Nucleation and Phase Transition

Crystallization of organic molecules, by and large, still remains as an art. Experiences and trials-and-errors are part of common practice. Unexpected appearance of polymorphs, failure to obtain a particular polymorph, concomitant polymorphs, process-induced phase transition, and difficulty to crystallize are just some typical challenges encountered in the manufacture of organic crystalline materials. The nucleation process is poorly understood and there is a huge missing gap between the chemistry of a molecule to be crystallized and the control of crystallization process. For any new molecule, finding proper conditions to crystallize requires a plethora of labors and resources. Crystallization process is thereby expensive to develop, often subjective to failures and difficulties to scale up.

Nucleation is the key step in which solute molecules self-assemble into well-defined crystal structures. For any given organic molecule to be crystallized out, questions often being asked include what crystal structures it will form and why it forms a particular structure under a specific set of growth conditions. Answers are generally speculative at best and, most often, there is no predictive answer. Whilst it suggests the elusive nature of nucleation and crystal growth, this also highlights the challenge in studying crystallization in which molecular events taking place are barely, or not at all, accessible to current experimental methods. Recognizing the underlying interconnection between a molecule’s conformation and its interaction potential in space with other molecules, we focus our efforts on detailed analyses of solute species in solution at the pre-nucleation stage. In particular, we examine at the molecular level how solute molecules behave and the extent to which solution conditions influence such behaviors with both experimental and computational tools.

This movie shows appearance of two polymorphs of tolfenamic acid formed simultaneously
from ethanol.  The title picture shows crystals
of these two forms.  The question we try to answer
is why these forms occur at the same time under the same conditions.

Our studies will help develop nucleation theories that take into account the chemical nature of a molecule and create novel methods and tools for crystal structure prediction. In addition, the knowledge gained throughout our research will help prompt the current practice of industrial crystallization toward a molecular-based manufacturing discipline. Solvent selection, use of additives, and optimization of other growth conditions will be scientifically justified to ensure process efficacy and product quality.

Moreover, we are interested in not just the nucleation mechanism from solution but also from other physical states including the amorphous and even another crystalline environment. As phase transition plays a very important role in formulation and manufacturing, we are motivated to discover fundamental mechanisms and facilitate drug development and product quality.