Solubilization of a Poorly Soluble B-Raf (Rapidly Accelerated Fibrosarcoma) Inhibitor: From Theory to Application.

The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and physicochemical properties. Among the physicochemical properties, solubility and dissolution rate often are the most critical factors affecting the oral bioavailability of a compound. The increasing challenge for the pharmaceutical industry is to achieve reasonable oral bioavailability of poorly water-soluble drug candidates. G-F is a potent and selective B-Raf (rapidly accelerated fibrosarcoma) inhibitor with poor water solubility and moderate permeability, which resulted in an absorption-limited exposure in preclinical safety studies. The intrinsic solubility of G-F is 8 μg/mL (i.e., 0.0188 nM). In this study, pH adjustment combined with cosolvency, micellization, or complexation was applied as a technique to enhance the solubility of G-F. pH 9.5 and 4 buffers were selected to combine with the solubilization agents based on G-F's acidic pKa of 7.47. The solubilization power of each solubilization agent was determined based on the experimental data. The solubility G-F can be increased up to 4000-fold in a selected combination. The advantage of combination over individual solubilization agent was demonstrated. In this study, the understanding of the solubilization power of each solubilization agent played an important role in the formulation development of this development candidate.