Working document QAS/15.636 August 2015 Draft document for comment
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2 Levomethorphan limit test for dextromethorphan containing 3 finished pharmaceutical products
4 (August 2015)
5 DRAFT FOR COMMENT
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7 © World Health Organization 2015 8 All rights reserved. 9 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 10 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 11 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 12 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 13 website. 14 Please send any request for permission to: 15 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential 16 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 17 Fax: (41-22) 791 4730; email: [email protected] . 18 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 19 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 20 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 21 border lines for which there may not yet be full agreement. 22 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 23 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 24 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 25 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 26 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 27 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 28 Organization be liable for damages arising from its use. 29 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 30 Working document QAS/15.636 page 2
31 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/15.636 32 Levomethorphan limit test for dextromethorphan containing finished pharmaceutical products
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34 Date Performance of laboratory investigations August 2014
Presentation to WHO Expert Committee on October 2014 Specifications for Pharmaceutical Preparations
Discussion at informal consultation on 13–15 April 2015 screening, sampling and specifications of new medicines
Confirmation of the procedures by a April–August 2015 national quality control laboratory
First draft sent out for public consultation August–October 2015
Presentation to WHO Expert Committee on October 2015 Specifications for Pharmaceutical Preparations
Further follow-up action as required 35 36
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39 [Note from the Secretariat. It is proposed to include in the supplementary information section of The 40 International Pharmacopoeia a levomethorphan limit test for dextromethorphan containing finished 41 pharmaceutical products.]
42 Working document QAS/15.636 page 3
43 Levomethorphan limit test for dextromethorphan containing finished pharmaceutical 44 products
45 Dextromethorphan-containing medicines shall contain Dextromethorphan hydrobromide which 46 complies with all the requirements of the respective monograph and other applicable chapters of The 47 International Pharmacopoeia . In particular, the concentration of impurity E (levomethorphan) shall 48 not exceed the limit of 0.1% (see monograph on Dextromethorphan hydrobromide).
49 The following tests allow control laboratories (e.g. national quality control laboratories) to test 50 suspicious dextromethorphan-containing medicines to establish whether or not an active 51 pharmaceutical ingredient (API) meeting the limit for impuritiy E (levomethorphan) had been used to 52 manufacture the product under examination.
53 In many cold and cough medicines dextromethorphan is used in combination with other active 54 ingredients, for example, chlorpheniramine, doxylamine, ephedrine, paracetamol, 55 phenylpropanolamine, pseudoephedrine, promethazine or triprolidine. Due to the diversity of these 56 substances the selectivity of the test procedures described below may not be sufficient for all products 57 under investigations. If the chromatogram obtained provides evidence that other active ingredients or 58 excipients interfere with the levomethorphan determination the analyst shall modify the analytical 59 procedure, e.g. by adding further extraction steps.
60 Also depending on the additional active ingredients or the excipients in the product to be examined it 61 may be necessary to flush the column with a mobile phase consisting of 950 volumes of 2-propanol R, 62 50 volumes of n-hexane R and 1 volume of diethylamine R after each run.
63 Limit test for levomethorphan in dextromethorphan containing oral solutions
64 Carry out the test as described under 1.14.4 High-performance liquid chromatography using a 65 stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has 66 been modified with chemically-bonded cellulose tris(4-methybenzoate) groups (5 µm).1 As the mobile 67 phase use a mixture of 940 volumes of n-hexane R, 60 volumes of 2-propanol R and 1 volume of 68 diethylamine R.
69 Operate with a flow rate of 0.5 mL per minute. As a detector use an ultraviolet spectrophotometer set 70 at a wavelength of 285 nm. Maintain the column at 30 °C.
71 Prepare the following solutions. For solution (1) transfer a quantity of the oral solution containing the 72 equivalent of 50 mg of Dextromethorphan hydrobromide to a separation funnel. Add sodium 73 hydroxide (~40 g/L) TS until the solution has a pH value greater than 11 (check the value using pH- 74 indicator paper). Extract the solution with three 50 mL volumes of hexane R. Dry the combined 75 extracts over 3 g anhydrous sodium sulphate R, filter, wash the residue with 30 mL of hexane R, 76 combine the hexane extracts in a round-bottom flask and evaporate to dryness. Add 2.0 mL of 2- 77 propanol R to dissolve the residue and transfer the solution to a 10.0 mL flask, wash the round-bottom 78 flask with further 2.0 mL of 2-propanol R and also transfer the solution to the 10.0 mL flask. Dilute to 79 volume with mobile phase. For solution (2) dilute 5.0 mL of solution (1) to 100.0 mL with mobile 80 phase. Dilute 2.0 mL of this solution to 100.0 mL with mobile phase. Prepare solution (3) as indicated 81 in the leaflet of Dextromethorphan for system suitability RS (containing a mixture of 82 dextromethorphan and levomethorphan).
1 A Chiralcel OJ-H column was found suitable. Working document QAS/15.636 page 4
83 Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the two principal 84 peaks due to levomethorphan (retention time about 9 minutes) and due to dextromethorphan (retention 85 time of about 12 minutes) is at least 3.
86 Inject alternately 20 µL each of solutions (1) and (2).
87 In the chromatogram obtained with solution (1) the area of any peak corresponding to 88 levomethorphan is not greater than the area of the principal peak in the chromatogram obtained with 89 solution (2) (0.1%).
90 Limit test for levomethorphan in dextromethorphan containing capsules and lozenges
91 Carry out the test as described under 1.14.4 High-performance liquid chromatography using the 92 chromatographic conditions given under Limit test for levomethorphan in dextromethorphan oral 93 solutions.
94 For solution (1) transfer a quantity of the contents of the capsules (hard gelatin capsules)/transfer a 95 number of capsules (soft gelatin capsules) or lozenges, containing the equivalent of about 50 mg of 96 Dextromethorpan hydrobromide to a 100 mL conical flask, add about 50 mL of water and heat and 97 shake on a steam bath for about 15 minutes. Allow to cool, filter and transfer the eluate to a separation 98 funnel. Wash the flask and the filtrate with 2 times 10 mL of water. Combine the aqueous solutions 99 and add sodium hydroxide (~40 g/L) TS until the solution has a pH value greater than 11 (check the 100 value using pH-indicator paper). Extract with three 50 mL volumes of hexane R. Dry the combined 101 extracts over 3 g anhydrous sodium sulphate R, filter, wash the residue with 30 mL of hexane R, 102 combine the hexane extracts in a round-bottom flask and evaporate to dryness. Add 2.0 mL of 2- 103 propanol R to dissolve the residue and transfer the solution to a 10.0 mL flask, wash the round-bottom 104 flask with further 2.0 mL of 2-propanol and also transfer the solution to the 10.0 mL flask. Dilute to 105 volume with mobile phase. For solution (2) dilute 5.0 mL of solution (1) to 100.0 mL with mobile 106 phase. Dilute 2.0 mL of this solution to 100.0 mL with mobile phase. Prepare solution (3) as indicated 107 in the leaflet of Dextromethorphan for system suitability RS (containing a mixture of 108 dextromethorphan and levomethorphan).
109 Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the two principal 110 peaks due to levomethorphan (retention time about 9 minutes) and due to dextromethorphan (retention 111 time of about 12 minutes) is at least 3.
112 Inject alternately 20 µL each of solutions (1) and (2).
113 In the chromatogram obtained with solution (1) the area of any peak corresponding to 114 levomethorphan is not greater than the area of the principal peak in the chromatogram obtained with 115 solution (2) (0.1%).
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