Study on several novel crystalline complexes of sorafenib with dicarboxylic acid: Nature identification and solubilization mechanism

The development of solid-state forms of drugs is an effective approach to increase solubility. This study developed three crystalline complexes of sorafenib (SF) with oxalic acid (OA) and malonic acid (MA) using a solvent method, named SF + ·OA - ·THF, SF + ·OA - , and SF-MA. The formation of these complexes was influenced by the crystalline method, solvent polarity, and the carbon chain length of the dicarboxylic acids. Single-crystal X-ray diffraction revealed proton transfer in SF + ·OA - ·THF, classifying it as a channel-type salt solvate and conformational polymorph due to hydrogen bond formation. 13 C solid-state nuclear magnetic resonance and X-ray photoelectron spectroscopy confirmed proton transfer in SF + ·OA - ·THF and SF + ·OA - , but not in SF-MA, indicating that SF + ·OA - is a salt while SF-MA is a co-crystal. Fourier Transform Infrared Spectroscopy further supported these findings. Compared with Form Ⅰ, SF + ·OA - , SF + ·OA - ·THF, and SF-MA increased the apparent solubility of SF by 8.3, 7.9, and 6.4 times in pH 1.2 HCl buffer, and by 4.0, 3.1, and 4.5 times in pH 6.8 PBS buffer, respectively. All crystalline complexes exhibited a “spring and parachute” phenomenon due to the solubility difference between the drug and the dicarboxylic acids. Notably, the intermolecular forces between SF and THF in SF + ·OA - ·THF prolonged the “spring and parachute” process. Additionally, these crystalline complexes demonstrated good stability. This study provides valuable insights into the development and identification of crystalline complexes and their dissolution mechanisms.