Interconvertible Hydrochlorothiazide–Caffeine Multicomponent Pharmaceutical Materials: A Solvent Issue Verdugo-Escamilla, Cristóbal Acebedo Martínez, Francisco Javier Domínguez Martín, Alicia Gómez Morales, Jaime Choquesillo Lazarte, Duane Cocrystal Codrug Hydrochlorothiazide Caffeine Mechanochemical synthesis The design of new multicomponent pharmaceutical materials that involve different active pharmaceutical ingredients (APIs), e.g., drug-drug cocrystals, is a novel and interesting approach to address new therapeutic challenges. In this work, the hydrochlorothiazide-caffeine (HCT–CAF) codrug and its methanol solvate have been synthesized by mechanochemical methods and thoroughly characterized in the solid state by powder and single crystal X-ray diffraction, respectively, as well as differential scanning calorimetry, thermogravimetric analyses and infrared spectroscopy. In addition, solubility and stability studies have also been performed looking for improved physicochemical properties of the codrug. Interestingly, the two reported structures show great similarity, which allows conversion between them. The desolvated HCT–CAF cocrystal shows great stability at 24 h and an enhancement of solubility with respect to the reference HCT API. Furthermore, the contribution of intermolecular forces on the improved physicochemical properties was evaluated by computational methods showing strong and diverse H-bond and π–π stacking interactions. 2021-02-16T08:12:28Z 2021-02-16T08:12:28Z 2020 info:eu-repo/semantics/article Verdugo-Escamilla, C.; Alarcón-Payer, C.; Frontera, A.; Acebedo-Martínez, F.J.; Domínguez-Martín, A.; Gómez-Morales, J.; Choquesillo-Lazarte, D. Interconvertible Hydrochlorothiazide–Caffeine Multicomponent Pharmaceutical Materials: A Solvent Issue. Crystals 2020, 10, 1088. https://doi.org/10.3390/cryst10121088 http://hdl.handle.net/10481/66592 10.3390/cryst10121088 eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España MDPI