The development of solid-state forms of drugs is an effective mean of solubility enhancement. In this study, two polymorphs named form C, form D, and two co-crystals of sorafenib (SF) with oxalic acid (SF-OA) and malonic acid (SF-MA), by evaporation and slurry method, have been developed and characterized. The single-crystal X-ray diffraction results showed that the structure of form C was similar to of form I. It had similar cellular parameters, but different arrangement of stacking due to π-π conjugation. The drug molecules in SF-OA underwent torsional folding through four hydrogen bonds of intermolecular and intramolecular. The solubility performance of solid-state forms improved significantly. Compared with form I, form C and form D were 1.59, 1.49 times at pH 1.2 HCl, 1.59, 1.87 fold at pH 6.8 PBS. In particular, the SF-OA and SF-MA increased the apparent solubility of SF at pH 1.2 by 8.3 and 6.4 times, at pH 6.8 by 4.0 and 4.5 times respectively. The dissolution mechanisms were analyzed. New solid-state forms showed strong stability at storage conditions of 40 °C/75% RH and 60 °C/0% RH. Notably, the crystal of SF preferred to transform in mixed solvents, and the formation of co-crystals confirmed the ∆pKa rule.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II showing low solubility and high permeability with a moderate F value (< 49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with improving 4-fold increase of the FBX solubility. Nevertheless, in vivo pharmacokinetic property of FBX-PG has not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX and FBX-PG-treated rats and mice was compared in this study. The results showed that the F values of FBX were 210% and 159% in FBX-PG rats and mice, respectively. The 2.10-fold greater AUC of FBX was due to the increased absorption (i.e., 2.60-fold higher Cmax,1 at 15 min) and entero-hepatic circulation of FBX (i.e., 1.68-fold higher Cmax,2 at 600 min) in FBX-PG rats compared to the FBX rats. The 1.59-fold greater AUC of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG mice than those in FBX mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG mice compared to FBX mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.