Piracetam and Oxiracetam Afford Molecular, Cocrystalline, and Ionic Cocrystalline Solid Solutions

Solid solutions (SSs) are relatively underexplored crystalline forms that allow precise dosage of multidrug formulations. The cocrystallization of the nootropic drugs Piracetam (PIR) and Oxiracetam (OXI) suggests that these phases have a richer scope than once thought. Despite their different H-bond capabilities, multiple solid solutions were obtained following a crystal engineering approach. A combination of the pure compounds produced multiple forms of PIR_xRS-OXI_1–xSS, whose structure depends on the PIR/OXI ratio. Such structural diversity is controlled when enantiopure S-OXI is used in PIR_xS-OXI_1–x, or when both drugs are cocrystallized with either a molecular coformer (gallic acid, GA) or an inorganic salt (MgCl₂) to produce cocrystalline (CC) and ionic cocrystalline (ICC) SS: PIR_x·RS-OXI_1–x·GA, PIR_x·S-OXI_1–x·GA, and PIR_xR/S-OXI_1–x·MgCl₂·5H₂O. Thermal and humidity stability of each form is discussed, as well as the solubility profile of the GA CCSS. Overall, a rich solid-form landscape has been demonstrated for the combined drugs that allows for designing and optimizing them into molecular, cocrystalline, and ionic cocrystalline solid solutions.