Competitive Mechanochemical Solvate Formation of Theophylline in the Presence of Miscible Liquid Mixtures

In this study, we investigated the mechanochemical competitive solvate formation of polymorphic Form II of theophylline in the presence of two solvate/hydrate-forming miscible liquids, namely, water and 2-pyrrolidone. It is known that theophylline transforms into a monohydrate in the presence of water, while 2-pyrrolidone gives a monosolvate or a sesquisolvate, depending on the experimental conditions. Different theophylline-to-liquid molar ratios and several water:2-pyrrolidone mixtures were used to understand the competitive formation and/or transformation between these solvates. Interconversion studies between hydrate/monosolvate/sesquisolvate forms were also conducted. The obtained results suggest that water:2-pyrrolidone mixtures have a detrimental effect on the formation of multicomponent phases, as they dramatically reduce the efficiency of incorporation of both liquids in the crystal. In fact, all milling experiments performed in the presence of water:2-pyrrolidone mixtures suggested that a higher stoichiometric ratio is needed to obtain a pure form of a specific solvate. Importantly, additional competitive milling experiments revealed a preferential inclusion of 2-pyrrolidone over water. Based on several experimental datasets performed, we conclude that the propensity of solvate formation in the presence of liquid mixtures is a consequence of a complex interplaying of physicochemical and kinetic factors.