Stable Fatty Acid Solvates of Dasatinib, a Tyrosine Kinase Inhibitor: Prediction, Process, and Physicochemical Properties

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 C 6 –C 8 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 ( 1 H NMR) spectroscopy. Unique powder X-ray diffraction patterns and powder indexing of C 6 –C 8 fatty acid solvates indicate the purity of the solid phase. The red shift in the acid carbonyl stretching frequency of C 6 –C 8 fatty acids in FT-IR spectra and the intactness of the fatty acid proton in 1 H-NMR spectra provide evidence for solvate formation. The stoichiometry of active pharmaceutical ingredients (APIs) with solvent in solvates is measured using TGA and 1 H-NMR spectroscopy. Dasatinib C 6 –C 8 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. C 8 fatty acid is a USFDA GRAS listed solvent, and hence may be a viable option for drug product development.

Investigating the effect of polyvinylpyrrolidone matrix on surface characteristics and dissolution rate of anticancer drug dasatinib

“…In the PVP thermogram, an inflection point at 184°C was detected, corresponding to the glass transition characteristic of amorphous polymers 40 . In the DAS sample thermogram, an endothermic minimum at approximately 120°C indicated the release of crystal water, given that the drug was supplied in monohydrate form 41 . Additionally, there was an endothermic peak at 288°C, signifying the phase transition of DAS melting.…”

“…40 In the DAS sample thermogram, an endothermic minimum at approximately 120 C indicated the release of crystal water, given that the drug was supplied in monohydrate form. 41 Additionally, there was an endothermic peak at 288 C, signifying the phase transition of DAS melting. This peak was notably narrow, suggesting the high purity and crystalline structure of the drug.…”