Acid
BRIEFING
Egg Phospholipids, page 757 of PF 31(3) [May–June 2005]. On

the basis of comments received, it is proposed to change the
Definition of Egg Phospholipids to reflect the various compositions
in available products. It is also proposed to revise the limits in the
tests for Acid value, Peroxide value, and Bacterial endotoxins; to add
a test for Heavy metals; and to update the HPLC method.
C8H8O4 168.15
(PPI: D. Hunt) RTS—C42713
Keto form: 2H-Pyran-2,4(3H)-dione, 3-acetyl-6-methyl-.
3-Acetyl-6-methyl-2H-pyran-2,4(3H)-dione, methylacetopyr-
onone [520-45-6]. Add the following:
Enol form: 2H-Pyran-2-one, 3-acetyl-4-hydroxy-6-methyl-. &Egg Phospholipids
3-Acetyl-4-hydroxy-6-methyl-2H-pyran-2-one
[771-03-9].
» Egg Phospholipids is a mixture of occurring
phospholipids obtained from the yolk of hens’ eggs
» Dehydroacetic Acid contains not less than 98.0
and is suitable for use as an emulsifying agent in
percent and not more than 100.5 percent of
In-Process Revision
injectable emulsions. It contains not less than 60
C8H8O4, calculated on the dried basis.
percent (w/w) of phosphatidylcholine and not less
Packaging and storage—Preserve in well-closed containers. than 5.0 percent (w/w) of phosphatidylethanola-
No storage requirements specified.
mine. The mixture may also contain not more than
USP Reference standards h11i—USP Dehydroacetic Acid
3 percent (w/w) of sphingomyelin. It may also
RS.
contain other related phospholipids. It may contain
not more than 0.2 percent (w/w) DL-a-tocopherol
Heavy Metals, Method II h231i: not more than 0.001%. when added as a preservative. Egg Phospholipids is
Loss on drying h731i: Dry it at 808 for 4 hours; it loses not a mixture of naturally occurring phospholipids
more than 1.0% of its weight. obtained from the yolk of hens’ eggs that is suitable
Pharmacopeial Forum
for use as an emulsifying agent in injectable Place a plug of glass wool on top of the bed. Rinse the beaker
emulsions. The content of phosphatidylcholine, and the column walls with 400 mL of Solvent, and drain to
about 0.5 cm above the silica gel. Discard the eluted rinses,
phosphatidylethanolamine, lysophosphatidylcholi-
and place a suitable flask beneath the column. Transfer 1000 g
ne,and other related phospholipids are indicated
of silica gel having a particle size of 0.05 to 0.2 mm into
in the labelingis to be reported in the certificate of
a container with well-closing screw caps. Add 150 g of water,
analysis. It may also contain a suitable stabilizer.
shake well, and allow to stand for 24 hours. Suspend 15 g of
Packaging and storage—Preserve under nitrogen in a sealed prepared adsorbent in 50 mL of Solvent, and introduce into
container, and store at a temperature of –108 or below. a 1- to 2-cm chromatographic column (see Column
Chromatography under Chromatography h621i). Drain the
Solvent through the column to a level of about 1 cm above the
Phosphatidylcholine RS. USP Phosphatidylethanolamine RS.
silica gel bed.
USP Sphingomyelin RS. USP Lysophosphatidylcholine RS.
Test solution—Transfer about 10 g of Egg Phospholipids,
Acid value h401i: not more than 4.5.3.0. 20.0.
accurately weighed, to a 150-mL beaker, add 50 mL of
Peroxide value h401i: not more than 10.20. 3. Solvent, and mix to dissolve. Transfer 500 mg of Egg
Microbial limits h61i—It meets the requirements of the test Phospholipids, dissolved in 15 mL of Solvent, into a 50-mL
for absence of Salmonella species and Escherichia coli. The conical flask.
total aerobic microbial count does not exceed 100 cfu per g. Procedure—Transfer the Test solution to the Chromato-
graphic column, and drain to about 0.5 cm above the silica
Bacterial endotoxins h85i—It contains not more than 20
gel at a rate of about 8 to 10 mL per minute. Rinse the column
6 USP Endotoxin Units per g.
containing the Test solution with three 20-mL portions of
Water, Method I h921i—Dissolve about 2 g: , accurately Solvent, allowing each rinse to pass through the column
weighed, in 50 mL of anhydrous methyl alcohol. Protect from before adding the next. Add additional Solvent onto the
atmospheric moisture during transfer. Determine the water column until 800 mL of eluate has been collected. Evaporate
content titrimetrically, using an accurately measured portion the eluate in a tared round-bottom, 250-mL flask to dryness,
of this solution not more that 6.0% is found. using a suitable rotary evaporator and a water bath maintained
Heavy metals, Method II h231i: not more than 0.001%. between 508 and 608. If silica gel is visible after evaporation,
In-Process Revision
redissolve the residue in Solvent, filter through a sintered-

Limit of nonphosphatidyl lipids—
glass, medium-porosity funnel, wash the funnel with 25 mL
Solvent: a mixture of chloroform and methyl alcohol
of Solvent, transfer back to the round-bottom flask, and
(9 : 1). diethyl ether.
evaporate to dryness. Place the flask in a vacuum oven at
Chromatographic column—Transfer 125 g of silica gel
about 558 for 1 hour. Transfer to a desiccator for not less than
having an average pore size of 6 nm into a 600-mL beaker.
1 hour, then weigh again. Repeat until the weight is constant
[NOTE—Silica gel containing between 3% and 5% of moisture
within 1 mg. Calculate the gain in weight: not more than 5%
volatiles when heated at 2008 has been found to be suitable.]
of the weight of the Egg Phospholipids taken is found.-
Prepare a slurry with 400 mL of Solvent, and transfer to a 4.5-
Transfer the Test solution to the Chromatographic column.
cm chromatographic column (see Column Chromatography
Rinse the column containing the Test solution with two 15-
under Chromatography h621i). Drain the Solvent through the
mL portions of Solvent, allowing each rinse to pass through
column to a level of about 1 cm above the silica gel bed.
Pharmacopeial Forum
the column before adding the next. After rinsing, elute with contains 3-mm packing L1. The flow rate is about 1.2 mL per
105 mL of Solvent. Evaporate the eluate (150 mL) in a tared, minute. The column temperature is maintained at a constant
round–bottom, 250-mL conical flask to dryness, using temperature of about 258. [NOTE—The parameters of detector
a suitable rotary evaporator. The volatiles are blown out operation may be adjusted to achieve an appropriate signal-
with a stream of nitrogen, and the residue is dried at 1058 for to-noise ratio.] The chromatograph is programmed as follows:
20 minutes. The weight of the residue gives the oil fraction,
Time Solution Solution Solution
determined as nonpolar lipids, in Egg Phospholipids.
(minutes) A (%) B (%) C (%) Elution
Calculate the percentage of the nonphosphatidyl lipids
0 58 40 2 equilibration
0–7 58?52 40 2?8 linear gradient
7–15 52 40 8 isocratic
100 A / W
Chromatograph the Standard solutions, and record the peak
responses as directed for Procedure: the relative retention
in which A is the weight, in mg, of the residue; and W is the
times are about 0.6 for phosphatidylethanolamine and 1.0 for
weight, in mg, of Egg Phospholipids taken: not more than 7%
phosphatidylcholine, and 1.2 for sphingomyelin; and the
is found.
Content of phospholipids—
than 2.0%.
Solution A—Use filtered and degassed isopropyl alcohol.
Solution B—Use filtered and degassed hexane.
of each of the Standard solutions and the Test solution into
Solution C—Use filtered and degassed water.
the chromatograph, record the chromatograms, and identify
Mobile phase—Use variable mixtures of Solution A,
the peaks of the relevant analytes in the chromatogram of the
Solution B, and Solution C as directed for Chromatographic
Test solution by comparison with the chromatograms
system. Make adjustments if necessary (see System Suitability
obtained from the Standard solutions. Measure the areas of
the analyte peaks. Plot the logarithms of the relevant
Solvent—Prepare a mixture of isopropyl alcohol, hexane,
responses versus the logarithms of the concentrations, in
and water (1 : 1 : 1).
mg per mL, of each analyte obtained from the Standard
Standard solutions—Transfer accurately weighed quantities
solutions, and determine the regression line using a least-
of USP Phosphatidylcholine RS and USP Phosphatidyletha-
squares analysis. The correlation coefficient for the regression
nolamine RS, and USP Sphingomyelin RS to separate flasks,
In-Process Revision
line is not less than 0.995. From the graphs so obtained,
dissolve each in Solvent, and dilute quantitatively and
determine the concentration, C, in mg per mL, of the relevant
stepwise, if necessary, with Solvent to obtain Standard
analyte in the Test solution. Separately calculate the
solutions having known concentrations of about 6 mg per
percentages of phosphatidylethanolamine and phosphatidyl-
mL, 1 mg per mL, and 0.5 mg per mL, respectively.
choline, and sphingomyelin in the portion of Egg Phospho-
Test solution—Transfer about 1 g of Egg Phospholipids,
lipids taken by the formula:
accurately weighed, to a 100-mL volumetric flask, add 50 mL
of Solvent, and mix. Dilute with Solvent to volume, and mix.
10(C/W)(rU / rS)
The liquid chromatograph is equipped with an evaporative
light-scattering detector and a 4.6-mm 6 10-cm column that
Pharmacopeial Forum
in which C is the concentration, in mg per mL, of the USP prepared on the basis of the expected content of phosphati-
Reference Standard in the relevant Standard solution; W is dylcholine, phosphatidylethanolamine, and lysophosphatidyl-
the weight, in g, of Egg Phospholipids taken to prepare the choline in the sample. The Standard solutions should cover
Test solution; and rU and rS are the peak areas of the relevant a range of 60% to 140%. Calculate the concentrations of the
analytes in the chromatograms obtained from the Test solution Standards using the following formula:
and the Standard solution, respectively.
Solution A—Mix 1341.6 g of n-hexane, 334.1 g of 2- W P/V
propanol, 39.4 g of acetic acid, and 1.45 g of triethylamine (or
in which W is the weight, in mg, of the Standard; P is the
2.0 mL triethylamine) in a 2500-mL bottle.
purity of the designated Reference Standard; and V is the
Solution B—Mix 663.5 g of 2-propanol, 140.0 g of water,
volume, in mL, of each of the Standard solutions.
15.8 g of acetic acid, and 0.58 g of triethylamine in a 1000-
Test solution—Transfer about 100 mg of Egg Phospholip-
mL bottle.
ids, accurately weighed, to a 25–mL volumetric flask,
dissolve in Solvent, dilute quantitatively, and mix. Calculate
the concentration, in mg per mL: this value is used as the
sample amount.
Solvent—Prepare a mixture of n- hexane, 2-propanol, and
The liquid chromatograph is equipped with an evaporative
water (46 : 46 : 8). [NOTE—To avoid the formation of two
phases, mix the 2-propanol and water first, and then add the light-scattering detector and a 4-mm 6 125-mm column that
contains 5-mm packing L20. The column temperature is
n-hexane.]
maintained at 558. Use the following gradient elution
Standard solutions—Transfer accurately weighed quantities
of USP Phosphatidylcholine RS, USP Phosphatidylethanola- program: Chromatograph the Standard solutions, and record
the peak responses as directed for Procedure: the relative
mine RS, and USP Lysophosphatidylcholine RS to separate
retention times are 1.00 for phosphatidylcholine, 0.85 for
flasks, dissolve each in Solvent, and dilute quantitatively.
Standard solutions of five different concentrations are
Program
(%) (%)
Step Time (min.) Flow (mL/min.)
In-Process Revision
1 0 1.0 95 5
2 5.0 1.0 80 20
3 8.5 1.0 60 40
4 15.0 1.0 0 100
5 17.5 1.0 0 100
6 17.6 1.0 95 5
7 21.0 1.0 95 5
8 22.0 2.0 95 5
9 27.0 2.0 95 5
10 29.0 1.0 95 5
Pharmacopeial Forum
phosphatidylethanolamine, and 1.25 for lysophosphatidylcho- packing L1. The typical retention times for gamma cyclodex-
trin, alfadex (alpha cyclodextrin), and betadex (beta cyclodex-
line; and the relative standard deviation for replicated trin) are 2.6, 3.3, and 6.4, respectively.
2. In the test for Reducing substances, the Copper citrate solution
injections is not more than 5.0%. is summarized as alkaline cupric citrate TS2. USP Dextrose RS
is used to replace dextrose monohydrate, and a calculation step
Procedure—Separately inject equal volumes (20 mL) of is added to clarify the test.
In addition, editorial style changes have been made.
each of the Standard solutions and the Test solution into the
(EM2: H. Wang) RTS—C43218
chromatograph, record the chromatograms, and identify the
peaks of the relevant analytes in the chromatogram of the Test
solution by comparison with the chromatograms obtained
from the Standard solutions. Measure the areas of the analyte Add the following:
peaks. Plot the logarithms of the relevant responses versus the &Gamma Cyclodextrin
logarithms of the concentrations, in mg per mL, of each
analyte obtained from the Standard solutions, and determine
the linear regression line using a least-squares analysis. The
correlation coefficient for the linear regression line is not less Cyclooctaamylose.
than 0.995. From the graphs so obtained, determine the
Cyclomaltooctaose.
concentration, C, in mg per mL, of the relevant analyte in the
Test solution. Separately calculate the percentages of
phosphatidylethanolamine, phosphatidylcholine, and lyso-
phosphatidylcholine in the portion of Egg Phospholipids
100 (CV / W)
in which V is the volume, in mL, of the relevant analyte in the

C48H80O40 (C6H10O5)8 1297.12 [17465-86-0].
Test solution; and W is the weight of Egg Phospholipids, in
mg, in the Test solution: not more than 3.0% of lysopho-
sphatidylcholine is found.&2S (NF26) » Gamma Cyclodextrin is composed of 8 gamma
alpha-(1–4) linked D-glycopyranosyl units. It
In-Process Revision
contains not less than 98.0 percent and not more
BRIEFING
than 102.0 percent of C48H80O40 (C6H10O5)8,
Gamma Cyclodextrin, page of 812 of PF 31(3) [May–June calculated on the dried basis.
2005]. Proposed revisions are made to this new NF monograph on
the basis of the following information: a new validation report, new
data for the Assay and the test for Related compounds, comments Packaging and storage—Preserve in well-closed containers,
received, the Gamma Cyclodextrin monograph in the Food
Chemicals Codex, Fifth Edition, page 129, and the Gamma and store at room temperature.
Cyclodextrin monograph in the 53rd Joint FAO/WHO Expert
Committee on Food Additives (JEFCA), 1999. USP Reference standards h11i—USP Alpha Cyclodextrin
1. The liquid chromatographic procedures in the Assay and the test
for Related compounds are revised. New procedures presented RS. USP Beta Cyclodextrin RS. USP Gamma Cyclodextrin
in the proposal are validated and based on analyses performed
with the YMC-pack ODS-A brand of column containing 5-mm RS. USP Dextrose RS.
Pharmacopeial Forum
Color and clarity of solution— System suitability solution—Dissolve an accurately
Test solution—Transfer about 2.5 g of Gamma Cyclodex- weighed quantity of USP Alpha Cyclodextrin RS, USP Beta
trin, accurately weighed, a quantity of Gamma Cyclodextrin, Cyclodextrin RS, and USP Gamma Cyclodextrin RS in water
equivalent to 2.5 g on the dried basis, into a 25-mL to obtain a solution having a known concentration of about
volumetric flask, dissolve in and dilute with water that has 0.5 mg of each per mL.
been previously boiled and cooled to room temperature to Standard solution—Transfer 25 mg of USP Gamma
volume, and mix. Cyclodextrin RS, accurately weighted, to a 25-mL volumetric
Procedure—Determine the absorbance of the Test solution flask, and dissolve in and dilute with water to volume.
in a 1-cm cell with a suitable spectrophotometer, after Test solution—Dissolve about 250 mg of Gamma Cyclo-
correcting for the blank: at 420 nm, the absorbance is not dextrin, previously dried, in water with the aid of heat. Cool,
greater than 0.20; and the solution is clear. and dilute with water to 25.0 mL.
Identification—
detector and a 4.6-mm 6 25-cm column that contains 10-mm
peak responses as directed for Procedure: the retention time
in the Assay.
of gamma cyclodextrin is about 3.2 minutes; the relative
C: It meets the requirements of the test for Specific
retention times are about 1.4 for alpha cyclodextrin and about
rotation.
3.1 for beta cyclodextrin; the resolution, R, between the alpha
Specific rotation h781Si: between +1748 and +1808.
cyclodextrin and beta cyclodextrin peaks is not less that 1.5
Test solution: 10 mg per mL, in water.
and the resolution, R, between the beta cyclodextrin and
Microbial limits h61i—It meets the requirements of the tests gamma cyclodextrin peaks is not less than 1.5; and the
for absence of Salmonella species and Escherichia coli. The relative standard deviation for replicate injections is not more
total aerobic microbial count does not exceed 1000 cfu per g, than 2.0%.
and the total combined molds and yeasts count does not Procedure—Separately inject equal volumes (about 50 mL)
exceed 100 cfu per g. of the Standard solution and the Test solution into the
In-Process Revision
Loss on drying h731i—Dry it at 1058 for 2 hours: it loses not chromatograph, record the chromatograms, and measure the
more than 11.0% of its weight. responses for the major peaks. For the Test solution, the areas
Residue on ignition h281i: not more than 0.1%, deter- of any peaks corresponding to beta cyclodextrin or alpha
mined on a 1.0-g specimen. cyclodextrin are not greater than the area of the corresponding
peaks in the chromatogram of the Standard solution (0.5%),
Heavy metals, Method II h231i: not more than 5 ppm.
and the sum of the areas of all the peaks, excluding the
principal peak and the peaks corresponging to beta cyclodex-
trin or to alpha cyclodextrin, is not greater than half of the
water and methanol (90 : 10).
area of the peak corresponding to gamma cyclodextrin in the
chromatogram of the Standard solution (0.5%).
Pharmacopeial Forum
Mobile phase and Chromatographic system—Prepare as mL conical flask, dissolve in 10 mL of water, and add 25 mL
directed in the Assay. of Copper citrate solution alkaline cupric citrate TS2. Cover
System suitability solution—Prepare as directed for System the flask with aluminum foil, and boil the solution for
suitability preparation in the Assay. 5 minutes. Cool in an ice bath to room temperature. Add 25
Standard solution—Transfer 5.0 mL of the System mL of 0.6 N acetic acid, 10 mL of 3 N hydrochloric acid, and
suitability solution into a 50-mL volumetric flask, and 10 mL of 0.1 N iodine solution. [NOTE—The addition of these
dilute with water to volume. solutions must be in the order given.] Titrate the solution with
Test solution—Use the Assay stock preparation, prepared as 0.1 N sodium thiosulfate VS, and determine the endpoint
directed in the Assay. potentiometrically. Perform a blank determination (see
Procedure—Separately inject equal volumes (about 50 mL) Residual Titrations under Titrimetry h541i). Calculate the
of the Standard solution and the Test solution into the difference in volumes required. Create a calibration curve by
chromatograph, record the chromatograms, and measure the similarly titrating 0.25, 0.5, 0.75, and 1.0 mL of Dextrose
responses for the major peaks. For the Test solution, the areas standard solution. Calculate the amount of reducing sub-
of any peaks corresponding to alfadex (alpha cyclodextrin) or stances in the sample by comparing the thiosulfate consump-
to betadex (beta cyclodextrin) are not greater than the area of tion in the sample titration with that in the titration of the
the corresponding peaks in the chromatogram of the Standard standard solutions of the calibration curve, and by dividing
solution (0.5%); and the sum of the areas of all the peaks, that amount by 10 to obtain the percentage: not more than
excluding the principal peak, the peaks corresponding to 0.5% is found. Plot the amount, in mg, of dextrose in each
alfadex or to betadex, and artifact peaks, is not greater than titrated Dextrose standard solution versus the volume
the area of the peak corresponding to Gamma Cyclodextrin in consumed, in mL, of 0.1 N sodium thiosulfate VS in the
the chromatogram of the Standard solution (0.5%). titration, and draw a straight line through the four points.
Reducing substances— From the line so obtained and the volume of 0.1 N sodium
Copper citrate solution—Dissolve, with the aid of heat, thiosulfate VS required in the titration of Gamma Cyclodex-
about 173 g of sodium citrate dihydrate and 117 g of sodium trin, determine the amount, W, in mg, of dextrose in the
carbonate monohydrate in about 700 mL of water, and filter. portion of Gamma Cyclodextrin taken. Calculate the
In a second flask, dissolve about 27.06 g of cupric sulfate in percentage of the reducing substances by the formula:
about 100 mL of water. Slowly combine the two solutions

0.1(W/WG)
while stirring, and dilute with water to 1000 mL.
In-Process Revision
Dextrose standard solution—Transfer 1.1 g of dextrose
in which WG is the weight, in g, of Gamma Cyclodextrin
monohydrate, accurately weighed, to a 100-mL volumetric
taken: not more than 0.5% is found.
flask, and dissolve in and dilute with water to volume.
Dissolve an accurately weighed quantity of USP Dextrose RS Assay—
in water to obtain a solution having a known concentration of Mobile phase—Prepare a filtered and degassed mixture of
about 10.0 mg per mL for USP Dextrose RS, calculated on acetonitrile and water (67 : 33).
the anhydrous basis. Standard preparation—Dissolve an accurately weighed
Procedure—Transfer about 1.0 g of Gamma Cyclodextrin, quantity of USP Gamma Cyclodextrin RS in water to obtain
accurately weighed, and calculated a quantity of Gamma a solution having a known concentration of about 10 mg per
Cyclodextrin, equivalent to 1.0 g on the dried basis, to a 500- mL.
Pharmacopeial Forum
Assay preparation—Transfer about 100 mg of Gamma Standard preparation—Dissolve an accurately weighed

Cyclodextrin, previously dried, to a 10-mL volumetric flask, quantity of USP Gamma Cyclodextrin RS in water to obtain
and dissolve in about 8 mL of water. Dilute with water to a solution having a known concentration of about 1.0 mg per
volume. mL, calculated on the dried basis.
Chromatographic system (see Chromatography h621i)— Assay stock preparation—Transfer a quantity of Gamma
The liquid chromatograph is equipped with a refractive index Cyclodextrin, equivalent to 250 mg on the dried basis, to
detector and a 4-mm 6 25-cm column that contains 10- mm a 25-mL volumetric flask, and dissolve in water, with the aid
packing L8. The flow rate is about 1.0 mL per minute. of heat if necessary. Cool, and dilute with water to volume.
Chromatograph the Standard preparation, and record the Assay preparation—Transfer 5.0 mL of the Assay stock
peak responses as directed for Procedure: the relative preparation to a 50-mL volumetric flask, and dilute with
standard deviation for replicate injections is not more than water to volume.
2.0%. Chromatographic system (see Chromatography h621i)—
Procedure—Separately inject equal volumes (about 20 mL) The liquid chromatograph is equipped with a refractive index
of the Standard preparation and the Assay preparation into detector and a 4.6-mm 6 15-cm column that contains 5-mm
the chromatograph, record the chromatograms, and measure packing L1. The temperature for the refractive index detector
the responses for the major peaks. Calculate the quantity, in is maintained at 408, and the temperature for the analytical
mg, of C48H80O40 in the portion of Gamma Cyclodextrin taken column is maintained at 308. The flow rate is about 1.5 mL
by the formula: per minute. Chromatograph the System suitability prepara-
tion, and identify the components based on their relative
100C(rU / rS) retention times, which are 0.8, 1.0, and 1.9 for Gamma
Cyclodextrin, alfadex, and betadex, respectively. Record the
Gamma Cyclodextrin RS in the Standard preparation; and rU
between the Gamma Cyclodextrin and alfadex peaks is not
and rS are the peak responses obtained from the Assay
less than 1.5; the tailing factors for the three cyclodextrins are
preparation and the Standard preparation, respectively.
between 0.8 and 2.0; and the relative standard derivation for
(see System Suitability under Chromatograph h621i).
In-Process Revision

System suitability preparation—Dissolve accurately
weighed quantities of USP Alpha Cyclodextrin RS, USP
the responses for the major peaks. Calculate the percentage of
Beta Cyclodextrin RS, and USP Gamma Cyclodextrin RS in
(C6H10O5)8 in the portion of Gamma Cyclodextrin taken by
water, and dilute if necessary, to obtain a solution having
the formula:
known concentrations of 0.5 mg of each per mL for USP
Alpha Cyclodextrin RS and USP Beta Cyclodextrin RS, each 25,000(C/W)(rU / rS)
calculated on the anhydrous basis, and 0.5 mg per mL for
USP Gamma Cyclodextrin RS, calculated on the dried basis. in which C is the concentration, in mg per mL, of USP
Gamma Cyclodextrin RS in the Standard preparation; W is
the weight, in mg, of Gamma Cyclodextrin taken to prepare
Pharmacopeial Forum
the Assay stock preparation; and rU and rS are the peak USP Reference standards h11i—USP Inositol RS. USP
responses obtained from the Assay preparation and the Mannitol RS.
Standard preparation, respectively.&2S (NF26) Clarity of solution—[NOTE—The Test solution is to be
compared to Reference suspension A in diffused daylight
5 minutes after preparation of Reference suspension A.]
BRIEFING
Test solution—Dissolve 10.0 g of Inositol in about 50 mL of
Inositol. Because there is no existing NF monograph for this water, dilute with water to 100 mL, and mix.
excipient, a new monograph, based on the monograph appearing in
European Pharmacopoeia 5.5 and submitted data, is being Hydrazine sulfate solution—Transfer 1.0 g of hydrazine
proposed. The liquid chromatographic procedures in the test for
Related compounds and in the Assay are based on analyses sulfate to a 100-mL volumetric flask, dissolve in and dilute
performed with the Transgenomic CARBOSEP CHO-820 brand of
L19 column. The typical retention time for inositol in the test for with water to volume, and mix. Allow to stand for 4 to
Related compounds is about 17.5 minutes. Interested parties are
encouraged to submit comments. 6 hours before use.
Methenamine solution—Transfer 2.5 g of methenamine to
(EM1: R. Lafaver; NOM: W. Paul) RTS—C51303
a 100-mL glass-stoppered flask, add 25.0 mL of water, insert
the glass stopper, and mix to dissolve.
Primary opalescent suspension—[NOTE—This suspension
is stable for 2 months, provided it is stored in a glass
Add the following:
container free from surface defects. The suspension must not
&Inositol
adhere to the glass and must be well mixed before use.]
Transfer 25.0 mL of Hydrazine sulfate solution to the
Methenamine solution in the 100-mL glass-stoppered flask,
and mix. Allow to stand for 24 hours.
Opalescence standard—[NOTE—This suspension should not
be used beyond 24 hours after preparation.] Transfer 15.0 mL
C6H12O6 180.2 of the Primary opalescent suspension to a 1000-mL

volumetric flask, dilute with water to volume, and mix.
cis-1,2,3,5-trans-4,6-Cyclohexanehexol.
Reference suspensions—Transfer 5.0 mL of the Opales-
myo-Inositol [87-89-8].
cence standard to a 100-mL volumetric flask, dilute with
In-Process Revision
water to volume, and mix to obtain Reference suspension A.
» Inositol contains not less than 97.0 percent and Transfer 10.0 mL of the Opalescence standard to a second
100-mL volumetric flask, dilute with water to volume, and
not more than 102.0 percent of C6H12O6, calculated
mix to obtain Reference suspension B.
on the anhydrous basis.
Procedure—Transfer a sufficient portion of the Test
Packaging and storage—Preserve in well-closed containers, solution to a test tube of colorless, transparent, neutral
and store at room temperature. glass, with a flat base and an internal diameter of 15 to 25
mm, to obtain a depth of 40 mm. Similarly transfer portions
of Reference suspension A, Reference suspension B, and
water to separate matching test tubes. Compare the Test
solution, Reference suspension A, Reference suspension B,
Pharmacopeial Forum
and water in diffused daylight, viewing vertically against Scattering h851i). The Test solution is not more intensely
a black background (see Visual Comparison under Spectro- colored than Standard solution A, Standard solution B,
photometry and Light-Scattering h851i). [NOTE—The diffu- Standard solution C, or water.
sion of light must be such that Reference suspension A can Identification—
readily be distinguished from water, and that Reference A: Infrared Absorption h197Ki.
suspension B can readily be distinguished from Reference B: The retention time of the major peak in the
suspension A.] The Test solution shows the same clarity as chromatogram of the Assay preparation corresponds to that
that of water. in the chromatogram of the Standard preparation, as obtained
Color of solution— in the Assay.
Standard stock solutions—Prepare three solutions, A, B, Conductivity—
and C, containing, respectively, the following parts of ferric Test solution—Transfer about 10.0 g of Inositol, accurately
chloride CS, cobaltous chloride CS, cupric sulfate CS, and weighed and calculated on the dried basis, to a 50-mL
diluted hydrochloric acid: volumetric flask, dissolve in and dilute with water (previously
Standard stock solution A: 2.4 : 0.6 : 0 : 7.0 boiled and cooled to room temperature) to volume, and mix.
Standard stock solution B: 2.4 : 1.0 : 0.4 : 6.2 Apparatus—Use a conductivity meter or a resistivity meter
Standard stock solution C: 9.6 : 0.2 : 0.2 : 0 that measures the resistance of the column of liquid between
Standard solutions—[NOTE—Prepare the Standard solu- the electrodes of the immersed measuring device. The
tions immediately before use.] Transfer 2.5 mL of Standard apparatus is supplied with alternating current to avoid the
stock solution A to a 100-mL volumetric flask, dilute with effects of electrode polarization. It is equipped with
diluted hydrochloric acid to volume, and mix to obtain a temperature compensation device or a precision thermom-
Standard solution A. Transfer 2.5 mL of Standard stock eter.
solution B to a 100-mL volumetric flask, dilute with diluted Reagents—Prepare three standard solutions of potassium
hydrochloric acid to volume, and mix to obtain Standard chloride containing 0.7455 g, 0.0746 g, and 0.0149 g, respec-
solution B. Transfer 0.75 mL of Standard stock solution C to tively, of potassium chloride per 1000.0 g of solution. These
a 100-mL volumetric flask, dilute with diluted hydrochloric solutions should be prepared with water that has been
acid to volume, and mix to obtain Standard solution C. previously boiled and cooled to room temperature and whose
Test solution—Use the Test solution prepared in the test for conductivity does not exceed 2 mS per cm. The conductivity
In-Process Revision
Clarity of solution. and resistivity of these three solutions at 208 are given in the
Procedure—Transfer a sufficient portion of the Test table below.
solution to a test tube of colorless, transparent, neutral
Concentration of Solution Conductivity Resistivity
glass, with a flat base and an internal diameter of 15 to 25
(g/1000.0 g) (mS per cm) (
cm)
mm, to obtain a depth of 40 mm. Similarly transfer portions
of Standard solution A, Standard solution B, Standard 0.7455 1330 752
solution C, and water to separate matching test tubes. 0.0746 133.0 7519
Compare the Test solution, Standard solution A, Standard 0.0149 26.6 37,594
solution B, Standard solution C, and water in diffused

daylight, viewing vertically against a white background (see
Visual Comparison under Spectrophotometry and Light-
Pharmacopeial Forum
Calibration—Choose a conductivity cell that is appropriate 1 h, any opalescence in the solution is not more intense than
for the conductivity of the solution to be examined. The that in a mixture of 1 mL of water and 10 mL of the Test
higher the expected conductivity, the higher the cell constant solution prepared in the test for Clarity of solution.
that must be chosen. Commonly used conductivity cells have Limit of lead—
cell constants of the order 0.1 cm–1, 1 cm–1, and 10 cm–1. Use Standard lead solution—Prepare as directed for Standard
a standard solution of potassium chloride that is appropriate Lead Solution in Special Reagents under Heavy Metals h231i.
for the measurement. The conductivity value of the standard Test solution—Dissolve 20.0 g of Inositol in diluted acetic
solution of potassium chloride should be near the expected acid, and dilute with diluted acetic acid to 100 mL. Add 2.0
conductivity value of the Test solution. Rinse the cell several mL of a saturated ammonium pyrrolidinedithiocarbamate
times with water that has been previously boiled and cooled solution (containing about 10 g of ammonium pyrrolidine-
to room temperature, and at least twice with the potassium dithiocarbamate per L) and 10.0 mL of methyl isobutyl
chloride solution used for the determination of the cell ketone, and shake for 30 seconds. Protect from bright light.
constant of the conductivity cell. Measure the resistance of Allow the two layers to separate, and use the methyl isobutyl
the conductivity cell, using the potassium chloride solution at ketone layer.
20 + 0.18. The constant C (in cm–1) of the conductivity cell is Blank solution—Prepare as directed for Test solution,
given by the expression: except to omit the use of Inositol.
Standard solutions—Prepare as directed for Test solution,
C = RKCl 6 KKCl
except to prepare three standard solutions by adding 0.5 mL,
1.0 mL, and 1.5 mL, respectively, of Standard lead solution
where RKCl is the measured resistance, expressed in mega-
in addition to the 20.0 g of Inositol to be examined.
ohms; and KKCl is the conductivity of the standard solution of
Procedure—Set the atomic absorption spectrophotometer to
potassium chloride used, expressed in mS per cm. The
zero, using methyl isobutyl ketone previously treated as
measured constant, C, of the conductivity cell must be within
described under Test solution, but without sample added. Use
5% of the given value.
a lead hollow-cathode lamp as the source of radiation, an air–
Procedure—Rinse the conductivity cell several times with
acetylene flame, and an analysis wavelength of 283.3 nm.
water that has been previously boiled and cooled to room
Introduce the Test solution and each of the three Standard
temperature, and at least twice with the Test solution. Measure
solutions into the instrument, and record the steady
the conductivity of the Test solution, while gently stirring
absorbance reading. Plot the absorbance readings against
In-Process Revision
with a magnetic stirrer: the conductivity is not more than 20
the known concentrations of added lead (in mg), and draw
mS per cm.
a straight line. Extrapolate the line until it meets the
Water, Method I h921i: not more than 0.5% determined on
concentration axis to obtain the concentration, in mg per
a 1.0 g sample.
kg, of lead in the sample. Not more than 0.5 mg per kg is
Barium— found.
Test solution—Use the Test solution prepared in the test for
Clarity of solution. To 10 mL of Test solution add 1 mL of
Mobile phase, System suitability solution, and
diluted sulfuric acid. When examined immediately and after
Pharmacopeial Forum
Standard solution—Transfer 2.0 mL of the Standard contains packing L19. The column temperature is maintained
preparation, prepared as directed in the Assay, to a 100-mL at 858. The flow rate is about 0.5 mL per minute.
volumetric flask, dilute with water to volume, and mix. This Chromatograph the System suitability solution, and record
solution contains about 1 mg of inositol per mL. the peak responses as directed for Procedure: the relative
Procedure—Separately inject equal volumes (about 20 mL) retention times are about 1.0 for inositol and 1.3 for mannitol;
of the Test solution and the Standard solution into the and the resolution, R, between inositol and mannitol is not
chromatograph, record the chromatograms, and measure the less than 4.0. Chromatograph the Standard preparation, and
peak responses. Calculate the percentage of each impurity record the peak responses as directed for Procedure: the
found by the formula: relative standard deviation for replicate injections is not more
than 2.0%.
VC / W(ri / rS) Procedure—Separately inject equal volumes (about 10 mL)
in which V is the volume, in mL, of the Test solution; C is the
the chromatograph, record the chromatograms over a period
concentration, in mg per mL, of inositol in the Standard
of two times the retention time of inositol, and measure the
solution; W is the quantity, in mg, of inositol taken to prepare
peak responses. Calculate the quantity, in mg, of C6H12O6 in
the Test solution; ri is the peak response of any impurity
the portion of Inositol taken by the formula:
obtained from the Test solution; and rS is the response of the
inositol peak obtained from the Standard solution: not more VC(rU / rS)
than 0.3% of any individual impurity is found, and not more
than 1.0% of total impurities is found. Disregard any impurity in which V is the volume, in mL, of the Assay preparation; C
peak that is less than 0.05%. is the concentration, in mg per mL, of USP Inositol RS in the
Assay— Standard preparation; and rU and rS are the peak responses for
Mobile phase—Use degassed water. inositol obtained from the Assay preparation and the
Standard preparation—Dissolve an accurately weighed Standard preparation, respectively.
quantity of USP Inositol RS in water to obtain a solution

having a known concentration of about 50 mg per mL.
BRIEFING
Assay preparation—Transfer about 500 mg of Inositol,
In-Process Revision

Poloxamer. NF 25 page 1178. On the basis of comments and data
and dilute with water to volume, and mix. received, it is proposed to make the following revisions.
1. ‘‘No storage requirements specified’’ is added in the Packaging
System suitability solution—Transfer accurately weighed and storage section.
2. An IR identification test is added, introducing two reference
quantities of USP Inositol RS and USP Mannitol RS to standards, USP Poloxamer Liquid RS and USP Poloxamer
Solid RS.
a suitable volumetric flask, and dissolve in and dilute with 3. In the Limit of free ethylene oxide, propylene oxide, and 1,4-
dioxane, relative standard deviation for replicate injections is
water to obtain a solution having known concentrations of added as a system suitability requirement; other changes are
editorial.
about 0.05 mg of each per mL.
(EM2: H. Wang) RTS—C51239
The liquid chromatograph is equipped with a refractive index Change to read:
detector maintained at a constant temperature of about 308 to
Packaging and storage—Preserve in tight containers.
358 and a 7.8-mm 6 30-cm column or equivalent that
&
No storage requirements specified.&2S (NF26)
Pharmacopeial Forum
Test preparation—Transfer 1.00 + 0.01 g of Poloxamer to a

Add the following: 22-mL pressure headspace vial, and add about 0.01 g of butylated
hydroxytoluene. Seal, cap, and crimp as directed for the Standard
&
USP Reference standards h11i—USP Poloxamer Liquid preparation.
RS. USP Poloxamer Solid RS.&2S (NF26) chromatograph is equipped with a balanced-pressure automated
headspace sampler, a flame-ionization detector, and a 0.32-mm
6 50-m fused-silica capillary column coated with a 5-mm layer of
Add the following: stationary phase G27. The column temperature is programmed from
708 (10-minute initial hold) to 2408 (10-minute final hold) at 108 per
&
Identification—Infrared Absorption h197Fi, using a thin minute, with the transfer line at 1408 and the detector and injection
port at 2508. The carrier gas is helium, flowing at a rate of about
film of melted test specimen if it is solid. Use USP Poloxamer 1.6 mL per minute.
Liquid RS for Poloxamer 124, and use USP Poloxamer Solid &
Chromatograph the Standard preparation, and identify the
RS for Poloxamer 188, 237, 338 and 407. Because of components on the basis of the following relative retention
differences in the ratio of copolymer composition, the times: about 1.0, 1.3, and 3.8, respectively, for ethylene
intensity of some absorption bands may vary.&2S (NF26) oxide, propylene oxide, and 1,4-dioxane. Record the peak
Change to read:
between ethylene oxide and propylene oxide is not less
Limit of free ethylene oxide, propylene oxide, and 1,4-dioxane—
Stripped poloxamer—Place about 500 g of Poloxamer 124 into than 2.0; and the relative standard deviation for replicate
a suitable 3-neck, round-bottom flask equipped with a stirrer,
a thermometer, a vacuum outlet, and a heating mantle. Evacuate the injections is not more than 15%.&2S (NF26)
flask carefully at room temperature to a pressure of less than 10 mm Procedure—Separately place the vials containing the Standard
of mercury, applying the vacuum slowly to avoid excessive foaming preparation and the Test preparation in the automated sampler, and
due to entrapped gases. After any foaming has subsided, heat the start the sequence so that the vial is heated at a temperature of 1108
flask to 808 and continue to apply vacuum for 2 hours; then cool to for 30 minutes before a suitable portion of its headspace is injected
room temperature. Shut off the vacuum pump, and introduce into the chromatograph. Set the automated sampler for a needle-
nitrogen to bring the flask pressure back to atmospheric pressure. withdrawal time of 0.3 minute, a pressurization time of 1 minute, an
Transfer the Stripped poloxamer to a suitable nitrogen-filled injection time of 0.08 minute, and a vial pressure of 22 psig with the
container. vial vent off. Chromatograph the Standard preparation and the Test
Standard preparation—[Caution—Ethylene oxide, propylene preparation, record the chromatograms, and measure the peak
oxide, and 1,4-dioxane are toxic and flammable. Prepare these responses. as directed for Procedure: the relative retention times are
solutions in a well-ventilated fume hood.] To a tared vial that can be about 1.0, 1.3, and 3.8, respectively, for ethylene oxide, propylene
sealed, add 50.0 g of Stripped poloxamer. Add 60 mL of 1,4-dioxane oxide, and 1,4-dioxane; and the resolution, R, between ethylene
and 75 mL of propylene oxide from a chilled syringe. Add ethylene oxide and propylene oxide is not less than 2.0.
oxide, using the following special handling procedure. Ethylene &
oxide—which is a gas at room temperature—is usually stored in &2S (NF26)
a lecture-type gas cylinder or a small, metal pressure-bomb. Chill the Calculate the concentrations, in mg per g, of ethylene oxide,
cylinder in a refrigerator before use. Transfer about 5 mL of the propylene oxide, and 1,4-dioxane in the portion of Poloxamer taken
liquid ethylene oxide to a 100-mL beaker chilled in wet ice. Using by the formula:
a gas-tight syringe that has been chilled in a refrigerator, transfer 15
mL of the liquid ethylene oxide to the mixture. Immediately seal the C(rU / rS)
vial, and shake on a vortex mixer for at least 30 seconds. Transfer in which C is the concentration, in mg per g, of ethylene oxide,
0.20 g of this solution to a tared vial that can be sealed, and add propylene oxide, or 1,4-dioxane in the Standard preparation; and rU
Stripped poloxamer to obtain a Standard preparation having a final and rS are the peak responses obtained from the Test preparation and
weight of 50.0 g. Each gram of this Standard preparation contains the Standard preparation, respectively: not more than 1 mg of
1 mg of ethylene oxide, 5 mg of propylene oxide, and 5 mg of 1,4- ethylene oxide per g, not more than 5 mg of propylene oxide per g,
dioxane. Transfer 1.00 + 0.01 g of this solution to a 22-mL pressure and not more than 5 mg of 1,4-dioxane per g are found.
In-Process Revision
headspace vial, and add about 0.01 g of butylated hydroxytoluene.
Seal with a silicone septum with or without a pressure-relief star
spring and with a pressure-relief, aluminum, safety sealing-cap, and
crimp the cap closed with a cap-sealing tool.
Pharmacopeial Forum
Add the following:

GENERAL CHAPTERS &
USP Dehydroacetic Acid RS.&2S (USP31)
General Tests and Assays Add the following:

&
USP (-)-Epigallocatechin-3-O-gallate RS.&2S (USP31)
General Requirements for Add the following:

Tests and Assays &
U S P P o w d e r e d D e c aff ei na t ed G r e e n Te a E x t r a c t
RS.&2S (USP31)
Add the following:

&
USP Inositol RS.&2S (USP31)
Add the following:

BRIEFING &
USP Poloxamer Liquid RS.&2S (USP31)
h11i USP Reference Standards, USP 30 page 37, page 1832 of Add the following:
PF 27(1) [Jan.–Feb. 2001], page 2022 of PF 29(6) [Nov.–Dec. 2003],
page 1338 of PF 30(4) [July–Aug. 2004], page 1674 of PF 30(5) &
USP Poloxamer Solid RS.&2S (USP31)
[Sept.–Oct. 2004], page 507 of PF 31(2) [Mar.–Apr. 2005], page
1154 of PF 31(4) [July–Aug. 2005], page 1433 of PF 31(5)
[Sept.–Oct. 2005], page 1680 of PF 31(6) [Nov.–Dec. 2005], page Add the following:
181 of PF 32(1) [Jan.–Feb. 2006], page 407 of PF 32(2) [Mar.–
Apr. 2006], page 829 of PF 32(3) [May–June 2006], page 1161 of &
USP Raloxifene Hydrochloride RS.&2S (USP31)
2006], page 1779 of PF 32(6) [Nov.–Dec. 2006], page 95 of PF
33(1) [Jan.–Feb. 2007], page 267 of PF 33(2) [Mar.–Apr. 2007],
and page 497 of PF 33(3) [May–June 2007].
(HDQ) RTS—C43218; C47067; C49043; C49277; C50926;

C50934; C51226; C51239; C51303 Apparatus for Tests and
Assays
Add the following:
&
USP Agar RS.&2S (USP31)
BRIEFING
Add the following:

h41i Weights and Balances, USP 30 page 79 and page 1781 of PF
&
USP Powdered Bilberry Extract RS.&2S (USP31) 32(6) [Nov.–Dec. 2006]. On the basis of comments received, it is pro-
In-Process Revision
posed to revise this chapter. In the Introduction, it is proposed to state

that the requirements in the chapter apply to balances used in proce-
Add the following: dures where the reportable value is expressed in at least three signif-
icant figures. Other changes are proposed in the sections
&
USP Cyanidin Chloride RS.&2S (USP31) Repeatability, Verification of Accuracy, and Weight Check.
Add the following: (GC: H. Pappa) RTS—C53568
&
USP Cyanidin-3-O-glucoside Chloride RS.&2S (USP31)
Add the following:

&
USP Gamma Cyclodextrin RS.&2S (USP31)
Add the following:

&
USP Cyromazine RS.&2S (USP31)
Pharmacopeial Forum
Analytical methods with less strict requirements need not nec-

Change to read:
essarily follow this standard. Measurement uncertainty from
the balance is only one contribution to overall weighing er-
&
INTRODUCTION&2S (USP31)
rors.1 Other contributions include changes in water content
of samples during weighing and a static charge on the sample.
The intent of this section is to bring the requirements for weights This chapter addresses the control of the analytical balance for
into conformity with American National Standard ANSI/ASTM
E617, ‘‘Laboratory Weights and Precision Mass Standards.’’ This routine operation. Unless otherwise specified, when substanc-
standard is incorporated by reference and should be consulted for full
descriptions and information on the tolerances and construction of es are to be ‘‘accurately weighed’’ (for example, in an Assay
weights.1
Pharmacopeial tests and assays require balances that vary in capa- analysis), the weighing is to be performed with a weighing de-
city, sensitivity, and reproducibility. Unless otherwise specified, when
substances are to be ‘‘accurately weighed’’ for Assay, the weighing is vice
to be performed with a weighing device whose measurement uncer-
tainty (random plus systematic error) does not exceed 0.1% of the Assessment of measurement uncertainty is typically done
reading. Measurement uncertainty is satisfactory if three times the
standard deviation of not less than ten replicate weighings divided prior to the balance being placed in operation (e.g., during
by the amount weighed, does not exceed 0.001. Unless otherwise
specified, for titrimetric limits tests, the weighing shall be performed IQ/OQ/PQ) and periodically thereafter. Two steps are per-
to provide the number of significant figures in the weight of the ana-
lyte that corresponds to the number of significant figures in the con- formed in measuring uncertainty: (1) measurement of repeat-
centration of the titrant.
ability and (2) verification of accuracy against certified
The class designations below are in order of increasing tolerances.
weights.does not exceed 0.1% of the reading. There are three
Class 1.1 weights are used for calibration of low-capacity, high-
sensitivity balances. They are available in various denominations requirements for control of the analytical balance: assessment
from 1 to 500 mg. The tolerance for any denomination in this class
is 5 mg. They are recommended for calibration of balances using op- of measurement uncertainty (represented mainly by the repeat-
tical or electrical methods for accurately weighing quantities below
20 mg. ability of the measurement), verification of accuracy, and a
Class 1 weights are designated as high-precision standards for cal-
ibration. They may be used for weighing accurately quantities below calibration check. that meets the following three requirements:
20 mg. (For weights of 10 g or less, the requirements of class 1 are
met by USP XXI class M.) repeatability of the measurement to within 0.1%, verification
Class 2 weights are used as working standards for calibration, of accuracy to within 0.1%, and a weight check. The first two
built-in weights for analytical balances, and laboratory weights for
routine analytical work. (The requirements of class 2 are met by requirements are typically performed prior to placing the bal-
USP XXI class S.)2
ance in operation (e.g., during IQ/OQ/PQ) and periodically
Class 3 and class 4 weights are used with moderate-precision labor-
atory balances. (Class 3 requirements are met by USP XXI class S-1; thereafter according to applicable standards operating proce-
class 4 requirements are met by USP XXI class P.)2
A weight class is chosen so that the tolerance of the weights used dures. The calibration weight check is typically performed
does not exceed 0.1% of the amount weighed. Generally, class 2 may
be used for quantities greater than 20 mg, class 3 for quantities of each day or prior to each series of weighings. on which the
greater than 50 mg, and class 4 for quantities of greater than 100
mg. Weights should be calibrated periodically, preferably against an balance is used or at appropriate intervals based on applicable
In-Process Revision
absolute standard weight.
standard operating procedures. &2S (USP31)
&
Pharmacopeial tests and assays require balances that vary Add the following:
in capacity, sensitivity, and repeatability. This chapter applies
to balances used in pharmacopeial procedures with a reporta- &
REPEATABILITY
ble value expressed in at least three significant figures (see In-
Assessment of repeatability may be performed using either
terpretation of Requirements under General Notices).
Method A or Method B.
1
Copies of ASTM Standard E 617-81 (Reapproved 1985) may be obtained
from the American Society for Testing and Materials, 1916 Race Street, Phil-
adelphia, PA 19103.
1
2
Note that the designations S and P no longer designate weight classes but Sources of measurement uncertainties with laboratory balances are
rather weight grades, that is, design limitations such as range of density of (including, but not limited to) readability, repeatability, nonlinearity,
materials, surface area, surface finish, corrosion resistance, and hardness. sensitivity, temperature, and buoyancy.
Pharmacopeial Forum
Method A— In this method, repeatability Repeatability is in which Urel represents the uncertainty factor of 0.001; and s is
determined at the lower end of the desired operating range the standard deviation from the repeatability measurements, in
(i.e., the range of weights for which the balance has been qual- mg, of not less than 10 replicate measurements of a mass near
ified to meet the requirements of this chapter). The measure- the low end of the operating range. Minimum weight may be
ment of repeatability using this method is satisfactory if two used to define the low end of the operating range. Because of
times the standard deviation of not less than 10 replicate scale resolution, it is possible to make measurements in which
weighings divided by the amount weighed does not exceed every one results in the same value. A true scale standard de-
0.001, as shown in the formula: viation of zero is not statistically possible, although the stan-
dard deviation may be less than one display increment d. In
2s/w0.001 this situation, the standard deviation of the scale can be esti-
mated as
in which s is the standard deviation of not less than 10 replicate
weighings; and w is the nominal mass, in mg, of the weight
used. Because of display resolution, it is possible to make
measurements in which every replicate measurement result
is the same value. A true repeatability standard deviation of
zero is not statistically possible, although the standard devia-
tion may be less than one display increment d. In this situation,
the standard deviation of the balance can be estimated as
&2S (USP31)
Add the following:
Method B Calculation of Minimum Weight—This method

&
VERIFICATION OF ACCURACY
may be used to determine the low end of the operating range Using multiple weights of suitable accuracy as described in
(e.g., minimum weight). Minimum weight can be derived the table Weights Used for Calibration Check of Balances, the
In-Process Revision
from the following formula: 2

measured weight is within 0.1% of the certified value over the
operating range of the balance. The operating range refers to
(2/Urel)s
the range used for performing the assay, and not necessarily to
the operating range for other weighing operations.
2
Derived from the expanded uncertainty equation in NISTIR 6919,
Recommended Guide for Determining and Reporting Uncertainties
for Balances and Scales, January 2002.
Pharmacopeial Forum
Weights Used for Calibration Check of Balances
Lowest Weight With a Tolerance
Application Appropriate Class of Weight Within 0.1%*
Calibration of the weights used for OIML Classes E1, E2, and ** OIML E1, 5 mg
other applications or other specialized ASTM Class 0 [NOTE—Special ** OIML E2, 10 mg
applications control of humidity and ** ASTM Class 0, 5 mg
temperature is needed.]
Routine analytical work using ASTM Classes 1, 2 ASTM Class 1, 10 mg
microbalances **OIML E2 ASTM Class 2, 20 mg
Routine analytical work using ASTM Classes 3, 4 ASTM Class 3, 50 mg
4–5 place analytical balances OIML Classes F1, F2 ASTM Class 4, 100 mg
OIML Class F1, 50 mg
OIML Class F2, 200 mg
*
ASTM standard E617 may be obtained from ASTM, 100 Barr Harbor Drive, West Conshohocken, PA 19428. OIML R111 may be obtained
from OIML (International Organization of Legal Metrology), 11 Rue Turgot, F-75009, Paris, France.
**
Special control temperature and humidity is needed.
&2S (USP31)
Add the following: Chemical Tests and Assays

&
CALIBRATION WEIGHT CHECK
IDENTIFICATION TESTS
Analytical balances vary greatly in the features they offer to

ensure that the balance is maintained in a calibrated state. A
BRIEFING
calibration weight check to ensure using an internal or external
check weight ensures that the balance is in a calibrated state is h191i Identification Tests—General, USP 30 page 139. The odor
ID tests have generated comments suggesting that they should be ex-
performed each day or before each series of weighings. Typi- cluded from or replaced in this general chapter. In some reported cas-
es the organoleptic methods are not consistent with environmental
cally, the calibration check uses internal or external weights to safety legislation and/or practices to conduct them. Alternative meth-
ods for acetate and ammonium have been proposed on the basis of the
verify that the balance is still in a calibrated state. suitable to prospective harmonization of this chapter.
In-Process Revision
use. The weight check is typically performed each day the bal- (GC: A. Hernandez-Cardoso) RTS—C46428
ance is used or at appropriate intervals based on applicable
standard operating procedures.&2S (USP31)
Change to read:
Under this heading are placed tests that are frequently referred to in
the Pharmacopeia for the identification of official articles.
&
Before using any acid or base to modify the pH of the sample
solution, make sure that the added substance will not interfere
with the results of the test.&2S (USP31)
[NOTE—The tests are not intended to be applicable to mixtures of sub-
stances unless so specified.]
Pharmacopeial Forum
Acetate—When acetic acid or an acetate is warmed with sulfuric Change to read:

acid and alcohol, ethyl acetate, recognizable by its characteristic odor,
is evolved. Total organic carbon (TOC) is an indirect measure of organic mol-
ecules present in pharmaceutical waters measured as carbon. Organic
&
Dissolve about 30 mg of the substance to be examined in 3 molecules are introduced into the water from the source water, from
purification and distribution system materials, and from biofilm
mL of water, or use 3 mL of the prescribed solution. Adjust the growing in the system. TOC can also be used as a process control
attribute to monitor the performance of unit operations comprising
pH of the solution with sodium hydroxide to slightly alkaline. the purification and distribution system.
Add successively 0.25 mL of lanthanum nitrate TS, 0.1 mL of &

A TOC measurement is not a replacement test for endotoxin
iodine and potassium iodide TS 3, and 0.1 mL of ammonia TS or microbiological control. While there can be a qualitative re-
2 to the solution. If no blue color is observed, heat carefully to lationship between a food source (TOC) and microbiological
boiling. In the presence of acetates, a dark color develops or a activity, there is no direct numerical correlation.&2S (USP31)
A number of acceptable methods exist for analyzing TOC. This
blue precipitate is formed.&2S (USP31) chapter does not limit or prevent alternative
With neutral solutions of acetates, ferric chloride TS produces a deep
red color that is destroyed by the addition of mineral acids. &
endorse, limit, or prevent any&2S (USP31)
Ammonium—Ammonium salts are decomposed by the addition technologies from being used, but
of an excess of 1 N sodium hydroxide, with the evolution of ammo-
nia, recognizable by its odor and by its alkaline effect upon moistened
&
this chapter&2S (USP31)
red litmus paper exposed to the vapor. Warming the solution acceler- provides guidance on how to qualify these analytical technologies for
ates the decomposition. use as well as guidance on how to interpret instrument results for use
as a limit test. The Standard Solution is a theoretically easy-to-oxidize
&
Add 0.2 g of magnesium oxide to the solution in the mono- solution that gives an instrument response at the attribute limit. The
analytical technology is qualified by challenging the capability of the
graph. Pass a current of air through the mixture, and direct the instrument using a theoretically difficult to oxidize solution in the sys-
tem suitability portion of the method.
gas that escapes just beneath the surface of a mixture of 1 mL Analytical technologies utilized to measure TOC share the objec-
tive of completely oxidizing the organic molecules in an aliquot of
of 0.1 M hydrochloric acid and 0.05 mL of methyl red TS 2, as sample water to carbon dioxide (CO2), measuring the resultant CO2
levels, and expressing this response as carbon concentration. All tech-
the indicator solution. In the presence of ammonium, the color nologies must discriminate between the inorganic carbon, which may
be present in the water from sources such as dissolved CO2 and bi-
of the indicator solution will change to yellow. After directing carbonate, and the CO2 generated from the oxidation of organic mol-
ecules in the sample.
the gas into the indicator solution for a sufficient period of Two general approaches are used to measure TOC. One approach
determines TOC by subtracting the measured inorganic carbon (IC)
time, add 1 mL of freshly prepared sodium cobaltinitrite TS from the measured total carbon (TC), which is the sum of organic
carbon and inorganic carbon:
to the indicator solution. Upon the addition of the sodium co- TOC = TC – IC.
baltinitrite TS, a yellow precipitate will form when ammonium
The other approach first purges the IC from the sample before any
is present.&2S (USP31) carbon measurement is performed. However, this IC purging step also
purges some of the organic molecules, which can be retrapped, oxi-
dized to CO2, and quantitated as purgeable organic carbon (POC).
The remaining organic matter in the sample is also oxidized to CO2
and quantitated as nonpurgeable organic carbon (NPOC). In this ap-
Physical Tests and proach, TOC is the sum of POC and NPOC:
Determinations TOC = POC + NPOC.

In-Process Revision
In pharmaceutical waters, the amount of POC is negligible and can

be discounted. Therefore, for the purpose of this methodology, NPOC
is equivalent to TOC.
BRIEFING
&
TOC measurement technologies should discriminate the in-
organic carbon, which may be present in the water from
h643i Total Organic Carbon, USP 30 page 257. This chapter has sources such as dissolved CO2 and bicarbonate, from any
been modified in response to inquiries regarding the following topics:
(1) to address the relationship between TOC and microbiological ac- CO2 that may be generated during the analysis of the organic
tivity, (2) to provide guidance to the analyst on the method, and (3) to
provide emphasis on the allowance of on-line measurements. components. In addition to other requirements listed below,
(PW: G. Ritchie) RTS—C52360 the System Suitability test is the challenge to the TOC tech-
nology.&2S (USP31)
Pharmacopeial Forum
Change to read: &

FOR OFF-LINE TESTING—Use caution when obtaining sam-
Apparatus Requirements—This test method is performed either ples for TOC analysis. Water samples can be easily contami-
as an on-line test or as an off-line laboratory test using a calibrated
instrument. nated during the process of sampling and transportation to a
&
On-line TOC measurements for bulk-produced waters such testing facility. Collect the Test Solution in a tight container
as Purified Water, Water for Injection, and Pure Steam conden- with minimal head space, and test in a timely manner to min-
sate have the advantage of providing real-time measurements imize the impact of organic contamination from the closure
and opportunities for real-time process control and decisions, and container.
in addition to recording the TOC quality attribute for release of FOR ON-LINE TESTING—Use caution when connecting the
water to production. Due to the high purity of these waters, on-line TOC measurement system to the water production sys-
off-line measurements of bulk waters have the disadvantage tem. The piping and measurement system may require sub-
of being impacted adversely by the sampling method, sam- stantial time to rinse depending on many factors.&2S (USP31)
pling container, and uncontrollable environmental factors such
Change to read:
as organic vapors. Because water production could be a batch
Other Control Solutions—Prepare appropriate reagent blank so-
operation or a continuous operation, the nature of the water lutions or other specified solutions needed for establishing the appa-
ratus baseline or for calibration adjustments following the
production should be considered when determining if off-line manufacturer’s instructions, and run the appropriate blanks to zero
the instrument,
or on-line measurement is to be used.&2S (USP31)
The suitability of the apparatus must be periodically demonstrated as &
if necessary.&2S (USP31)
described below. In addition, it must have a manufacturer’s specified
limit of detection of 0.05 mg of carbon per L (0.05 ppm of carbon) or
lower. Change to read:
System Suitability—Test the Reagent Water Control in the appa-

Change to read: ratus, and record the response, rw. Repeat the test using the Standard
Solution, and record the response, rS. Calculate the corrected Stan-
Glassware Preparation— dard Solution response, which is also the limit response, by subtract-
ing the Reagent Water Control response from the response of the
&
Container Preparation—&2S (USP31) Standard Solution. The theoretical limit of 0.50 mg of carbon per L
Organic contamination of glassware is equal to the corrected Standard Solution response, rS – rw. Test the
System Suitability Solution in the apparatus, and record the response,
&
containers&2S (USP31) rss. Calculate the corrected System Suitability Solution response by
results in higher TOC values. Therefore, use glassware and sample subtracting the Reagent Water Control response from the response
of the System Suitability Solution, rss – rw. Calculate the response ef-
&
&2S (USP31) ficiency for the System Suitability Solution by the formula:
containers that have been scrupulously cleaned of organic residues.
Any method that is effective in removing organic matter can be used 100[(rss – rw) / (rS – rw)]
(see Cleaning Glass Apparatus h1051i). Use Reagent Water for the
final rinse.
&
where rS is the instrument response to the Standard Solution;
Change to read:
rss is the instrument response to the System Suitability Solu-
In-Process Revision
Standard Solution—Unless otherwise directed in the individual tion; and rw is the instrument response to the Reagent Water
monograph, dissolve in the Reagent Water an accurately weighed
quantity of USP Sucrose RS, to obtain a solution having a concentra- Control.&2S (USP31)
tion of about The system is suitable if the response efficiency is not less than 85%
&
and not more than 115% of the theoretical response.
&2S (USP31)
1.2 mg of sucrose per L (0.50 mg of carbon per L).
Change to read:
Change to read:
Procedure—Perform the test on the Test Solution, and record the
response, rU. The Test Solution meets the requirements if rU is not
Test Solution—[NOTE—Use extreme caution when obtaining sam- more than the limit response, rS – rw. This method also can be per-
ples for TOC analysis. Water samples can be easily contaminated dur- formed alternatively
ing the process of sampling and transportation to a testing facility.]
Collect the Test Solution in a tight container with minimal head space, &
&2S (USP31)
and test in a timely manner to minimize the impact of organic con- using on-line
tamination from the closure and container.
&
or off-line &2S (USP31)
Pharmacopeial Forum
instrumentation that has been appropriately calibrated, standardized, is included in this allowed impurity level to maintain electroneutral-
and has demonstrated acceptable system suitability. The acceptability ity. Extraneous ions such as these may have significant impact on the
of such on-line instrumentation for quality attribute testing is depend- water’s chemical purity and suitability for use in pharmaceutical ap-
ent on its location(s) in the water system. These instrument location(s) plications. The combined conductivities of the intrinsic and extrane-
and responses must reflect the quality of the water used. ous ions vary as a function of pH and are the basis for the
conductivity specifications described in the accompanying table
&
meets the Apparatus Requirements. For both on-line and off- and used when performing Stage 3 of the test method. Two prelimi-
nary stages are included in the test method. If the test conditions and
line measurements, the suitability of instrumentation for qual- conductivity limits are met at either of these preliminary stages, the
water meets the requirements of this test. Proceeding to the third stage
ity control testing is also dependent on the sampling loca- of the test in these circumstances is unnecessary. Only in the event of
failure at the final test stage is the sample judged noncompliant with
tion(s) in the water system. The selected sampling the requirements of the test.
location(s) must reflect the quality of the water used.&2S (USP31) &
The procedure described in the section Bulk Water is de-
signed for measuring the conductivity of waters such as Puri-
fied Water, Water for Injection, Water for Hemodialysis, and
the condensate of Pure Steam produced in bulk. For water
BRIEFING
packaged in bulk but manufactured elsewhere or for Sterile
h645i Water Conductivity, USP 30 page 258. This chapter is be- Purified Water, Sterile Water for Injection, Sterile Water for
ing modified by the addition of a verification step on the entire
conductivity-measuring instrument to increase the assurance of using Inhalation, and Sterile Water for Irrigation, some additional
a properly calibrated system. Individual electronic and sensor calibra-
tion steps are already in place. The addition of the verification step conductivity tests may be required. Such tests are described
aims to ensure the use of a properly calibrated instrument for the
measurements in low conductivity ranges and to prevent the oversight in the section Packaged Water.
of unique electronic effects. Also being added to the chapter is a sec-
tion on planned conductivity testing of monographed packaged On-line conductivity testing provides real-time measure-
waters. The proposed limits in this test will be harmonized with
existing conductivity tests in the current European Pharmacopoeia. ments and opportunities for real-time process control, deci-
(PW: G. Ritchie) RTS—C51630 sion, and intervention. Because of the high purity of the
water tested, with ionic and organic impurities in the
sub-mg/L range, off-line measurements of water may be ad-
Change to read: versely affected by the sampling method, the sampling con-
Electrical conductivity in water is a measure of the ion-facilitated tainer, and environmental factors such as ambient carbon
electron flow through it. Water molecules dissociate into ions as a
function of pH and temperature and result in a very predictable con- dioxide concentration and organic vapors. Except for
ductivity. Some gases, most notably carbon dioxide, readily dissolve
in water and interact to form ions, which predictably affect conduc- p ac k ag e d w a t e r, o n - l i n e m e a s u r em en t s m a y b e
tivity as well as pH. For the purpose of this discussion, these ions and
their resulting conductivity can be considered intrinsic to the water. preferred.&2S (USP31)
Water conductivity is also affected by the presence of extraneous
ions. The extraneous ions used in modeling the conductivity specifi-
cations described below are the chloride and sodium ions. The con-
ductivity of the ubiquitous chloride ion (at the theoretical endpoint
In-Process Revision
concentration of 0.47 ppm when it was a required attribute test in

USP XXII and earlier revisions) and the ammonium ion at the limit
of 0.3 ppm represents a major portion of the allowed water impurity
level. A balancing quantity of cations, such as sodium ion,
&
ions,&2S (USP31)
Pharmacopeial Forum
INSTRUMENT SPECIFICATIONS AND the measuring equipment with those of an external calibrated
OPERATING PARAMETERS conductivity-measuring device. The two non-temperature-
Water conductivity must be measured accurately using calibrated compensated conductivity or resistivity values must be equiv-
instrumentation. The conductivity cell constant, a factor used as a
multiplier for the scale reading from the meter, alent to within +20% of each other, or at a difference that is
&
that represents the geometrical properties of the conductivity acceptable on the basis of product water criticality and/or the
sensor,&2S (USP31) water conductivity ranges in which the measurements are tak-
must be known within +2%. The cell constant can be verified direct-
ly by using a solution of known en. The two conductivity sensors should be positioned close
&
or traceable&2S (USP31) enough together to measure the same water sample in the same
conductivity, or indirectly by comparing the instrument reading taken
with the cell environmental conditions.
&
conductivity sensor&2S (USP31) In addition to the verification method performed in non-
in question to readings from a cell
temperature-compensated mode, a similar verification per-
&
conductivity sensor&2S (USP31)
of known or certified formed in temperature-compensated mode could be performed
&
traceable&2S (USP31) to ensure an appropriate accuracy of the equipment when such
cell constant.
Meter calibration is accomplished by replacing the conductivity a mode is used for trending or other purposes.&2S (USP31)
cell
Because temperature has a substantial impact on conductivity read-
&
sensor&2S (USP31) ings of specimens at high and low temperatures, many instruments
with NIST automatically correct the actual reading to display the value that the-
oretically would be observed at the nominal temperature of 258. This
&
(or equivalent local national authority)&2S (USP31) is done using a temperature sensor
-traceable precision resistors (accurate to +0.1% of the stated value)
or an equivalently accurate adjustable resistance device, such as a &
embedded&2S (USP31)
Wheatstone Bridge, to give a predicted instrument response. Each in the conductivity cell probe
scale on the meter may require separate calibration prior to use.
The frequency of recalibration is a function of instrument design, de- &
sensor&2S (USP31)
gree of use, etc. However, because some multiple-scale instruments and an algorithm in the instrument’s circuitry.
have a single calibration adjustment, recalibration may be required
between each use of a different scale. The instrument must have a &
An external temperature sensor is also acceptable.&2S (USP31)
minimum resolution of 0.1 mS/cm* on the lowest range. This temperature compensation algorithm may not be accurate. Con-
& ductivity values used in this method are nontemperature-compensat-
&2S (USP31) ed
Excluding the
&
non-temperature-compensated&2S (USP31)
&
conductivity sensor&2S (USP31) measurements. Accuracy of the temperature measurement must be
cell +28
The procedure described below is designed for measuring the con-
&
constant&2S (USP31) ductivity of Purified Water and Water for Injection. Stage 1 of the
accuracy, the instrument accuracy must be +0.1 mS/cm. procedure below may alternatively be performed (with the appropri-
ate modifications to Step 1) using on-line instrumentation that has
&
In order to increase the measurement accuracy on the con- been appropriately calibrated, whose cell constants have been ac-
curately determined, and whose temperature compensation function
ductivity ranges used, which can be large, and to ensure a has been disabled. The suitability of such on-line instrumentation for
In-Process Revision
quality control testing is also dependent on its location(s) in the water
complete equipment calibration, it is suggested that verifica- system. The selected instrument location(s) must reflect the quality of
the water used.
tion of the entire equipment be performed. This could be done
&
&2S (USP31)
by comparing the conductivity/resistivity values displayed by
*
mS/cm (microsiemens per centimeter) = mmho/cm = reciprocal of megohm-
cm.
Pharmacopeial Forum
Add the following: conductivity reading. The measurement may be performed in a suit-
able container or as an on-line measurement.
&
&2S (USP31)
&
BULK WATER 2. Using the Stage 1—Temperature and Conductivity Requirements
table, find the temperature value that is not greater than the measured
temperature, i.e., the next lower temperature. The corresponding con-
The procedure below shall be performed using instrumenta- ductivity value on this table is the limit. [NOTE—Do not interpolate.]
3. If the measured conductivity is not greater than the table value,
tion that has been calibrated, and has conductivity sensor cell the water meets the requirements of the test for conductivity. If the
conductivity is higher than the table value, proceed with Stage 2.
constants that have been accurately determined and tempera-
Stage 1—Temperature and Conductivity Requirements
ture compensation function that has been disabled. For both (for non-temperature-compensated conductivity measurements only)
on-line and off-line measurements, the suitability of instru- Temperature Conductivity Requirement (mS/cm)
mentation for quality control testing is also dependent on the 0 0.6
5 0.8
sampling location(s) in the water system. The selected sam- 10 0.9
15 1.0
pling instrument location(s) must reflect the quality of the wa- 20 1.1
25 1.3
ter used during its application. 30 1.4
35 1.5
The combined conductivities of the intrinsic and extraneous 40 1.7
45 1.8
ions vary as a function of pH and are the basis for the conduc- 50 1.9
55 2.1
tivity specifications described in the Stage 3—pH and Con- 60 2.2
65 2.4
ductivity Requirements table and used when performing 70 2.5
75 2.7
Stage 3 of the test method. Two preliminary stages are includ- 80 2.7
85 2.7
ed in the test method. If the test conditions and conductivity 90 2.7
95 2.9
limits are met at either of these preliminary stages, the water 100 3.1
meets the requirements of this test. Proceeding to the third Stage 2

stage of the test in these circumstances is unnecessary. Only 4. Transfer a sufficient amount of water (100 mL or more) to a suit-
able container, and stir the test specimen. Adjust the temperature, if
in the event of failure at the final test stage is the sample judged necessary, and, while maintaining it at 25 + 18, begin vigorously agi-
tating the test specimen while periodically observing the conductivi-
noncompliant with the requirements of the test.&2S (USP31) ty. When the change in conductivity (due to uptake of atmospheric
carbon dioxide) is less than a net of 0.1 mS/cm per 5 minutes, note
the conductivity.
5. If the conductivity is not greater than 2.1 mS/cm, the water meets
PROCEDURE the requirements of the test for conductivity. If the conductivity is
greater than 2.1 mS/cm, proceed with Stage 3.
Stage 1
&
Stage 1 is intended for on-line testing. Proceed to Stage 2 if Stage 3
In-Process Revision
6. Perform this test within approximately 5 minutes of the conduc-

off-line testing is intended.&2S (USP31) tivity determination in Step 5, while maintaining the sample temper-
ature at 25 + 18. Add a saturated potassium chloride solution to the
1. Determine the temperature of the water and the conductivity of same water sample (0.3 mL per 100 mL of the test specimen), and
the water using a nontemperature-compensated determine the pH to the nearest 0.1 pH unit, as directed under pH
h791i.
&
non-temperature-compensated&2S (USP31)
Pharmacopeial Forum
7. Referring to the Stage 3—pH and Conductivity Requirements are derived from Purified Water or Water for Injection, and
table, determine the conductivity limit at the measured pH value. If
the measured conductivity in Step 4 is not greater than the conductiv- therefore have been determined to be compliant with the Bulk
ity requirements for the pH determined in Step 6, the water meets the
requirements of the test for conductivity. If either the measured con- Water requirements before being stored in the container. The
ductivity is greater than this value or the pH is outside the range of 5.0
to 7.0, the water does not meet the requirements of the test for con- specification provided represents the maximum allowable
ductivity.
conductivity value, taking into consideration the limitation
Stage 3—pH and Conductivity Requirements
(for atmosphere- and temperature-equilibrated samples only) of the measurement method and reasonable container leach-
pH Conductivity Requirement (mS/cm) ing. Such specification and the sampling volume choices
5.0 4.7 should be defined and validated on the basis of the intended
5.1 4.1
5.2 3.6 purpose of the water.&2S (USP31)
5.3 3.3
5.4 3.0
5.5 2.8 Add the following:
5.6 2.6
5.7 2.5
5.8 2.4
5.9 2.4 &
PROCEDURE
6.0 2.4
6.1 2.4
6.2 2.5 Transfer a sufficient amount of water to a suitable container,
6.3 2.4
6.4 2.3 and stir the test specimen. Adjust the temperature, if necessary,
6.5 2.2
6.6 2.1 and, while maintaining it at 25 + 18, begin vigorously agitat-
6.7 2.6
6.8 3.1 ing the test specimen while periodically observing the conduc-
6.9 3.8
7.0 4.6 tivity. When the change in conductivity (due to uptake of
ambient carbon dioxide) is less than a net of 0.1 mS/cm per
Add the following: 5 minutes, note the conductivity.

&
PACKAGED WATER For containers with a nominal volume of 10 mL or less, if
the conductivity is not greater than 25 mS/cm, the water meets
The procedure and test limits are intended for water pack-
the requirements. For containers with a nominal volume great-
aged in bulk but manufactured elsewhere or for Sterile Puri-
er than 10 mL, if the conductivity is not greater than 5 mS/cm,
fied Water, Sterile Water for Injection, Sterile Water for
the water meets the requirements.&2S (USP31)
Inhalation, and Sterile Water for Irrigation. All these waters
In-Process Revision
Pharmacopeial Forum
GENERAL CHAPTERS is likely that these properties comply with given requirements. The
resulting statistical analyses should address the variability associated
with the measurement process as well as that of the entity being
measured. Statistical measures used to assess the direction and
magnitude of these errors include the mean, standard deviation, and
expressions derived therefrom, such as the coefficient of variation
General Information (CV, also called the relative standard deviation, RSD)
&
percent coefficient of variation (%CV, also called the percent
relative standard deviation, %RSD).&2S (USP31)
The estimated variability can be used to calculate confidence
intervals for the mean, or measures of variability, and tolerance
intervals capturing a specified proportion of the individual
measurements.
BRIEFING The use of statistical measures must be tempered with good
judgment, especially with regard to representative sampling. Most
h1010i Analytical Data—Interpretation and Treatment, USP

&
Data should be consistent with the statistical assumptions
30 page 390. The Statistics Expert Committee has addressed several used for the analysis. If one or more of these assumptions
outstanding issues regarding this general information chapter. The
following changes are proposed: appear to be violated, alternative methods may be required in
1. Add a reference pertaining to the testing of normality and
a reference on sample size for equivalence studies. the evaluation of the data. In particular, most&2S (USP31)
2. Add an explanation on the proper use of Dixon’s Test for the of the statistical measures and tests cited in this chapter rely on the
detection of outliers for the one-tailed case versus the two-tailed assumptions that the distribution of the entire population is
case. represented by a normal distribution and that the analyzed sample
3. Add a statement in Appendix B: Precision Study explaining is a representative subset of this population. The normal (or
how the variance of the mean decreases and, as a result, the Gaussian) distribution is bell-shaped and symmetric about its center
precision of the experiment is improved as the number of runs and has certain characteristics that are required for these tests to be
and the number of replicates per run increase. valid. If the assumption of a normal distribution for the population is
4. Change ‘‘relative standard deviation’’ to ‘‘percent relative not warranted, then normality can often be achieved (at least
standard deviation’’ (‘‘RSD’’ to ‘‘%RSD’’). approximately) through an appropriate transformation of the
In addition, typographical errors regarding the F value and the measurement values.
degrees of freedom in Table 1a have been corrected.
&
The data may not always be expected to be normally
(STAT: H. Pappa; G. Ritchie) RTS—C54231
distributed and may require a transformation to better fit
a normal distribution.&2S (USP31)
Change to read: For example, there exist variables that have distributions with longer
right tails than left. Such distributions can often be made
approximately normal through a log transformation. An alternative
approach would be to use ‘‘distribution-free’’ or ‘‘nonparametric’’
MEASUREMENT PRINCIPLES AND statistical procedures that do not require that the shape of the
population be that of a normal distribution. When the objective is to
VARIATION construct a confidence interval for the mean or for the difference
between two means, for example, then the normality assumption is
All measurements are, at best, estimates of the actual (‘‘true’’ or not as important because of the central limit theorem. However, one
‘‘accepted’’) value for they contain random variability (also referred must verify normality of data to construct valid confidence intervals
to as random error) and may also contain systematic variation (bias). for standard deviations and ratios of standard deviations, perform
Thus, the measured value differs from the actual value because of some outlier tests, and construct valid statistical tolerance limits. In
variability inherent in the measurement. If an array of measurements the latter case, normality is a critical assumption. Simple graphical
consists of individual results that are representative of the whole,
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methods, such as dot plots, histograms, and normal probability plots,

statistical methods can be used to estimate informative properties of are useful aids for investigating this assumption.
the entirety, and statistical tests are available to investigate whether it
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A single analytical measurement may be useful in quality

assessment if the sample is from a whole that has been prepared
using a well-validated, documented process and if the analytical
errors are well known. The obtained analytical result may be
qualified by including an estimate of the associated errors. There
may be instances when one might consider the use of averaging
because the variability associated with an average value is always
reduced as compared to the variability in the individual measure-
ments. The choice of whether to use individual measurements or and expressed as a percentage. If the data requires log transformation
averages will depend upon the use of the measure and its variability. to achieve normality (e.g., for biological assays), then alternative
For example, when multiple measurements are obtained on the same methods are available.2
sample aliquot, such as from multiple injections of the sample in an A control sample is defined as a homogeneous and stable sample
HPLC method, it is generally advisable to average the resulting data that is tested at specific intervals sufficient to monitor the
for the reason discussed above. performance of the method for which it was established. Test data
Variability is associated with the dispersion of observations from a control sample can be used to monitor the method variability
around the center of a distribution. The most commonly used statistic or be used as part of system suitability requirements.3 The control
to measure the center is the sample mean ( x ): sample should be essentially the same as the test sample and should
be treated similarly whenever possible. A control chart can be
constructed and used to monitor the method performance on
a continuing basis as shown under Appendix A.
A precision study should be conducted to provide a better estimate
of method variability. The precision study may be designed to
determine intermediate precision (which includes the components of
both ‘‘between run’’ and ‘‘within-run’’ variability) and repeatability
(‘‘within-run’’ variability). The intermediate precision studies should
allow for changes in the experimental conditions that might be
expected, such as different analysts, different preparations of
Method variability can be estimated in various ways. The most reagents, different days, and different instruments. To perform
common and useful assessment of a method’s variability is the a precision study, the test is repeated several times. Each run must be
determination of the standard deviation based on repeated indepen- completely independent of the others to provide accurate estimates
dent1 measurements of a sample. The sample standard deviation, s, of the various components of variability. In addition, within each
is calculated by the formula: run, replicates are made in order to estimate repeatability. See an
example of a precision study under Appendix B.
2
When data have been log (base e) transformed to achieve normality, the
in which xi is the individual measurement in a set of n measurements; RSD
&
and x is the mean of all the measurements. The relative standard %RSD&2S (USP31)
deviation (RSD) is:
&
percent relative standard deviation (%RSD)&2S (USP31)
is then calculated as:
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This can be reasonably approximated by:
1
Multiple measurements (or, equivalently, the experimental errors associated
with the multiple measurements) are independent from one another when they
can be assumed to represent a random sample from the population. In such
a sample, the magnitude of one measurement is not influenced by, nor does it
influence the magnitude of, any other measurement. Lack of independence
implies the measurements are correlated over time or space. Consider the
example of a 96-well microtiter plate. Suppose that whenever the unknown
causes that produce experimental error lead to a low result (negative error)
when a sample is placed in the first column and these same causes would also
lead to a low result for a sample placed in the second column, then the two
resulting measurements would not be statistically independent. One way to
avoid such possibilities would be to randomize the placement of the samples where s is the standard deviation of the log (base e) transformed data.
3
on the plate. See System Suitability under Chromatography h621i.
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A confidence interval for the mean may be considered in the to achieve virtually any desired precision. That is, by basing
interpretation of data. Such intervals are calculated from several data
points using the sample mean (x) and sample standard deviation (s) the reportable value on an average across replicates and/or
according to the formula:
runs, rather than on any single result, one can reduce the
%RSD, and reduce it in a predictable fashion.&2S (USP31)
Table 2 shows the computed variance and RSD
&
%RSD&2S (USP31)
of the mean (i.e., of the reportable value) for different combinations
in which ta/2,n–1 is a statistical number dependent upon the sample size of number of runs and number of replicates per run using the
(n), the number of degrees of freedom (n – 1), and the desired following formulas:
confidence level (1 – a). Its values are obtained from published
tables of the Student t-distribution. The confidence interval provides
an estimate of the range within which the ‘‘true’’ population mean
(m) falls, and it also evaluates the reliability of the sample mean as an
estimate of the true mean. If the same experimental set-up were to be
replicated over and over and a 95% (for example) confidence interval
for the true mean is calculated each time, then 95% of such intervals
would be expected to contain the true mean, m. One cannot say with
certainty whether or not the confidence interval derived from
a specific set of data actually collected contains m. However,
assuming the data represent mutually independent measurements
randomly generated from a normally distributed population the
procedure used to construct the confidence interval guarantees that
95% of such confidence intervals contain m. Note that it is important
to define the population appropriately so that all relevant sources of
variation are captured.
Change to read:
APPENDIX B: PRECISION STUDY

Table 1 displays data collected from a precision study. This study
consisted of five independent runs and, within each run, results from
three replicates were collected.
Performing an analysis of variance (ANOVA) on the data in Table
1 leads to the ANOVA table (Table 1A). Because there were an equal
number of replicates per run in the precision study, values for Vari-
anceRun and VarianceRep can be derived from the ANOVA table in
a straightforward manner. The equations below calculate the
variability associated with both the runs and the replicates where
the MSwithin represents the ‘‘error’’ or ‘‘within-run’’ mean square, and
MSbetween represents the ‘‘between-run’’ mean square. For example, the Variance of the mean, Standard deviation of the
VarianceRep = MSwithin = 0.102 mean, and RSD
&
%RSD&2S (USP31)
of a test involving two runs and three replicates per each run are
0.592, 0.769, and 0.76% respectively, as shown below.
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Estimates can still be obtained with unequal replication, but the

formulas are more complex. Studying the relative magnitude of the
two variance components is important when designing and
interpreting a precision study. For example, for these data the
between-run component of variability is much larger than the within-
run component. This suggests that performing additional runs would
be more beneficial to reducing variability than performing more
replication per run (see Table 2).
&
The insight gained can be used to focus any on-going
method improvement effort and, more importantly, it can be
used to ensure that methods are capable of supporting their
intended uses. By carefully defining what constitutes a result
(i.e., reportable value), one harnesses the power of averaging
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Dixon-Type Tests
Similar to the ESD test, the two smallest values will be tested as
outliers; again assuming the data come from a single normal
population.
&
Dixon’s Test can be one-sided or two-sided, depending on
an a priori decision as to whether outliers will be considered
Where
on one side only. As with the ESD Test, Dixon’s Test assumes
&
where&2S (USP31)
100.96 is the mean for all the data points in Table 1. As illustrated in that the data, in the absence of outliers, come from a single
Table 2, increasing the number of runs from one to two provides
a more dramatic reduction in the variability of the reportable value normal population. Following the strategy used for the ESD
than does increasing the number of replicates per run.
No distributional assumptions were made on the data in Table 1 as Test, we proceed as if there were no a priori decision as to
the purpose of this Appendix is to illustrate the calculations involved
in a precision study. side, and so use a two-sided Dixon’s Test. From examination
Change to read: of the example data, we see that it is the two smallest that are
to be tested as outliers.&2S (USP31)
Stage 1 (n = 10)—The results are ordered on the basis of their
APPENDIX C: EXAMPLES OF OUTLIER magnitude (i.e., Xn is the largest observation, Xn–1 is the second
largest, etc., and X1 is the smallest observation). Dixon’s Test has
TESTS FOR ANALYTICAL DATA different ratios based on the sample size (in this example, with n =
10), to declare X1 an outlier, the following ratio, r11, is calculated by
Given the following set of 10 measurements: 100.0, 100.1, 100.3, the formula:
100.0, 99.7, 99.9, 100.2, 99.5, 100.0, and 95.7 (mean = 99.5,
standard deviation = 1.369) are there any outliers?
Generalized Extreme Studentized Deviate (ESD) Test

This is a modified version of the ESD Test that allows for testing
up to a previously specified number, r, of outliers from a normally A different ratio would be employed if the largest data point was
distributed population. tested as an outlier. The r11 result is compared to an r11, 0.05 value in
a table of critical values. If r11 is greater than r11, 0.05, then it is declared
&
For the detection of a single outlier (r = 1), the generalized an outlier. For the above set of data, r11 = (99.5 – 95.7)/(100.2 – 95.7)
= 0.84. This ratio is greater than r11, 0.05, which is 0.534 at the 5%
ESD procedure is also known as Grubb’s test. Grubb’s test is significance level for a two-sided Dixon’s Test. Sources for r11, 0.05
values are included in many statistical textbooks.
not recommended for the detection of multiple outli- Stage 2—Remove the smallest observation from the original data
set, so that n is now 9. The same r11 equation is used, but a new
ers.&2S (USP31) critical r11, 0.05 value for n = 9 is needed (r11, 0.05 = 0.570). Now r11 =
Let r equal 2, and n equal 10. (99.7 – 99.5)/(100.2 – 99.5) = 0.29, which is less than r11, 0.05 and not
Stage 1 (n = 10)—Normalize each result by subtracting the mean significant at the 5% level.
from each value and dividing this difference by the standard Conclusion—Therefore, 95.7 is declared to be an outlier. This
deviation (see Table 3).5 stepwise procedure is not an exact procedure for testing for the
Take the absolute value of these results, select the maximum value second outlier as the result of the second test is conditional upon the
(|R1| = 2.805), and compare it to a previously specified tabled critical first. Because the sample size is also reduced in the second stage, the
value l1 (2.290) based on the selected significance level (for end result is a procedure that usually lacks the sensitivity of the exact
example, 5%). The maximum value is larger than the tabled value procedures that Dixon provides for testing for two outliers
and is identified as being inconsistent with the remaining data. simultaneously; however, these procedures are beyond the scope
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Sources for l-values are included in many statistical textbooks. of this Appendix.
Caution should be exercised when using any statistical table to
ensure that the correct notations (i.e., level of acceptable error) are
used when extracting table values. Hampel’s Rule
Stage 2 (n = 9)—Remove the observation corresponding to the
maximum absolute normalized result from the original data set, so Step 1—The first step in applying Hampel’s Rule is to normalize
that n is now 9. Again, find the mean and standard deviation (Table the data. However, instead of subtracting the mean from each data
3, right two columns), normalize each value, and take the absolute point and dividing the difference by the standard deviation, the
value of these results. Find the maximum of the absolute values of median is subtracted from each data value and the resulting
the 9 normalized results (|R2| = 1.905), and compare it to l2 (2.215). differences are divided by MAD (see below). The calculation of
The maximum value is not larger than the tabled value. MAD is done in three stages. First, the median is subtracted from
Conclusion—The result from the first stage, 95.7, is declared to be each data point. Next, the absolute values of the differences are
an outlier, but the result from the second stage, 99.5, is not an outlier. obtained. These are called the absolute deviations. Finally, the
median of the absolute deviations is calculated and multiplied by the
constant 1.483 to obtain MAD6.
6
Assuming an underlying normal distribution, 1.483 is a constant used so
5
The difference between each value and the mean is termed the residual. that the resulting MAD is a consistent estimator of the population standard
Other Studentized residual outlier tests exist where the residual, instead of deviation. This means that as the sample size gets larger, 1.483 6 MAD
&
being divided by the standard deviation, can be divided by the standard MAD&2S (USP31)
deviation times the square root of n –1 divided by n. gets closer to the population standard deviation.
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Step 2—The second step is to take the absolute value of the In this case the power was only 63%; that is, even if the two methods
normalized data. Any such result that is greater than 3.5 is declared had exactly equal variances, with only 11 samples per method, there
to be an outlier. Table 4 summarizes the calculations. is only a 63% chance that the experiment will lead to data that permit
The value of 95.7 is again identified as an outlier. This value can a conclusion of no more than a four-fold increase in variance. Most
then be removed from the data set and Hampel’s Rule re-applied to commonly, sample size is chosen to have at least 80% power, with
the remaining data. The resulting table is displayed as Table 5. choices of 90% power or higher also used. To determine the
Similar to the previous examples, 99.5 is not considered an outlier. appropriate sample size, various numbers can be tested until
a probability is found that exceeds the acceptable limit (e.g.,
power 4 0.90). For example, the power determination for sample
sizes of 12–20 are displayed in Table 6. In this case, the initial guess
at a sample size of 11 was not adequate for comparing precision, but
Change to read: 15 samples per method would provide a large enough sample size if
80% power were desired, or 20 per method for 90% power.
Typically the sample size for precision comparisons will be larger
than for accuracy comparisons. If the sample size for precision is so
APPENDIX D: COMPARISON OF METHODS— large as to be impractical for the laboratory to conduct the study,
PRECISION there are some options. The first is to reconsider the choice of an
allowable increase in variance. For larger allowable increases in
The following example illustrates the calculation of a 90% variance, the required sample size for a fixed power will be smaller.
confidence interval for the ratio of (true) variances for the purpose of Another alternative is to plan an interim analysis at a smaller sample
comparing the precision of two methods. It is assumed that the size, with the possibility of proceeding to a larger sample size if
underlying distribution of the sample measurements are well- needed. In this case, it is strongly advisable to seek professional help
characterized by normal distributions. For this example, assume from a statistician.
the laboratory will accept the alternative method if its precision (as Now, suppose the laboratory opts for 90% power and obtains the
measured by the variance) is no more than four-fold greater than that results presented in Table 7 based on the data generated from 20
of the current method. independent runs per method.
To determine the appropriate sample size for precision, one
possible method involves a trial and error approach using the
following formula: Ratio = alternative method variance/current method variance = 45.0/
25.0 = 1.8
Lower limit of confidence interval = ratio/F.05 = 1.8/2.168 = 0.83
where n is the smallest sample size required to give the desired

power, which is the likelihood of correctly claiming the alternative
method has acceptable precision when in fact the two methods have Upper limit of confidence interval = ratio/F.95 = 1.8/0.461 = 3.90
equal precision; a is the risk of wrongly claiming the alternative
method has acceptable precision; and the 4 is the allowed upper limit
for an increase in variance. F-values are found in commonly For this application, a 90% (two-sided) confidence interval is used
available tables of critical values of the F-distribution. Fa,n–1,n–1 is the when a 5% one-sided test is sought. The test is one-sided, because
upper a percentile of an F-distribution with n – 1 numerator and n – only an increase in standard deviation of the alternative method is of
1 denominator degrees of freedom; that is, the value exceeded with concern. Some care must be exercised in using two-sided intervals in
probability a. Suppose initially the laboratory guessed a sample size this way, as they must have the property of equal tails—most
of 11 per method was necessary (10 numerator and denominator common intervals have this property. Because the one-side upper
degrees of freedom); the power calculation would be as follows:7 confidence limit, 3.90, is less than the allowed limit, 4.0, the study
has demonstrated that the alternative method has acceptable
precision. If the same results had been obtained from a study with
a sample size of 15—as if 80% power had been chosen—the
laboratory would not be able to conclude that the alternative method
had acceptable precision (upper confidence limit of 4.47).
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Change to read:
APPENDIX E: COMPARISON OF METHODS—

DETERMINING THE LARGEST ACCEPTABLE
DIFFERENCE, d, BETWEEN TWO METHODS
This Appendix describes one approach to determining the
difference, d, between two methods (alternative-current), a difference
that, if achieved, still leads to the conclusion of equivalence between
the two methods. Without any other prior information to guide the
laboratory in the choice of d, it is a reasonable way to proceed.
Sample size calculations under various scenarios are discussed in
this Appendix.
7
This could be calculated using a computer spreadsheet. For example, in
Microsoft1 Excel the formula would be: FDIST((R/A)*FINV(alpha, n – 1, Tolerance Interval Determination
n – 1), n – 1, n – 1), where R is the ratio of variances at which to determine
power (e.g., R = 1, which was the value chosen in the power calculations Suppose the process mean and the standard deviation are both
provided in the above table) and A is the maximum ratio for acceptance (e.g., unknown, but a sample of size 50 produced a mean and standard
A = 4). Alpha is the significance level, typically 0.05. deviation of 99.5 and 2.0, respectively. These values were calculated
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using the last 50 results generated by this specific method for Choosing a larger d leads to a smaller n but at the cost of
a particular (control) sample. Given this information, the tolerance increasing the risk of reaching the wrong conclusion.
limits can be calculated by the following formula:
x + Ks
Sample Size
in which x is the mean; s is the standard deviation; and K is based on
the level of confidence, the proportion of results to be captured in the Formulas are available that can be used for a specified d, under the
interval, and the sample size, n. Tables providing K values are assumption that the population variances are known and equal, to
available. In this example, the value of K required to enclose 95% of calculate the number of samples required to be tested per method, n.
the population with 95% confidence for 50 samples is 2.3828. The The level of confidence and power must also be specified. [NOTE—
tolerance limits are calculated as follows: Power refers to the probability of correctly concluding that two
identical methods are equivalent.] For example, if d = 4.7, and the
99.5 + 2.382 6 2.0; two population variances are assumed to equal 4.0, then, for a 5%
level test9 and 80% power (with associated z-values of 1.645 and
hence, the tolerance interval is (94.7, 104.3). 1.282, respectively), the sample size is approximated by the
following formula:
Comparison of the Tolerance Limits to the
Specification Limits
Assume the specification interval for this method is (90.0, 110.0)
and the process mean and standard deviation have not changed since
this interval was established. The following quantities can be
defined: the lower specification limit (LSL) is 90.0, the upper
specification limit (USL) is 110.0, the lower tolerance limit (LTL) is
94.7, and the upper tolerance limit (UTL) is 104.3. Calculate the
acceptable difference, (d), in the following manner:
A = LTL – LSL for LTL LSL
(A = 94.7 – 90.0 = 4.7);
B = USL – UTL for USL UTL
(B = 110.0 – 104.3 = 5.7); and
d = minimum (A, B) = 4.7. Thus, assuming each method has a population variance, s2, of 4.0,
the number of samples, n, required to conclude with 80% probability
that the two methods are equivalent (90% confidence interval for the
difference in the true means falls between –4.7 and +4.7) when in
fact they are identical (the true mean difference is zero) is 4. Because
the normal distribution was used in the above formula, 4 is actually
a lower bound on the needed sample size. If feasible, one might want
Figure 2. A graph of the quantities calculated above. to use a larger sample size. Values for z for common confidence
levels are presented in Table 8. The formula above makes three
assumptions: 1) the variance used in the sample size calculation is
With this choice of d, and assuming the two methods have based on a sufficiently large amount of prior data to be treated as
comparable precision, the confidence interval for the difference in known; 2) the prior known variance will be used in the analysis of
means between the two methods (alternative-current) should fall the new experiment, or the sample size for the new experiment is
within –4.7 and +4.7 to claim that no important difference exists sufficiently large so that the normal distribution is a good
between the two methods. approximation to the t distribution; and 3) the laboratory is confident
Quality control analytical laboratories sometimes deal with 99% that there is no actual difference in the means, the most optimistic
tolerance limits, in which cases the interval will widen. Using the case. It is not common for all three of these assumptions to hold. The
previous example, the value of K required to enclose 99% of the formula above should be treated most often as an initial
population with 99% confidence for 50 samples is 3.390. The approximation. Deviations from the three assumptions will lead to
tolerance limits are calculated as follows: a larger required sample size. In general, we recommend seeking
assistance from someone familiar with the necessary methods.
99.5 + 3.390 6 2.0; When a log transformation is required to achieve normality, the
the resultant wider tolerance interval is (92.7, 106.3). Similarly, the sample size formula needs to be slightly adjusted as shown below.
new LTL of 92.7 and UTL of 106.3 would produce a smaller d: Instead of formulating the problem in terms of the population
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A = LTL – LSL for LTL LSL variance and the largest acceptable difference, d, between the two
(A = 92.7 – 90.0 = 2.7); methods, it now is formulated in terms of the population RSD
B = USL – UTL for USL UTL
(B = 110.0 – 106.3 = 3.7); and
&
%RSD&2S (USP31)
d = minimum (A, B) = 2.7.
8 9
There are existing tables of tolerance factors that give approximate values When testing equivalence, a 5% level test corresponds to a 90% confidence
and thus differ slightly from the values reported here. interval.
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and the largest acceptable proportional difference between the two 2. Cohen, J., Statistical Power Analysis for the Behavioral
methods. Sciences, 2nd ed., Lawrence Erlbaum Associates, Hillsdale, NJ,
1988.
&
3. Diletti, E., Hauschke, D., Steinijans, V.W., ‘‘Sample size
determination for bioequivalence assessment by means of
where confidence intervals’’, International Journal of Clinical

Pharmacology, Therapy and Toxicology, 1991; 29,
1–8.&2S (USP31)
4. Fleiss, J.L., The Design and Analysis of Clinical Experiments,
John Wiley and Sons, New York, 1986, pp. 369–375.
5. Juran, J.A., Godfrey, B., Juran’s Quality Handbook, 5th ed.,
McGraw-Hill, 1999, Section 44, Basic Statistical Methods.
6. Lipsey, M.W., Design Sensitivity Statistical Power for Exper-
imental Research, Sage Publications, Newbury Park, CA, 1990.
7. Montgomery, D.C., Design and Analysis of Experiments, John
Wiley and Sons, New York, 1984.
8. Natrella, M.G., Experimental Statistics Handbook 91, National
and r represents the largest acceptable proportional difference Institute of Standards and Technology, Gaithersburg, MD, 1991
between the two methods ((alternative-current)/current) and the (reprinting of original August 1963 text).
population RSDs 9. Kraemer, H.C., Thiemann, S., How Many Subjects?: Statistical
Power Analysis in Research, Sage Publications, Newbury Park,
&
%RSDs&2S (USP31) CA, 1987.
are assumed known and equal. 10. van Belle G., Martin, D.C., ‘‘Sample size as a function of
coefficient of variation and ratio of means’’, American
Change to read: Statistician 1993; 47(3): 165–167.
11. Westlake, W.J., response to Kirkwood, T.B.L.: ‘‘Bioequivalence
testing—a need to rethink,’’ Biometrics 1981; 37 : 589–594.
General Statistics Applied to Pharmaceutical Data:
1. Bolton, S., Pharmaceutical Statistics: Practical and Clinical
APPENDIX F: ADDITIONAL SOURCES OF Applications, 3rd ed., Marcel Dekker, New York, 1997.
INFORMATION 2. Bolton, S., ‘‘Statistics’’ Remington: The Science and Practice of
Pharmacy, 20th ed., Gennaro, A.R., ed., Lippincott Williams and
There may be a variety of statistical tests that can be used to Wilkins, Baltimore, 2000, pp. 124–158.
evaluate any given set of data. This chapter presents several tests for 3. Buncher, C.R., Tsay, J., Statistics in the Pharmaceutical
interpreting and managing analytical data, but many other similar Industry, Marcel Dekker, New York, 1981.
tests could also be employed. The chapter simply illustrates the 4. Natrella, M.G., Experimental Statistics Handbook 91, National
analysis of data using statistically acceptable methods. As mentioned Institute of Standards and Technology (NIST), Gaithersburg,
in the Introduction, specific tests are presented for illustrative MD, 1991 (reprinting of original August 1963 text).
purposes, and USP does not endorse any of these tests as the sole 5. Zar, J., Biostatistical Analysis, 2nd ed., Prentice Hall, Engle-
approach for handling analytical data. Additional information and wood Cliffs, NJ, 1984.
alternative tests can be found in the references listed below or in General Statistics Applied to Analytical Laboratory Data:
many statistical textbooks. 1. Gardiner, W.P., Statistical Analysis Methods for Chemists, The
Control Charts: Royal Society of Chemistry, London, England, 1997.
1. Manual on Presentation of Data and Control Chart Analysis, 2. Kateman, G., Buydens, L., Quality Control in Analytical
6th ed., American Society for Testing and Materials (ASTM), Chemistry, 2nd ed., John Wiley and Sons, New York, 1993.
Philadelphia, 1996. 3. Kenkel, J., A Primer on Quality in the Analytical Laboratory,
2. Grant, E.L., Leavenworth, R.S., Statistical Quality Control, 7th Lewis Publishers, Boca Raton, FL, 2000.
ed., McGraw-Hill, New York, 1996. 4. Mandel, J., Evaluation and Control of Measurements, Marcell
3. Montgomery, D.C., Introduction to Statistical Quality Control, Dekker, New York, 1991.
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3rd ed., John Wiley and Sons, New York, 1997. 5. Melveger, A.J., ‘‘Statististics in the pharmaceutical analysis
4. Ott, E., Schilling, E., Neubauer, D., Process Quality Control: laboratory,’’ Analytical Chemistry in a GMP Environment,
Troubleshooting and Interpretation of Data, 3rd ed., McGraw- Miller J.M., Crowther J.B., eds., John Wiley and Sons, New
Hill, New York, 2000. York, 2000.
Detectable Differences and Sample Size Determination: 6. Taylor, J.K., Statistical Techniques for Data Analysis, Lewis
1. CRC Handbook of Tables for Probability and Statistics, 2nd ed., Publishers, Boca Raton, FL, 1990.
Beyer W.H., ed., CRC Press, Inc., Boca Raton, FL, 1985.
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&
7. Thode, H.C., Jr., Testing for Normality, Marcel Dekker, 8. Rosner, B., ‘‘Percentage points for a generalized ESD many-
outlier procedure,’’ Technometrics, 1983; 25: 165–172.
New York, NY, 2002.&2S (USP31) 9. Standard E-178-94: Standard Practice for Dealing with
8. Taylor, J.K., Quality Assurance of Chemical Measurements, Outlying Observations, American Society for Testing and
Lewis Publishers, Boca Raton, FL, 1987. Materials (ASTM), West Conshohoken, PA, September 1994.
9. Wernimont, G.T., Use of Statistics to Develop and Evaluate 10. Rorabacher, D.B., ‘‘Statistical Treatment for Rejections of
Analytical Methods, Association of Official Analytical Chemists Deviant Values: Critical Values of Dixon’s ‘‘Q’’ Parameter and
(AOAC), Arlington, VA, 1985. Related Subrange Ratios at the 95% Confidence Level,’’
10. Youden, W.J., Steiner, E.H., Statistical Manual of the AOAC, Analytical Chemistry, 1991; 63(2): 139–146.
AOAC, Arlington, VA, 1975. Precision and Components of Variability:
Nonparametric Statistics: 1. Hicks, C.R., Turner, K.V., Fundamental Concepts in the Design
1. Conover, W.J., Practical Nonparametric Statistics, 3rd ed., John of Experiments, 5th ed., Oxford University Press, 1999 (section
Wiley and Sons, New York, 1999. on Repeatability and Reproducibility of a Measurement
2. Gibbons, J.D., Chakraborti, S., Nonparametric Statistical System).
Inference, 3rd ed., Marcel Dekker, New York, 1992. 2. Kirk, R.E., Experimental Design: Procedures for the Behav-
3. Hollander, M., Wolfe, D., Nonparametric Statistical Methods, ioral Sciences, Brooks/Cole, Belmont, CA, 1968, pp. 61–63.
2nd ed., John Wiley and Sons, NY, 1999. 3. Kirkwood, T.B.L., ‘‘Geometric means and measures of
Outlier Tests: dispersion,’’ Letter to the Editor, Biometrics, 1979; 35(4).
1. Barnett, V., Lewis, T., Outliers in Statistical Data, 3rd ed., John 4. Milliken, G.A., Johnson, D.E., Analysis of Messy Data, Volume
Wiley and Sons, New York, 1994. 1: Designed Experiments, Van Nostrand Reinhold Company,
2. Davies, L., Gather, U., ‘‘The identification of multiple outliers,’’ New York, NY, 1984, pp. 19–23.
Journal of the American Statistical Association (with com- 5. Searle, S.R., Casella, G., McCulloch, C.E., Variance Compo-
ments), 1993; 88 : 782–801. nents, John Wiley and Sons, New York, 1992.
3. Dixon, W.J., ‘‘Processing data for outliers,’’ Biometrics 1953; 6. Snedecor, G.W., Cochran, W.G., Statistical Methods, 8th ed.,
9(1):74–89. Iowa State University Press, Ames, IA, 1989.
4. Grubbs, F.E., ‘‘Procedures for detecting outlying observations 7. Standard E-691-87: Practice for Conducting an Interlabora-
in samples,’’ Technometrics 1969; 11 : 1–21. tory Study to Determine the Precision of a Test Method, ASTM,
5. Hampel, F.R., ‘‘The breakdown points of the mean combined West Conshohoken, PA, 1994.
with some rejection rules,’’ Technometrics, 1985; 27 : 95–107. Tolerance Interval Determination:
6. Hoaglin, D.C., Mosteller, F., Tukey, J., eds., Understanding 1. Hahn, G.J., Meeker, W.Q., Statistical Intervals: A Guide for
Robust and Exploratory Data Analysis, John Wiley and Sons, Practitioners, John Wiley and Sons, New York, 1991.
New York, 1983. 2. Odeh, R.E., ‘‘Tables of two-sided tolerance factors for a normal
7. Iglewicz B., Hoaglin, D.C., How to Detect and Handle distribution,’’ Communications in Statistics: Simulation and
Outliers, American Society for Quality Control Quality Press, Computation, 1978; 7: 183–201.
Milwaukee, WI, 1993.
In-Process Revision
Pharmacopeial Forum
Change to read:
TABLES
Table 1. Data from a Precision Study
Replicate Run Number
Number 1 2 3 4 5
1 100.70 99.46 99.96 101.80 101.91
2 101.05 99.37 100.17 102.16 102.00
3 101.15 99.59 101.01 102.44 101.67
Mean 100.97 99.47 100.38 102.13 101.86
Standard Deviation 0.236 0.111 0.556 0.321 0.171
&
%&2S (USP31)
RSD1 0.234% 0.111% 0.554% 0.314% 0.167%
1
RSD
&
%RSD (percent&2S (USP31)
relative standard deviation) = 100% 6 (standard deviation/mean)
Table 1A. Analysis Variance Table for Data Presented in Table 1

Source of Degrees of Freedom Sum of Squares Mean Squares1
Variation (df) (SS) (MS) F =MSB /MSW
Between Runs 4 14.200 3.550 34.80
&
34.886&2S (USP31)
Within Runs 10 1.018 0.102
Total 14 15.217
1
The Mean Squares Between (MSB) = SSBetween/dfBetween and the Mean Squares Within (MSW) = SSWithin/dfWithin
Table 2. Computed Variance and RSD of the Mean

Precision of the Mean Corresponding to Various Test Plans
(# of Runs, # of Reps per Run)
No. of No. of Variance SD of the
Runs Replicates of the Mean Mean Mean1 RSD (%)
1 1 1.251 1.118 100.96 1.11
1 2 1.200 1.095 100.96 1.09
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1 3 1.183 1.088 100.96 1.08

2 1 0.625 0.791 100.96 0.78
2 2 0.600 0.775 100.96 0.77
2 3 0.592 0.769 100.96 0.76
1
Sample mean is based on the 15 data points presented in Table 1.
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&
Table 2. The Predicted Impact of the Test Plan (No. of Runs and No. of Replicates per Run) on the Precision of the Mean
No. of No. of Variance SD of the % RSD1

Runs Replicates per Run of the Mean Mean
1 1 1.251 1.118 1.11

1 2 1.200 1.095 1.09
1 3 1.183 1.088 1.08
2 1 0.625 0.791 0.78
2 2 0.600 0.775 0.77
2 3 0.592 0.769 0.76
1
A mean value of 100.96, based on the 15 data points presented in Table 1, was used (as the divisor) to compute the %RSD.&2S (USP31)
Table 3. Generalized ESD Test Results

n = 10 n=9
Data Normalized Data Normalized
100.3 +0.555 100.3 +1.361
100.2 +0.482 100.2 +0.953
100.1 +0.409 100.1 +0.544
100.0 +0.336 100.0 +0.136
100.0 +0.336 100.0 +0.136
100.0 +0.336 100.0 +0.136
99.9 +0.263 99.9 –0.272
99.7 +0.117 99.7 –1.089
99.5 –0.029 99.5 –1.905
95.7 –2.805
Mean = 99.54 99.95
SD = 1.369 0.245
Table 4. Test Results Using Hampel’s Rule

n = 10
Deviations
from the Absolute Absolute
Data Median Deviations Normalized
100.3 0.3 0.3 1.35
100.2 0.2 0.2 0.90
100.1 0.1 0.1 0.45
100 0 0 0
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100 0 0 0
100 0 0 0
99.9 –0.1 0.1 0.45
99.7 –0.3 0.3 1.35
99.5 –0.5 0.5 2.25
95.7 –4.3 4.3 19.33
Median = 100 0.15
MAD = 0.22
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Table 5. Test Results of Re-Applied Hampel’s Rule

n=9
Deviations
from the Absolute Absolute
Data Median Deviations Normalized
100.3 0.3 0.3 2.02
100.2 0.2 0.2 1.35
100.1 0.1 0.1 0.67
100 0 0 0
100 0 0 0
100 0 0 0
99.9 –0.1 0.1 0.67
99.7 –0.3 0.3 2.02
99.5 –0.5 0.5 3.37
Median = 100 0.1
MAD = 0.14
Table 6. Power Determinations for Various Sample Sizes (Specific to the Example in Appendix D)
Sample Size Pr[F 4¼ F0.05, n-1, n-1]
12 0.7145
13 0.7495
14 0.7807
15 0.8083
16 0.8327
17 0.8543
18 0.8732
19 0.8899
20 0.9044
Table 7. Example of Measures of Variance for Independent Runs (Specific to the Example in Appendix D)
Variance Sample Degrees of
Method (standard deviation) Size Freedom
Alternative 45.0 (6.71) 20 19
Current 25.0 (5.00) 20 19
Table 8. Common Values for a Standard Normal Distribution

z-values
Confidence level One-sided (a) Two-sided (a/2)
99% 2.326 2.576
95% 1.645 1.960
90% 1.282 1.645
80% 0.842 1.282
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Pharmacopeial Forum
and quantitative assessment of the chemical composition of samples.

BRIEFING It may also be sensitive to physical properties of the sample. Measure-
ments can be made directly on in-situ samples, in addition to standard
sampling and testing procedures. Typical applications of NIR spectra
utilize both wavelength and wavenumber units.
h1119i Near-Infrared Spectroscopy, USP 30 page 601. The Gen- Vibrational spectroscopy in the NIR region is dominated by over-
eral Chapters Expert Committee Advisory Panel on this general infor- tones and combinations that are much weaker than the fundamental
mation chapter has proposed revisions in order that the chapter may mid-IR vibrations from which they originate. Because molar absorp-
be in accord with the pharmaceutical industry’s Near-Infrared Spec- tivities in the NIR range are low, radiation typically penetrates several
troscopy best practices. The charge for the Advisory Panel was to millimeters into materials, including solids. Furthermore, many ma-
complete the revised draft of chapter h1119i, which was begun in terials such as glass are relatively transparent in this region. Fiber-op-
the 2000–2005 cycle by Work Group #1 of Project Team 18—Pro- tic technology is readily implemented in the NIR range, which allows
cess Analytical Technology (PAT). The Advisory Panel has proposed monitoring of processes in inaccessible, remote, and challenging en-
revisions in acceptance criteria and recommended standards for in- vironments.
strumentation performance acceptance criteria—most notably, revi- The tests and criteria given in this chapter may not be appropriate
sions in the subsection ‘‘Wavelength Uncertainty’’ in the section for all instrument configurations, particularly on-line process analyt-
Characterizing Instrument Performance under the section Qualifica- ical technology measurements. In such cases, alternative instrument
tion of NIR Instruments. Other changes proposed are based on recom- qualification and performance checks should be scientifically justi-
mendations from Project Team 18 and the Advisory Panel for better fied.
alignment with PAT. Significant improvements have been made in ac-
cord with spectroscopy best practices throughout the chapter with re-
gard to terminology; for instance, the chapter title has been changed
from Near-Infrared Spectrophotometry to Near-Infrared Spectrosco- Transmittance and Reflectance
py. Another major area in the chapter that has been revised for better Two different measurements commonly performed in the NIR
alignment with PAT is the Method Validation section. Editorial spectral range are transmittance and reflectance.
changes have also been made throughout to improve the clarity and TRANSMITTANCE, T, measures the decrease in radiation intensity as
readability of the chapter. a function of wavelength when radiation is passed through the sam-
The USP Council of Experts General Chapters Expert Committee ple. The sample is placed in the optical beam between the source and
is in the process of preparing or revising six general chapters for spec- the detector. This arrangement is similar to many conventional spec-
troscopic and allied techniques for use in quality control or similar trophotometers, and the results can be presented directly in terms of
laboratory settings. These chapters are Spectophotometric Identifica- absorbance. A variation of this technique, transflectance, places a re-
tion Tests h197i, Spectrophotometry and Light-Scattering h851i, flector behind the sample so as to double the path length. This con-
Acoustic Emission h1005i, Effusivity h1073i, Near-Infrared Spectros- figuration can be adapted to share the same instrument geometry with
copy h1119i, and Raman Spectroscopy h1120i. reflectance or fiber-optic probe systems where the source and the de-
In addition to these six general chapters, the General Chapters Ex- tector are on the same side of the sample.
pert Committee is preparing two additional general chapters. One, en- REFLECTANCE, R, measures the ratio of the intensity of light re-
titled Chemical Imaging h1038i, describes the collection, flected from the sample, I, to that reflected from a background or
identification, and quantitative and spatial analysis of large data sets reference reflective surface, Ir . NIR radiation can penetrate a substan-
from spectroscopic studies in laboratory and/or on- or near-line set- tial distance into the sample, where it can be absorbed by the vibra-
tings. The other, entitled Chemometrics h1039i, provides multivariate tional combinations and overtones of the analyte species present in
analytical data processing tools to evaluate data from these spectro- the sample. Nonabsorbed radiation is reflected back from the sample
scopic as well as other analytical techniques. to the detector. NIR reflectance spectra are accessed by calculating
The General Chapters Expert Committee believes these eight gen- and plotting log (1/R) versus wavelength. This logarithmic form is
eral chapters may be referenced in monographs at some future date commonly called absorbance.
and may also be useful in pharmaceutical manufacturing and quality
control. The chapters should support sound approaches to spectro-
scopic and allied measurement science.
Factors Affecting Quantitation
(GC: G. Ritchie) RTS—C43903 The following list, although not exhaustive, includes many of the
major factors affecting spectral response.
Sample Temperature—This parameter is most important for
aqueous solutions, where a difference of a few degrees can result in
Change to read: significant spectral changes. Temperature is also an important param-
eter for solids and powders containing water. Various methods exist to
calculate the appropriate temperature correction.
In-Process Revision
Moisture and Residual Solvents—Moisture present in the sample
and analytical system will contribute to bands in the NIR region. Oth-
h1119i NEAR-INFRARED er residual solvents may also contribute to the spectrum.
Sample Thickness—Sample thickness is a known source of spec-
SPECTROPHOTOMETRY tral variability and must be understood and/or controlled. For exam-
ple, in reflectance, the sample must be ‘‘infinitely’’ thick, or thinner
samples of constant thickness must have a stable, diffusely reflecting
&SPECTROSCOPY&2S backing material of constant, and preferably high, reflectivity.
(USP31)
Sample Optical Properties—In solids, both surface and bulk scat-
tering properties of calibration standards and analytical samples must
INTRODUCTION be taken into account. Spectra of physically, chemically, or optically
heterogeneous samples may require sample averaging by increasing
Near-infrared (NIR) spectroscopy is a branch of spectroscopy that the beam size or examining multiple samples. Certain factors, such as
shares many of the principles that apply to other spectroscopic mea- differing degree of compaction or particle size in powdered materials
surements discussed in Spectrophotometry and Light-Scattering and surface finish of samples, can cause significant spectral differenc-
h851i. The NIR spectral region includes two subranges. The short- es.
wavelength or Herschel range extends from approximately 750 to
1100 nm (~13,333–9000 cm–1), while longer wavelengths between Polymorphism—Because NIR reflectance can be measured di-
1100–2500 nm comprise the traditional NIR region. In common with rectly for solid crystalline substances, variations in crystalline struc-
other spectrophotometric measurements, NIR is for both qualitative ture (polymorphism) influence the spectra. Hence, polymorphs, as
well as the amorphous form of a solid, may be distinguished from
Pharmacopeial Forum
one another on the basis of their NIR spectra. Where multiple poly- Installation Qualification (IQ)
morphs can coexist in an otherwise chemically pure bulk drug sub- Operational Qualification (OQ)
stance, care must be taken to ensure that the calibration standards Performance Qualification (PQ)
have a distribution of polymorphs relevant to the intended applica- Installation Qualification—The IQ requirements help ensure that
tion. the hardware and software are installed according to vendor and safe-
Age of Samples—Samples may exhibit changes in their chemical, ty specifications at the desired location.
physical, or optical properties over time. Care must be taken to ensure Operational Qualification—In operational qualification, the instru-
that samples for NIR analysis are representative of those for calibra- ment’s performance is controlled with respect to external certified
tion. If samples of different age are to be analyzed, potential differ- standards to verify that the system operates within target specifica-
ences in properties must be accounted for in the calibration sample tions. The purpose of operational qualification is to ensure that an in-
set. strument is suitable for its intended application. Because there are so
many different approaches to measuring NIR spectra, operational
qualification with traceable external standards that can be on any in-
INSTRUMENTATION strument is desired. The most important property of a reference ma-
terial is its stability. For example, the commonly employed internal
Apparatus polystyrene-film reference may be subject to aging and attack by sol-
vents and vapors in the laboratory environment. The use of external
All NIR measurements are based on passing light radiation through traceable reference standards does not imply the omission of the in-
or into a sample and measuring the attenuation of the emerging (trans- strument’s internal quality control procedures. Similiar to any spec-
mitted, scattered, or reflected) beam. There are a variety of spectro- trophotometric device, NIR instruments need to be qualified for both
photometers available based on different operating principles. wavelength and photometric scale. Maximum and reduced light-flux
Some examples of currently available spectrophotometers are the noise tests are also included.
following: filter and grating-based dispersive, acousto-optical tunable Peformance Qualification—In performance qualification, a quality
filter (AOTF), Fourier-transform (FT-NIR), and liquid crystal tunable of fit to an initial scan or group of scans included in the operational
filters (LCTF) systems. Silicon, lead sulfide, indium gallium arsenide qualification is employed. In such an analysis, it is assumed that ref-
and deuterated triglycine sulphate are commonly detector materials. erence standard spectra collected on a new or a newly repaired, pro-
Conventional cuvette sample holders, fiber-optic probes, transmis- perly operating instrument represent the best ones available.
sion dip cells, and spinning or traversing sample holders are some Comparisons of spectra taken over time on the identical reference
of the more common sampling arrangements. standards form the basis for evaluating the long-term stability of an
The selection of the equipment should be based on the intended NIR measurement system. The objective is to ensure that no wave-
application, with particular attention being paid to the suitability of length calibration shift or change in sensitivity occurs during ongoing
the sampling device for the type of sample to be analyzed. analysis.
Previous operational qualification has shown that the equipment is
acceptable for use; therefore, a single performance qualification stan-
Near-Infrared Reflectance References dard can be to reverify performance on a continuing basis. The user
may have a method-specific reference sample to perform this kind of
NIR references, by providing a known stable measurement against control, provided the sample is stable.
which other measurements can be compared, are to eliminate instru- Test Details—The specific tests and how frequently they are per-
mental variations that would affect the measurements. formed for each level of qualification is dependent on the instrument
Transmittance Mode—The measurement of transmittance is de- and intended application.
pendent on a background transmittance spectrum for its calculation. Wavelength Uncertainty—Potential problems with internal calibra-
A transmittance reference can be air, an empty cell, a solvent blank, or tion schemes are avoided by specifying appropriate independent ex-
in special cases, a reference sample. ternal wavelength standards. For the reflectance mode, USP Near-
Reflectance Mode—The measurement of reflectance is dependent Infrared Calibrator RS1 and NIST SRM 20352 in the transflectance
on a background reflectance spectrum for its calculation. Most mea- mode are available. The nature and type of background reference
surements are performed in single-beam instruments; the reflectance standard must be specified. In transmittance measurements, NIST
of a background reference is scanned to obtain a baseline, and then SRM 2035 rare earth oxide in glass standard, or NIST SRM 2036,3
the reflectance of one or more analytical samples is measured. Com- is available. Alternative standards may be with appropriate justifica-
mon reflectance references are ceramic, perfluorinated polymers, and tion.
gold; other suitable materials may be . Only spectra measured against Take one spectrum (with the same spectral resolution to obtain the
a background possessing the same optical properties can be directly certified value) and measure the position of at least three peaks to cov-
compared with one another. er the entire available range. The acceptance limits for USP Near-In-
frared Calibrator RS are reported in Table 1.
In-Process Revision
Qualification of NIR Instruments

Elements of Qualification—The qualification of an NIR instru- 1
USP Near-Infrared Calibrator RS is a mixture of dysprosium, holmium, er-
ment can be divided into three elements: bium, and talc and may be obtained from USP. ‘‘Accurate Wavelength Mea-
surements of a Putative Standard for Near-Infrared Diffuse Reflection
Spectrometry,’’ by Tomas Isaksson, Husheng Yang, Gabor J. Kemeny, Rich-
ard S. Jackson, Qian Wang, M. Kathleen Alam, and Peter R. Griffiths (Depart-
ment of Chemistry, University of Idaho, Moscow, Idaho 83844-2343, USA)
Appl Spectrosc 2003, 57(2) 176–185. This reference material exhibits peaks in
both the 700- to 1100-nm and 1100- to 2500-nm ranges.
2
SRM 2035, a rare earth oxide in glass, is intended for transmission wave-
length qualification and has been certified recently by NIST. This standard
consists of samarium, ytterbium, holmium, and neodymium rare earth oxide
(REO). ‘‘Production and Verification of SRM 2035. Near Infrared Transmis-
sion Wavelength Standard’’, NIST Special Publication 1999, 260-102 (in
preparation). This standard may be in transflectance mode, but it is not cur-
rently certified for such use.
3
SRM 2036, a rare earth oxide in glass, is intended for NIR diffuse reflectance
wavelength qualification and is available from NIST. This standard also con-
sists of samarium, ytterbium, holmium, and neodymium rare earth oxide
(REO). In addition, SRM 2036 contains a piece of sintered polytetrafluoroeth-
ylene (PTFE) that provides a nearly ideal diffuse reflector.
Pharmacopeial Forum
Table 1. Recommended Near-IR Instrument Specificationsa

Wavelength Uncertainty USP Near-Infrared Calibrator RS peaksb occur at 1261, 1681, and 1935 nm
Tolerances +1 nm at 1200 nm or +8 cm–1 at 8300 cm–1
+1 nm at 1600 nm or +4 cm–1 at 6250 cm–1
+1.5 nm at 2000 nm or +4 cm–1 at 5000 cm–1
Photometric Linearity AOBS vs AREF at 1200, 1600, and 2000 nm;c
slope = 1.0 + 0.05; intercept = 0.0 + 0.05
Spectrophotometric Noise measured for 100-nm (300 cm–1) segments between 1200 and 2200 nm (8300 and 4500 cm–1)
Average RMS for measurements less than 0.3 6 10–3; no RMS noise greater than 0.8 6 10–3
at high-light flux
Average RMS for measurements less than 1 6 10–3; no RMS noise greater than 2.0 6 10–3
at low-light flux
a
A maximum nominal instrument bandwidth of 10 nm at 2500 nm or 16 cm–1 at 4000 cm–1 is appropriate for most applications.
b
The nominal 1935-nm peak is sensitive to instrument bandwidth. Use the wavelength value supplied with USP Near-Infrared Calibrator RS at
the appropriate instrument bandwidth to determine wavelength uncertainty.
c
AOBS is the observed absorbance, and AREF is the tabulated absorbance of the reference reflectors at each of the three specified wavelengths.
Photometric Linearity—Verification of photometric linearity is METHOD VALIDATION

demonstrated with a set of transmission standards of known relative
transmittance or reflectance standards of known relative reflectance, Introduction
usually expressed as percent transmittance or reflectance. For reflec-
tance measurements, traceable carbon-doped polymer standards are The objective of the validation of an NIR method, as in the case
available. Spectra obtained from reflectance standards are subject to with the validation of any analytical procedure, is to demonstrate that
variability as a result of the difference between the experimental con- it is suitable for its intended purpose. Quantitation by NIR is per-
ditions under which they were factory-calibrated and those under formed by reference to data obtained from a primary method or a cal-
which they are subsequently put to use. Hence, the percent reflectance ibration set of samples having known composition.
values supplied with a set of calibration standards may not be useful Although NIR is somewhat different from conventional analytical
in the attempt to establish an ‘‘absolute’’ calibration for a given instru- techniques such that validation is generally achieved through the as-
ment. Provided that (1) the standards do not change chemically or sessment of specialized chemometric parameters, these parameters
physically, (2) the same reference background is as was to obtain can still be related to the fundamental validation characteristics re-
the certified values, and (3) the instrument measures each standard quired for any analytical method.
under identical conditions (including precise sample positioning), Data pretreatment is often a vital step in the chemometric analysis
the reproducibility of the photometric scale will be established over of NIR spectral data. It can be defined as the mathematical transfor-
the range of standards . Subsequent measurements on the identical set mation of the NIR spectral data to enhance spectral features and/or
of standards give information on long-term stability. Use at least four remove or reduce unwanted sources of variation prior to the develop-
reference standards in the range 10% to 90%. [NOTE—A typical set of ment of the calibration model. Calibration is the process of construct-
four reflectance references might be 10%, 20%, 40%, and 80% with ing a mathematical model to relate the response from an analytical
1.0, 0.7, 0.4, and 0.1 as their respective absorbances.] If the system is instrument to the properties of samples. Many suitable chemometric
for analytes with absorbances higher than 1.0, add a 2% or a 5% stan- algorithms for data pretreatment and calibration exist; the selection
dard, or both, to the set. The specifications are reported in Table 1. should be based on suitability for the intended use. Any available data
Spectrophotometric Noise—NIR instrument software may include transformation or algorithm that can be clearly defined in an exact
built-in procedures to automatically determine system noise and to mathematical expression and gives suitable results can be used.
provide a statistical report of noise or signal-to-noise ratio over its
operating range. As previously discussed, it is desirable to supple-
ment such checks with measurements that do not rely directly on Validation Parameters
manufacturer-supplied procedures. If the qualification procedures in
the NIR software do not comply with the contents of this chapter, it is Analytical performance characteristics that should be considered
recommended to supplement such checks with measurements that do for demonstrating the validation of NIR methods are similar to those
not rely directly on manufacturer-supplied procedures. The method required for any analytical procedure. A discussion of the general
In-Process Revision
involves measuring spectra of high- and low-reflectance traceable ref- principles that apply is found in Validation of Compendial Methods
erence materials. For transmittance modules there are no standards for h1225i. These principles should be considered typical for NIR proce-
the low-flux noise test at this time, so it is only possible to perform the dures, but exceptions should be dealt with on a case-by-case basis.
high-flux noise test. For qualitative NIR methods, refer to Analytical Performance Char-
HIGH-FLUX NOISE—The instrument noise is evaluated at high-light acteristics for Category IV assays under Validation of Compendial
flux by measuring reflectance or transmittance of the reference stan- Methods h1225i; quantitative NIR methods will correspond to the
dard, with the reference material (e.g., 99%, reflectance standard) act- Analytical Performance Characteristics for Category I and Category
ing as both the sample and the background reference. The analysis is II assays in the chapter. Specific acceptance criteria for each valida-
performed by tabulating RMS noise levels in successive nominal tion parameter must be consistent with the intended use of the meth-
100-nm (300 cm–1) spectral segments across the instrument’s range. od. The samples for validation should be independent of the
The limits are reported in Table 1. calibration set.
LOW-FLUX NOISE—The same procedure may be with a lower-reflec- Specificity—The extent of specificity testing is dependent on the
tivity reference material (e.g., 10% reflectance standard) to determine intended application. Lack of specificity of the NIR method can be
system noise at reduced light flux. The source, optics, detector, and compensated by other supporting analytical procedures.
electronics make significant contributions to the noise under these Demonstration of specificity in NIR methods may be accomplished
conditions. The limits are reported in Table 1. by using the following approaches:
Qualitative
Potential challenges should be presented to the spectral refer-
ence library. These can be materials received on site that are sim-
ilar to library members in visual appearance, chemical structure,
or by name. These challenges must fail identification. Indepen-
Pharmacopeial Forum
dent samples of materials represented in the library, but not to Precision—Precision of an NIR method expresses the closeness of
create it (i.e., different batches, blends), must give positive iden- agreement between a series of measurements under the prescribed
tifications when analyzed. conditions. There are two levels of precision that may be considered:
Quantitative repeatability and intermediate precision. The precision of an NIR
Wavelengths in the calibration model can be compared to the method is typically expressed as the relative standard deviation of a
known bands of the analyte of interest and those of the matrix series of predictions and should be equivalent or better than the pre-
to verify that the bands of the analyte of interest are being in the cision of the reference method for validation.
calibration. Demonstration of precision in NIR methods may be accomplished
Wavelengths for the calibration (e.g., for multiple linear regres- using the following approaches:
sion models (MLR) or the loadings for the factors (e.g., for par- Repeatability
tial least squares [PLS] or principal component regression [PCR] Statistical evaluation of a number of replicate measurements of
models) can be examined to verify that the actual spectroscopic the same sample without variation in sample position.
information results from the analyte of interest. Statistical evaluation of multiple sample positionings or ali-
For PLS and PCR calibrations, the coefficients can be plotted quots, as appropriate.
and the regions of large coefficients compared with the spectrum Intermediate Precision
of the analyte. Statistical evaluation of a number of replicate measurements by
Variations in the sample matrix may be shown to have no signif- different analysts on different days.
icant effect on quantitation of the analyte within the specified Robustness—The challenges performed in this category will vary
method range. depending on the application and sampling technique. Some of the
Linearity—The validation of NIR linearity involves the demon- challenges may be covered as part of the development of the method.
stration of correlated NIR response to samples distributed throughout Typical challenges are the following:
the defined range of the calibration model. Effect of environmental conditions (e.g., temperature, humidity)
Demonstration of linearity in NIR methods may be accomplished Effect of sample temperature
using the following approaches: Sample handling (e.g., probe depth, compression of material,
The slope and y-intercept (bias) for the predicted validation set sample depth/thickness, sample position)
can be together with a plot of the data. Many statistical methods Influence of instrument changes (e.g., lamp change, warm-up
are available for evaluation of the significance of the slope and time)
bias. Other applicable statistics may be as appropriate.
Statistical tests such as Durbin–Watson are available for the de-
termination of linearity. Other applicable statistics may be as ap- Ongoing Model Evaluation
propriate.
The correlation coefficient, r, is not a true measure of linearity, but NIR models validated for use should be the subject of ongoing per-
is rather a measure of the fraction of variation in the data that is ade- formance evaluation, which may include the monitoring of accuracy,
quately modeled by the equation. It is dependent on the standard error precision, or other suitable parameters. If unacceptable performance
of the calibration equation (and hence the reference method) and on is indicated, corrective action will be necessary. This will involve ini-
the range of the calibration data. tial investigations into the cause of the discrepancy and may indicate
Range—The range of analyte reference values in the validation set that the calibration model is not performing satisfactorily. Mainte-
defines the range of the NIR method. The range of analyte reference nance of the model will then be required and may involve revalidation
values also effectively defines the quantitation limits for an NIR of the model. The degree of revalidation required depends on the na-
method. Controls must be in place to ensure that results outside the ture of the changes. Appropriate change controls should be estab-
validated range are not accepted. In certain circumstances, it may not lished to cover these procedures.
be possible or desirable to extend the validated range to cover the Revalidation of a qualitative model may be necessary as a result of
specifications or expected process variability for the entire life cycle the following:
of the process. Examples of situations in which only a limited sample Addition of a new material to the spectral reference library
range may be available are samples from a controlled manufacturing Changes in the physical properties of the material
process and in-process samples. A limited sample set does not pre- Changes in the source of supply
clude the use of an NIR method. Coverage of a wider range of characteristics of a material
The validation procedure for a quantitative NIR method should Revalidation of a quantitative model may be necessary as a result
generate an outlier result when a sample containing analyte outside of the following:
of the calibration range is measured. This outlier result does not nec- Changes in the composition of the finished product
essarily indicate an out-of-specification result. An outlier result from Changes in the manufacturing process
the NIR measurement indicates that further testing of the sample is Changes in the sources or grades of raw materials
required. If subsequent testing of the sample by an appropriate meth- Changes in the reference analytical method
od indicates that the analyte content is within specifications, then the Major changes to the instrument hardware
sample should be considered to have met those specifications. Thus,
In-Process Revision
measurement of a sample by NIR may generate an outlier result and

the sample may still meet specifications for the analyte of interest. For Model Transfer
qualitative methods, a batch of material may be outside the space of
the original calibration data and fail the identification specification. The model for an NIR method is developed, stored and applied in
Acceptable identification of the material must then be established electronic form as part of an appropriate instrument/software pack-
by other appropriate methods. age. When a model is transferred to another instrument, procedures
Accuracy—Accuracy for NIR methods is demonstrated by corre- and criteria must be applied to demonstrate that the model remains
lation of NIR results with analytical reference data. valid on the second instrument. In general, electronic model transfer
Demonstration of accuracy in NIR methods may be accomplished is only recommended for another instrument of the same type and
using the following approaches: configuration. A number of model transfer procedures exist and can
Accuracy can be indicated by how close the standard error of be applied as appropriate. Procedures involve the use of various che-
prediction (SEP) is to the standard error of the reference method mometric (mathematical and statistical) approaches with appropriate
for validation. The error of the reference method may be known validation.
on the basis of historical data, or a determination of standard er-
ror of the laboratory (SEL) may be carried out.
Several statistical comparison methods can be applied to the pre-
dicted validation set and reference values to determine if there is
any statistical difference between the results of each method at a
specified confidence limit (e.g., paired t-test, bias evaluation).
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GLOSSARY ROOT-MEAN-SQUARE (RMS) NOISE is calculated by the equation:
ABSORBANCE, A, is represented by the equation:

A = –log T = log (1/T) or A = log (I/R)
in which T and R are the transmittance and the reflectance, respec-
tively. in which N is the number of points per segment; Ai is the absorbance
BACKGROUND SPECTRUM is also referred to as a reference spectrum for each data point; and A is the mean absorbance over the spectral
or background reference. A ratio of this spectrum to that of the sample segment.
radiation intensities produces a transmittance or reflectance spectrum. SPECTRAL REFERENCE LIBRARY is a collection of spectra of known
For example, in reflectance measurements, a highly reflective stan- materials for the purpose of comparison with unknown materials. The
dard reference material is used. term is commonly in connection with qualitative methods of spectral
CALIBRATION MODEL is a mathematical expression to relate the re- analysis (e.g., identification of materials).
sponse from an analytical instrument to the properties of samples. STANDARD ERROR OF THE LABORATORY (SEL) is a calculation based
DIFFUSE REFLECTANCE is that portion of radiated light penetrating on repeated readings of one or more samples to estimate the precision
the sample surface, interacting with the analyte material, and being and/or accuracy of the reference laboratory method, depending on
reflected back to the detector. This is the component of the overall how the data was collected.
reflectance that produces the absorbance spectrum of the sample. STANDARD ERROR OF PREDICTION (SEP) is a measure of accuracy of
DURBIN–WATSON is a method of testing the linearity of a calibration an analytical method based on applying a given calibration model to
by comparing the sum of squares of successive calibration residuals the spectral data from a set of samples different from but similar to
to the sum of squares of the calibration residuals around their mean. those to calculate the calibration model. The SEP is the standard de-
The expected value of the Durbin–Watson statistic for random, inde- viation of the residuals obtained from comparing the values from the
pendent, normally distributed residuals is two. reference laboratory to those from the method under test, for the spec-
FIBER-OPTIC PROBES consist of two components: optical fibers, ified samples. The SEP provides a measure of the accuracy expected
which may vary in length and in the number of fibers, and a terminus, when measuring future samples.
which contains specially designed optics for examination of the sam- SURFACE REFLECTANCE, also known as specular reflection, is that
ple matrix. portion of the radiation not interacting with the sample but simply
INSTRUMENT BANDWIDTH is a measure of the ability of a spectrom- reflecting back from the sample surface layer (sample-air interface).
eter to separate radiation of similar wavelengths. TRANSFLECTANCE is a transmittance measurement technique in
MULTIPLE LINEAR REGRESSION is a calibration algorithm to relate which the radiation traverses the sample twice, the second time after
the response from an analytical instrument to the properties of sam- being reflected from a surface behind the sample.
ples. The distinguishing feature of this algorithm is the use of a lim- TRANSMITTANCE is represented by the equation:
ited number of independent variables. Linear-least-squares
calculations are performed to establish a relationship between these T = I/I0 or T = 10–A
independent variables and the properties of the samples.
OPERATIONAL QUALIFICATION is the process by which it is demon- in which I is the intensity of the radiation transmitted through the
strated and documented that the instrument performs according to sample; I0 is the intensity of the radiant energy incident on the sample
specifications, and that it can perform the intended task. This process and includes losses due to solvent absorption, refraction, and scatter-
is required following any significant change such as instrument instal- ing; and A is the absorbance.
lation, relocation, major repair, etc.
PARTIAL LEAST SQUARES (PLS) is a calibration algorithm to relate
instrument responses to the properties of samples. The distinguishing
feature of this algorithm is that, while similar to PCR, this algorithm
includes data concerning the properties of the samples for calibration
&
INTRODUCTION
in the calculation of the factors to describe the instrument responses.
PERFORMANCE QUALIFICATION is the process of using one or more
well-characterized and stable reference materials to verify consistent Near-infrared (NIR) spectroscopy is a branch of vibrational
instrument performance. Qualification may employ the same or dif- spectroscopy that shares many of the principles that apply to
ferent standards for different performance characteristics.
PHOTOMETRIC LINEARITY, also referred to as photometric verifica-
tion, is the process of verifying the response of the photometric scale other spectroscopic measurements. The NIR spectral region
of an instrument. comprises two subranges associated with detectors used in
PRINCIPAL COMPONENT REGRESSION (PCR) is a calibration algo-
rithm to relate the response from an analytical instrument to the pro- the initial development of NIR instrumentation. The short-
In-Process Revision
perties of samples. This algorithm, which expresses a set of
independent variables as a linear combination of factors, is a method
of relating those factors to the properties of the samples for which the wavelength (Herschel or silicon region) extends from approx-
independent variables were obtained. imately 750 to 1100 nm (~13,333–9000 cm–1); and longer
REFERENCE SPECTRUM—See Background Spectrum.
REFLECTANCE is described by the equation:
wavelengths, between 1100 and 2500 nm, compose the tradi-
R = I/Ir
tional (lead sulfide) NIR region. Applications of NIR spectros-
in which I is the intensity of radiation reflected from the surface of the
sample; and Ir is the intensity of radiation reflected from a background copy use spectra displayed in either wavelength or
reference material and its incorporated losses due to solvent absorp-
tion, refraction, and scattering. wavenumber units. As is the case with other spectroscopy
measurements, interactions between NIR radiation and matter
provide information that can be for both qualitative and quan-
titative assessment of the chemical composition of samples. In
addition, qualitative and quantitative characterization of a
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sample’s physical properties can be made because of the sam- Transmission and Reflection
ple’s influence on NIR spectra. Measurements can be made di-
The most common measurements performed in the NIR
rectly on samples in situ in addition to applications during
spectral range are transmission and reflection spectroscopy. In-
standard sampling and testing procedures.
cident NIR radiation is absorbed or scattered by the sample
Applications of qualitative analysis include identification of
and is measured as transmittance or reflectance, respectively.
raw material, in-process sample, or finished product. These ap-
Transflection spectrometry is a hybrid of transmission and re-
plications often involve comparing an NIR spectrum from a
flection wherein a reflector is placed behind the sample so that
sample to reference spectra and assessing similarities against
the optical path through the sample and back to the detector is
acceptance criteria developed and validated for a specific ap-
doubled compared to a transmission measurement of a sample
plication. In contrast, applications of quantitative analysis in-
of the same thickness. This configuration can be adapted to
volve the development of a predictive relationship between
share instrument geometry with certain reflection or fiber-optic
NIR spectral attributes and sample properties. These applica-
probe systems in which the source and the detector are on the
tions typically use numerical models to quantitatively predict
same side of the sample.
chemical and/or physical properties of the sample on the basis
TRANSMITTANCE, T, is a measure of the decrease in radiation
of NIR spectral attributes.
intensity as a function of wavelength when radiation is passed
Vibrational spectroscopy in the NIR region is dominated by
through a sample. The sample is placed in the optical beam
overtones and combinations that are much weaker than the
between the source and the detector. The results of both trans-
fundamental mid-IR vibrations from which they originate. Be-
mission and transflection measurements are usually presented
cause molar absorptivities in the NIR range are low, radiation
directly in terms of absorbance, i.e., log10(1/T).
can penetrate several millimeters into materials, including sol-
REFLECTANCE, R, is a measure of the ratio of the intensity of
ids. Many materials, such as glass, are relatively transparent in
light reflected from the sample, I, to that reflected from a back-
this region. Fiber-optic technology is readily implemented in
ground or reference reflective surface, IR. Most reflection mea-
the NIR range, which allows monitoring of processes in envi-
surements in the NIR are made of scattering samples such as
ronments that might otherwise be inaccessible.
powders and slurries. For such materials NIR radiation can
The instrument qualification tests and acceptance criteria
penetrate a substantial distance into the sample, where it can
provided in this chapter may not be appropriate for all instru-
be absorbed when the wavelength of the radiation corresponds
ment configurations. In such cases, alternative instrument
to a transition between the ground vibrational state of the ana-
qualification and performance checks should be scientifically
In-Process Revision
lyte and either a harmonic of a given vibrational mode (an

justified and documented. In addition, validation parameters
overtone) or the sum of two or more different modes (a com-
discussed in this chapter may not be applicable for all applica-
bination band). Nonabsorbed radiation is scattered back from
tions of NIR spectroscopy. Validation parameters character-
the sample to the detector. NIR reflection spectra are accessed
ized for a specific NIR application should demonstrate
by calculating and plotting log(1/R) versus wavelength. This
suitability of the NIR application for its intended use.
logarithmic form is the pseudo-absorbance of the material and
is commonly called absorbance.
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Factors That Affect Spectral Response tral properties. Similarly, different crystalline hydration or sol-
vation states of the same material can display different NIR
The following list is not exhaustive, but it includes many of
spectral properties.
the major factors that affect NIR spectral response.
Age of Samples—Samples may exhibit changes in their
Sample Temperature—Sample temperature influences
chemical, physical, or optical properties over time. Care must
spectra obtained from aqueous solutions and other hydro-
be taken to ensure that both samples and standards used for
gen-bonded liquids, and a difference of a few degrees can re-
NIR analysis are suitable for the intended application.
sult in significant spectral changes. Temperature can also
affect spectra obtained from less polar liquids, as well as solids
INSTRUMENTATION
that contain solvents and/or water.
Moisture and Solvent—Moisture and solvent present in Apparatus
the sample material and analytical system contribute to NIR
All NIR measurements are based on exposing material to
spectral response. Both absorbance by moisture and solvent
incident NIR light radiation and measuring the attenuation
and their influence on hydrogen bonding within materials
of the emerging (transmitted, scattered, or reflected) light. Sev-
can influence NIR spectral response.
eral spectrophotometers are available; they are based on differ-
Sample Thickness—Sample thickness is a known source of
ent operating principles—for example, filter and grating-based
spectral variability and must be understood and/or controlled.
dispersive, acousto-optical tunable filter (AOTF), Fourier–
The sample thickness in transmission mode is typically con-
transform NIR (FT–NIR), and liquid crystal tunable filter
trolled by using a fixed optical path length for the sample.
(LCTF). Silicon, lead sulfide, indium gallium arsenide, and
In reflection mode, the sample thickness is typically controlled
deuterated triglycine sulphate are commonly detector mate-
by using samples that are ‘‘infinitely thick’’ relative to the de-
rials. Conventional cuvette sample holders, fiber-optic probes,
tectable penetration depth of NIR light into a solid material.
transmission dip cells, and spinning or traversing sample hold-
Here ‘‘infinite thickness’’ implies that the reflection spectrum
ers are common examples of sample interfaces for introducing
does not change if the thickness of the sample is increased.
the sample to the optical train of a spectrometer.
Sample Optical Properties—In solids, both surface and
The selection of specific NIR instrumentation and sampling
bulk scattering properties of calibration standards and analyt-
accessories should be based on the intended application, and
ical samples must be taken into account. Surface morphology
particular attention should be paid to the suitability of the sam-
and refractive index properties affect the scattering properties
In-Process Revision
pling interface for the type of sample that will be analyzed.
of solid materials. For powder materials, particle size and par-
ticle density influence scattering properties and NIR spectral
response. Near-Infrared Reference Spectra
Polymorphism—Variation in crystalline structure (poly- NIR references, by providing known stable measurements
morphism) from materials with the same chemical composi- to which other measurements can be compared, are to mini-
tion can influence NIR spectral response. Different mize instrumental variations that would affect the measure-
polymorphs and amorphous forms of solid material may be ment.
distinguished from one another on the basis of their NIR spec-
Transmittance—The measurement of transmittance re-
quires a background reference spectrum for determining the
absorption by the sample relative to the background. Suitable
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transmittance reference materials depend on the specific NIR

Performance Qualification—Performance qualification
application and include air, an empty cell, a solvent blank, or a
demonstrates that the NIR measurement consistently operates
reference sample.
within target specifications defined by the user for a specific
Reflectance—The measurement of reflectance requires the
application; it is often referred to as system suitability. Perfor-
measurement of a reference reflection spectrum to determine
mance qualification for NIR measurements can include com-
the attenuation of reflected light relative to the unattenuated
paring a sample or standard spectrum to previously recorded
incident beam. The reflectance spectrum is calculated as the
spectra. Comparisons of spectra taken over time from identical
ratio of the single-beam spectrum of the sample to that of
samples or reference standard materials can form the basis for
the reference material. Suitable reflectance reference materials
evaluating the long-term stability of an NIR measurement sys-
depend on the specific NIR application and include ceramic,
tem. The objective is to demonstrate that no wavelength shift
perfluorinated polymers, gold, and other suitable materials.
or change in detector sensitivity has occurred during ongoing
analysis.
Qualification of NIR Instruments Characterizing Instrument Performance—Specific pro-
cedures, acceptance criteria, and time intervals for characteriz-
Qualification—Qualification of an NIR instrument can be
ing NIR instrument performance depend on the instrument and
divided into three elements: Installation Qualification (IQ);
intended application. Many NIR applications use previously
Operational Qualification (OQ); and Performance Qualifica-
validated models that relate NIR spectral response to a phys-
tion (PQ). For further discussion, see the proposed general in-
ical or chemical property of interest. Demonstrating stable in-
formation chapter Analytical Instrument Qualification h1058i
strument performance over extended periods of time provides
(page 1784 of PF 32(6) [Nov.–Dec. 2006]).
some assurance that reliable measurements can be taken from
Installation Qualification—The IQ requirements help en-
sample spectra using previously validated NIR models.
sure that the hardware and software are installed to accommo-
Wavelength Uncertainty—NIR spectra from sample and/or
date safe and effective use of the instrument at the desired
reference standard materials can be used to demonstrate an in-
location.
strument’s suitable wavelength dispersion performance
Operational Qualification—In operational qualification, an
against target specifications. The USP Near IR System Suita-
instrument’s performance is characterized using standards to
bility Reference Standard or the National Institute of Stan-
verify that the system operates within target specifications.
dards and Technology (NIST) Standard Reference Material
In-Process Revision
The purpose of operational qualification is to demonstrate that

(SRM) 2036 for reflectance measurement and NIST SRM
instrument performance is suitable for the intended applica-
2035 for transmittance measurement can be used for wave-
tion. Because there are so many different approaches for mea-
length verification. Suitable materials for demonstrating wave-
suring NIR spectra, operational qualification using standards
length dispersion performance include polystyrene,
with known spectral properties is recommended. Using exter-
trichlorobenzene, mixtures of rare earth oxides, and absor-
nal traceable reference standard materials does not justify o-
bance from water vapor for instruments that use an interferom-
mitting the instrument’s internal quality control procedures.
eter for wavelength dispersion. With appropriate justification,
As is the case with any spectrophotometric device, wavelength
alternative standards may be used. Wavelength uncertainty
uncertainty, photometric linearity, and noise characteristics of
typically is characterized from a single spectrum (collected
NIR instruments should be qualified against target specifica-
with the same spectral resolution to obtain the standard value)
tions for the intended application.
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using a minimum of three peaks that cover a suitable spectral the intercept of a plot of the measured photometric response
range of the instrument. Typical tolerances for agreement with versus standard photometric response. Alternative tolerances
standard values are +1.0 nm from approximately 700 to 2000 may occur when justified for specific applications.
nm and +1.5 nm above 2000 nm to approximately 2500 nm Spectrophotometric Noise—NIR spectra from samples and/
(+8 cm–1 below 5000 cm–1 and +4 cm–1 from 5000–1 to ap- or reference standards can be to characterize the signal-to-
proximately 14,000 cm ). Alternative tolerances may be used
–1
noise ratio (S/N) of instruments under conditions of high-light
when justified for specific applications. flux (low absorption) and low-light flux (high absorption).
Photometric Linearity and Response Stability—NIR spectra NIR instrument software may include built-in procedures to
from samples and/or reference standard materials with known automatically determine system noise and to provide a statis-
relative transmittance or reflectance can be used to demon- tical report of noise or S/N over the instrument’s operating
strate a suitable relationship between NIR light attenuation range. In addition, it may be desirable to supplement such
(due to absorption) and instrument response. For reflectance checks with measurements that do not rely directly on manu-
measurements, carbon-doped polymer standards are often facturer-supplied procedures. Typical procedures involve
used. Spectra obtained from reflection standards are subject measuring spectra of traceable reference materials with high
to variability as a result of the difference between the experi- and low reflectance. Tolerances for these procedures should
mental conditions under which they were factory calibrated demonstrate suitable S/N for the intended application.
and those under which they are subsequently put to use. HIGH-FLUX NOISE—Instrument noise is evaluated at high-
Hence, the reflectance values supplied with a set of calibration light flux by measuring reflectance or transmittance of the ref-
standards may not be useful in the attempt to establish an ‘‘ab- erence standard, with the reference material (e.g., 99% reflec-
solute’’ calibration for a given instrument. Provided that (1) tion standard) acting as both the sample and the background
the standards do not change chemically or physically, (2) the reference.
same reference background is also to obtain the standard val- LOW-FLUX NOISE—The same procedure may be with a low-
ues, and (3) the instrument measures each standard under iden- er-reflectivity reference material (e.g., 10% reflectance stan-
tical conditions (including precise sample positioning), the dard) to determine system noise at reduced light flux. The
reproducibility of the photometric scale will be established o- source, optics, detector, and electronics make significant con-
ver the range of standards. Subsequent measurements on the tributions to the noise under these conditions.
identical set of standards give information on long-term stabil-
ity. Photometric linearity is typically characterized using a METHOD VALIDATION
In-Process Revision
minimum of four reference standards in the range from 10%
to 90% reflection (or transmission). NIR applications based on Introduction
measuring an absorbance larger than 1.0 may require stan-
The objective of NIR method validation, as is the case with
dards with reflectivity properties between 2% and 5% reflec-
the validation of any analytical procedure, is to demonstrate
tion (or transmission) for characterizing instrument
that the measurement is suitable for its intended purpose.
performance at low reflectance. One hopes to demonstrate a
NIR spectroscopy is somewhat different from conventional
linear relationship between NIR reflectance and/or transmit-
analytical techniques because validation of the former gener-
tance and instrument response. Typical tolerances for a linear
ally is achieved by the assessment of chemometric parameters,
relationship are 1.00 + 0.05 for the slope and 0.00 + 0.05 for
but these parameters can still be related to the fundamental va-
lidation characteristics required for any analytical method.
Pharmacopeial Forum
tion. Materials to demonstrate specificity should be based on

Data pretreatment is often a vital step in the chemometric
sound scientific judgment and can include materials similar in
analysis of NIR spectral data. Data pretreatment can be de-
visual appearance, chemical structure, or name.
fined as the mathematical transformation of NIR spectral data
Quantitative—Quantitative applications of NIR spectrosco-
to enhance spectral features and/or remove or reduce un-
py typically involve establishing a mathematical relationship
wanted sources of variation prior to using the spectrum. Cal-
between NIR spectral response and a physical or chemical pro-
ibration is the process of developing a mathematical
perty of interest. Demonstrating specificity against a physical
relationship between NIR spectral response and properties of
or chemical property of interest is based on interpreting both
samples. Many suitable chemometric algorithms for data pre-
NIR spectral attributes and chemometric parameters in terms
treatment and calibration exist; the selection should be based
of the intended application and may include the following:
on sound scientific judgment and suitability for the intended
Spectral regions in the calibration model can be correlated
application.
to a known NIR spectral response associated with the pro-
perty of interest.
Validation Parameters Wavelengths used by regression analysis for the calibra-
tion (e.g., for multiple linear regression [MLR] models) or
Performance characteristics that demonstrate the suitability
the loading vector for each factor (e.g., for partial least
of NIR methods are similar to those required for any analytical
squares [PLS] or principal component regression [PCR]
procedure. A discussion of the applicable general principles is
models) can be examined to verify relevant spectroscopic
found in Validation of Compendial Procedures h1225i. These
information that is used for the mathematical model.
principles should be considered typical for NIR procedures,
Variation in spectra from samples for calibration can be
but exceptions should be dealt with on a case-by-case basis.
examined and interpreted as expected spectral observa-
For qualitative NIR methods, see chapter h1225i, Data Ele-
tions.
ments Required for Validation, Category IV assays. For quan-
Variation in material composition and sample matrix may
titative NIR methods, see chapter h1225i, Data Elements
be shown to have no significant effect on quantification of
Required for Validation, Category I and Category II assays.
the property of interest within the specified method range.
Specific acceptance criteria for each validation parameter must
be consistent with the intended use of the method. The sam- Linearity—Quantitative NIR methods generally attempt to
ples for validation should be independent of the calibration set. demonstrate a linear relationship between NIR spectral re-
sponse and the property of interest. Although demonstrating
In-Process Revision
Specificity—The extent of specificity testing depends on

a linear response is not required for all NIR applications, the
the intended application. Demonstration of specificity in
model chosen, whether linear or not, should properly represent
NIR methods is typically accomplished by using the following
the relationship.
approaches:
Validation of linearity in NIR methods may be accom-
Qualitative—Identification testing is a common application
plished by examining a plot of NIR spectral response versus
of qualitative NIR spectroscopy. Identification is achieved by
actual or accepted values for the property of interest. Many
comparing a sample spectrum to a reference spectrum or a li-
statistical methods are available for evaluation of the goodness
brary of reference spectra. The specificity of the NIR identifi-
of fit of the linear relationship. Other applicable statistics and
cation method is demonstrated by obtaining positive
graphical methods may be as appropriate.
identification from samples coupled with negative results from
materials that should not meet criteria for positive identifica-
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The correlation coefficient, r, may not be an informative The error of the reference method may be known on the basis
measure of linearity. The square of the (Pearson) correlation of historical data, through validation results specific to the ref-
coefficient is a measure of the fraction of the data’s variation erence method, or by calculating the standard error of the la-
that is adequately modeled by the equation. Linearity depends boratory (SEL). Suitable agreement between SEP and SEL is
on the standard error of the calibration equation (and hence the based on required measurement capability for a specific appli-
reference method) and on the range of the calibration data. cation.
Thus, although values very near 1.00, such as 0.99 or greater, Precision—The precision of an NIR method expresses the
typically indicate a linear relationship, lower values do not dis- closeness of agreement between a series of measurements un-
tinguish between nonlinearity and variability around the line. der prescribed conditions. Two levels of precision should be
Range—The specified range of an NIR method depends on considered: repeatability and intermediate precision. The pre-
the specific application. The range typically is established by cision of an NIR method typically is expressed as the relative
confirming that the NIR method provides suitable measure- standard deviation of a series of NIR method results and
ment capability (accuracy and precision) when applied to sam- should be suitable for the intended application. Demonstration
ples within extreme limits of the NIR measurement. Controls of precision in NIR methods may be accomplished using the
must be used to ensure that results outside the validated range following approaches:
are not accepted. In certain circumstances, it may not be pos- Repeatability—Repeatability can be demonstrated by the
sible or desirable to extend the validated range to include sam- following:
ple variability outside the validated range. Extending the range Statistical evaluation of a number of replicate measure-
of an NIR method requires demonstration of suitable measurements of the same sample without variation in sample in-
ment capability within the limits of the expanded range. Ex- terface to the NIR instrument or
amples of situations in which only a limited sample range Statistical evaluation of multiple NIR method results,
may be available are samples from a controlled manufacturing each result from a unique replicate interface between
process and in-process samples. A limited method range does the sample and the NIR instrument, as appropriate over
not preclude the use of an NIR method. a short period of time
Accuracy—Accuracy in NIR methods is demonstrated by Intermediate Precision—Intermediate precision can be
showing the closeness of agreement between the value that shown by the following:
is accepted as either a conventional true value or an accepted Statistical evaluation of a number of replicate NIR mea-
reference value. Accuracy can be determined by direct com-
In-Process Revision
surements of the same or similar samples in the Repeata-
parison between NIR validation results and actual or accepted bility study by different analysts on different days.
reference values. Suitable agreement between NIR and refer- Robustness—NIR measurement parameters selected to
ence values is based on required measurement capability for a demonstrate robustness will vary depending on the application
specific application. One hopes to demonstrate a linear rela- and the sample’s interface with the NIR instrument. Critical
tionship between NIR results and actual values. measurement parameters associated with robustness often
Model Assessment—Accuracy can be determined by are identified and characterized during method development.
agreement between the standard error of prediction (SEP)
and the standard error of the reference method for validation.
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Typical measurement parameters include the following: Changes in the composition of the test sample or finished
Effect of environmental conditions (e.g., temperature, hu- product
midity, and vibration) Changes in the manufacturing process
Effect of sample temperature Changes in the sources or grades of raw materials
Sample handling (e.g., probe depth, compression of ma- Changes in the reference analytical method
terial, sample depth/thickness, sample presentation) Major changes in instrument hardware
Influence of instrument changes (e.g., lamp change, Outliers—Sample spectra that produce an NIR response
warm-up time) that is not incorporated into qualitative or quantitative calibra-
tion models may produce an outlier, which does not necessar-
ily indicate an out-of-specification result. An outlier from an
Ongoing Method Evaluation
NIR measurement indicates that further testing of the sample
Validated NIR methods should be subject to ongoing perfor- is required. If subsequent testing of the sample by an appropri-
mance evaluation, which may include monitoring accuracy, ate method indicates that the property of interest is within spe-
precision, and other suitable method parameters. If perfor- cifications, then the sample meets its specifications. Thus,
mance is unacceptable, corrective action is necessary. It in- measurement of a sample by NIR may generate an outlier,
volves conducting an investigation to identify the cause of and the sample may still meet specifications for the property
change in method performance and may indicate that the of interest. Samples that produce an outlier may be incorporat-
NIR method is not suitable for continued use. Improving the ed into an updated calibration model subsequent to execution
NIR method to meet measurement suitability criteria may re- and documentation of suitable validation studies.
quire additional method development and documentation of
validation experiments demonstrating that the improved meth-
Method Transfer
od is suitable for the intended application. The extent of reva-
lidation required depends on the cause of change in method Controls and measures for demonstrating the suitability of
performance and the nature of corrective action required in or- NIR method performance following method transfer are sim-
der to establish suitable method performance. Appropriate ilar to those required for any analytical procedure. Exceptions
change controls should be implemented to document ongoing to general principles for conducting method transfer for NIR
method improvement activities. methods should be justified on a case-by-case basis. The trans-
Revalidation of a qualitative model may be necessary as a fer of an NIR method is often performed by using an NIR cal-
In-Process Revision
result of the following: ibration model on a second instrument that is similar to the
Addition of a new material to the spectral reference li- primary instrument used to develop and validate the method.
brary When a calibration model is transferred to another instrument,
Changes in the physical properties of the material procedures and criteria must be applied to demonstrate that the
Changes in the source of material supply calibration model meets suitable measurement criteria on the
Identification of previously unknown critical attribute(s) second instrument. Several calibration model transfer proce-
of material(s) dures have been developed and implemented. The selection
Revalidation of a quantitative model may be necessary as a of an appropriate calibration model transfer procedure should
result of the following: be based on sound scientific judgment.
Pharmacopeial Forum
GLOSSARY INSTALLATION QUALIFICATION is the documented collection

of activities necessary to establish that an instrument is deliv-
ered as designed and specified, is properly installed in the se-
ABSORBANCE, A, is represented by the equation:
lected environment, and that this environment is suitable for
the instrument’s intended purpose.
A = –log T = log (1/T)
INSTRUMENT BANDWIDTH is a measure of the ability of a
where T is the transmittance of the sample. Absorbance is also spectrometer to separate radiation of similar wavelengths.
frequently given as:
MULTIPLE LINEAR REGRESSION is a calibration algorithm to
relate the response from an analytical instrument to the proper-
A = log (I/R)
ties of samples. The distinguishing feature of this algorithm is
the use of a limited number of independent variables. Linear-
where R is the reflectance of the sample.
least-squares calculations are performed to establish a relation-
BACKGROUND SPECTRUM is used for generating a sample
ship between these independent variables and the properties of
spectrum with minimal contributions from instrument re-
the samples.
sponse. It is also referred to as a reference spectrum or back-
ground reference. The ratio of the sample spectrum to the OPERATIONAL QUALIFICATION is the process by which it is
background spectrum produces a transmittance or reflectance demonstrated and documented that an instrument performs ac-
spectrum dominated by NIR spectral response associated with cording to specifications and that it can perform the intended
the sample. In reflection measurements, a highly reflective task. This process is required following any significant change
standard reference material is for the measurement of the back- such as instrument installation, relocation, or major repair.
ground spectrum. For transmission measurement, the back- OVERALL REFLECTANCE is the sum of diffuse and specular
ground spectrum may be measured with no sample present reflectance.
in the spectrometer or using a cell with the solvent blank or PARTIAL LEAST SQUARES (PLS) is a calibration algorithm to
filled with appropriate reference material. relate instrument responses to the properties of samples. The
CALIBRATION MODEL is a mathematical expression to relate distinguishing feature of this algorithm is that data concerning
the response from an analytical instrument to the properties of the properties of the samples for calibration are used in the cal-
samples. culation of the factors to describe instrument responses.
DIFFUSE REFLECTANCE is the ratio of the spectrum of ra-
PERFORMANCE QUALIFICATION is the process of using one or
In-Process Revision
diated light penetrating the sample surface, interacting with
more well-characterized and stable reference materials to ver-
the sample, passing back through the sample’s surface, and
ify consistent instrument performance. Performance qualifica-
reaching the detector to the background spectrum. This is
tion may employ the same or different standards for different
the component of the overall reflectance that produces the ab-
performance characteristics.
sorption spectrum of the sample.
PHOTOMETRIC LINEARITY, also referred to as photometric
FIBER-OPTIC PROBES consist of two components: optical fi-
verification, is the process of verifying the response of the
bers that may vary in length and in the number of fibers and
photometric scale of an instrument.
a terminus, which contains specially designed optics for exam-
ination of the sample matrix. PRINCIPAL COMPONENT REGRESSION (PCR) is a calibration
algorithm to relate the response from an analytical instrument
to the properties of samples. This algorithm, which expresses a
Pharmacopeial Forum
set of independent variables as a linear combination of factors, STANDARD ERROR OF CROSS-VALIDATION (SECV) is the stan-
is a method of relating these factors to the properties of the dard deviation calculated using the leave-one-out method. In
samples for which the independent variables were obtained. this method, one calibration sample is omitted from the cali-
REFERENCE SPECTRUM—See Background Spectrum. bration, and the difference is found between the value for this
REFLECTANCE is described by the equation: sample calculated from its reference value and the value ob-
tained from the calibration calculated from all the other sam-
R = I/IR ples in the set. This process is repeated for all samples in the
set, and the SECV is the standard deviation of the differences
in which I is the intensity of radiation reflected from the sur-
calculated for all the calibration samples that are calculated in
face of the sample and IR is the intensity of radiation reflected
this way. The SECV is a measure of the model accuracy that
from a background reference material and its incorporated
one can expect when measuring future samples if not enough
losses due to solvent absorption, refraction, and scattering.
samples are available for the SEP to be calculated from a com-
ROOT-MEAN-SQUARE (RMS) NOISE is calculated by the equa-
pletely independent validation set.
tion:
STANDARD ERROR OF THE LABORATORY (SEL) is a calcula-
tion based on repeated readings of one or more samples to es-
timate the precision and/or accuracy of the reference
laboratory method, depending on how the data were collected.
STANDARD ERROR OF PREDICTION (SEP) is a measure of mo-
del accuracy of an analytical method based on applying a gi-
in which Ai is the absorbance for each data point; A is the mean
ven calibration model to the spectral data from a set of samples
absorbance over the spectral segment; and N is the number of
different from but similar to those to calculate the calibration
points per segment.
model. SEP is the standard deviation of the residuals obtained
SPECTRAL REFERENCE LIBRARY is a collection of spectra of
from comparing the values from the reference laboratory to
known materials for comparison with unknown materials. The
those from the method under test for the specified samples.
term is commonly in connection with qualitative methods of
SEP provides a measure of the model accuracy expected when
spectral analysis (e.g., identification of materials).
one measures future samples.
SPECULAR REFLECTANCE is the reflectance of the front sur-
SURFACE REFLECTANCE, also known as specular reflection,
face of the sample.
is that portion of the radiation not interacting with the sample
In-Process Revision
STANDARD ERROR OF CALIBRATION (SEC) is a measure of

but simply reflecting back from the sample surface layer (sam-
the capability of a model to fit reference data. SEC is the stan-
ple–air interface).
dard deviation of the residuals obtained from comparing the
TRANSFLECTANCE is a transmittance measurement technique
known values for each of the calibration samples to the values
in which the radiation traverses the sample twice. The second
that are calculated from the calibration. SEC should not be as
time occurs after the radiation is reflected from a surface be-
an assessment tool for the expected method accuracy (trueness
hind the sample.
and precision of prediction) of the predicted value of future
TRANSMITTANCE is represented by the equation:
samples. The method accuracy should generally be verified
by calculating the standard error of prediction (SEP), using
T = I/I0 or T = 10A
an independent validation set of samples.
Pharmacopeial Forum
in which I is the intensity of the radiation transmitted through Stage 2: Investigation

the sample; I0 is the intensity of the radiant energy incident on For a subject to be harmonized retrospectively, the coordinating
pharmacopeia collects the information on the existing specifications
the sample and includes losses due to solvent absorption, re- in the three pharmacopeias, on the grades of products marketed, and
on the potential analytical procedures.
fraction, and scattering; and A is the absorbance.&2S (USP31) The coordinating pharmacopeia prepares a draft monograph or
chapter, accompanied by a report giving the rationale for the proposal
with validation data.
Stage 2 ends with the proposal draft, which is mentioned in this
procedure as a Stage 3 draft. The Stage 3 draft, accompanied by sup-
porting comments or data that explain the reasons for each test pro-
cedure or limit proposed, is sent by the coordinating pharmacopeia to
the secretariats of the other two PDG pharmacopeias.
BRIEFING
Stage 3: Proposal for Expert Committee Review

h1196i Pharmacopeial Harmonization, USP 30 page 658. It is
proposed to update this general information chapter to include the fol- The three pharmacopeias forward the Stage 3 draft to their expert
lowing changes. The PDG working procedures were revised in Octo- committee (through meetings or consultation by correspondence).
ber 2006, and thus the text of h1196i has been aligned to reflect those Comments by the experts resulting from this preliminary survey
changes, most notably the addition of Stage 6C—Indication of Har- are sent to their respective pharmacopeial secretariat, preferably with-
monization. Secondly, the Status of Harmonization Tables have been in 2 months. However, the comment period should not exceed 4
updated to reflect the current harmonization stage for each mono- months. Within 2 months of receipt of the comments, the pharmaco-
graph and general chapter. peial secretariat should consolidate the comments and forward them
to the coordinating pharmacopeia.
(HDQ: K. Moore) RTS—C54388 The coordinating pharmacopeia reviews the comments received
and prepares a harmonized document (Stage 4 draft) accompanied
by a commentary discussing comments received about the previous
text and providing reasons for action taken in response to those com-
ments.
The Stage 4 draft, as far as possible written in global style—a style
Change to read: easily understood by a variety of readers—together with the commen-
tary, is sent to the secretariats of the other pharmacopeias (end of
Stage 3).
PDG WORKING PROCEDURES

Stage 4: Official Inquiry
&
Working Procedures of the PDG were updated at the Oc- The Stage 4 draft and the commentary are published in the revision
document
tober 2006 PDG meeting.&2S (USP31)
&
or forum&2S (USP31)
General of each pharmacopeia in a section entitled International Harmoniza-
tion. The draft is published in its entirety.
Harmonization may be carried out retrospectively for existing The corresponding secretariats may have to add information essen-
monographs or chapters or prospectively for new monographs or tial to the understanding of the implementation of the texts (e.g., the
chapters. description of an analytical procedure or of reagents that do not exist
The three pharmacopeias have a commitment to respect the agreed in the pharmacopeia), and a translation is added by the European and
working procedures and the associated time deadlines as an essential Japanese Pharmacopoeias. The style may be adapted to that of the
part of the harmonization procedure. pharmacopeia concerned, or global style may be used. A pharmaco-
Harmonization of pharmacopeial documents in the PDG is per- peia can add text, either to amplify some of the requirements with
formed on the basis of decisions of the expert bodies of each pharma- additional information or because national requirements and compen-
copeia. The PDG works transparently in many ways, but principally dial policy dictate that the addition is necessary. However, there must
through the public notice and comment procedures of each pharma- be a clear indication that this additional information is not part of the
In-Process Revision
copeia. harmonized document. This will avoid additional text being included
Where necessary, meetings of experts are held to identify potential after the harmonization process is completed, but will allow interest-
solutions to difficult problems. ed parties to review a complete text.
The specific stages of the PDG process
&
&2S (USP31)
&
procedure (Process)&2S (USP31) The three pharmacopeias endeavor to publish the drafts simultane-
involved in harmonization are described below. ously or as closely as possible.
Comments regarding this draft are sent by readers of the revision
document to their respective pharmacopeial secretariat, preferably
Stage 1: Identification within 4 months and at most within 6 months of its publication.
Each pharmacopeia analyzes the comments received and submits
On the basis of an inquiry among its users, the PDG identifies sub- its consolidated comments to the coordinating pharmacopeia within 2
jects to be harmonized among PDG pharmacopeias and nominates a months of the end of the review or comment period.
coordinating pharmacopeia for each subject. The coordinating pharmacopeia reviews the comments received
The PDG distributes the work by consensus among the three phar- and prepares a draft harmonized document (Stage 5A draft), accom-
macopeias and strives for a balance in the distribution of assignments panied by a commentary discussing comments received regarding the
to coordinating pharmacopeias. previous text and providing reasons for action taken in response to
those comments.
The Stage 5A draft, together with the commentary, is sent to the
secretariats of the other two PDG pharmacopeias.
Pharmacopeial Forum
Stage 5. Consensus If necessary, the Stage 5B draft may be adopted with some amend-
ments (local requirements) corresponding to a general policy in the
5A. PROVISIONAL national or regional (European) area. If a pharmacopeia includes a
local attribute after the sign-off of a text, it will inform the PDG. It
The Stage 5A draft is reviewed and commented on by the other two is, however, preferred to include the nonharmonized text in Stage 5B
PDG pharmacopeias within 4 months of receipt. The three pharma- as an alert to the other pharmacopeias that there will be some differ-
copeias shall do their utmost to reach full agreement at this stage to ences in text in the final document.
obtain a final consensus document. Users of the pharmacopeias are appropriately informed of the har-
If a consensus has not been reached, the coordinating pharmaco- monization status of monographs and general chapters. In the Euro-
peia prepares a revised version (Stage 5A/2), taking into considera- pean Pharmacopoeia (EP) and USP–NF, for general chapters, this is
tion relevant, substantiated comments on the Stage 5A document done via a preliminary paragraph. For the Japanese Pharmacopoeia
from the two other pharmacopeias. The revised document (Stage (JP), a notification is made by the MHLW, and information is given in
5A/2), together with the commentary, is sent to the secretariats of a general chapter.
the other two PDG pharmacopeias. The revised document is reviewed
and commented on by the other two PDG pharmacopeias, preferably
within 2 months of receipt. This review or comment and revision pro- 6B. IMPLEMENTATION
cess of the 5A document is repeated (Stage 5A/n) until the three PDG
pharmacopeias reach a consensus or until the coordinating pharmaco- The pharmacopeias will inform each other of the date of implemen-
peia considers that harmonization by attribute should be applied. tation in their particular region.
If the coordinating pharmacopeia considers certain attributes in the The date of implementation of a harmonized document varies in
monograph or provisions in a general chapter (especially for retroac- the three PDG regions depending on their legal requirements, need
tive harmonization) are such that it will not be possible to harmonize of translation, and publication schedules. Each pharmacopeia gener-
within a reasonable time period, harmonization by attribute will be ally allows some period of time after publication for implementation
applied. If harmonization by attribute is applied, a special cover page to allow manufacturers and other users to achieve conformity. Har-
(see the table in the Appendix) indicating harmonization is included monization is not achieved until the text becomes official in all three
with the draft. The text contains harmonized attributes and provi- pharmacopeias.
sions, and nonharmonized and local attributes are not included. The
nonharmonized attributes are clearly indicated in the text as such. The
table is prepared as follows: if three pharmacopeias agree on the at-
tribute, there will be a (+) in all columns; if two pharmacopeias agree
that the attribute should be included and have agreed on the method &
6C. INDICATION OF HARMONIZATION
and limit, there will be a (+) in the column for those two pharmaco-
peias, and a (–) in the column for the pharmacopeia that will not stip-
ulate the test. Each pharmacopoeia will introduce a statement indicating
For nonharmonized or local requirements, if three pharmacopeias
agree that the attribute should be included, but have not come to the harmonization status. EP and USP reference the corre-
agreement on the method or limit: state attribute under ‘‘nonharmo-
nized attributes.’’ If only one pharmacopeia will include an attribute: sponding text of the other PDG pharmacopeias. JP references
state under ‘‘local requirement.’’
If the Stage 5A draft is substantially different from the Stage 4 the harmonized text. In case of residual differences, these are
draft, the PDG may decide that it should be published again in the
revision documents; the draft then reverts technically to Stage 4, re- indicated by a specific symbol (black diamond ^).
vised.
Harmonization is achieved when all pharmacopeias have
5B. DRAFT SIGN-OFF highlighted harmonization and any residual differences, based
When agreement is reached, the 5B draft is sent by the coordinat- on a general policy in the national or regional area.
ing pharmacopeia to the other pharmacopeias no later than 4 weeks
before a PDG meeting for final confirmation. The document is then Concurrent to Stages 6A, B, and C, a dialogue is opened
presented for sign-off at the PDG meeting.This document includes
nonharmonized attributes clearly marked as such. between PDG and ICH Q4B Expert Working Group for the
purpose of obtaining regulatory acceptance of the harmonized
Stage 6: Regional Adoption and Implementation
In-Process Revision
text. The coordinating pharmacopeia provides documents to

NOTE—The last two stages of the implementation of the ‘‘har-
monized’’ chapters and monographs take place independently ac- I C H Q 4 B E W G a s d e fi n e d i n t h e I C H Q 4 B
cording to the procedures established by each pharmacopeial
organization. Guideline.&2S (USP31)
6A. REGIONAL ADOPTION

Stage 7: Inter-Regional Implementation
&
AND PUBLICATION&2S (USP31) &
Acceptance&2S (USP31)
The document is submitted for adoption to the organization respon-
sible for each pharmacopeia. Each pharmacopeia incorporates the When a harmonized text has become official in all three pharma-
harmonized draft according to its own procedures. Stylistic and edi- copeias, EP and USP publish a statement indicating the harmoniza-
torial differences may occur. tion status of the text; JP publishes a statement to the same effect at
Stage 6B. These statements are intended to promote regulatory accep-
& tance of interchangeability of harmonized monographs and general
&2S (USP31)
Adopted texts are published by the three pharmacopeias in their chapters.
supplements, or where applicable, in a new edition.
Pharmacopeial Forum
&
Following the Q4B evaluation process, a formal notifica- As with other USP–NF revisions, draft harmonization texts are
published for comment in Pharmacopeial Forum. Final harmonized
tion of regulatory acceptance is posted by ICH. official text in USP–NF is presented in the latest edition, Supplement,
or Interim Revision Announcement. The current status of all harmo-
A topic-specific annex to the Q4B guideline for each mono- nization projects appears in Table 1 and Table 2. These status tables
will be updated in subsequent editions of USP–NF and its Supple-
graph or chapter concerned is processed for publishing and ments.
In the U.S., cases of noncompliance or dispute are resolved
implementation by each regional authority.&2S (USP31) through performance of the official procedure in USP or NF. If the
procedure and its acceptance criteria are harmonized in the PDG, then
a manufacturer may follow the relevant compendial instructions in
USP–NF, EP, or JP.
Revision
The procedure for the revision of harmonized monographs and Table 1. Status of Harmonization—Excipient
chapters is as follows. Monographs
The pharmacopeias participating in the PDG have agreed not to
revise unilaterally any harmonized document (monograph or chapter) Coordinating Harmonization
after sign-off or after publication. Excipient Name Pharmacopeia Stage
A pharmacopeia requesting the revision of a monograph or chapter
shall apply the following criteria for justification of the revision: Alcohol EP 6
&
(Rev 2)&2S (USP31) &
4&2S (USP31)
— Public health and safety reasons.
— Insufficient supply of pharmacopeial-quality product on the Benzyl Alcohol EP 6
market. &
(Rev 1)&2S (USP31)
— Specified analytical reagents or equipment unavailable.
— New methods of preparation of products or reagents not covered Dehydrated Alcohol EP 6
by the current monograph. &
(Rev 2)&2S (USP31)
— Analytical procedures capable of being replaced by more appro-
&
4&2S (USP31)
priate, accurate, or precise procedures. Butylparaben EP 6
The PDG as a whole has to agree to initiate the revision. A coor- Calcium Carbonate USP 2
dinating pharmacopeia will be nominated. The coordinating pharma-
copeia will prepare a Stage 3 draft, based on the validation of data &
4&2S (USP31)
provided by the pharmacopeia requesting the revision.
The PDG Working Procedures will then be followed. The revisions Calcium Disodium Edetate JP 5A2
of a sign-off document prepared for this or other reasons are indicated
as revision 1, 2, 3, etc.
&
6&2S (USP31)
In case of health and safety issues, and whenever agreed to by the Calcium Phosphate Dibasic JP 5B
PDG, an accelerated procedure shall be applied (shortening or elim- (and anhydrous)
inating stages).
&
6&2S (USP31)
Carboxymethylcellulose USP 6
Calcium
Discussion
Harmonization of general chapters and monographs benefits man-
&
Carmellose Calcium
ufacturers of pharmaceutical products intended for human use, regu-
latory agencies, and ultimately, practitioners and patients. Benefits are (Rev 1)&2S (USP31)
derived from (1) reduced development effort; (2) simplification of Carboxymethylcellulose USP 4
regulatory filings; and (3) reduced release testing. Sodium
Pharmacopeial harmonization amplifies the work of the ICH, par-
ticularly for Quality topics. While the PDG is not part of the ICH, the &
Carmellose Sodium
PDG periodically provides updates to the ICH Steering Committee,
and in the past participated in a joint task force. This task force fo- &2S (USP31)
cused on harmonization of general chapters considered important to Carmellose JP 2
the ICH harmonized document Specifications: Test Procedures and
In-Process Revision
Acceptance Criteria for New Drug Substances and New Drug Prod- &
4&2S (USP31)
ucts: Chemical Substances (Q6A). USP also participates in the Inter- Cellulose Acetate USP 6
national Cooperation on Harmonization of Technical Requirements
for Registration of Veterinary Products (VICH). As with the ICH, &
(Rev 1)&2S (USP31)
some of the quality guidelines developed in VICH depend upon har- Cellulose Acetate Phthalate USP 6
monization of pharmacopeial general chapters. A major difference
between the PDG and ICH/VICHs is that the ICH/VICH guidelines Microcrystalline Cellulose USP 6
generally are applicable only to ingredients and drug products not &
(Rev 1)&2S (USP31)
previously registered in an ICH/VICH region or nation, whereas
the PDG harmonization applies to all marketed products in the appli- Cellulose, Powdered USP 6
cable region or nation. &
(Rev 1)&2S (USP31)
In the case of harmonization by attribute, nonharmonization or di-
vergence will be indicated in USP–NF and EP by the symbol ^. For Citric Acid, Anhydrous EP 6
these nonharmonized attributes, reliance upon the individual pharma- &
(Rev 1)&2S (USP31)
copeia is required. A monograph or general chapter in one PDG phar- Citric Acid, Monohydrate EP 6
macopeia may unilaterally include additional local or national
attributes that are not included in the corresponding text of the other &
(Rev 1)&2S (USP31)
pharmacopeias. Such text is not considered by the PDG to be a diver- Copovidone JP 2
gence from the PDG harmonized text.
&
4&2S (USP31)
Pharmacopeial Forum
Table 1. Status of Harmonization—Excipient Table 1. Status of Harmonization—Excipient

Monographs (Continued) Monographs (Continued)
Coordinating Harmonization Coordinating Harmonization

Excipient Name Pharmacopeia Stage Excipient Name Pharmacopeia Stage
Croscarmellulose Sodium USP 6 Silicon Dioxide JP 4
Crospovidone EP 4
Ethylcellulose EP 6
&
4 rev
&2S (USP31)
Ethylparaben EP 6 Silicon Dioxide, Colloidal JP 4
Gelatin EP 2
&
4 rev
&
3&2S (USP31) &2S (USP31)
Glucose EP 2 Sodium Chloride EP 6
&
Monohydrate/Anhy- &
3&2S (USP31)
&
(Rev 2)&2S (USP31)
Sodium Lauryl Sulfate USP 2
drous&2S (USP31)
Glycerin USP 3 &
3&2S (USP31)
Glyceryl Monostearate USP 2 Sodium Starch Glycolate USP 6
Hydroxyethyl Cellulose EP 4 &
(Rev 1)&2S (USP31)
&
4/2&2S Starch, Corn USP 6
(USP31)
Hydroxypropyl Cellulose USP 4 &
(Rev 2)&2S (USP31)
Hydroxypropyl Cellulose, USP 4 Starch, Potato EP 6
Low Substituted Starch, Pregelatinized JP 2
Hydroxypropylmethyl JP 6
Cellulose &
3&2S (USP31)
Hydroxypropylmethyl USP 5A Starch, Rice EP 4 rev
Cellulose
&
6&2S (USP31)
&
6&2S (USP31)
&
Hypromellose&2S (USP31) Starch, Wheat EP 6
Phthalate Stearic Acid EP 4
Lactose, Anhydrous USP 6
&
(Rev 2)&2S (USP31)
&
5B&2S (USP31)
Lactose, Monohydrate USP 6 Sucrose EP 3

Magnesium Stearate USP 4 &
4&2S (USP31)
&
5A&2S (USP31)
Mannitol EP 2 &
Sterile Water for Injec- &
USP &
3&2S (USP31)
&2S (USP31)
&
3&2S (USP31) tion in Containers
Methylcellulose JP 6
Methylparaben EP 6 &2S (USP31)
Talc EP 6
Titanium Dioxide JP 5A2
&
Petrolatum&2S (USP31) &
USP &
4&2S (USP31)
&2S (USP31)
In-Process Revision
Petrolatum, White USP 4

Polyethylene Glycol USP 4 Table 2. Status of Harmonization—General Chapters
Polysorbate 80 EP 3
Coordinating Harmonization
&
4 rev Chapter Title Pharmacopeia Stage
&2S (USP31) Amino Acid Determination USP 6
Povidone JP 5A Bacterial Endotoxins JP 7
&
6&2S (USP31)
&
(Rev 1)&2S (USP31) &
4 rev
Propylene Glycol EP 3 &2S (USP31)
Bulk Density and Tapped EP 3
&
4&2S (USP31) Density
Propylparaben EP 6 &
5A2&2S (USP31)
Saccharin USP 6 Conductivity EP 2
Saccharin, Calcium USP 6
Saccharin, Sodium USP 6
&
(Rev 1)&2S (USP31)
Pharmacopeial Forum
Table 2. Status of Harmonization—General Chapters (Continued) Table 2. Status of Harmonization—General Chapters (Continued)
Coordinating Harmonization Coordinating Harmonization

Chapter Title Pharmacopeia Stage Chapter Title Pharmacopeia Stage
Degree of Color of Liquids; EP 3 Peptide Mapping USP 6
Clarity and Degree of Porosimetry by Mercury EP 3
Opalescence of Liquids Intrusion
&
Color (Instrumental
&
4&2S (USP31)
Powder Fineness USP 5A
Method)&2S (USP31)
Density of Solids EP 3
&
Powder Flow&2S (USP31)
&
USP &
6&2S (USP31)
&
5B&2S (USP31) &2S (USP31)
Disintegration USP 4 Protein Determination USP 6
Residue on Ignition JP 6
&
6&2S (USP31) (Revision 1)
Dissolution USP 4 &
(Rev 2)&2S (USP31)
&
(Rev 1)&2S (USP31) &
6&2S (USP31) Specific Surface Area EP 6
Capillary Electrophoresis EP 6 Sterility Tests EP 6
Polyacrylamide Gel EP 6 Tablet Friability USP 3
Electrophoresis
Extractable Volume of EP 6
&
6&2S (USP31)
Parenterals Thermal Behavior of Powders EP 2
&
(Rev 1)&2S (USP31)
&
3&2S (USP31)
Flowability (Powder Flow) USP 4 Uniformity of Content/Mass USP 5A2
&
& &
&2S (USP31)
&2S (USP31) &2S (USP31)
&
6&2S (USP31)
Heavy Metals USP 3
Inhalation EP 3
&
Uniformity of Delivered &
EP&2S (USP31) &
2&2S (USP31)
&
4&2S (USP31)
Isoelectric Focusing EP 6 Dose of Inhalations
Light EP 3 &2S (USP31)
&
Laser&2S (USP31)
&
4&2S (USP31)
Diffraction Measure of
Particle Size
&
Water-Solid Interaction &
EP&2S (USP31) &
3&2S (USP31)
&2S (USP31)
&
Limits for Nonsterile &
EP&2S (USP31) &
6&2S (USP31) X-Ray Diffraction—Solids 3
Products&2S (USP31)
&
X-Ray Powder &
EP&2S (USP31) &
4&2S (USP31)
Microbial Contamination Diffraction&2S (USP31)

&
EP&2S (USP31) &
6&2S (USP31)
Tests for Specified Microorga- EP 4 Harmonized Monographs and Chapters
nisms
In-Process Revision
&
6&2S (USP31) h85i Bacterial Endotoxins Test—This chapter has been harmo-
Microbial Enumeration EP 4 nized by PDG and published in the European Pharmacopoeia and
in the Japanese Pharmacopoeia. Portions of the chapter that are
&
6&2S (USP31) not harmonized with the other two pharmacopeias are marked by
Microbial Attributes EP 4 the symbol ^. Footnotes 1, 2, and 4 are in the USP but are not in
the EP or JP. These footnotes give additional information, such as
&
&2S (USP31) & & the calculation of endotoxin limits for different classes of products
&2S (USP31) &2S (USP31)
(Footnote 4) or reference USP chapters (Footnote 2).
Optical Microscopy USP 5A The USP Endotoxin Reference Standard is harmonized with the
International Reference Standard for Endotoxin and the EP Endo-
&
6&2S (USP31) toxin Reference Standard and indirectly harmonized with the JP
Particle Size Distribution USP 5A Endotoxin Reference Standard that is indexed to the International
Estimation by Analytical Reference Standard. The result is that 1 USP Endotoxin Unit = 1 In-
Sieving &
5B&2S (USP31) ternational Endotoxin Unit = 1 EP Endotoxin Unit.
&
(Rev 1)&2S (USP31) &
&2S (USP31)
&
Particulate Contamination &
EP&2S (USP31) &
6&2S (USP31)
(Rev 1)&2S (USP31)
Pharmacopeial Forum
BRIEFING Delete the following:
h1251i Weighing on an Analytical Balance, USP 30 page 707. &

The General Chapters Expert Committee is proposing new text for CHECKING THE BALANCE
this existing general information chapter. The new text considers
the following aspects of the balance and weighing process: In the next step it is important to remember that, unless the balance
1. Installation is checked before each weighing operation is performed, errors can
2. Qualification and routine checks easily occur, resulting in faulty analytical data. The balance user
3. Operation of the analytical balance should check the Balance Environment, Calibration, and Balance
4. Calibration Uncertainties. Do not assume that the balance has been left in the
5. Receivers proper operating condition by the previous user.
6. Types of weighing
7. Problem samples
8. Safety considerations Balance Environment
9. Buoyancy corrections
The content of this new text has been aligned with the recent pro- The balance is placed in a suitable location with sufficiently low
posal on the general chapter Weights and Balances h41i (see page levels of vibration and air current. It must have a constant electrical
1781 of PF 32(6) [Nov.–Dec. 2006]. supply. The balance and the surrounding work area have to be kept
Readers are encouraged to submit comments on this proposal no neat and tidy. It is good practice to use a camel’s hair brush or its
later than October 15, 2007. equivalent to dust the balance pan before any weighing so as to re-
move any materials that may have been left by the previous operator.
[NOTE—Individuals must clean up debris, dispose of any spilled ma-
(GC: H. Pappa) RTS—C54547 terials or paper, and remove the vessels and apparatus used in making
the measurements.] When a balance is moved, it must be allowed to
adjust to the temperature of its new environment and be recalibrated.
Change to read: Calibration

Weighing is a frequent step in analytical procedures, and the bal- If necessary, turn on the power, and allow the balance to equilibrate
ance is an essential piece of laboratory equipment in most analyses. In for at least 1 hour before proceeding with the calibration. (Micro-
spite of this, weighing is a common source of error that can be diffi- balances may require up to 24 hours to reach equilibrium.) If the bal-
cult to detect in the final analytical results. The procedure described ance power has gone off and then has come back on, as in a power
here applies directly to electronic balances ; therefore, certain por- outage, certain types of balance may display a message indicating that
tions of the procedure are not applicable to other types of balance. the balance must be calibrated before a weighing is made. If the
The weighing procedure can be separated into three basic steps: plan- operator touches the balance bar, the message may be cleared and
ning, checking the balance, and weighing the material. the balance may display zeros; however, the balance will not give
the correct weighing until it has been calibrated. Electronic analytical
&
used in analytical procedures, and certain portions of the balances have an internal calibration system based on an applied load.
The calibration applies for the current ambient temperature.
chapter are not applicable to other types of balances. This
chapter should not be considered all-inclusive, and there are Balance Uncertainties
other sources of information that may be useful and applicable DRIFT REDUCTION
(e.g., NIST, FDA, and balance manufacturers).&2S (USP31) Drift is one of the most common errors, and it is also one of the
easiest to reduce or eliminate. Balance drift can be present without
the operators being aware of the problem. Check the sample, the bal-
ance, and the laboratory environment for the following causes of er-
Delete the following: rors, and eliminate them:
1. A balance door is open.
2. Temperatures of the balance and the material to be weighed are
not the same.
In-Process Revision
&
PLANNING 3. The sample is losing or gaining weight.
4. The balance has been recently moved but has not been allowed
The initial step is to assemble the proper equipment, such as con- to equilibrate to its surroundings or has not been recalibrated.
tainers for weighing, receiving vessels, forceps, pipets, spatulas of 5. Air currents are present in the laboratory.
proper size, and so forth. Use containers of size such that the loading 6. Temperatures in the laboratory vary.
capacity of the balance is not exceeded. Make sure that the containers 7. The balance is not properly leveled.
selected to receive the weighed material are clean and dry. Assemble 8. Laboratory operations are causing vibration.
the necessary chemicals if solutions or reagents are required. 9. Hysteresis of the mechanical parts occurs during weighing.
Preparation of the material to be weighed is often necessary. The
material may require grinding or drying. Some materials may have
been heated or stored in a refrigerator. Materials must be brought to
the temperature of the balance before they are weighed. To avoid con- MECHANICAL HYSTERESIS
densation of moisture, refrigerated materials must be allowed to come
to room temperature before the container is opened.&2S (USP31) Hysteresis in the balance is caused by excessive stretching of the
springs, and it is primarily due to overloading or to the accidental
dropping of an object onto the pan. Microbalances are very sensitive
to overload and shock. When using a microbalance, set the lever to
the rest position when adding or removing material; turn the lever to
the weigh position to register the weight. In some cases, drift due to
hysteresis can be eliminated by allowing the balance to stand without
weighing long enough for it to recover. If stretching of the springs is
Pharmacopeial Forum
excessive, an expensive balance overhaul may be needed. In the case Delete the following:
of electronic force restoration balances, springs are replaced by flex-
tures, and the term creep is more appropriate than hysteresis.
&
WEIGHING THE MATERIAL
QUALITY ASSURANCE PROCEDURE FOR MEASUREMENT
In this final step, select the number of decimal places required for
OF BALANCE DRIFT the analytical procedure. In most pharmaceutical analyses small
Over an extended period of time, balance drift and other day-to-day quantities of material are used, requiring the balance reading to be
variations are monitored by weighing a fixed check-weight on a reg- set to the fifth decimal place to achieve the necessary accuracy.
ular basis; this check should be performed after the balance has been Weighing read with four decimal places is preferred for weighing
calibrated at the ambient laboratory temperature. The check should be near-gram quantities. Do not allow the material to remain on the bal-
made before the first weighing of the day or after any event that might ance for an extended period of time because changes, caused by in-
disturb the balance’s calibration (power failure, moving the balance to teraction with atmospheric water or carbon dioxide, may take place.
a new location, etc.). The check-weight may be any object whose
mass remains constant and does not exceed the load limit of the bal-
ance. A balance weight makes a reliable check-weight. Each balance Load Limit
should be provided with a check-weight, which should be stored in a
protective container near the balance. Select the appropriate balance for the quantity and accuracy need-
Perform the following procedures to reduce balance errors and the ed. Each balance has a load limit, which should not be exceeded.
possibility of an incorrect reading because of drift: Each balance manufacturer supplies the maximum loading condition,
1. Make certain that the electrical power to the balance is on and and this limit varies with the type of balance. The operator should
that the level bubble is in the center of the indicator. know this limit so that the balance will not be damaged. [NOTE—Elec-
2. Calibrate the analytical balance or the microbalance. [NOTE— tronic balances operate on a ‘‘load cell’’ principle that produces an
Some balances have a calibration lever, which must be returned electrical output proportional to the movement of the strain gauge
fully to its original weighing position. Do not depend upon any and is linear over the range.]
prior calibration.]
3. The first person to use the balance each day should weigh the
check-weight and record the weight in the log book for compar- Receivers
ison with previous readings. If a deviation greater than those in-
dicated below for Analytical Balances and Microbalances is The proper receiver for the material must be selected. The recei-
observed, the balance should be reported for service. [NOTE— ver’s weight plus the weight to be measured must not exceed the max-
Check-weights tend to gain weight upon standing because of imum load for the balance; the size and shape of the receiver should
mishandling and exposure to contaminants in the atmosphere. permit it to fit into the space and on the balance pan without interfer-
These weights can be cleaned by wiping with a lint-free cloth ing with any operation. It is important that the receiver be clean and
moistened with a small amount of an appropriate solvent such dry. Common receivers are weighing bottles, weighing funnels,
as diethyl ether.] flasks, and weighing paper. The correct receiver depends upon the
Analytical Balances—Select a check-weight of an appropriate quantity and type of material (liquid, solid, or powder) to be weighed.
mass to examine an analytical balance. If possible, set the balance All other things being equal, a vessel of low mass should be chosen
to read to 5 decimal places. Follow the manufacturer’s operating in- when small amounts of material are to be weighed. It is recommended
structions. Pick up the check-weight with a forceps, place it carefully that gloves, forceps, or another type of gripping device be used when
on the balance pan, and weigh it. [NOTE—Do not drop the weight on handling receivers, because oils from the hands will add weight.
the balance pan, because damage to the balance could result.] Place The weighing funnel is often the most satisfactory receiver, be-
the weight in the center of the pan to eliminate corner-weighing dif- cause it can function as both a weighing dish and a transfer funnel,
ferences. The accuracy of the weight is not important: the only factor allowing easy transfer to volumetric flasks. Weighing funnels come in
of interest is whether any drift has occurred. If no drift has taken various sizes; the size suitable for the operation should be selected.
place, the value should remain constant. Periodic weighing of a fixed Weighing paper may be used for solids. Paper receivers must be
weight will determine whether the boards (or knife edges in mechan- handled by hand, and great care must be used to prevent spills.
ical balances) in the instrument are defective. The check for drift at
the most sensitive position will show whether a problem exists; the
variation in the observed weight does not exceed +0.2 mg. For ex- Weighing by Difference
ample, with a 20-g weight, if the mean value of the readings were
19.9984, the tolerance would be from 19.9982 to 19.9986 g. Thus, Weighing is usually done by difference. The following methods are
several readings must be taken before one can establish a tolerance. acceptable for good analytical results.
[NOTE—The check-weight need not be of high accuracy, but it is es-
In-Process Revision
sential that its mass remain constant. In addition, the tolerance does
not correspond to the value of 0.1%, specified under Weights and Bal- METHOD 1
ances h41i, for weighing material accurately. Rather, the tolerance is
purposefully tight to reveal possible drift or calibration errors; this Tare the empty receiver as follows. Place the receiver on the bal-
tolerance is readily achievable with modern electronic balances.] ance in the center of the pan, and press the appropriate tare key on the
Microbalances—Proceed as directed for Analytical Balances, but balance. This operation electrically sets the signal from the strain
use a check-weight appropriate for the particular balance. For exam- gauge to zero so that the weight of the receiver is no longer indicated.
ple, a 100-mg check-weight might be selected for a balance that has a Add the material to the receiver, and record the weight. Transfer the
load limit of 150 mg; or a 10-mg check-weight might be used for an weighed material to the final flask or receiver; then reweigh the orig-
ultramicrobalance with a load limit of 15 mg. (The operator must inal weighing receiver by placing it in the same position on the pan.
know the maximum capacity of the balance to select the correct [NOTE—Do not change the set tare of the balance between these two
check-weight.) The balance indicates the weight in milligrams. Re- weighings.] The second weight represents the untransferred material
cord the weight as soon as the reading is stable for a few seconds. and is subtracted from the total material weight to determine the
The variation in weighings ought to be within a range commensurate weight of the transferred material.
with the specifications given by the balance manufacturer, but not
greater than 0.1% of the amount of material typically weighed on
the particular balance. For example, if 10-mg samples are routinely METHOD 2
weighed, the variation in the weighings of the check-weight cannot
exceed 0.01 mg.&2S (USP31) If the empty receiver is not going to be tared, add the material to the
receiver, and place the receiver on the balance in the center of the pan.
Record the weight, and transfer the weighed material to the final flask
Pharmacopeial Forum
or receiver; then reweigh the original weighing receiver by returning SPILLS

it to the same position on the pan. The second weight represents the
sum of the weights of the receiver and the untransferred material; sub- If solids are spilled, remove the receiver, and sweep out all of the
tract this sum from the sum of the total material weight and the re- spilled material from the balance. The spilled material must be
ceiver weight to determine the weight of the transferred material. properly disposed of and must not be swept out onto the balance table
where other operators may come in contact with the chemical. Then
either start the process over or reweigh the remaining material.
METHOD 3 [NOTE—Never return any excess material to the original container.
Any excess material must be disposed of in a proper manner.]
This method may be described as quantitative transfer. The mate-
rial is added to the tared receiver, the amount is determined by differ-
ence, and then the whole amount is transferred quantitatively (e.g., by Weighing Liquids
using a solvent) to the final receiver.
Liquids may be volatile or nonvolatile and viscous or nonviscous.
Each type requires special attention.
Materials-Handling Safety Procedures
The operator must be familiar with precautions described in the WEIGHING PROCEDURE
Material Safety Data Sheet for the substance before weighing it. Haz-
ardous materials must be handled in an enclosure having appropriate Weigh as directed for Weighing by Difference, with the following
air filtration. Many substances are extremely toxic, are possibly aller- additions. Liquids should always be weighed into a container that can
genic, and may be liquids or finely divided particles. A mask that be closed so that none of the material is lost. It is best if the liquid can
covers the nose and mouth should be used to prevent any inhalation be added to its receiving container outside the balance because of the
of chemical dust. Gloves should be used to prevent any contact with possibility of a spill. [NOTE—Liquids spilled within the balance hous-
the skin. [NOTE—The use of gloves is good practice for handling any ing can cause serious damage to the balance, and they may be difficult
chemical. If it is necessary to handle the container being weighed, the to remove.]
operator should put on gloves, not only for self-protection but also to Nonviscous liquids can be handled with a Pasteur capillary pipet
prevent moisture and oils from being deposited on the weighed con- equipped with a small rubber bulb such as a medicine dropper bulb.
tainer.] During a weighing, the operator may be exposed to high con- The liquid is discharged into its receiver, the top is closed or stop-
centrations of the pure substance; therefore, the operator must pered, and the receiver and contents are weighed. Small quantities
carefully consider these possibilities at all times. of viscous liquids can be handled by touching a glass stirring rod
Weighings are made on many different types of materials, such as to the surface of the liquid and then carefully touching the rod to
large solids, finely divided powders, and liquids (viscous or nonvis- the side of the receiving vessel, which allows some of the material
cous, volatile or nonvolatile). Each type of material requires its own to be transferred.
special handling.
Weighing Corrosive Materials

Weighing Solids
Many chemicals, such as salts, are corrosive, and materials of this
Solids come in two forms: large chunks, with or without powdery nature should not be spilled on the balance pan or inside the balance
surface, and finely divided powders or small crystals. If large chunks housing. Extreme care is essential when materials of this nature are
with a powdery surface are to be weighed, at least a piece of weighing being weighed.&2S (USP31)
paper must be placed on the balance pan to protect it from damage.
Large nonreactive chunks that have no powdery surface may be
placed directly on the pan (for example, a coated tablet). [NOTE—Sol- Delete the following:
id pieces must be handled with forceps, never by hand.]
&
CONCLUSION
STATIC CHARGE
By carefully following the procedures outlined above, laboratory
Fine powders have a tendency to pick up static charge, which will personnel will eliminate many errors that might be introduced into
cause the particles to fly around. This static charge must be eliminated weighing procedures. However, it is important for each balance to
before a suitable weighing can be made. An antistatic device may be be serviced and calibrated regularly by a specially trained internal
used to minimize this problem. [NOTE—Such devices may use piezo- or external service person. The balance should be tested using
electric components or a very small amount of a radioactive element
In-Process Revision
weights traceable to standardization by the National Institute of Stan-

(typically polonium) to generate a stream of ions that dissipate the dards and Technology. No repairs should be made to any balance by
static charge when passed over the powder to be weighed.] The static anyone other than a qualified maintenance person.&2S (USP31)
charge depends upon the relative humidity of the laboratory, which in
turn depends upon the atmospheric conditions. In certain conditions,
static charge is caused by the type of clothing worn by the operator; Add the following:
this charge causes large errors in the weighing when discharged.
WEIGHING PROCEDURE
&
INSTALLATION
Place the receiver on the balance pan, close the balance door, and
weigh as indicated for Weighing by Difference, with the following A balance’s performance is dependent on the conditions of
additions. Carefully add the powdered material from a spatula until
the desired amount is added. Use care to avoid spilling. Close the bal- the facility where it is installed. Information provided by the
ance door, and record the weight as soon as the balance shows a stable
reading. manufacturer should be consulted prior to installing a balance.
Pharmacopeial Forum
Support Surface due to pickup or loss of water. Low humidity increases

buildup of static electricity.
The balance should be mounted on a solid, level, nonmag-
netic surface that minimizes the transmission of vibration 4. Adjacent facility operations are causing vibration.
(e.g., a floor-mounted, polished-granite weigh bench). If a me-
5. Corrosive materials are used nearby or are routinely
tallic support surface is used, the surface should be grounded
weighed.
in order to prevent the buildup of static electricity.
6. The balance is located within a fume hood because it is
used to weigh corrosive or hazardous materials.
Location
7. The balance is adjacent to equipment producing a mag-
The balance should be located in a room that is temperature
netic field (e.g., a magnetic stirrer).
and humidity controlled. The location should have a clean,
In these cases, the performance of the balance should be as-
consistent electrical power supply. The location should be free
sessed following installation and prior to use in order to dem-
of drafts and should not be near ovens, furnaces, air condition-
onstrate adequate performance. In situations where the balance
er ducts, or cooling fans from equipment or computers. The
is located near equipment or systems that induce vibration,
balance should be positioned away from outside windows so
drafts, electromagnetic radiation, magnetic fields, or changes
that direct sunlight does not strike the balance. The balance
in temperature or humidity, the assessment should be conduct-
should not be installed near sources of electromagnetic radia-
ed with those systems operating in order to duplicate a worst-
tion such as radio frequency generators, electric motors, hand-
case scenario.&2S (USP31)
held communication devices (including cordless telephones,
cellular telephones, and walkie-talkies). The balance should Add the following:
not be located near magnetic fields induced by laboratory in-

strumentation or other equipment. &
QUALIFICATION AND ROUTINE CHECKS
In some situations, it may not be possible to position the bal-
To ensure the long-term reliability of the balance, the user
ance in an optimum environment. Examples of potential facil-
should consider the need for the following tests:
ity issues include the following:
Performance checks that are performed periodically: linear-
1. Air currents are sometimes present in the laboratory. ity, reproducibility, hysteresis, and eccentricity.
Time-of-use, daily, or other periodic checks (consistent with
In-Process Revision
2. Temperatures in the laboratory vary excessively (check
in-house procedures and applicability): calibration check (au-
manufacturer’s literature on temperature sensitivity).
tomatic electronic calibration) or check-weights (using weigh-
3. Humidity is either very low or very high. Either condition ing artifacts).
may increase the rate at which the sample weight varies
Pharmacopeial Forum
In addition, Weights and Balances h41i gives specific re- during the performance qualification), the balance should be
quirements for weighing of standards for Assay that include qualified at the time it is put into service (i.e., during the instal-
an option for calculating minimum weight. Minimum weight lation and operational qualification) with k = 3 to provide
in Weights and Balances h41i can be derived from the follow- greater assurance that the balance will meet Weights and Bal-
ing formula: ances h41i recommendations between testings.
Table 1 provides examples for accomplishing performance
(k / Urel)s checks. Table 2 provides information on check-weighing and
the use of check-weights. The examples in the tables are not
in which k is the coverage factor; Urel represents the uncertainty
all-inclusive. Any procedures used should be consistent with
factor of 0.001; and s is the standard deviation, in mg, of not
in-house standard operating procedures, applicable for the
less than 10 replicate measurements of a mass near the low end
specific balance, and adequately justified.
of the operating range. Although the recommended k factor is
2 for use of balance under Weights and Balances h41i (i.e.,
Table 1. Performance Checks
Test Example Considerations for Criteria
Linearity From 3 to 10 points over the range of No more than 0.1% deviation for Assay
the balance. (Weights and Balances h41i); for other
uses consider how the balance is used,
but errors should not exceed the larger of
0.1% or 1 mg.
Reproducibility 10 replicates (near minimum weight or Manufacturer’s specification;
1/10 of range). Weights and Balances h41i requirements,
In-Process Revision
as applicable.
Hysteresis Three measurements covering the range of Consider how the balance is used, but errors
the balance, e.g., should not exceed the larger of 0.1%
1. 50% of load or 1 mg.
2. 100% of load
3. 150% of load
Eccentricity Eccentricity test should be performed at Consider how the balance is used, but errors
four corners of the balance pan at should not exceed the larger of 0.1%
approximately 50% of the balance or 1 mg.
capacity.
Pharmacopeial Forum
Table 2. Use of Check-Weights
Topic Example Criteria
Type of material Stable but not necessarily a NIST-traceable Possible need for calibration certificate or
external weight. weight history.
Mass of weight Large enough to minimize variation from Below the maximum weight for the balance
handling, e.g., 20 g for a 4- or 5-place and above the minimum weight for the
balance, near the upper limit for balance (if established).
microbalances.
Frequency of use Time-of-use, daily, or other periodic check. A justified fixed interval needs to be used.
Measurement result Statistical process control and control Justified action limit (e.g., no more than
charts with limits based on measured 0.1% deviation from check-weight)
performance. based on control charts with the failure
limit based on balance application.
Routine weight checks using external weights should be re- Add the following:
corded in a manner where the data can be used to easily track
balance performance in order to allow for setting of meaning- &
OPERATION OF THE ANALYTICAL BALANCE
ful action and failure limits (such as control charts) and to as-
Select the appropriate balance for the quantity and accuracy
sist in laboratory investigations as needed.
needed. Weights and Balances h41i provides requirements for
The check-weights that are used should be stored and han-
Assay determination. For other types of procedures, Table 3
dled in such a manner as to minimize contamination. Proce-
provides some suggested minimum weights based on the re-
dures should be in place to address check-weight results that
quired RSD of the procedure (e.g., System Suitability) and
are observed to be outside acceptable ranges and to provide
the standard deviation of the balance. The calculations show
assurance that the balance cleanliness and environment have
the minimum weight where the balance standard deviation is
not affected the result. Also, a procedure for removing a bal-
In-Process Revision
1/10 and 1/3 of the allowed standard deviation of the proce-
ance from service due to observed results outside acceptable
dure; e.g., SD = 0.2 mg for balance, allowed procedure RSD
ranges needs to be in place.&2S (USP31)
= 1%, and balance is NMT 1/10 of allowed variability; then,
minimum weight (mg) = SDbalance 6 (100/RSD procedure) 6
(1 / Fvariability); or, 0.2 mg 6 (100/1) 6 (1/ 1/10) = 200 mg.
The suggested minimum weights assume that the required ac-
curacy of the balance is controlled with the performance
checks in Table 1 and Table 2.
Pharmacopeial Forum
Table 3. Suggested Minimum Weight Based on Allowed Procedure RSD and Variability of the Balance
Calculated Minimum Weight (mg)
Balance with not more than 1/10 total variability
Allowed RSD for procedure (%) SD = 0.002 mg SD = 0.02 mg SD = 0.2 mg

1 2 20 200
2 1 10 100
5 0.4 4 40
Balance with not more than 1/3 total variability
Allowed RSD for procedure (%) SD = 0.002 mg SD = 0.02 mg SD = 0.2 mg

1 0.6 6 60
2 0.3 3 30
3 0.12 1.2 12
The balance user should check the balance environment (vi- Add the following:
bration, air currents, cleanliness) and status of calibra-
tion.&2S (USP31)
&
RECEIVERS
Add the following: To ensure suitable accuracy in measuring the weight of a

specimen, consideration needs to be given to selecting a
&
CALIBRATION proper receiver for the material.
All receivers must be clean, dry, and inert. The total weight
If necessary, turn on the power and allow the balance to
of the receiver plus the specimen must not exceed the weight
equilibrate according to the manufacturer’s instructions (1 to
capacity of the balance. Therefore, receivers of a low mass are
24 hours, depending on type of balance). If power has gone off
the most desirable, especially in cases where specimens of low
and then has come back on, as in a power outage, certain types
weight are being measured. Receivers should be constructed
of balances may display a message indicating that the balance
from nonmagnetic materials in order to prevent magnetic in-
must be calibrated before a weighing is made. If the operator
terference of electronic balance components. Receivers should
In-Process Revision
touches the balance bar, the message may be cleared and the
be at ambient temperature in order to prevent the formation of
balance may display zeros; however, the balance will not give
air currents within the balance cell.
the correct weighing until it has been calibrated. Electronic an-
Receivers for weighing solid materials include weighing pa-
alytical balances have an internal calibration system based on
per, weighing dishes, weighing funnels, or enclosed vessels,
an applied load. The calibration applies for the current ambient
including bottles, vials, and flasks. Papers that are hygroscopic
temperature.
in nature are not recommended for weighing because they may
Select the number of decimal places required for the analyt-
have a detrimental effect on the observed results.
ical procedure. In most pharmaceutical analyses, small quan-
tities of material are used, requiring the balance reading to be
set to the fifth decimal place to achieve the necessary accura-
cy.&2S (USP31)
Pharmacopeial Forum
Weighing dishes are typically constructed from a polymer or Addition Weighing

from aluminum. Specialty ‘‘anti-static’’ weighing dishes are
Addition weighings are typically used for the weighing of
available for measuring the weights of materials that retain sta-
solid samples. The receiver is placed on the balance. After
tic electricity.
the balance display stabilizes, tare the balance. Add the desired
Weighing funnels are typically constructed from glass or
amount of material to the receiver, and allow the balance dis-
from a polymer. The design of this type of receiver combines
play to stabilize. Record the weight and quantitatively transfer
attributes of a weighing dish and a transfer funnel, which can
the material to an appropriate vessel.
simplify the analytical transfer of a weighed powder to a
narrow-necked vessel, such as a volumetric flask.
For solid samples that are volatile or deliquescent, it is nec- Dispense Weighing
essary to weigh the material into an enclosed vessel. Where
Dispense weights are typically used for the weighing of
practical, an enclosed vessel with a small opening should be
emulsions or viscous liquids such as a topical ointment. In
used in order to reduce sample weight loss from volatilization
these situations, it is not practical to weigh the material into
or weight gain from the adsorption of water from the at-
a typical receiver. Tare the balance. Fill a small transfer pipet
mosphere.
or a syringe with an amount of sample greater than the desired
Receivers for liquid samples will typically be inert, enclosed
specimen weight. Wipe the outside of the pipet or syringe
vessels. For liquid samples that are volatile or deliquescent, an
clean and place on the balance. After the balance display sta-
enclosed vessel with a small opening should be used, and the
bilizes, record the weight. Transfer the desired amount of sam-
enclosure should be replaced rapidly following the transfer of
ple to an appropriate receiving vessel, such as a volumetric
material. Special precautions should be taken to be certain that
flask. Place the pipet or syringe back onto the balance. The
the receiver and the enclosure are constructed from a material
difference in the two weighings is equal to the weight of the
that is compatible with the liquid sample. The receiver and en-
transferred specimen.
closure must have a seal sufficient to prevent leaks from a liq-
Alternatively, the sample can be weighed directly into a
uid that is of low viscosity or has low surface tension or a low
tared vessel such as a volumetric flask, provided that the
boiling point.&2S (USP31)
weight of the vessel is sufficiently small to allow an accurate
Add the following: tare and that the total weight of the vessel and the sample spec-
imen do not exceed the accurate range of the balance.&2S (USP31)
In-Process Revision
&
TYPES OF WEIGHING
Add the following:
Quantitative Analysis
&
PROBLEM SAMPLES
The initial step for many quantitative analyses is to ac-
curately weigh a specified amount of a sample. Errors intro- Electrically Charged Samples
duced during the weighing of a sample will affect the
Dry, finely divided powders may be charged with static elec-
accuracy of all subsequent analytical measurements.
tricity. The static charge will make the powder either attracted
to or repelled by the receiver or the balance. This can cause
inaccurate weight measurements and specimen loss during
transfer. A rapid change in the balance readings should alert
Pharmacopeial Forum
the operator to the possibility that the material has a static Hygroscopic Samples
charge. Commercially available balances with a built-in anti-
Hygroscopic materials readily absorb moisture from the at-
static device can be used to remedy the problem. Such devices
mosphere and will steadily gain weight if left exposed. There-
may use piezoelectric components or a very small amount of a
fore, hygroscopic samples must be either weighed promptly or
radioactive element (typically polonium) to generate a stream
placed in a vessel with a gas-tight enclosure. For a gas-tight
of ions that dissipate the static charge when passed over the
vessel, tare the vessel and enclosure. Add the desired amount
powder to be weighed. Anti-static weigh boats, anti-static
of sample and replace the enclosure. After the balance display
guns, and anti-static screens are also commercially available.
stabilizes, record the specimen weight.
The static charge depends on the relative humidity of the
laboratory, which in turn depends on atmospheric conditions.
In certain conditions, static charge is caused by the type of Aseptic or Biohazardous Samples
clothing worn by the operator; this charge causes large errors
The weighing of sterile or biohazardous samples will take
in the weighing. Plastic containers will have a greater tenden-
place within the confines of a laminar flow hood or similar
cy to pick up a static charge, especially at low relative humid-
containment cabinet. The flow of air within the hood will po-
ity. The gloves used to protect the operator may also increase
tentially cause balance instability. It is recommended that, up-
the potential for a static charge problem. Placing the plastic
on installation of the balance in the hood, a rigorous
container in a metal holder may help to dissipate the static
qualification study be performed with suitable weight artifacts
charge; special anti-static gloves also may help to alleviate
(see Weights and Balances h41i) in order to determine the ac-
the problem.
ceptability of the balance performance in this environment.
Volatile Samples
Weighing Corrosive Materials
When weighing a liquid that has a low boiling point, the
specimen must be received in a vessel with a gas-tight enclo- Many chemicals, such as salts, are corrosive, and materials
sure of small diameter. Tare the vessel and enclosure. Add the of this nature should not be spilled on the balance pan or inside
desired amount of sample, and replace the enclosure. After the the balance housing. Extreme care is essential when materials
balance display stabilizes, record the specimen weight. of this nature are being weighed. The use of sealed containers
such as weighing bottles or syringes should be considered. In
In-Process Revision
the event of a spill, requalification of balance may be neces-

Warm or Cool Samples
sary, depending on the nature of the spill.&2S (USP31)
Samples that are warm or cool should be equilibrated in the Add the following:
laboratory, or the weight readings may be erroneous. With re-
gard to warm samples, the apparent weight will be higher than &
SAFETY CONSIDERATIONS WHEN WEIGHING
the true weight because of heat convection.
During a weighing, the operator may be exposed to high
concentrations of the pure substance. The operator must care-
fully consider this possibility at all times and should be famil-
iar with the precautions described in the Material Safety Data
Sheet for a substance before weighing it. Hazardous materials
Pharmacopeial Forum
should be handled in an enclosure having appropriate air filtra- For powders, the buoyancy correction strictly applies only
tion. Many extremely toxic—and possibly allergenic—sub- to the true density (gas pycnometer) and not the bulk density.
stances present as liquids or finely divided particles. When The true density of most organic solids is greater than 1. Many
weighing these substances, a mask that covers the nose and balances have a program to correct for buoyancy that uses a
mouth should be used to prevent any inhalation of the sub- value for sample density provided by the user. The manufac-
stance, and gloves should be used to prevent any contact with turer’s instructions should be consulted for the proper way to
the skin. [NOTE—The use of gloves is good practice for han- correct for buoyancy. For single-pan electronic balances, the
dling any chemical. If it is necessary to handle the container error is generally 0.1% for densities 1 g/cm3. Buoyancy
being weighed, the operator should put on gloves, not only for corrections are crucial only when the weighing error must
self-protection but also to prevent moisture and oils from be- be minimized or when the densities of the weighed materials
ing deposited on the weighed container.]&2S (USP31) are low. Examples of buoyancy errors for a single-pan elec-
tronic balance are shown in the accompanying table.
Add the following:
Density Error (%)

&
BUOYANCY CORRECTION
2 0.05
Buoyancy corrections are not generally needed for typical 0.8 0.1
pharmaceutical applications. In general, buoyancy corrections 0.5 0.2
are applied to mass measurements by calculating the differ- 0.4 0.3
ence in volume between the material being weighed and the 0.2 0.6
weight standard, multiplying the volume difference by the 0.1 1

&2S (USP31)
density of air (which is dependent on temperature, relative hu-
midity, and atmospheric pressure) at the balance or scale, and
adding the product to the mass of the standard. The correction
also depends on the type of balance and method of calibra-
tion.1
In-Process Revision
1
NIST SOP 2, ‘‘Recommended Standard Operations Procedure for
Applying Air Buoyancy Corrections.’’
Pharmacopeial Forum
REAGENTS, INDICATORS, Add the following:
AND SOLUTIONS
&
Cetyltrimethylammonium Bromide (CTAB; Cetrimide;
Hexadecyltrimethylammonium Bromide), C19H42BrN—364.46
[57-09-0]—Use a suitable grade. For any chromatographic
application, use a suitable grade with a content of not less
Reagent Specifications
than 99.0%.&2S (USP31)
BRIEFING
BRIEFING
1-Butanesulfonic Acid Sodium Salt. It is proposed to add this

new reagent used to prepare the Mobile phase in the Assay in the Diethylamine Phosphate. It is proposed to add this new reagent
monograph for Sibutramine Hydrochloride, which also appears in used to prepare the Buffer in the Assay for ciprofloxacin in the
this issue of PF. monograph for Ciprofloxacin and Dexamethasone Otic Suspension.
(HDQ: M. Marques) RTS—C54584 (HDQ: M. Marques) RTS—C55186

&
1-Butanesulfonic Acid Sodium Salt (Sodium 1- &
Diethylamine Phosphate (Phosphoric Acid:
butanesulfonate), C 4H 9NaO 3S—160.16 [2386-54-1]—Use Diethylamine), C 4 H 1 1 N H 3 P O 4 — 1 7 1 . 1 3
a suitable grade with a content of not less than [68109-72-8]—Use a suitable grade.
99.0%.&2S (USP31) [NOTE—A suitable grade is available from
www.richmanchemical.com.]&2S (USP31)
BRIEFING
BRIEFING
Butyrophenone. It is proposed to add this new reagent used in the
Internal standard solution in the Assay for Naproxen Tablets.
Fuchsin, Basic, USP 30 page 770 and page 910 of PF 32(3)
(HDQ: M. Marques) RTS—C37615 [May–June 2006]. It is proposed to update the specification of this
Add the following: (HDQ: M. Marques) RTS—C54826
&
Butyrophenone (Phenyl propyl ketone), C10H12O—148.21
In-Process Revision
Change to read:
[495-40-9]—Use a suitable grade with a content of not less Fuchsin, Basic—
than 98.0%.&2S (USP31) &
[632-99-5]&1S (USP30)
&
(Basic Red 9, Parafuchsin Hydrochloride), C19H17N3—
323.82[569-61-9]&2S (USP31)
BRIEFING —A mixture of rosaniline and pararosaniline hydrochlorides.
Crystals or crystalline fragments with a glossy, greenish-bronze
luster. Soluble in water, in alcohol, and in amyl alcohol.
Cetyltrimethylammonium Bromide. It is proposed to add this To 10 mL of a solution (1 in 500) add 10 mL of ammonia TS and
new reagent. 500 mg of zinc dust, and agitate the mixture: the solution becomes
colorless. Place a few drops of the decolorized solution on filter
paper and nearby, on the same paper, place a few drops of diluted
(HDQ: M. Marques) RTS—C55247 hydrochloric acid: a red color develops at the zone of contact.
Pharmacopeial Forum
Loss on drying h731i—Dry it at 1058 to constant weight: it loses Add the following:
Residue on ignition (Reagent test)—Ignite 1 g with 0.5 mL of &
Hexadecyltrimethylammonium Bromide—See Cetyltri-
sulfuric acid: the residue weighs not more than 3 mg (0.3%).
methylammonium Bromide.&2S (USP31)
&
—Use a suitable grade.&2S (USP31)
BRIEFING
BRIEFING
Octanesulfonic Acid Sodium Salt. It is proposed to add this new

n-Heptane, Chromatographic, USP 30 page 772 and page 659 reagent used to prepare the Mobile phase in Dissolution Test 2 in the
of PF 32(2) [Mar.–Apr. 2006]. It is proposed to update the monograph for Hydrocodone Bitartrate and Homatropine Methyl-
specifications of this reagent to reflect the products currently bromide Tablets, also appearing in this issue of PF.
available on the market.
Add the following:

Change to read:
&
Octanesulfonic Acid Sodium Salt (Sodium
n-Heptane, Chromatographic
1-octanesulfonate), C8H17NaO3S H2O—234.29[5324-84-5]—
&
C7H16—100.21 [142-82-5]&2S (USP31)
—Clear, colorless, volatile, flammable liquid consisting essentially Use a suitable grade with a content of not less than
of C7H16. Practically insoluble in water; soluble in absolute alcohol.
Miscible with ether, with chloroform, with benzene, and with most 99.0%.&2S (USP31)
fixed and volatile oils. [NOTE—n-Heptane may require purification by
passage through a column of silica gel, a ratio of about 25 g of the
gel for each 100 mL of n-heptane being used, and subsequent
fractional distillation.]
Boiling range (Reagent test): between 94.58 and 99.08.
Spectral purity—Measure in a 1-cm cell at 250 nm, with a suitable BRIEFING
spectrophotometer, against water as the blank: its absorbance is not
more than 0.10.
Residue on evaporation—It meets the requirements of the test for Potassium Pyroantimonate, USP 30 page 787 and page 1252 of
Residue on evaporation under Hexane, Solvent.&Evaporate 150 PF32(4) [July–Aug. 2006]. It is proposed to correct the information
regarding this reagent.
mL (100 g) on a steam bath, and dry at 1058 for 30 minutes:
(HDQ:M. Marques) RTS—C53504
the residue weighs not more than 1 mg (0.001%).&1S (USP30)
&
Use a suitable grade, chromatographic or HPLC, with Change to read:
a content of not less than 99%.&2S (USP31) Potassium Pyroantimonate (Potassium
hexahydroxyantimonate), KSbO3 3H2O
&
KSb(OH)6&2S (USP31)
—262.90
&
[10090-54-7]&2S (USP30)
In-Process Revision
BRIEFING
&
[12208-13-8]&2S (USP31)
—White crystals or a white, crystalline powder. Sparingly soluble in
Hexadecyltrimethylammonium Bromide. It is proposed to add water. Use a suitable grade.
this new reagent used to prepare the Medium in Dissolution Test 4 in
the monograph for Glyburide Tablets, appearing elsewhere in this
issue of PF.
(HDQ: M. Marques) RTS—C55246 BRIEFING
Selenium, USP 30 page 789 and page 1258 of PF 32(4) [July–

Aug. 2006]. It is proposed to update the specifications of this reagent
to reflect the products currently available on the market.
Pharmacopeial Forum
Change to read:
Change to read:
Selenium, Se—At. Wt. 78.96
Triethylamine, (C2H5)3N—101.19
&
[7782-49-2]&2S (USP30)
—Dark-red amorphous, or bluish-black, crystalline powder. Soluble
&
[121-44-8]&2S (USP30)
in solutions of sodium and potassium hydroxides or sulfides; —Colorless liquid. Slightly soluble in water. Miscible with alcohol,
insoluble in water. with ether, and with cold water. Store in well-closed containers.
Residue on ignition (Reagent test)—One g yields not more than Boiling range (Reagent test): between 898 and 908.
2 mg (0.2%). Absorbance—To 1 mL in a 50-mL volumetric flask add 10 mL of
Heavy metals—To the Residue on ignition add 3 mL of methanol and 1 mL of hydrochloric acid, and add chloroform to
hydrochloric acid and 2 mL of nitric acid, evaporate on a steam volume. The absorbance of this solution, determined at the
bath to dryness, take up the residue in a mixture of 2 mL of diluted wavelength of maximum absorbance at about 285 nm, with a suitable
hydrochloric acid and 50 mL of hot water, cool, filter, and wash the spectrophotometer, does not exceed 0.01. [NOTE—If the absorbance
filter with sufficient water to make 100 mL of filtrate (Test Solution). exceeds 0.01, purify the triethylamine as follows. Reflux 100 mL
To a 30-mL aliquot of the Test Solution add 10 mL of water and 10 with 20 mL of water and 2 g of sodium hydrosulfite for not less than
mL of hydrogen sulfide TS: the color produced is not darker than 8 hours, wash with water, dry by refluxing, using a Dean-Stark trap,
that of a Control Solution prepared from 3 mL of Standard Lead and distill, collecting only the first 75 mL of the filtrate. Store over
Solution (see Heavy Metals h231i; 0.03 mg of Pb), 0.2 mL of 1 N anhydrous sodium carbonate or anhydrous potassium carbonate.]
hydrochloric acid, 37 mL of water, and 10 mL of hydrogen sulfide ~
TS (0.01%). Use a suitable HPLC&&2S (USP31) grade with a content of not
Iron h241i—To 20 mL of the Test Solution prepared in the test for less than 99.5%.~USP31
Heavy metals add 2 mL of hydrochloric acid, and dilute with water
to 47 mL: the solution shows not more than 0.01 mg of Fe (0.005%).
Nitrogen—
STANDARD NITROGEN SOLUTION—Dissolve 382 mg of ammonium
chloride in water to make 1 L. Each mL of this solution contains the
equivalent of 0.1 mg of nitrogen (N).
PROCEDURE—Heat 1.0 g with 10 mL of sulfuric acid in a Kjeldahl
flask until the test specimen is dissolved and the volume of acid is
reduced to about 5 mL. Cool, cautiously dilute with 100 mL of Test Solutions
water, render strongly alkaline with sodium hydroxide solution (3 in
10), and distill about 75 mL of the solution into 5 mL of water
containing 2 drops of 1 N hydrochloric acid. Dilute the distillate with
water to 250 mL. To a 50-mL aliquot of the solution add 1 mL of
sodium hydroxide solution (1 in 10) and 2 mL of mercuric– BRIEFING
potassium iodide TS: the color produced is not darker than that
produced by 0.1 mL of Standard nitrogen solution (0.01 mg of N)
treated in the same manner as the test specimen (0.005%).
Sulfur—To 1.0 g in a beaker add, successively, 5 mL of nitric acid, Test Solutions, USP 30 page 807 and page 1804 of PF 32(6)
then 10 mL of hydrochloric acid, and evaporate on a steam bath to [Nov.–Dec. 2006]. Two new test solutions are being proposed:
dryness. Add 10 mL of hydrochloric acid, and slowly evaporate Cupric Citrate TS2, Alkaline, used in the test for Reducing
again to dryness. Take up the residue in 30 mL of dilute hydrochloric substances under Gamma Cyclodextrin, a monograph with a pro-
acid (1 in 30), filter, and wash the filter with water to make about 100 posed revision that appears elsewhere in this issue of PF; and
mL of the filtrate. Heat the filtrate to boiling, and add slowly, with Sodium Hydroxide TS 2, used in the Assay under Formaldehyde
stirring, 5 mL of barium chloride TS. Digest on the steam bath for Solution, a monograph with proposed revisions that appears
4 hours. Pass through a fine-porosity filter paper, wash the precipitate elsewhere in this issue of PF.
until it is free from chloride, ignite, and weigh. The weight of the
barium sulfate residue, multiplied by 0.1374, represents sulfur (S). (HDQ: M. Marques) RTS—C54580; C54634
Not more than 0.5 mg of S is found (0.05%).
&
Use a suitable grade with a content of not less than
In-Process Revision
Add the following:

99.99%.&2S (USP31)
&
Acetic Acid, Strong, TS—Add 300.0 mL of glacial acetic
acid, and dilute with water to 1000 mL. This solution contains
BRIEFING about 30% (v/v) of CH3COOH and has a concentration of
about 5 N.&2S (USP30)
Triethylamine, USP 30 page 800 and page 101 of PF 33(1)
[Jan.–Feb. 2007]. It is proposed to update the specifications for this
Pharmacopeial Forum
Add the following:

&
Alkaline Cupric Citrate TS 2—See Cupric Citrate TS 2,
Alkaline.&2S (USP31)
BRIEFING
Add the following:
&
Ammonium Pyrrolidinedithiocarbamate, Saturated, Volumetric Solutions, USP 30 page 815 and page 101 of PF
33(1) [Jan.–Feb. 2007]. It is proposed to correct the amount of
TS—Add about 10 g of ammonium pyrrolidinedithiocarba- lithium used to prepare the volumetric solutions Lithium Methoxide,
Tenth-Normal (0.1 N) in Chlorobenzene; Lithium Methoxide, Tenth-
mate to a 1000-mL volumetric flask, and dilute with water to Normal (0.1 N) in Methanol; and Lithium Methoxide, Tenth-Normal
(0.1 N) in Toluene.
volume.&2S (USP30)
Add the following:

&
Cupric Citrate TS 2, Alkaline—With the aid of heat,
Add the following:
dissolve about 173 g of sodium citrate dihydrate and 117 g of
sodium carbonate monohydrate in about 700 mL of water,
&
and filter. In a second flask, dissolve about 27.06 g of cupric Bismuth Nitrate, 0.01 mol/L
Bi(NO3)3 5H2O, 485.07
sulfate (Cu2O4 5H2O) in about 100 mL of water. Slowly
1000 mL of this solution contains 4.851 g of bismuth
combine the two solutions while stirring, and dilute with
nitrate pentahydrate
water to 1000 mL.&2S (USP31)
Dissolve 4.86 g of bismuth nitrate pentahydrate in 60 mL of
dilute nitric acid, add water to make 1000 mL, and
~
standardize the solution as follows.
Dicyclohexylamine Acetate TS—Dissolve 50 g of dicyclohex-
ylamine in 150 mL of acetone, cool in an ice bath, and add, with Accurately measure 25 mL of the prepared bismuth nitrate
stirring, a solution consisting of 18 mL of glacial acetic acid in 150
mL of acetone. Recrystallize the precipitate that forms, by heating solution, add 50 mL of water and 1 drop of xylenol orange
the mixture to boiling and allowing it to cool in an ice bath, then
collect the crystals on a filtering funnel, wash with a small volume of TS, and titrate the solution with 0.01 mol/L disodium
acetone, and air-dry. Dissolve 300 mg of the dicyclohexylamine
acetate so obtained in 200 mL of a mixture of 6 volumes of dihydrogen ethylenediamine tetraacetate VS until the red
chloroform and 4 volumes of water-saturated ether. Use immedia-
tely.~USP31 color changes to yellow. Calculate the molarity
factor.&2S (USP30)
Add the following:
&
Sodium Hydroxide TS 2—Transfer 8.5 g of sodium
In-Process Revision
Change to read:
hydroxide to a 100-mL volumetric flask, and dissolve in
and dilute with water to volume.&2S (USP31)
Ceric Sulfate, Tenth-Normal (0.1 N)
Ce(SO4)2, 332.24
33.22 g in 1000 mL
Use commercially available volumetric standard solution. Stan-
dardize the solution as follows.
Accurately weigh about 0.2 g of sodium oxalate, primary standard,
previously dried for 2 hours at 105 8,
~
dried according to the instructions on its label,~USP31
and dissolve in 75 mL of water. Add, with stirring, 2 mL of sulfuric
acid that has previously been mixed with 5 mL of water, mix well,
add 10 mL of hydrochloric acid, and heat to between 708 and 758.
Pharmacopeial Forum
Titrate with 0.1 N ceric sulfate to a permanent slight yellow color. Change to read:
Each 6.700 mg of sodium oxalate is equivalent to 1 mL of 0.1 N
ceric sulfate.
Lithium Methoxide, Tenth-Normal (0.1 N) in Toluene

CH3OLi, 37.97
3.798 g in 1000 mL
Dissolve 500
&
700&2S (USP31)
mg of freshly cut lithium metal in 150 mL of methanol, cooling the
flask during addition of the metal. When reaction is complete, add
850 mL of toluene. If cloudiness or precipitation occurs, add
sufficient methanol to clarify the solution. Store preferably in the
reservoir of an automatic delivery buret suitably protected from
Change to read: carbon dioxide and moisture. Standardize the solution by titration
against benzoic acid as described under Sodium Methoxide, Tenth-
Normal (0.1 N) (in Toluene).
NOTE—Restandardize the solution frequently.
Lithium Methoxide, Tenth-Normal (0.1 N) in Chlorobenzene
CH3OLi, 37.97
3.798 g in 1000 mL
Dissolve 500
&
700&2S (USP31)
flask during addition of the metal. When reaction is complete, add
850 mL of chlorobenzene. If cloudiness or precipitation occurs, add
reservoir of an automatic delivery buret suitably protected from Add the following:
carbon dioxide and moisture. Standardize the solution by titration
NOTE—Restandardize the solution frequently. &
Magnesium Chloride, 0.01 M
MgCl2 6H2O, 203.30
2.0330 g in 1000 mL
Dissolve about 2.04 g of magnesium chloride in 1000 mL
of freshly boiled and cooled water, and standardize the
solution as follows.
Change to read:
Accurately measure 25 mL of the prepared magnesium
chloride solution. Add 50 mL of water, 3 mL of ammonia–
Lithium Methoxide, Tenth-Normal (0.1 N) in Methanol
CH3OLi, 37.97 ammonium chloride buffer TS and 0.04 g of eriochrome black
3.798 g in 1000 mL
Dissolve 500 T–sodium chloride reagent. Titrate with 0.05 M edetate
disodium VS until the red-purple color of the solution
In-Process Revision
&
700&2S (USP31)
flask during addition of the metal. When reaction is complete, add changes to blue-purple.
850 mL of methanol. If cloudiness or precipitation occurs, add
reservoir of an automatic delivery buret suitably protected from
carbon dioxide and moisture. Standardize the solution by titration
NOTE—Restandardize the solution frequently.
Pharmacopeial Forum
Mercuric Nitrate, Tenth-Molar (0.1 M) Potassium Permanganate, Tenth-Normal (0.1 N)

Hg(NO3)2, 324.60 KMnO4, 158.03
32.46 g in 1000 mL 3.161g in 1000 mL
Dissolve about 35 g of mercuric nitrate in a mixture of 5 mL of Dissolve about 3.3 g of potassium permanganate in 1000 mL of
nitric acid and 500 mL of water, and dilute with water to 1000 mL. water in a flask, and boil the solution for about 15 minutes. Insert the
Standardize the solution as follows. stopper in the flask, allow it to stand for at least 2 days, and filter
Transfer an accurately measured volume of about 20 mL of the through a fine-porosity, sintered-glass crucible. If necessary, the
solution to a conical flask, and add 2 mL of nitric acid and 2 mL of bottom of the sintered-glass crucible may be lined with a pledget of
ferric ammonium sulfate TS. Cool to below 208, and titrate with glass wool. Standardize the solution as follows.
0.1 N ammonium thiocyanate VS to the first appearance of Accurately weigh about 200 mg of sodium oxalate, previously
a permanent brownish color. dried at 1108 to constant weight,
~
dried according to the instructions on its label,~USP31
and dissolve it in 250 mL of water. Add 7 mL of sulfuric acid, heat to
about 708, and then slowly add the permanganate solution from
a buret, with constant stirring, until a pale pink color, which persists
for 15 seconds, is produced. The temperature at the conclusion of the
titration should be not less than 608. Calculate the normality. Each
6.700 mg of sodium oxalate is equivalent to 1 mL of 0.1 N
potassium permanganate.
Since potassium permanganate is reduced on contact with organic
substances such as rubber, the solution must be handled in apparatus
entirely of glass or other suitably inert material. It should be
frequently restandardized. Store in glass-stoppered, amber-colored
bottles.
Change to read:
Change to read:
Potassium Hydroxide, Normal (1 N)
KOH, 56.11
56.11 g in 1000 mL
Dissolve 68 g of potassium hydroxide in about 950 mL of water. Sodium Hydroxide, Normal (1 N)
Add a freshly prepared saturated solution of barium hydroxide until NaOH, 40.00
no more precipitate forms. Shake the mixture thoroughly, and allow 40.00 g in 1000 mL
it to stand overnight in a stoppered bottle. Decant the clear liquid, or Dissolve 162 g of sodium hydroxide in 150 mL of carbon dioxide-
filter the solution in a tight, polyolefin bottle, and standardize by the free water, cool the solution to room temperature, and filter through
procedure set forth for Sodium Hydroxide, Normal (1 N). hardened filter paper. Transfer 54.5 mL of the clear filtrate to a tight,
polyolefin container, and dilute with carbon dioxide-free water to
1000 mL.
Accurately weigh about 5 g of potassium biphthalate, previously
crushed lightly and dried at 1208 for 2 hours, and dissolve in 75 mL
of carbon dioxide-free water. Add 2 drops of phenolphthalein TS,
and titrate with the sodium hydroxide solution to the production of
In-Process Revision
a permanent pink color. Each 204.2 mg
&
204.23 mg&1S (USP30)
of potassium biphthalate is equivalent to 1 mL of 1 N sodium
hydroxide.
Pharmacopeial Forum
NOTES—(1) Solutions of alkali hydroxides absorb carbon dioxide NOTE—Prepare this solution just before use.
when exposed to air. They should be preserved in bottles having
well-fitted, suitable stoppers, provided with a tube filled with
a mixture of sodium hydroxide and lime (soda-lime tubes) so that air
entering the container must pass through this tube, which will absorb Change to read:
the carbon dioxide. (2) Prepare solutions of lower concentration
(e.g., 0.1 N, 0.01 N) by quantitatively diluting accurately measured
volumes of the 1 N solution with sufficient carbon dioxide-free water
to yield the desired concentration. Sodium Thiosulfate, Tenth-Normal (0.1 N)
Restandardize the solution frequently. Na2S2O3 5H2O, 248.19
24.82 g in 1000 mL
Dissolve about 26 g of sodium thiosulfate and 200 mg of sodium
carbonate in 1000 mL of recently boiled and cooled water.
Change to read: Standardize the solution as follows.
Accurately weigh about 210 mg of primary standard potassium
dichromate, previously pulverized and dried at 1208 for 4 hours,
Sodium Tetraphenylboron, Fiftieth-Molar (0.02 M) &
according to the instructions on its label, if neces-
NaB(C6H5)4, 342.22
6.845 g in 1000 mL sary,&1S (USP30)
Dissolve an amount of sodium tetraphenylboron, equivalent to and dissolve in 100 mL of water in a glass-stoppered, 500-mL flask.
6.845 g of NaB(C6H5)4, in water to make 1000 mL, and standardize Swirl to dissolve the solid, remove the stopper, and quickly add 3 g
the solution as follows. of potassium iodide, 2 g of sodium bicarbonate, and 5 mL of
Pipet two 75-mL portions of the solution into separate beakers, hydrochloric acid. Insert the stopper gently in the flask, swirl to mix,
and to each add 1 mL of acetic acid and 25 mL of water. To each and allow to stand in the dark for exactly 10 minutes. Rinse the
beaker add, slowly and with constant stirring, 25 mL of potassium stopper and the inner walls of the flask with water, and titrate the
biphthalate solution (1 in 20), and allow to stand for 2 hours. Filter liberated iodine with the sodium thiosulfate solution until the
one of the mixtures through a filtering crucible, and wash the solution is yellowish green in color. Add 3 mL of starch TS, and
precipitate with cold water. Transfer the precipitate to a container, continue the titration until the blue color is discharged. Perform
add 50 mL of water, shake intermittently for 30 minutes, filter, and a blank determination.
use the filtrate as the saturated potassium tetraphenylborate solution Restandardize the solution as frequently as supported by
in the following standardization procedure. Filter the second mixture laboratory stability data. In the absence of such data, restandardize
through a tared filtering crucible, and wash the precipitate with three the solution weekly.
5-mL portions of saturated potassium tetraphenylborate solution.
Dry the precipitate at 1058 for 1 hour. Each g of potassium
tetraphenylborate (KTPB) is equivalent to 955.1 mg of sodium
tetraphenylboron.
In-Process Revision
Pharmacopeial Forum

Container
Add the following:

&
BRIEFING
Add the following:
Container Specifications for Capsules and Tablets, USP 30 page
&
825 and page 505 of PF 33(3) [Mar.–Apr. 2007].
(HDQ) RTS—C47067; C55249
Add
~
the following:
Didanosine Tablets
T~USP31
The following table is provided as a reminder for the pharmacist
with the Packaging and storage requirements set forth in the individ- Add the following:
ual monographs. It lists the capsules and tablets that are official in the
&
Doxazosin, Tablets T&1S (USP30)
well-closed (W), and light-resistant (LR) specifications applicable Add the following:
to containers in which the drug that is repackaged should be dis- ~
Estradiol Vaginal Tablets
pensed. T~USP31
This table is not intended to replace, nor should it be interpreted as
replacing, the definitive requirements stated in the individual mono-
graphs. Add the following:
&
Container Specifications for Capsules and Tablets Tablets W&1S (USP30)
Container Add the following:

Monograph Title Specification &

&
Acetaminophen, Chlorpheniramine, and &
Fexofenadine Hydrochloride and
Dextromethorphan Tablets T&2S (USP30) Pseudoephedrine Hydrochloride
Add the following:

Tablets, Extended Release W&1S (USP30)
&
Acitretin Capsules W, LR&1S (USP31)
Add the following:
&
Fish Oil Containing Omega-3 Acids T&1S (USP31)
Add the following:
&
Capecitabine Tablets T&1S (USP31) Capsules
Add
~
the following: Add the following:
Carprofen Tablets &
T~USP31
In-Process Revision
Add the following:
Add
~
the following: &
Fosinopril Sodium and Hydrochloro-
Cat’s Claw Capsules
T, LR~USP31 thiazide Tablets T&1S (USP30)
Add
~
Cat’s Claw Tablets ~
Gabapentin Tablets
T, LR~USP31 W~USP31
Change to read: Add the following:
Cefaclor &
Galantamine Tablets W&1S (USP31)
&
Chewable&2S (USP31) Change to read:
Tablets T Asian Ginseng Capsules T, LR
~
~USP31

&
Cilostazol Tablets T, LR&1S (USP31) &
Glimepiride Tablets W&1S (USP31)
Pharmacopeial Forum
Container Container
Add the following: Add

~
the following:
&
Glipizide and Metformin Hydrochloride Metformin Hydrochloride Tablets,
Tablets W&2S (USP30) Extended-Release W, LR~USP31

&
Glucosamine, Chondroitin Sulfate &
Sodium, and Methylsulfonylmethane
Add the following:
Tablets T, LR&2S (USP30)
&

&
Glucosamine and Methylsulfonyl-
&
methane Tablets T, LR&2S (USP30) Add the following:

&
Add the following:
&
Hydrocodone Bitartrate and Add the following:
&
Norgestimate and Ethinyl Estradiol Tablets W&1S (USP30)
Homatropine Methylbromide Tablets T, LR&1S (USP30)
Add the following:
Ofloxacin Tablets
&
Irbesartan Tablets W&1S (USP30) W~USP31

&
Irbesartan and Hydrochlorothiazide ~
Orlistat Capsules
T~USP31
Add the following:
Oxycodone Hydrochloride Tablets,
&
Isosorbide Mononitrate Tablets
T&1S (USP30) Extended-Release T, LR~USP31
Add
~
Isosorbide Mononitrate Tablets, &
Pentazocine and Acetaminophen
Extended-Release T~USP31 Tablets T, LR&1S (USP30)
Add
~
Ketoprofen Capsules, Extended-Release &
T~USP31
In-Process Revision
Add the following:

Add
~
the following: &
Quinapril Tablets W&1S (USP31)
Loratadine and Pseudoephedrine Sulfate
Tablets, Extended-Release LR~USP31 Add the following:
&
Raloxifene Hydrochloride Tablets T&2S (USP30)
Add the following:
&
Meloxicam Tablets Add the following:
W&2S (USP31) &
Add
~
the following:
Valganciclovir Tablets
T~USP31
Pharmacopeial Forum
Add the following:

BRIEFING
&
Gamma Cyclodextrin: White or almost white, amor-
Description and Relative Solubility of USP and NF Articles,
USP 30 page 832, page 8589 of PF 25(4) [July–Aug. 1999], page phous or crystalline powder. Freely soluble in water and in
1908 of PF 27(1) [Jan.–Feb. 2001], page 1953 of PF 28(6) [Nov.–
Dec. 2002], page 266 of PF 29(1) [Jan.–Feb. 2003], page 1405 of propylene glycol; very slightly soluble in alcohol. NF catego-
2004], page 2183 of PF 30(6) [Nov.–Dec. 2004], page 122 of PF ry: Sequestering agent; emulsifying and/or solubilizing
31(1) [Jan.–Feb. 2005], page 591 of PF 31(2) [Mar.–Apr. 2005], page
861 of PF 31(3) [May–June 2005], page 1193 of PF 31(4) [July– agent.&2S (NF26)
Aug. 2005], page 1491 of PF 31(5) [Sept.–Oct. 2005], page 1703
of PF 31(6) [Nov.–Dec. 2005], page 188 of PF 32(1) [Jan.–Feb.
2006], page 662 of PF 32(2) [Mar.–Apr. 2006], page 942 of PF Add the following:
32(3) [May–June 2006], page 1301 of PF 32(4) [July–Aug. 2006],
page 1541 of PF 32(5) [Sept.–Oct. 2006], page 1811 of PF 32(6)
[Nov.–Dec. 2006], page 110 of PF 33(1) [Jan.–Feb. 2007], page
&
Inositol: White or almost white, crystalline powder. Very
285 of PF 33(2) [Mar.–Apr. 2007], and page 507 of PF (33)3
[May–June 2007]. soluble in water; practically insoluble in absolute alcohol and
in ether. NF category: Humectant.&2S (NF26)
(HDQ) RTS—C43218; C47067; C49277; C51303
Add the following:
&
Raloxifene Hydrochloride: Off-white to pale yellow
Add the following: solid. Freely soluble in dimethylsulfoxide; sparingly soluble
in methanol; slightly soluble in alcohol; very slightly soluble
&
Cyromazine: White or off-white, odorless, crystalline
in water, in isopropyl alcohol, and in octanol; practically insol-
powder. Slightly soluble in methanol and in water.&2S (USP31)
uble in ether and in ethyl acetate.&2S (USP31)
In-Process Revision
Pharmacopeial Forum
Pending Proposals
published in the USP–NF, its Supplements, or an IRA. Those items that have not yet been adopted are marked as Pending Pro-
posals.
monographs; Dietary Supplements Monographs; General Chapters; Reference Tables; Excipients; and NF Monographs. Each
entry in the Pending Proposals list contains the monograph title and the citation of the most recent publication of the monograph.
When the appropriate USP Expert Committee is considering advancing to official status a pending proposal that is more than 2
years old, it is republished in PF for additional opportunity for public review and comment. Reprints of PF proposals may be
purchased from USP by sending a written request for information to custsvc@usp.org.
The briefing accompanying the monograph or general chapter lists the names of the Scientific Liaisons responsible for the proposed revi-
sions. The contact information (phone number and email) for the Scientific Liaison is available in the Staff Directory section of How to Use
PF. For USP–NF Online subscribers, the name and contact information for the assigned Scientific Liaison is available in the Auxiliary
Information portion of each monograph.
the email.

USP Monographs
Acarbose (new) 33 3 388
Acitretin (new) 33 3 390
Acitretin Capsules (new) 33 3 392
In-Process Revision

(add)
Title (name change)
Tablets (new)
Title (name change)
(new)
Pharmacopeial Forum
and storage
Baclofen—Assay 33 2 211
compounds, Assay
Benzonatate Capsules—Dissolution 33 3 394
Bupropion Hydrochloride—Identification, Content of chloride (delete) 33 2 211
Bupropion Hydrochloride Tablets—Identification 33 2 211
Dissolution
Calcium Carbonate and Magnesia Tablets (title change)—Labeling 33 2 211
Title (name change)
Tablets (new)
In-Process Revision
Carbachol—Identification 33 2 213
Carbachol Intraocular Solution—Identification 33 2 213
Carbachol Ophthalmic Solution—Identification 33 2 214
compounds
Pharmacopeial Forum
Cilostazol Tablets (new) 33 3 395
USP Reference standards, Identification,
Colchicine—Definition 33 3 396
Desogestrel (new) 28 6 1785
Assay
Dihydrocodeine Bitartrate—Definition 33 3 396
Title (name change)
Tablets (new)
In-Process Revision

Minimum fill (add)
Assay (add)
Pharmacopeial Forum
Enalapril Maleate and Hydrochlorothiazide Tablets— 33 2 220
Dissolution
Esomeprazole Magnesium (new) 33 3 397
Estradiol Benzoate (new) 33 2 220
Ethinyl Estradiol Tablets—Disintegration (delete), Dissolution (add) 31 4 1067
Flucytosine Oral Suspension (new) 32 1 92
Fludarabine Phosphate Injection (new) 33 2 232
Assay
Flumazenil Injection—Bacterial endotoxins 33 2 234
content (delete)
In-Process Revision
Fluvastatin Sodium—Labeling (add), 33 1 64
Identification, Water,
Galantamine Hydrobromide (new) 33 2 234
Galantamine Tablets (new) 33 3 407
Glimipiride Tablets (new) 33 3 411
compounds, Assay
Pharmacopeial Forum
Dissolution (add)
Heparin Sodium—Definition, Anti-factor Xa 33 2 238
activity, Assay
Tablets (new)
Hydroxyzine Hydrochloride—Definition, 32 5 1456
dosage units (add)
Ipratropium Bromide (new) 33 2 241
Irbesartan—Limit of azide 32 4 1084
Letrazole Tablets—Related compounds 33 2 244
In-Process Revision

Levothyroxine Sodium—Definition, Identification, 33 3 422
Water, Method III (delete), Water, Method I (add),
Limit of inorganic iodides (delete),
Limit of liothyronine sodium (delete),
Liothyronine Sodium—Identification, Limit of 33 3 426
inorganic iodide (delete), Limit of
levothyroxine sodium, Assay
Lorazepam—USP Reference standards, Identification, 33 3 427
Lorazepam Tablets—Related compounds 33 3 429
Pharmacopeial Forum
to January 1, 2009)
to January 1, 2009)
Limit of lead (add)
Meclizine Hydrochloride—Chromatographic purity 33 2 244
Meclizine Hydrochloride Tablets—Identification, 33 2 245
Dissolution, Assay
Methylphenidate Hydrochloride Tablets—USP Reference 33 2 246
standards, Assay
Related compounds
In-Process Revision
Dissolution (add)
Octinoxate—Chromatographic purity, Assay 33 2 246
compounds (add)
Omeprazole Magnesium (new) 33 3 436
Ondansetron—Packaging and storage 30 6 2021
Pharmacopeial Forum
Ondansetron Orally Disintegrating Tablets—Labeling (add), 33 3 439
Disintegration, Dissolution
Oxandrolone—Ordinary impurities (delete) 33 2 247
Oxybutynin Chloride Extended-Release Tablets—Drug release 32 6 1742
Pamidronate Disodium for Injection— 33 1 81
Paricalcitol—Identification, Chromatographic 33 2 252
purity, Assay
to January 1, 2009)
In-Process Revision

Assay
Identification
Related compounds
Protein A (new) 33 3 442
rProtein A, C-Cys (new) 33 3 444
rProtein A (new) 33 3 446
rProtein A, B4, C-Cys (new) 33 3 452
Pharmacopeial Forum
Reserpine Tablets—Uniformity of dosage units 33 3 453
Related compounds
Related compounds
of ammonia
Sodium Fluoride and Acidulated Phosphate Topical Solution— 33 3 454
Labeling, pH, Assay
Sodium Fluoride and Phosphoric Acid Gel—pH 33 3 455
Sucralfate—Identification 33 2 254
Sulfadimethoxine Sodium—Loss on drying 33 2 254
Sulfamethoxazole—Packaging and storage 33 3 455
Sulisobenzone—Definition, Identification, 33 3 456
Water (add), Assay
Sumatriptan Succinate (new) 33 3 456
Terbinafine Hydrochloride (new) 33 3 459
standards, Assay
Thalidomide—Microbial limits 32 5 1467
In-Process Revision
Pharmacopeial Forum
Valsartan—Related compounds 33 3 467
Warfarin Sodium—Chemical information, Identification, 33 3 468
Assay
Warfarin Sodium for Injection—Assay 33 3 469
Warfarin Sodium Tablets—Identification, 33 3 470
Dissolution, Assay
In-Process Revision

Limit of fluoride
Fish Oil Containing Omega-3 Acids (new) 33 3 471
Fish Oil Containing Omega-3 Acids Capsules (new) 33 3 477
Ginger—Definition, Packaging and storage, 33 3 478
Powdered Ginger—Packaging and storage, 33 3 479
Asian Ginseng Capsules (new) 30 2 571
Pharmacopeial Forum
Lutein—Residue on ignition, Zeaxanthin and 33 2 255
other related compounds, Content of lutein
Lutein Preparation—Definition, Water, Residue on 33 2 255
ignition, Heavy metals, Zeaxanthin and other related
compounds, Content of lutein
Identification
Valerian Capsules (new) 27 1 1825
Definition
Definition
Definition
Definition
Definition
Definition
In-Process Revision
h1i Injections—Packaging—Information on Ferrules and 33 3 496
Pharmacopeial Forum
28 3 839
28 5 1468
29 3 710
29 5 1601
29 6 2022
30 2 613
30 4 1338
30 5 1674
30 6 2092
31 1 99
31 2 507
31 3 822
31 4 1154
31 5 1433
31 6 1680
32 1 181
32 2 407
32 3 829
32 4 1161
32 5 1491
32 6 1779
33 1 95
33 2 267
33 3 497
h85i Bacterial Endotoxins Test—Harmonization 33 3 539
h381i Elastomeric Closures for Injections—(entire submission) 30 1 220
Harmonization
Procedure
In-Process Revision
h503i Acetic Acid in Peptides (new) 33 2 268

h525i Sulfur Dioxide (new) 33 3 498
h601i Aerosols, Nasal Sprays, Metered-Dose Inhalers, 33 3 550
and Dry Powder Inhalers—Harmonization
h644i Conductivity (new) 31 3 841
Pharmacopeial Forum
Emulsions (new)
In-Process Revision
Analysis (new)
h1082i Genotoxicity Testing (new) 30 1 264
h1087i Apparent Intrinsic Dissolution—Dissolution Testing 33 2 269
Procedures for Rotating Disk and Stationary Disk
(entire chapter revised)
Pharmacopeial Forum
Excipients (new)
Training and Safety
In-Process Revision

Waters (new)
Reagents, Indicators, and Solutions
Reagent Specifications—Introduction 33 3 503
Acetone 32 2 608
Pharmacopeial Forum
Alum 32 2 611
Aluminon 32 2 611
Aluminum 32 2 611
Amaranth 32 2 612
In-Process Revision
Aniline 32 2 619
Anisole 32 2 619
Anthracene 32 2 619
Anthrone 32 2 620
Pharmacopeial Forum
Benzene 32 2 623
Benzhydrol 32 2 623
Bibenzyl 32 2 625
Biphenyl 32 2 625
Boric Acid 32 2 628
Bromine 32 2 629
In-Process Revision
Pharmacopeial Forum
Carbazole 32 2 636
Casein 32 2 637
Cation-exchange Resin 30 1 1043
Catechol 32 2 637
Cedar Oil 32 2 637
Chlorine 32 2 638
Chloroform 32 2 640
Cholestane 32 2 641
Cinchonine 32 2 643
Congo Red 32 2 643
Copper 32 2 644
Cortisone 32 2 644
In-Process Revision
a-Cyclodextrin (new) 33 2 276
L-Cystine 32 2 646
Decanol 32 2 646
Dextrin 32 2 647
Pharmacopeial Forum
Digitonin 32 2 652
In-Process Revision

Dioxane 32 3 902
Dithizone 32 3 903
Docusate Sodium (delete) 33 3 504
n-Eicosane 32 3 904
Eicosanol 32 3 904
Pharmacopeial Forum
Equilenin 32 3 904
Fluorene 32 3 909
Formamide 32 3 909
Gitoxin 32 3 910
Glucose 32 3 911
Glycerin 32 3 911
Guaiacol 32 3 912
Hematein 32 3 912
In-Process Revision
n-Hexane 32 3 913
Pharmacopeial Forum
Imidazole 32 3 918
Indene 32 3 918
Inosine 32 3 918
Inositol 32 3 918
Iodic Acid 32 3 919
Iodine 32 3 919
Kerosene 32 3 921
Lactose 33 1 100
Litmus 32 3 923
L-Lysine 32 3 923
Magnesium 32 3 923
In-Process Revision

Mercury 32 3 926
Methanol 32 3 927
Pharmacopeial Forum
Morpholine 32 3 933
1-Naphthol 32 3 934
2-Naphthol 32 3 934
Nickel 32 3 935
Ninhydrin 32 3 936
In-Process Revision
Nonadecane 32 3 939
Orange G 32 4 1240
Orcinol 32 4 1240
Pharmacopeial Forum
Pentane 32 4 1242
Pepsin 32 4 1242
Phenol 32 4 1243
In-Process Revision

Pharmacopeial Forum
Purine 32 4 1253
Pyrazole 32 4 1254
Pyrene 32 4 1254
Pyridine 32 4 1254
Pyrrole 32 4 1255
Selenium 32 4 1258
Sodium 32 4 1260
In-Process Revision
Sodium H

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Table of Contents*

PHARMACOPEIAL FORUM VOL. 33 NO. 1 JAN.–FEB. 2007

Valganciclovir Hydrochloride [new] (USP 31) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

THE JOURNAL OF STANDARDS DEVELOPMENT AND OFFICIAL COMPENDIA REVISION

Proposed and Adopted Revisions to the USP–NF

Policies and Announcements

Stimuli to the Revision Process

Chromatographic Reagents Used in USP–NF and Pharmacopeial Forum

EXPERT COMMITTEE DESIGNATIONS*

BB VV B&B Vaccines and Virology

EXPERT COMMITTEE DESIGNATIONS* (Continued)

RMI Radiopharmaceuticals and Medical Imaging Agents

STAFF E-MAIL PHONE ASSIGNMENT

Clydewyn M. Anthony, Ph.D., cma@usp.org (301) 816-8139 Monograph Development—

STAFF E-MAIL PHONE ASSIGNMENT

STAFF E-MAIL PHONE ASSIGNMENT

Leonel Santos, lxs@usp.org (301) 816-8168 International Health (IH)

Policies and Announcements

Policies and Announcements

Calendar of Forthcoming Pharmacopeial Education Courses as of November 15, 2006

Policies and Announcements

Noncomplex Actives (Drug Substances) (Continued)

Pantoprazole Sodium Pemirolast Potassium Pemoline

Policies and Announcements

Noncomplex Actives (Drug Products)

Noncomplex Actives (Drug Products) (Continued)

Dextroamphetamine Sulfate Extended- Dextromethorphan Polistirex Extended- Diazepam Injectable Emulsion

Noncomplex Actives (Drug Products) (Continued)

Policies and Announcements

Noncomplex Actives (Drug Products) (Continued)

Noncomplex Actives (Drug Products) (Continued)

Policies and Announcements

Methylisothiazolinone Microcrystalline Cellulose, Silicified Mineral Spirits

Policies and Announcements

Interim Revision Announcement

FIRST INTERIM REVISION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

By authority of the United States Pharmacopeial Convention, Inc.

John W. Mauger, Chair Roger L. Williams, Executive Vice President

Roger L. Williams, M.D., Chief Standards Officer, Acting

Official February 1, 2007 Released January 1, 2007

Interim Revision Announcement

New USP Reference Standards USP Amifostine Thiol RS

Interim Revision Announcement

TEST 2 (for products labeled as 0.9-mg tablets)—If the product

Page USP–NF Title Section Description

Interim Revision Announcement

Briefings Each Proposal is preceded by a Briefing in the following format:

Volumetric Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Identiﬁcation— blank to set the spectrophotometer. Calculate the quantity, in

h191i. the formula:

B: It meets the requirements of the tests for Salicylate

pH h791i: between 3.0 and 5.0.

Standard preparation—Transfer about 500 mg of bismuth

volume. Centrifuge about 20 mL at 4500 rpm for at least 10

Tolerances—The percentages of the labeled amount of

Acceptance Table 2. (MD-GRE: E. Gonikberg) RTS—C44147; C46392

Time (hours) Amount dissolved

2 not more than 20%

16 not less than 80%

account for calculation of the assay content of the article.’’

Change to read: Procedure—Separately inject equal volumes (about 50 mL)

USP Reference standards h11i—USP Calcitriol RS.

Chromatographic purity—[NOTE—Avoid Carry out the pre-calcitriol