A thermodynamic approach for predicting thermodynamic phase behaviors of pharmaceuticals in biorelevant media

Biorelevant solubilities of drugs are important fundamental data in pharmaceutical development. However, there is still no effective theoretical model to quantitatively describe and predict biorelevant solubility. Therefore, a theoretical modeling approach was proposed for predicting biorelevant solubility. Probenecid (PBD) and flurbiprofen (FBU) were chosen as model drugs. A pH-dependent solubility model was developed to accurately capture the influence of pH adjusted by various buffer systems on solubility, and the micellar effect was described by a micellar solubilization model. Based on the combination of the two models, biorelevant solubility was successfully modeled as a function of temperature, pH, surfactant type and concentration. Several predictive applications were proposed, including predicting the solubility of crystalline and amorphous drugs in biorelevant media with different formulations. These findings demonstrated that the developed theoretical approach achieved quantitative prediction of biorelevant solubility, which is expected to provide important theoretical prediction methodology and fundamental data for the development of drugs as well as their formulations.