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
Recommended Citation
Bookwala, M. (2023). The Implications of the Halogen Atom on the Physical Stability of Amorphous Solid Dispersions (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/2298