Defense Date

10-31-2023

Graduation Date

Fall 12-15-2023

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

School of Pharmacy

Committee Chair

Peter L. D. Wildfong

Committee Member

Ira S. Buckner

Committee Member

Carl A. Anderson

Committee Member

Jennifer A. Aitken

Committee Member

Lian Yu

Keywords

Halogen bonding, Hydrogen bonding, Amorphous solid dispersions, Solubility, Miscibility, Mobility, Physical stability, Time-temperature-transformation plots, Crystal structures, Polymorphs

Abstract

Amorphous solid dispersions (ASD), although a promising formulation strategy for poorly water-soluble drugs, are susceptible to rapid, spontaneous recrystallization owing to their metastable nature. Non-covalent interactions (NCI) between the drug and polymer are known to help prevent ASD physical destabilization. Conventionally, hydrogen-bonding (H-bonding) is considered important for ASD formation and persistence. However, carbon-bound halogen atoms, which are frequently present on drug molecules and can form specific halogen-bonds (X-bond) with the polymer, remain relatively unexplored with respect to their ability to stabilize ASDs. It was, therefore, hypothesized that the presence of a peripheral Br on bromopropamide, and Cl on chlorpropamide will enable the formation of specific X-bonds with the carrier polymer polyvinylpyrrolidone vinyl acetate (PVPVA), which can contribute to increasing its crystallization onset time (tcrys) for recrystallization, relative to analogous unhalogenated tolbutamide, which is incapable of X-bonding. In this work, strong and relatively weaker X-bonds were spectroscopically determined for bromopropamide-PVPVA and chlorpropamide-PVPVA, respectively. The rank-ordering of the interaction landscapes directly correlated with the thermodynamic and kinetic properties where the solubility, favorable mixing free energy, and relaxation time for bromopropamide were all higher with PVPVA, relative to chlorpropamide. The non-halogenated tolbutamide had the least favorable of these properties, consistent with it having the weakest interaction landscape with the polymer. Physical stability was evaluated by measuring the tcrys for each analogue in the presence of PVPVA under several isothermal conditions, which allowed the construction of time-temperature-transformation (TTT) plots. The phase boundary in the TTT diagrams separated the completely amorphous phase from the amorphous/crystalline phase mixture. The addition of increasing quantities of PVPVA shifted the phase boundaries to longer tcrys for all analogues. Nevertheless, a clear rank-ordering was observed in which bromopropamide consistently had the highest tcrys, followed respectively by chlorpropamide and tolbutamide across all PVPVA loadings. These data confirmed the influential role of peripheral halogens on ASD physical stability.

Language

English

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