–
May 7, 2025
Kennedy A. Borchardt-Setter, Pharmsci graduate student (Yu Research Group), will be defending her PhD research thesis:
Solid-State Chemistry of Drugs: Chiral Separation, Polymorphism, and Surface Enrichment of Formulation Components
Abstract. This dissertation focuses on several areas concerning solid-state chemistry of drugs: (1) chiral resolution by crystallization, (2) effect of surfactants on polymorphism and crystallization, and (3) surface enrichment of formulation components in an amorphous solid dispersion (ASD).
When a drug interacts with a living system, a change of chirality can make a medicine into a toxin. Among the methods to obtain enantiopure compounds, crystallization is the most economical. We first show that the relative energies of the chiral and achiral crystals influence the success of chiral separation by crystallization. In the cases where crystallization can generate chirality, the chiral crystal usually has lower energy than the achiral, while the opposite is true if no chiral separation occurs. This simple result helps assess the potential for a given system to undergo chiral separation by crystallization. We then investigate arabitol, showing it satisfies the rule we developed previously and that it indeed shows chiral separation by crystallization, using a seeding method to control the course of crystallization.
ASDs, typically containing a drug, a surfactant, and a polymer, can be used to enhance the solubility and bioavailability of poorly soluble drugs. The surfactant is often present to aid wetting and dissolution, but can reduce the glass transition of the system, thus promoting the drug’s crystallization and reducing its solubility. We investigate the effect of two common surfactants, Span 80 and Tween 80, on the crystallization and polymorphism of the antifungal posaconazole. We find that posaconazole, known to crystallize only the Form I polymorph in the bulk when pure, crystallizes Form I and Form II when doped. When either surfactant is present, the growth rates similarly increase but does not cause proportional increase of the polymorphs’ nucleation rates. The effects are quantitatively accounted for by the Classical Nucleation Theory where surfactants are treated as ideal diluents of the host molecules.
Work in binary ASDs has observed significant differences between the surface and bulk compositions. In the final part of this thesis, we extend the previous work to a realistic ternary ASD composed of posaconazole, Span 80, and a dispersion polymer (PVP or PVP/VA). Using Xray photoelectron spectroscopy, we observe strong enrichment of the surfactant at the surface with simultaneous depletion of the drug. Between the two polymers, the more hydrophilic PVP causes a larger enhancement of the surface enrichment effect. This effect already exists in the binary drugsurfactant mixture and is substantially enhanced by the addition of the polymers. The results demonstrate the importance of component interactions in altering the surface concentrations of ASDs and their performance.
