Gefitinib salts/cocrystals with phenolic acids as a promising solid-state approach to improve solubility

Abstract

To employ crystal engineering for the design and synthesis of a series of novel salts/cocrystals incorporating phenolic acids, aiming to modulate the solubility of gefitinib (GEF), a multifunctional antineoplastic drug, five distinct solid forms of GEF salts/cocrystals were successfully obtained for the first time, including two salts (3-hydroxybenzoic acid, 3-HBA, and ferulic acid, FA), one cocrystal (4-hydroxybenzoic acid, 4-HBA), and two salt cocrystals (3,5-dinitrobenzoic acid, 35DNB, and salicylic acid, SA). Characterization of the new forms was conducted using single crystal and powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. ΔpK_a analyses and C–O bond length analyses were applied to differentiate between the salts and cocrystals of GEF with various phenolic acids. The solubility and stability of the solid samples were also assessed, revealing significant enhancements in solubility and superior stability under specific temperature, humidity, and light conditions for the new salts/cocrystals. These findings suggest that the newly synthesized salts/cocrystals GEF–SA, GEF–3-HBA, and GEF–4-HBA hold promise as potential candidates for improving the aqueous solubility of GEF.