ABSTRACT
Exploration of alternate solid forms for dasatinib, a potent oncogene tyrosine kinase inhibitor classified under Biopharmaceutics Classification System (BCS) class II drugs with low water solubility and high permeability, has been performed using COSMO-RS excess enthalpy (Hex) to increase dissolution. The theoretical prediction resulted in the potential for the formation of C6-C8 fatty acid solvates with dasatinib. A crystallization process has been identified for the preparation of the predicted solvates and successfully scaled up till the 100 g level. The fatty acid solvates are completely characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR) spectroscopy, and proton nuclear magnetic resonance (1H NMR) spectroscopy. Unique powder X-ray diffraction patterns and powder indexing of C6-C8 fatty acid solvates indicate the purity of the solid phase. The red shift in the acid carbonyl stretching frequency of C6-C8 fatty acids in FT-IR spectra and the intactness of the fatty acid proton in 1H-NMR spectra provide evidence for solvate formation. The stoichiometry of active pharmaceutical ingredients (APIs) with solvent in solvates is measured using TGA and 1H-NMR spectroscopy. Dasatinib C6-C8 fatty acid solvates were found to retain their solid form under various stress and pharmaceutical processing conditions. In addition, they exhibited improved powder dissolution over dasatinib Form H1-7 by 2.2-fold. They also showed stability at 40 °C and 75% RH for 3 months. C8 fatty acid is a USFDA GRAS listed solvent, and hence may be a viable option for drug product development.
