WHO Drug Information Vol. 18, No. 2, 2004 - World Health ...

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WHO Drug Information Vol 18, No. 2, 2004 Consultation Document The International Pharmacopoeia: monographs for antiretrovirals (second draft) Within the framework of the Pilot Procurement Project for Quality and Sourcing of HIV Drugs (http:// www.who.int/medicines), the International Pharmacopoeia is collaborating with manufacturers, independent analytical drug quality control laboratories, national and regional pharmacopoeial bodies, research, governments, and regulatory bodies to provide specifications and monographs for the following antiretroviral agents: abacavir, didanosine, efavirenz, indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir, stavudine, zidovudine Specifications for the respective dosage forms are now being developed and a draft monograph for didanosine is now available for consultation as presented below. This second draft monograph has been developed following comments received on the first draft published in WHO Drug Information, Vol. 17, No. 3 2003. Comments should be sent to: Quality and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland or kopps@who.int. Molecular formula: C 10 H 12 N 4 O 3 Relative Molecular Mass: 236.23 Graphic formula: DIDANOSINUM Didanosine Chemical name: 9-[(2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl]-1,9-dihydro-6H-purin-6-one; 9- (2,3-dideoxy-ß-D-glycero-pentofuranosyl)-1,9-dihydro-6H-purin-6-one; 2',3'-dideoxyinosine (DDI); CAS Reg. No. 69655-05-6. 143
Consultation Document Description: A white to almost white powder. 144 WHO Drug Information Vol 18, No. 2, 2004 Solubility: Sparingly soluble in water; slightly soluble in methanol R and ethanol (95 per cent) R Melting point: about 170 ˚C with decomposition. Category: Antiretroviral (nucleoside reverse transcriptase inhibitor). Storage: Didanosine should be kept in a tightly closed container. REQUIREMENTS Didanosine contains not less than 98.5% and not more than 101.0% of C 10 H 12 N 4 O 3 calculated with reference to the dried substance. Identity test Carry out the examination as described under “Spectrophotometry in the infrared region” (Vol. 1, p. 40*). The infrared absorption spectrum is concordant with the spectrum obtained from didanosine RS or with the reference spectrum of didanosine. If the spectra are not concordant, use didanosine RS. Dissolve the sample in a small amount of methanol R, evaporate and carry out the IR spectrum as mentioned above. Treat didanosine RS in the same way. The infrared absorption spectrum is concordant with the spectrum obtained from didanosine RS. Specific Optical Rotation. Use a 10 mg/ml solution and calculate with reference to the dried substance; –24˚ to –28˚. Heavy metals. Use 1.0 g for the preparation of the test solution as described under “Limit test for heavy metals”, Procedure 1 (Vol. 1, p. 118*); determine the heavy metal content according to Method A (Vol. 1, p. 119*); not more than 20 µg/g. Sulfated ash. Not more than 1.0 mg/g. Loss on drying. Dry for 4 hours at 105 ˚C; it loses not more than 5 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. 257*), using a stainless steel column (25 cm x 4.6 mm), packed with octadecylsilyl base-deactivated silica gel for chromatography R (5µm). (Hypersil BDS is suitable.) Maintain the column temperature at 20 – 25 ˚C. The mobile phases for gradient elution consist of a mixture of aqueous phase (Mobile phase A) and methanol (Mobile phase B), using the following conditions : Mobile phase A: A 0.05 M solution of ammonium acetate R adjusted to pH 8.0 using a 20% v/v ammonia solution. Mobile phase B: Methanol. * Refers to The international Pharmacopoeia
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