Investigation of Poor Solubility of a Salt-Cocrystal Hydrate: A Case Study of the Common-Ion Effect in Betrixaban, an Anticoagulant Drug.

Achieving the desired solubility and dissolution of active pharmaceutical ingredients (APIs) continues to be a big challenge in the pharmaceutical industry. In this regard, multicomponent solids of APIs such as salts and cocrystals have shown significant promise in resolving such solubility/dissolution issues. However, very little is known on how the APIs' solubility or dissolution is affected by the drug to coformer ratio in multicomponent solids. Betrixaban, is an anticoagulant drug approved in 2017 for the prevention of venous thromboembolism. During the alternate solid form development studies of the known betrixaban maleate, a rare multicomponent solid form, salt-cocrystal hydrate of betrixaban, was discovered and characterized thoroughly by spectroscopic, thermal, and X-ray crystallographic methods. Significantly, the new betrixaban maleate maleic acid hydrate (1:1:2:1) form has shown lower melting point (80 °C) as compared to its parent salt (197.5 °C). From such a large melting difference (117 °C) between the salt and salt-cocrystal hydrate of API, we anticipated substantially better solubility for the salt-cocrystal hydrate (low enthalpy). Furthermore, the predicted solubility also supported our anticipation. However, the powder dissolution tests at different pH conditions provided contrary results, that is, the salt-cocrystal hydrate showed 10 times lower solubility as compared to its salt. A detailed investigation, considering all the potential factors, revealed that "common-ion effect" could be a critical factor for the low solubility of the salt-cocrystal hydrate in which the API to coformer ratio is 1:3. To the best of our knowledge, this is the first case study on the solubility of pharmaceutical salt-cocrystal hydrates with an emphasis on "common-ion effect" or drug to coformer ratio.

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

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.

Crystal structure of 3-bromo-acetyl-6-chloro-2H-1-benzo-pyran-2-one.

In the title compound, C11H6BrClO3, the benzo-pyran ring system is essentially planar, with a maximum deviation of 0.036 (2) Šfor the O atom. The Cl and Br atoms are displaced by -0.0526 (8) and 0.6698 (3) Å, respectively, from the mean plane of this ring system. In the crystal, two pairs of weak C-H⋯O hydrogen bonds to the same acceptor O atom link mol-ecules into inversion dimers.