Page 56 - 2024

Ph.D.
(Science)
PHYSICO-CHEMICAL STUDIES AND POLYMORPHIC STABILITY
EVALUATION OF ANTI-HIV PROTEASE INHIBITORS IN FIXED DOSE
COMBINATION DRUG PRODUCT USING NOVEL ANALYTICAL METHODS

Ph.D. Scholar : Buch Munishkumar Kiritbhai
Research Supervisor : Dr. Hasit V. Vaghani

Regi. No.: 19276461002
Abstract :
The present work represents evaluation of polymorphism for active ingredients and its
stability during manufacturing and storage which is critical task for pharmaceutical firms. For
solubility and bioavailability enhancement of Ritonavir, hot melt extrusion process was
selected through conversion of commercially available crystalline form to amorphous.
Powder X-Ray diffraction method (with normal scan and slow scan), Differential scanning
calorimetry method and Raman spectroscopy method was considered for polymorphic
evaluation in tablet formulation comprising Darunavir 800 mg and Ritonavir 100 mg. The
Ritonavir polymorph conversion was estimated quantitatively by validated slow scan X-Ray
diffraction method in addition to qualitative evaluation by Differential scanning calorimetry
method and Raman spectroscopy method. Further the polymorphic stability of both the
active ingredients was verified by accelerated stability study of drug product.

The research work also involves impurity profiling of degradation products related to
Darunavir ethanolate, Ritonavir and its possible interaction with excipients during
manufacturing process and on storage. The study was designed to develop first base HPLC
method for separation of all possible degradation impurities within single chromatogram. The
same HPLC method was further transferred to short run time cost effective, LC-MS
compatible UPLC method. Through forced degradation study and accelerated stability
sample analysis of fixed dose combination drug product, impurity specification was designed
as per ICH Q3B (R2). According to manufacturing process and stoichiometric equation
observed Hydantoin amino alcohol as major degradation product of Ritonavir and also bi-
product generated monitored as unknown impurity. This unknown impurity was identified and
qualified through characterization study as Thiazolyl N-methyl Methanamine impurity and
considered under impurity profiling. The optimized UPLC method was validated as per ICH Q2
(R2) guidance including forced degradation study to justify as stability indicating. The
developed methods were found simple, sensitive, accurate, precise and robust and can be
utilized for the routine quantitative analysis of selected drug formulation. Further theoretical
risk assessment of drug product was carried out for volatile and inorganic impurities and
concluded suitability as per ICH Q3 requirements.
Key words: Polymorphism, Impurity profiling, Impurity Characterization, Method Validation,
Stability study.

01