title: Predicting the Solubility Advantage of Amorphous Pharmaceuticals: A Novel Thermodynamic Approach.
abstract: For the solubility and bioavailability of poorly soluble active pharmaceutical ingredients (APIs) to be improved, the transformation of crystalline APIs to the amorphous state has often been shown to be advantageous. As it is often difficult to measure the solubility of amorphous APIs, the application of thermodynamic models is the method of choice for determining the solubility advantage. In this work, the temperature-dependent solubility advantage of an amorphous API versus its crystalline form was predicted for five poorly soluble APIs in water (glibenclamide, griseofulvin, hydrochlorothiazide, indomethacin, and itraconazole) based on modeling the API/solvent phase diagrams using the perturbed-chain statistical associating fluid theory (PC-SAFT). Evaluation of the performance of this approach was performed by comparing the predicted solubility advantage to experimental data and to the solubility advantage calculated by the commonly applied Gibbs-energy-difference method. For all of the systems considered, PC-SAFT predictions of the solubility advantage are significantly more accurate than the results obtained from the Gibbs-energy-difference method.
authors.affiliation: TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge Straße 70, D-44227 Dortmund, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Paus
authors.affiliation: TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge Straße 70, D-44227 Dortmund, Germany.
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Ji
authors.affiliation: TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge Straße 70, D-44227 Dortmund, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Vahle
authors.affiliation: TU Dortmund, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Emil-Figge Straße 70, D-44227 Dortmund, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sadowski
mesh_terms: D003460:Crystallization; D005905:Glyburide / Q000737:chemistry*; D006118:Griseofulvin / Q000737:chemistry*; D006852:Hydrochlorothiazide / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D017964:Itraconazole / Q000737:chemistry*; D008962:Models, Theoretical; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D012997:Solvents; D014867:Water; D006852:Hydrochlorothiazide; D017964:Itraconazole; D006118:Griseofulvin; D005905:Glyburide; D007213:Indomethacin
keywords: PC-SAFT; amorphous; phase behavior; poorly soluble drug; solubility; thermodynamic model