Pentamidine isetionate Pentamidine isetionate for injection

Transcription

1 July 2013 RESTRICTED Pentamidine isetionate Pentamidine isetionate for injection (July 2013) DRAFT FOR COMMENT Should you have any comments on DRAFT this draft, FOR please COMMENTS send these to Dr Herbert Schmidt, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) or schmidth@who.int by 20 September World Health Organization 2013 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 the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) ; kopps@who.int. 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. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

2 page SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.553: Pentamidine isetionate and Pentamidine isetionate for injection Date Preparation of first draft revisions of the monographs on Pentamidine isetionate and Pentamidine isetionate for injection. April 2013 Discussion at informal consultation to discuss new medicines, quality control and laboratory standards June 2013 Draft revisions mailed out for comments July 2013 Collation of comments September 2013 Presentation to 48th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations for discussion October 2013 Further follow-up action as required

3 page [Note from the Secretariat. Following investigations into the polymorphism of Pentamidine isetionate it is proposed to revise the monograph on Pentamidine isetionate for injection. Concurrently, editorial changes are suggested. Pentamidine isetionate exhibits polymorphism. It is not intended to place a restriction on a particular polymorphic form. Therefore it is proposed to revise the identification test by IR of the monograph on Pentamidine isetionate for injection. Laboratory investigations by a WHO Collaborating Centre have confirmed that in case the IR spectra of the sample and of the reference substance are not similar the proposed additional sample preparations steps (a recrystallization and a subsequent heating of the obtained crystals) will result in the same polymorphic form of pentamidine isetionate and thus even out potential differences in the spectra. For simplicity, only the sections of the two monographs, which contain changes, are given below. Sections left out are indicated by. Changes from the current monograph are indicated in the text by insert or delete.] Pentamidini isetionas Pentamidine isetionate Category. Antitrypanosomal activitydrug; antileishmaniasis drug. Additional information. Pentamidine isetionate is hygroscopic and exhibits polymorphism. Identity tests A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from pentamidine isetionate RS or with the reference spectrum of pentamidine isetionate. If the spectra thus obtained are not concordant, repeat the test using the residues obtained by separately dissolving the sample and pentamidine isetionate RS in a small amount of methanol R and evaporating to dryness. Dry the evaporated samples at C for approximately 1 hour. The infrared absorption spectrum is concordant with the spectrum obtained from pentamidine isetionate RS.

4 page BA. CB. The absorption spectrum of a 10 µg/ml solution in hydrochloric acid (0.01 mol/l) VS, when observed between 230 nm and 350 nm, exhibits a maximum at about 262 nm; the absorbance of a 1 cm layer at this wavelength is about To 0.5 g add 5 ml of water and heat to 80 C to dissolve. Add 10 ml of sodium hydroxide (~50 g/l) TS, cool in ice and filter. To 2 ml of the nitrate add 0.2 ml of nitric acid (~1000 g/l) TS followed by 0.2 ml of ceric ammonium nitrate TS; a red-orange colour is produced C. Melting temperature, about 190 C. ph value (1.13). ph of a 0.05 g/ml solution, Related substances. Carry out the test as described under Thin-layer chromatography, using silica gel R6, activated at 105 C for 1 hour, as the coating substance (a precoated plate from a commercial source is suitable), and as the mobile phase the upper layer obtained by shaking together 10 volumes of water, 8 volumes of 1- butanol R, and 2 volumes of glacial acetic acid R. Apply separately to the plate 10 µl of each of 2 solutions in methanol R containing (A) 50 mg of the test substance per ml and (B) 0.25 mg of the test substance per ml. After removing the plate from the chromatographic chamber allow it to dry in air and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B. 116

5 page Pentamidini isetionatis pulvis ad injectionem Pentamidine isetionate powder for injections Description. A white or almost white, crystalline powder; odourless. Category. Antitrypanosomal medicine Antileishmaniasis drug. Labelling. The designation on the container should state that Pentamidine isetionate injection should be used immediately after preparation. Expiry date. Additional information. Strength in the current WHO Model list of essential medicines: 200 mg (as isetionate) in vial. Pentamidine isetionate is hygroscopic. The injection deteriorates on storage. Definition. Pentamidine isetionate powder for injections is a sterile powder of pentamidine isetionate. The powder is sterilized by a suitable method (see 5.8 Methods of sterilization). The container of Pentamidine isetionate powder for injections contains not less than 90.0% and not more than 110.0% of the amount of C 19 H 24 N 4 O 2,2C 2 H 6 O 4 S stated on the label. Identity tests Either test A alone or tests B and C may by applied. A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from pentamidine isetionate RS or with the reference spectrum of pentamidine isetionate. If the spectra thus obtained are not concordant, repeat the test using the residues obtained by separately dissolving the sample and pentamidine isetionate RS in a small amount of methanol R and evaporating to dryness. Dry the evaporated samples at C for approximately 1 hour. The infrared absorption spectrum is concordant with the spectrum obtained from pentamidine isetionate RS. Clarity and colour of solution. A solution of the powder for injections equivalent to 0.5 g of Pentamidine isetionate in 10 ml of carbon-dioxide-free water R is clear and colourless. (Keep this solution for the "ph value".)

6 page ph value (1.13). ph of the solution prepared above for the test of clarity and colour, Related substances. Carry out the test as described under Thin-layer chromatography, using silica gel R6, activated at 105 C for 1 hour, as the coating substance (a precoated plate from a commercial source is suitable) and as the mobile phase the upper layer obtained by shaking together 10 volumes of water, 8 volumes of 1- butanol R and 2 volumes of glacial acetic acid R. Apply separately to the plate 10 µl of each of the following two solutions. For solution (A) dissolve a quantity of the powder for injections equivalent to 0.1 g of Pentamidine isetionate in 2 ml of methanol R. For solution (B) dilute 1 ml of solution A to 200 ml with methanol R. After removing the plate from the chromatographic chamber, allow it to dry in air and examine the chromatogram in ultraviolet light (254 nm). Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B. ***