The role of higher coformer stoichiometry ratio in pharmaceutical cocrystals for improving their solid-state properties: The cocrystals of progesterone and 4-hydroxybenzoic acid

Progesterone (PROG) is a naturally occurring and poorly water soluble steroid hormone that belongs to the broad category of progestins. In this study, the poor aqueous solubility of PROG had been addressed through its cocrystallization with suitable coformer, 4-hydroxybenzoic acid (4-HBA). Investigation of the role of higher coformer concentration in cocrystals to enhance the aqueous solubility of PROG was the main objective of this study. For this purpose, cocrystals of PROG and 4-HBA were prepared in different stoichimetry ratios such as 1: 1_A, 2: 1 and 1: 2 of PROG to 4-HBA,. All cocrystals were systematically characterized through X-ray powder diffraction, DSC, H-1 NMR, IR and optical microscopy techniques. The crystal structure for 2: 1 and 1: 2 cocrystals was obtained from single crystal X-ray diffraction and analysed. A mixture of kinetic forms (named as 1: 1_B) was obtained with grinding of equimolar mixture of PROG and 4-HBA, which produced thermodynamically stable 1: 1_A cocrystal upon recrystallization. Cocrystals were characterized with single crystal X-ray diffraction, XRPD, DSC and FTIR. The equilibrium solubility measurements for the cocrystals were carried out in water and ethanol where the cocrystal forms exhibited enhanced solubility profiles than PROG.