Regulating the Physical and Chemical Properties of Gefitinib and Its Positional Isomer Through Salt Formation

Abstract

The structural differences between Gefitinib (GFN) and its positional isomers, specifically N-(2-Fluoro-3-chlorophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-4-quinazolinamine(ISOGFN), appear minimal on a two-dimensional level. Despite their similar crystallization packing styles, the physical and chemical properties of the two solid states differ significantly, obstructing the development of the isomer into pharmaceutical drugs. Can cocrystallization with an identical ligand bridge this gap? In this study, we first prepared crystal of the GFN positional isomer. We then synthesized two distinct salts of GFN and its isomer using fumaric acid (FA, pKa:3.03) as the ligand, comparing the physicochemical properties of these samples. X-ray diffraction was conducted to characterize these crystals, alongside vibrational spectrum and thermal analysis. Additionally, their dissolution and permeability properties were evaluated to identify and summarize similarities and differences. Theoretical computational studies, including crystal packing similarity, proton transfer, Gibbs free energy, and interaction energy, were employed to elucidate the differences in properties from the structural and energy perspectives. The results indicated that introducing FA diminished the differences in properties between GFN and its positional isomer, especially in terms of solubility, permeability, thermostability, and packing similarity. For the isomer, its improvement in permeability after salt formation, which overcomes its shortcoming, providing a valuable reference for isomer drug research and development.