Comparative evaluation of cocrystalline and coamorphous forms comprised of gefitinib and dasatinib for performance optimization

Abstract

Drug–drug cocrystals and coamorphous systems, both comprising two drugs in a single phase, can be applied to concurrently improve the physicochemical properties of the involved drugs. The comparative evaluation of cocrystalline and coamorphous forms comprised of a given drug combination aid in finding the optimal solid form for the development of synergistic formulations. Gefitinib (GTB) and dasatinib (DAS) are oral tyrosine kinase inhibitors exhibiting synergistic effects against cancer cells. However, they both belong to BCS II drugs showing solubility that differ by several times. To optimize the performance of hybrid drugs, one cocrystal (GTB-DAS·2H₂O) and one coamorphous solid form (GTB-DAS CM) were successfully prepared and fully characterized by XRD, ¹H NMR, TG, DSC, FTIR and DVS measurements. Crystal structural and Hirshfeld surface analysis shows GTB molecular layers are intercalated with layers of DAS via van der Waals interactions and weak hydrogen bonding interactions in the cocrystal. The stability and tabletability properties of GTB-DAS·2H₂O and GTB-DAS CM were evaluated, and the dissolution performance was studied in terms of T_max (time to peak drug concentration), C_max (maximum drug concentration) and AUC (area under the curve of dissolution profiles). Overall, GTB-DAS·2H₂O shows superior stability and tabletability properties, and synchronized drug release with improved dissolution performance, making it a more promising and reliable solid form for the development of combinational therapy.