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172 August 2006 RESTRICTED
ABACAVIR ORAL SOLUTION Draft proposal for The International Pharmacopoeia ( August 2006)
This document was provided by a contracted quality control laboratory. Comments have been provided by collaborating laboratories following discussion at an informal meeting held in Geneva on 4 May 2006, and also by the WHO Secretariat. Please address any comments you may have on this draft monograph, by 10 October 2006, to Dr S. Kopp, Quality Assurance and Safety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730 or e-mail: firstname.lastname@example.org, with a copy to email@example.com.
© World Health Organization 2006 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations’ concerned staff and member organizations) without the permission of WHO. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards (PSM), World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; e-mails: firstname.lastname@example.org; email@example.com The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this draft is complete and correct and shall not be liable for any damages incurred as a result of its use.
Working document QAS/06.172 International Pharmacopoeia monograph on abacavir oral solution Date Preparation of first draft Discussion and rectification of first draft at informal meeting between collaborating laboratories April 2006 4 May 2006 Circulation of first draft for comments September 2006 Comments received (deadline 10 October 2006) October 2006 Presentation to WHO Expert Committee on Specifications for Pharmaceutical Preparations 16-20 October 2006 Eventual circulation of second draft. depending on Expert November 2006 Committee's decision .172 page 2 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/06.
0% of the amount of abacavir. allow it to dry exhaustively in air or in a current of cool air. Either tests A and C or tests B and C may be applied. or. Carry out test A. .14.0% and not more than 110. Requirements Complies with the monograph for "Liquids for Oral Use". The designation of the container of Abacavir oral solution should state that the active ingredient is in the sulfate form and the quantity should be indicated in terms of the equivalent amount of abacavir. For solution (B) use 6 mg abacavir sulfate RS per ml of methanol R. Examine the chromatogram in ultraviolet light (254 nm). It contains not less than 90. and intensity with that obtained with solution B.Working document QAS/06. 2 volumes of 2-propanol R as the mobile phase. A. appearance. Apply separately to the plate 5 µl of each of the following 2 solutions.2.] Definition. For solution (A) dilute a volume of the oral solution with methanol R to give a solution containing the equivalent of 5 mg of abacavir per ml. The principal spot obtained with solution A corresponds in position. After removing the plate from the chromatographic chamber.1. Identity tests • A. C14H18N6O2 stated on the label. Additional information. 1. Labelling.1 Thin–layer chromatography. Abacavir oral solution is a solution of Abacavir sulfate in a suitable flavoured vehicle. Antiretroviral (Nucleoside Reverse Transcriptase Inhibitor) Storage. using silica R6 as the coating substance and a mixture of 8 volumes of dichloromethane R. Abacavir oral solution should be kept in a well-closed container. Carry out the test as described under 1. [Note from the Secretariat: A general monograph is in preparation.172 page 3 ABACAVIR ORAL SOLUTION: Draft proposal for The International Pharmacopoeia (August 2006) Category. where UV detection is not available. Strength in the WHO Model List of Essential Medicines: 100 mg of abacavir (as sulfate) per 5ml (20 mg per ml). test A.
Carry out the test as described under 1. Time (min) 0 20 35 40 45 Mobile phase A (%) 95 70 10 95 95 Mobile phase B (%) 5 30 90 5 5 .14. and intensity with that obtained with solution B. Examine the chromatogram in daylight. Apply separately to the plate 5 µl of each of the following 2 solutions. C. pH of the oral solution: 3.0 ml with the same solvent.14.8 . (filter if necessary???) . Related substances Carry out the test as described under 1. shake.05 % trifluoroacetic acid aqueous solution. The mobile phases for gradient elution consist of a mixture of Mobile phase A and Mobile phase B.172 page 4 A.Working document QAS/06. The absorption spectrum of resulting solution.4 High-performance liquid chromatography. B. Spray with vanillin/sulfuric acid TS1.5. Heat the plate for a few minutes at 120°C. when observed between 220 nm and 320 nm. using silica gel R5 as the coating substance and a mixture of 8 volumes of dichloromethane R. To a volume of oral solution containing the equivalent of 15 mg of abacavir add 100 ml of water R. Dilute 5 ml of the filtrate to 50. After removing the plate from the chromatographic chamber. Mobile phase B: 85 vol of methanol and 15 vol of water. 2 volumes of 2-propanol R as the mobile phase. appearance. using the following conditions: Mobile phase A: 0. See the test described under Assay. For solution (A) dilute a volume of the oral solution with methanol R to give a solution containing the equivalent of 5 mg of abacavir per ml. and filter if necessary.6 mm).2. using a stainless steel column (15 cm x 4. The principal spot obtained with solution A corresponds in position. allow it to dry exhaustively in air or in a current of cool air. pH value.1 Thin–layer chromatography. The retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that in the chromatogram obtained with solution (2). exhibits a maximum at about 291 nm.4. For solution (B) use 6 mg abacavir sulfate RS per ml. packed with octadecylsilyl silica gel for chromatography (5 µm).
3%). Prepare the following solutions in the dissolution solvent prepared by diluting 1 ml of phosphoric acid (~ 1440 g/l) TS in 1 litre of water.0%).1%).14. the impurity peaks are eluted at the following relative retention with reference to abacavir (retention time about 19 minutes): impurity C about 0.0%). For solution (3) dissolve 5 mg of abacavir sulfate for system suitability RS (containing abacavir sulfate and impurities B to F) in the dissolution solvent and dilute to 25 ml with the same solvent. The sum of the areas of all peaks.4 High-performance liquid chromatography.3 times the area of the principal peak in the chromatogram obtained with solution (2) (0.1 times the area of the principal peak in the chromatogram obtained with solution (2) (0. is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1. impurity E about 1.7.8 ml per minute and the column oven temperature at 30 °C. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 254 nm.0 ml with the same solvent.Working document QAS/06. impurity F about 1.3. shake mechanically for about 10 minutes and make up the volume .5. For solution (1) transfer a volume of the oral solution containing the equivalent of 10 mg of abacavir in the dissolution solvent and dilute to 50.0 ml of solution (1) to 50. apart from the principal peak. Inject separately 20µl each of solutions (1). Add about 40 ml of dissolution solvent. Use the same chromatographic conditions as described under Related substances. the area of any peak with a relative retention less than that of impurity C (impurity G) is not greater than the 0. For solution (2) dilute 5.5%). (2) and (3) and of dissolution solvent in the chromatographic system. the area of any other peak.0 ml with the same solvent. Assay Carry out the test under 1. For solution (1) transfer an accurately measured volume of the oral solution containing the equivalent of about 10 mg abacavir into a 50 ml volumetric flask.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.0 ml of this solution to 50. is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2. In the chromatogram obtained with solution (1) the area of any peak corresponding to impurity C.7 The test is not valid unless the resolution between the peaks corresponding to abacavir and impurity D is at least 1.0 ml with the dissolution solvent.05. impurity D about 1.10: impurity B about 1. In the chromatogram obtained with solution (3). Examine the blank chromatogram for any extraneous peaks and disregard the corresponding peaks observed in the chromatogram obtained with solution (1). Prepare the following solutions in the dissolution solvent prepared by diluting 1 ml of phosphoric acid (~ 1440 g/l) TS in 1 litre of water. Then dilute 5. other than the principal peak. Disregard any peak with an area less than 0. is not greater than 0.172 page 5 Operate with a flow rate of 0.
or and calculate the content of abacavir.Working document QAS/06.: HN N H2N N N NH G.172 page 6 using the same solvent. C14H18N6O2 in the oral solution using the declared content of C14H18N6O2 in abacavir sulfate RS. unless otherwise specified in the monograph) could be added to the Ph.3. A general method for determining weight per ml (defined as the weight in g of 1 ml of a liquid when weighed in air at 20°C. Each mg of C14H18N6O2 . Measure the areas of the peak responses obtained in the chromatograms from solution (1) and (2). H2SO4 is equivalent to 0. Inject alternatively 20 µl each of solution (1) and (2) and record the chromatograms. as method 1.1.] Impurities The impurities limited by the requirements of this monograph include those listed in the monograph for Abacavir sulfate and the following. (name to be provided) *** . H2SO4 in abacavir sulfate RS. and calculate the content of abacavir.23 mg of abacavir sulfate RS per ml of dissolution solvent. C14H18N6O2 in the oral solution using the declared content of C14H18N6O2 . [Note from the Secretariat: It is proposed that an accurately weighed quantity (rather than an accurately measured volume) of the oral solution should be taken for assay and the weight per ml determined in order to calculate the content as weight in volume (g or mg per ml). Int.??? mg of C14H18N6O2 . For solution (2) use 0.
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