Solubility Advantage (and Disadvantage) of Pharmaceutical Amorphous Solid Dispersions.
The solubility of a drug is ultimately governed by its chemical potential as it is present in the undissolved solute. For a pharmaceutical amorphous solid dispersion (ASD), its solubility depends on the state and composition of the undissolved solute when the ASD is equilibrated with water. Concerning the undissolved solute phase that can contain up to 3 components (drug, polymer, and water), we developed a complete thermodynamic model to calculate the chemical potential of a drug in the multicomponent, amorphous system. This approach enables the estimation of the true solubility advantage of ASD from calorimetric measurements and moisture sorption isotherms. Both theoretical estimation and experimental studies, using indomethacin (IMC)/Eudragit E ASD systems, show that the solubility advantage of the amorphous IMC is significantly reduced through ASD formation and water partitioning. For the ASD with 70% drug loading, the solubility of IMC is lower than its crystalline counterpart. Our results show that stabilization through the ASD formation and water sorption can be manifested by the lowering of drug solubility; they demonstrate that the core property in ASD development is the drug chemical potential, which is essentially the thermodynamic driving force and can be quantitated using the model presented in this work.
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712.
Siyuan
S
Huang
Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California 94080. Electronic address: mao.chen@gene.com.
Chen
C
Mao
Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712.
Robert O
RO
Williams
Small Molecule Pharmaceutical Sciences, Genentech, Inc., South San Francisco, California 94080.
Chia-Yi
CY
Yang
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004355:Drug Stability; D007213:Indomethacin / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D014867:Water / Q000737:chemistry* / Q000378:metabolism; D014961:X-Ray Diffraction
D014867:Water; D007213:Indomethacin
amorphous; dissolution; physical stability; polymers; solid dispersion; solubility; thermodynamics; water sorption