Saladi, VN and Kammari, BR and Maruthapillai, A and Mahapatra, S and Chennuru, R and Sajja, E and Rajan, ST and Mathad, VT (2022) Stable Fatty Acid Solvates of Dasatinib, a Tyrosine Kinase Inhibitor: Prediction, Process, and Physicochemical Properties. In: ACS Omega, 7 (8). 7032 -7044.
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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.
| Item Type: | Journal Article |
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| Publication: | ACS Omega |
| Publisher: | American Chemical Society |
| Additional Information: | The copyright for this article belongs to the American Chemical Society. |
| Department/Centre: | Division of Chemical Sciences > Solid State & Structural Chemistry Unit |
| Date Deposited: | 10 Mar 2022 07:32 |
| Last Modified: | 30 Jun 2022 05:28 |
| URI: | https://eprints.iisc.ac.in/id/eprint/71530 |
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