Physico chemical studies and polymorphic stability evaluation of anti hiv protease inhibitors in fixed dose combination drug product using novel analytical methods

Abstract

The present work represents evaluation of polymorphism for active ingredients and its newlinestability during manufacturing and storage which is critical task for pharmaceutical firms. newlineFor solubility and bioavailability enhancement of Ritonavir, hot melt extrusion process was newlineselected through conversion of commercially available crystalline form to amorphous. newlinePowder X-Ray diffraction method (with normal scan and slow scan), Differential scanning newlinecalorimetry method and Raman spectroscopy method was considered for polymorphic newlineevaluation in tablet formulation comprising Darunavir 800 mg and Ritonavir 100 mg. The newlineRitonavir polymorph conversion was estimated quantitatively by validated slow scan X-Ray newlinediffraction method in addition to qualitative evaluation by Differential scanning calorimetry newlinemethod and Raman spectroscopy method. Further the polymorphic stability of both the active newlineingredients was verified by accelerated stability study of drug product. newlineThe research work also involves impurity profiling of degradation products related to newlineDarunavir ethanolate, Ritonavir and its possible interaction with excipients during newlinemanufacturing process and on storage. The study was designed to develop first base HPLC newlinemethod for separation of all possible degradation impurities within single chromatogram. The newlinesame HPLC method was further transferred to short run time cost effective, LC-MS newlinecompatible UPLC method. Through forced degradation study and accelerated stability newlinesample analysis of fixed dose combination drug product, impurity specification was designed newlineas per ICH Q3B (R2). According to manufacturing process and stoichiometric equation newlineobserved Hydantoin amino alcohol as major degradation product of Ritonavir and also biproduct newlinegenerated monitored as unknown impurity. This unknown impurity was identified newlineand qualified through characterization study as Thiazolyl N-methyl Methanamine impurity newlineand considered under impurity profiling. The optimized UPLC method was validated as per newlineICH Q2 (R2) guidance including forced degradation st