Nevirapinum anhydricum
Nevirapine anhydrous
Molecular formula: C15H14N4O
Relative molecular mass: 266.30
Graphic formula:
Chemical name: 11-cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one CAS Reg. No. 129618-40-2.
Description: White to almost white powder.
Solubility: Very slightly soluble in water and soluble in acidic solution.
Melting point: 242 - 246 °C.
Category: Antiretroviral (non-nucleoside reverse transcriptase inhibitor).
Storage: Nevirapine should be kept in a well closed container.
REQUIREMENTS
Nevirapine contains not less than 99.0 % and not more than 101.0 % of C15H14N4O, calculated with reference to the dried substance.
Identity test
Carry out the examination as described under “Spectrophotometry in the infrared region” (Vol. 1, p. 401). The infrared absorption spectrum is concordant with the spectrum obtained from nevirapine RS.
1 Refers to The International Pharmacopoeia.
Sulfated ash. Not more than 1.0 mg/g.
Loss on drying. Dry for 4 hours at 105 °C; it loses not more than 10 mg/g.
Related Substances
Note: Prepare fresh solutions and perform the tests without delay
Carry out the test as described under “High-performance liquid chromatography” (Vol. 5, p. 2571), using a stainless steel column (15cm x 4.6mm), packed with hexadecylamidylsilyl silica gel for chromatography (5 μm). (Supelcosil LC-ABZ is suitable.)
1 Refers to The International Pharmacopoeia.
Maintain the column temperature at 35 °C.
The mobile phase consists of a filtered and degassed mixture of 20 volumes of acetonitrile R and 80 volumes of a buffer of 25 mM ammonium dihydrogen phosphate adjusted to pH 5.0 using a 20 % w/w ammonia solution.
Operate with a flow rate of 1.0 ml per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 220 nm.
Prepare the following solutions in the mobile phase (dissolution solvent).
For solution (1) dissolve 25 mg of nevirapine in 4 ml of acetonitrile R and dilute to 100.0 ml with the dissolution solvent. For solution (2) dilute 5.0 ml of solution (1) to 50.0 ml with the dissolution solvent. Then dilute 5.0 ml of this solution to 50.0 ml with the same solvent.
Inject separately 50 ml of solution (2) in replicate injections in the chromatographic system. The relative standard deviation for peak areas of Nevirapine in replicate injections of solution (2) is not more than 5.0%.
Inject separately 50 ml each of solution (1) and of mobile phase in the chromatographic system. Continue the chromatography for 5 times the retention time of nevirapine. Examine the mobile phase chromatogram for any extraneous peaks and disregard the corresponding peaks observed in the chromatogram obtained with solution (1).
The test is not valid unless the column efficiency determined from the solution (2) is not less than 10000. The peak symmetry should be between 0.8 and 1.2.
In the chromatogram obtained with solution (1), the following impurity peaks are eluted at the following relative retention time with reference to nevirapine: (A) = about 0.7; (B) = about 1.5 and (C) = about 2.8.
Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2), and calculate the content of related substances as a percentage.
In the chromatogram obtained with solution (1) the area of any individual peaks corresponding to impurity peaks A, B and C is not greater than 0.2 times the area of the principal peak obtained with solution (2) (0.2%). Any other impurity peak is not greater than 0.1 times the area of the principal peak obtained with solution (2) (0.1%). The sum of the areas of all peaks, other than the principal peak, is not greater than the area of the principal peak obtained with solution (2) (1.0%). Disregard any peak with an area less than 0.05 times the area of the principal peak obtained with solution (2) (0.05%).
Assay
Dissolve about 0.200 g, accurately weighed, in 50 ml of acetic anhydride R and titrate with perchloric acid (0.1 mol/l) VS as described under “Non-aqueous titration”; Method A (Vol. 1, p.1311) determining the end point potentiometrically.
1 Refers to The International Pharmacopoeia.
Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 26.63 mg of C15H14N4O.
Tested impurities
A. 5,11-Dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
B. 11-Ethyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
C. 11-Propyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2’,3’-e][1,4]diazepin-6-one
Reagents
Silica gel for chromatography, hexadecylamidylsilyl
Particles of silica gel, the surface of which has been modified with chemically bonded hexadecylamidylsilyl groups.
International Nonproprietary Names for Pharmaceutical Substances (INN)
Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are under consideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a name in the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy.
Lists of Proposed (1-85) and Recommended (1-45) International Nonproprietary Names can be found in Cumulative List No. 10, 2002 (available in CD-ROM only). The statements indicating action and use are based largely on information supplied by the manufacturer. This information is merely meant to provide an indication of the potential use of new substances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a position either to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature, these descriptors will neither be revised nor included in the Cumulative Lists of INNs.
Dénominations communes internationales des Substances pharmaceutiques (DCI)
Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont mises à l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées. L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisation de la substance correspondante en médecine ou en pharmacie.
On trouvera d'autres listes de Dénominations communes internationales proposées (1-85) et recommandées (1-45) dans la Liste récapitulative No. 10, 2002 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et les indications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'à donner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet de propositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacité du mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listes récapitulatives de DCI.
Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)
De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que las denominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Salud como Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCI Propuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.
Las listas de Denominaciones Comunes Internacionales Propuestas (1-85) y Recomendadas (1-45) se encuentran reunidas en Cumulative List No. 10, 2002 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecen se basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una idea únicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. La OMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que se atribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listas recapitulativas de DCI.
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