Pharmaceutical Chemical Analysis: Methods for Identification and Limit Tests

Ole Pedersen

2006 by Taylor & Francis Group, LLC

Published in 2006 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 2006 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-1978-1 (Hardcover) International Standard Book Number-13: 978-0-8493-1978-5 (Hardcover) Library of Congress Card Number 2005052909 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data

Pederson, Ole. Pharmaceutical chemical analysis : methods for identification and limit tests / Ole Pederson. p. ; cm. Includes bibliographical references and index. ISBN 0-8493-1978-1 1. Drugs--Analysis--Laboratory manuals. 2. Drugs--Standards--Laboratory manuals. 3. Pharmaceutical chemistry. I. Title. [DNLM: 1. Pharmaceutical Preparations--analysis--Laboratory Manuals. 2. Pharmaceutical Preparations--standards--Laboratory Manuals. 3. Drug Compounding--standards--Laboratory Manuals. 4. Quality Control--Laboratory Manuals. 5. Reference Standards--Laboratory Manuals. QV 25 P371p 2005] RS189.P39 2005 615'.1901--dc22

2005052909

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Preface
The obvious potential severity of wrongfully giving an already weak patient the wrong medication, or giving medicine with a harmful content of unwanted substances, led relatively early (compared to other industries) to formal governmental demands on the quality of pharmaceutical products and pharmaceutical ingredients. One aspect of these demands includes chemical tests specied in pharmacopeias dening requirements on identity and chemical purity with which raw materials bound for pharmaceutical dosage from production must comply. The methodology of the tests adapted has in principle reected the current knowledge and technological expertise of the pharmaceutical society at the time of adaptation of the test methods in question. Early monographs relied largely on appearance, taste, and smell as well as microscopic characterizing, whereas recently adapted monographs are often based on sophisticated and expensive analytical techniques such as capillary electrophoresis, X-ray spectroscopy, and an extensive use of highperformance liquid chromatography. There is, however, some tardiness in the process of replacing methods relying on outdated analytical techniques with more modern ones for several reasons. First, the pharmaceutical industry is in general a rather conservative one with respect to bringing in new technology, again for several reasons. Huge economical interests are at stake so no one wants to jeopardize the product development time line by using technology that has not already proven its quality. So, newer methods are often run in parallel with older ones for a long time, thereby not fully releasing its cost saving and knowledge enrichment potential. In addition, the pharmaceutical industry has increasingly been the subject of goods manufacturing procedure (GMP) requirements, and are therefore, the subject of periodic inspections. Also, one must justify methodology used when ling for approval of a new drug product. Obviously it will be easier to prove the validity of a well known and widely used technique and a manufacturer could be tempted not to spend time and effort in justifying the capability of novel techniques to ensure consistent and sufcient drug product quality. Also, it is a substantial bureaucratic maneuver to effect the change in a European Pharmacopoeia general test referendum referenced in many individual monographs in a supernational organization like the European Pharmacopoeia Commission. A last reason for not replacing old methods is that some tests actually perform

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quite well and one could question why something simple and economical should be replaced with expensive instrumental techniques. This, however, leaves us with a number of rather old chemical methods, which are based on analytical principles, like colorimetry, using selective reagents and precipitation-based techniques, which have largely been abandoned in modern analytical chemistry. The basic assumptions and theoretic background of these techniques are to only a limited extent a part of the training of the contemporary and very instrumentally orientated analytical chemist. Even less likely will he or she have enough knowledge about specic color reagents. The literature dealing with the techniques is so old that nothing is found in an electronic literature search and information is therefore less accessible. The specic knowledge collected by national medicinal agencies is to a large extent closed to the public. The past few decades have seen a massive increase in GMP requirements, and this has been reected in recruitment especially in the analytical quality control laboratory. Very often, within the department, job candidates have been screened for their GMP experience and attitude as compared to analytical chemistry skills. The prerequisites of the typical quality control analytical chemist are to understand the tests performed and thereby being capable of solving any occurring problems, which very often does not equal the outside pressure and potential economic implications an unsolved analytical problem might cause. This book is intended to aid the quality control chemist, but also in general to make knowledge about these tests easily accessible to academics and technicians working with these tests. It is organized into two parts dealing with the tests of European Pharmacopoeia 2.3.1 and 2.4, identication and limit tests, respectively. Each part contains three general chapters where subjects relevant to all the pharmacopoeial identication/limit tests are discussed, and then the individual tests are described and discussed in sections organized and named as in the European Pharmacopoeia. The test sections start with a few short remarks about the purpose and rationale of the tests, followed by a review of the physical and chemical characters of the ion or compound that is the target of the test. Then the chemical background and logic of the individual procedural steps of the test are described, with formulas and reaction, including remarks about the strengths and weaknesses in terms of specicity, ruggedness, and potential procedural pitfalls. All chapters include a list of references that could be the starting point of further investigations. The methods of the two European Pharmacopoeia general test chapters are among the oldest in the pharmacopoeia. Many of the tests on the simple inorganic ions are based on selective precipitation using only simple inorganic reagents. Many of these tests were developed in response to the needs of the mining industry in the nineteenth century. A wealth of information on the specicity, strengths, and weaknesses of these techniques can be found in older inorganic qualitative and quantitative analytical chemistry literature, but very often it is not possible to nd evaluations on methods carried out exactly as adapted by the pharmacopoeia. The use of colored derivatives

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began in the early 20th century, gained much attention with the development of more sophisticated optical equipment during the middle of the century, until their application declined dramatically toward the end of the century as a result of the success of chromatographic techniques. Such methods are dealt with in analytical chemistry handbooks and also in scientic journals published prior to the 1980s.

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Acknowledgment
The author wishes to thank Tina, QC GEA 20022004, and Albert Bentz.

2006 by Taylor & Francis Group, LLC

About the Author

Ole Pedersen is a pharmacist of the Danish University of Pharmaceutical Sciences and has throughout his career worked with various aspects of analytical chemistry in the pharmaceutical industry. His work led to his broad expertise in the elds of analytical quality control and analytical development, and a thorough knowledge of GMP and regulatory affairs requirements.

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Table of Contents
Part I: Identications Chapter 1 Precipitation in identications......................................................3 Precipitate selectivity..............................................................................................3 Precipitate appearance ...........................................................................................5 Chapter 2 Color reactions in identications .................................................9

Chapter 3 Tests ................................................................................................. 11 3.1 Acetates (European Pharmacopoeia 2.3.1)...................................................12 3.2 Acetyl (European Pharmacopoeia 2.3.1) ......................................................14 3.3 Alkaloids (European Pharmacopoeia 2.3.1).................................................16 3.4 Aluminum (European Pharmacopoeia 2.3.1) ..............................................18 3.5 Amines, primary aromatic (European Pharmacopoeia 2.3.1)...................20 3.6 Ammonium salts (European Pharmacopoeia 2.3.1)...................................22 3.7 Ammonium salts and salts of volatile bases (European Pharmacopoeia 2.3.1) .....................................................................................24 3.8 Antimony (European Pharmacopoeia 2.3.1)................................................25 3.9 Arsenic (European Pharmacopoeia 2.3.1) ....................................................26 3.10 Barbiturates, nonnitrogen substituted (European Pharmacopoeia 2.3.1) .....................................................................................28 3.11 Benzoates (European Pharmacopoeia 2.3.1) ................................................31 3.12 Bismuth (European Pharmacopoeia 2.3.1)...................................................33 3.13 Bromides (European Pharmacopoeia 2.3.1).................................................34 3.14 Calcium (European Pharmacopoeia 2.3.1)...................................................39 3.15 Carbonates and bicarbonates (European Pharmacopoeia 2.3.1) ..............41 3.16 Chlorides (European Pharmacopoeia 2.3.1) ................................................43 3.17 Citrates (European Pharmacopoeia 2.3.1) ....................................................47 3.18 Esters (European Pharmacopoeia 2.3.1) .......................................................50 3.19 Iodides (European Pharmacopoeia 2.3.1).....................................................52 3.20 Iron (European Pharmacopoeia 2.3.1) ..........................................................54 3.21 Lactates (European Pharmacopoeia 2.3.1) ...................................................57 3.22 Lead (European Pharmacopoeia 2.3.1) .........................................................60 3.23 Magnesium (European Pharmacopoeia 2.3.1).............................................62

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3.24 3.25 3.26 3.27 3.28 3.29 3.30 3.31 3.32 3.33 3.34 3.35

Mercury (European Pharmacopoeia 2.3.1)...................................................63 Nitrates (European Pharmacopoeia 2.3.1) ...................................................66 Phosphates (Orthophosphates) (European Pharmacopoeia 2.3.1)...........68 Potassium (European Pharmacopoeia 2.3.1) ...............................................71 Salicylates (European Pharmacopoeia 2.3.1) ...............................................73 Silicates (European Pharmacopoeia 2.3.1) ...................................................75 Silver (European Pharmacopoeia 2.3.1)........................................................76 Sodium (European Pharmacopoeia 2.3.1)....................................................77 Sulfates (European Pharmacopoeia 2.3.1)....................................................80 Tartrates (European Pharmacopoeia 2.3.1) ..................................................82 Xanthines (European Pharmacopoeia 2.3.1) ................................................86 Zinc (European Pharmacopoeia 2.3.1)..........................................................89

Part II: Limit tests Chapter 4 Chapter 5 Precipitation in limit tests ...........................................................93 Color reactions in limit tests .......................................................97

Chapter 6 Tests ...............................................................................................103 6.1 Ammonium (European Pharmacopoeia 2.4.1) ..........................................104 6.2 Arsenic (European Pharmacopoeia 2.4.2) ..................................................107 6.3 Calcium (European Pharmacopoeia 2.4.3)................................................. 110 6.4 Chlorides (European Pharmacopoeia 2.4.4) .............................................. 113 6.5 Fluorides (European Pharmacopoeia 2.4.5) ............................................... 116 6.6 Magnesium (European Pharmacopoeia 2.4.6)........................................... 119 6.7 Magnesium and alkaline-earth metals (European Pharmacopoeia 2.4.7) ...................................................................................122 6.8 Heavy metals (European Pharmacopoeia 2.4.8) .......................................126 6.9 Iron (European Pharmacopoeia 2.4.9) ........................................................132 6.10 Phosphates (European Pharmacopoeia 2.4.11)..........................................135 6.11 Potassium (European Pharmacopoeia 2.4.12) ...........................................137 6.12 Sulfates (European Pharmacopoeia 2.4.13)................................................139 6.13 Sulfated ash (European Pharmacopoeia 2.4.14)........................................140 6.14 Total ash (European Pharmacopoeia 2.4.16)..............................................143 6.15 Free formaldehyde (European Pharmacopoeia 2.4.18)............................145 6.16 Alkaline impurities in fatty oils (European Pharmacopoeia 2.4.19) .....149

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