Investigating the Physicochemical Stability of Highly Purified Darunavir Ethanolate Extracted from PREZISTA® Tablets

Understanding physicochemical stability of darunavir ethanolate is expected to be of critical importance for the development and manufacturing of high-quality darunavir-related pharmaceutical products. However, there are no enabling monographs for darunavir to illustrate its solid-state chemistry, impurity profile, and assay methods. In addition, the US Pharmacopeia reference standard of darunavir is still not commercially available. It has been also challenging to find reliable vendors to obtain highly purified darunavir ethanolate crystals to conduct the physicochemical stability testing. In the present research, we developed a straightforward and cost-effective approach to extract and purify darunavir ethanolate from PREZISTA® tablets using reverse-engineering and crystallization. Using these highly purified crystals, we thoroughly evaluated the potential risks of degradation and form conversions of darunavir ethanolate at stressed conditions to define the manufacturing and packaging specifications for darunavir-related products. Amorphization was observed under thermal storage caused by desolvation of darunavir ethanolate. The ethanolate-to-hydrate conversion of darunavir was observed at high relative humidity conditions. Moreover, acid/base-induced degradations of darunavir have been investigated herein to determine the possible drug-excipient compatibility issues in formulations. Furthermore, it is of particular interests to allow the production of high-quality darunavir-ritonavir fixed dose combinations for marketing in Africa. Thus, a validated HPLC method was developed according to ICH guideline to simultaneously quantify assays of darunavir and ritonavir in a single injection. In summary, the findings of this study provide important information for pharmaceutical scientists to design and develop reliable formulations and processings for darunavir-related products with improved stability.