Improving the Solubility and Bioavailability of Apixaban via Apixaban-Oxalic Acid Cocrystal

Apixaban (apx), with a trade name of Eliquis, is a highly selective and efficacious inhibitor of blood coagulation factor Xa. Apixaban has poor solubility in water (0.028 mg/mL at 24 degrees C) and a relatively low oral bioavailability (about 50% for a single 10 mg dose). The purpose of this study is to improve the solubility and consequently the oral bioavailability of apixaban via a cocrystal. A cocrystal of apixaban with oxalic acid (apx-oxa-H2O, 4:3:0.5) was successfully obtained and characterized. The structure of the cocrystal was determined by single-crystal X-ray diffraction. The solubility of the cocrystal in 0.1 M HCl (pH 1.0) and phosphate buffer of pH 6.8 was evaluated, and the results show the solubility values of the cocrystal are approximately 2.2 and 2.1 times as large as those of apixaban form N-1 (the marketed product), respectively. The pharmacokinetics in beagle dogs was also investigated, and the mean AUC(0-24h) of the cocrystal is approximately 2.7 times as large as that of apixaban form N-1, indicating that both solubility and bioavailability of apixaban can be improved via a cocrystal.