Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Industrial and Physical Pharmacy

Committee Chair

Tonglei Li

Committee Member 1

Stephen R. Byrn

Committee Member 2

Lynne S. Taylor

Committee Member 3

Paul Luner


Combinatorial chemistry and high-throughput screening approaches utilized during drug discovery have resulted in many potent pharmacologically active molecules with low aqueous solubility and consequently poor bioavailability. Enabling technologies, such as amorphous solid dispersions (ASD’s), can obviate these challenges and provide an efficient route to formulate the drug as an oral solid dosage form. However, high-energy amorphous materials have an inherent tendency to crystallize and in doing so can negate the apparent solubility advantage achieved by using such formulations. Crystallization can occur during (1) cooling the drug molecule from the melt state (such as during hot melt extrusion); (2) during storage of an amorphous formulation; (3) during pharmaceutical processing unit operations such as compression, granulation etc. Current knowledge with regards to the relationship between crystallization propensity of an active pharmaceutical ingredient (API) from the amorphous state (supercooled liquid and glass) and its thermodynamic, kinetic and molecular properties is limited. Furthermore, examining the mechanistic steps involved in crystallization of organic molecules under conditions of supercooling provides an opportunity to examine supramolecular aggregation events occurring during early stages of crystallization. Studying crystallization mechanism from amorphous state is important for pharmaceutical formulation development because a molecular-level understanding of the crystallization process would provide clues regarding the intermolecular interactions at the early stages of nucleation and help in rational selection of polymeric excipients to hinder such events.

The primary goal of this research is to develop an understanding of phase transition from amorphous pharmaceuticals, specifically focusing on the role of thermodynamic, kinetic and molecular properties of a series of structurally similar compounds. It is hypothesized that the there exists a link between thermodynamics quantities, kinetic properties, molecular interactions and glass forming ability. Furthermore, it is hypothesized that the molecular heterogeneity in supercooled liquids and glassy state, manifested through intermolecular interactions and conformational flexibility impacts the observed crystallization behavior.

Understanding the phase transition kinetics and mechanism of crystallization from amorphous pharmaceuticals is critical for development of stable formulations for drug delivery. The specific goals of this research include:

(1) Investigating the link between thermodynamic and kinetic factors affecting the crystallization propensity of organic compounds from supercooled liquid state.

(2) Evaluating the role of intermolecular interactions and conformational distribution on glass forming ability and stability.

(3) Examining the relationship between supramolecular aggregates present in glassy state and polymorphic outcome.

It is believed that successful completion of this research will provide a fundamental understanding of amorphous solid-state chemistry as well as provide useful tools for the implementation of ASD’s as solid oral dosage forms.