Stability and Mechanical Properties of Darunavir Isostructural Solvates: An Experimental and Computational Study

A search for suitable solid forms was an integral part of pharmaceutical manufacturing. In this study, nine isostructural solvates of darunavir (DLNW), an oral nonpeptidyl HIV-1 protease inhibitor, were prepared in different solvent systems (water [Shen, J. . CrystEngComm 2019, 1102], methanol, ethanol [Shen, J. CrystEngComm 2019, 1102], isopropanol, 1-propanol, ethyl acetate, acetone, N,N-dimethyl formamide, and dimethyl sulfoxide). The phase compositions of prepared samples were confirmed by single-crystal X-ray diffraction studies. The relationship between crystal structure and mechanical properties of each solvate was also investigated through the inspection of crystal structures, with a focus on hydrogen bonding interactions. We further compared the thermal stabilities and mechanical properties of different DLNW solvates, experimentally determined using thermal methods and nanoindentation, in combination with the simulation of topological analysis, energy framework, and core-valence bifurcation, respectively. The results showed that nine solvates were isostructural with varying proportions of solvent and different thermal stabilities because of the differences in solvent molecules. Darunavir dihydrate (DLNW-2H) showed the best compressibility and therefore could be regarded as a sensible choice for active pharmaceutical ingredients. A new solvent-free crystalline DLNW form was also obtained through the transformation of darunavir ethyl acetate solvate (DLNW-EAC), paving a feasible way to develop novel polymorphs, which were worthy of further research and attention in manufacturing.