Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)




Molecular dynamics (MD) simulation has been widely used in understanding the physical basis of the structure and function of biological macromolecules. However, its application in pharmaceutical research is still at an early stage. This dissertation attempts to establish the use of MD simulation in studying several important pharmaceutical mass transfer processes. The three-series study included (1) the understanding of drug crystal dissolution at molecular level, (2) the elucidation of an unique mechanism for facile polymorphic transformation of crystalline drugs in solutions, and (3) the determination of drug-polymer interactions at water-crystal interface and the implications to crystallization inhibition.

A drug crystal dissolution into aqueous solution was simulated successfully for the first time on acetaminophen crystal Form I. The results revealed distinct corner & edge effect and differentiated dissolution rate among the three crystal surfaces of (001), (101) and (100), which correlated strongly with total interaction energies among the drug molecules and between the drug and water molecules. This study helped us gain additional fundamental understanding in the relationship between dissolution rate and particle size and morphology.

A series of MD simulations and experimental methods were utilized to evaluate the thermodynamic and kinetic forces that control the polymorphic transformation in solutions. Acetaminophen Form II, a metastable crystalline form which readily converts to the themodymically stable Form I when in contact with solution was studied. It was found that the facile polymorphic transformation is not attributed to the solubility differences; rather it is caused by a unique mechanism of surface facilitated phase transformation (SurFPT). This new mechanism is able to promote faster polymorphic transformation than the well-known mechanism of solution-mediated phase transformation (SMPT), thus it is more detrimental.

In the third study, the molecular mechanism of crystal surface specific drug-polymer interaction was investigated by simulating tolazamide crystals in the presence of hydrated PEG-b-PLA, a diblock copolymer. The results from the simulations demonstrated the polymer's strong interaction with the (001) face, weaker interaction with the (010) face and minimal to no interaction with the (100) face, which matched remarkably well with the reported crystal habit alteration by the preferential interaction of PEG-b-PLA primarily with the (001) and partially with (010). Interestingly, van der Waals interactions were identified as the dominant forces (accounts for 77-93% of total interaction energies) that enabled such strong drug-polymer interactions. These findings suggest that polymers capable of forming strong hydrophobic interactions are more effective in inhibiting crystallization of poorly-water soluble and hydrophobic drugs in aqueous media than those with hydrogen bonding capacities. Such in-depth analysis and understanding facilitate the rational selection of polymers in designing supersaturation-based enabling formulations.

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