Screening of Organic Small Molecule Excipients on Ternary Solid Dispersions Based on Miscibility and Hydrogen Bonding Analysis: Experiments and Molecular Simulation

Abstract

The preparation of solid dispersions by mixing insoluble drugs with polymers is the main way to improve the aqueous solubility of drugs. The introduction of organic small molecule excipients into binary solid dispersions is expected to further enhance drug solubility by regulating intermolecular hydrogen bonding within the system at the microscopic level. In this study, we used carbamazepine (CBZ) as the target drug and polyvinylpyrrolidone as the solid dispersion matrix and screened the third component from 13 organic small molecules with good miscibility in the solid dispersion based on the principle of similarity of solubility parameters. The hydrogen bonding parameters and dissociation Gibbs free energy of the 13 organic small molecule-CBZ dimer were calculated by quantum mechanical simulation, and the tryptophan (Try) was identified as the optimal third component of organic small molecule. The migration of CBZ in binary and ternary systems was also analyzed by molecular dynamics simulation. On this theoretical basis, the corresponding solid dispersions were prepared, characterized, and tested for solubility analysis, which verified that the drug solubility was stronger for the system with the addition of polar fractions and the Try was indeed the best third component of organic small molecule compound, which was consistent with the simulation predictions. This screening method may provide theoretical guidance for drug modification design and clinical studies.

Keywords: dissolution; intermolecular hydrogen bonding; molecular simulation; organic small molecule excipients; ternary solid dispersions.