Multicomponent Solid Forms of Pioglitazone and Their Influence on Drug Dissolution

Abstract

Pioglitazone (PIO), a type 2 diabetes medication, effectively decreases blood glucose levels. It exhibits poor aqueous solubility and falls in the category of the biopharmaceutics classification system (BCS)-II. To enhance solubility and dissolution characteristics of the lipophilic drug, cocrystallization with organic acids such as 2-naphthalenesulfonoic acid (NSA), oxalic acid (OXA), maleic acid (MLE), and dihydroxy benzoic acid (DHBA) were successfully carried out via the solvent-drop grinding method. The multicomponent solid forms were characterized by powder X-ray diffraction (PXRD), infrared spectroscopy, and thermal analysis. The crystal structures of the PIO–NSA and PIO–MLE solid forms were obtained through Rietveld refinement from the high-resolution PXRD data as their crystallization was challenging. The N–H···N hydrogen-bonded PIO homodimer in the drug is replaced by the O–H···N neutral hydrogen bond in the cocrystal monohydrate (PIO–NSA 1:1:1) and N⁺–H···O^– ionic interactions in the salt hemihydrate (PIO–MLE 1:1:0.5). Spectroscopic analysis confirmed the formation of 1:1 salts between PIO and OXA/DHBA. However, the structural prediction was compromised due to the nonmonophasic behavior of these salts. Solubility of novel multicomponent solid forms was performed in pH 6.8 phosphate buffer at 37 °C and determined using UV–vis spectroscopy. The PIO–NSA cocrystal hydrate dissolved 7 times compared to PIO, which may be useful for further pharmaceutical application during drug formulation. The solubility data was correlated with the synthon modulation, lower melting point, and coformer solubility.