(527f) Mechanistic Insights into the Process of Crystallization Using a Kinetic, Multiscale Model

Polymorphism, an ability of a molecule to exist in more than one crystal structure is an issue usually encountered during the process of crystallization in pharmaceutical industries. To ensure maximum bioavailability, optimum dissolution rate and to comply with standards of federal institutions, it is necessary to produce a drug with uniform physical properties which depend on crystal structure. The operating conditions affect the outcome of crystallization. To predict the outcome of the crystallization, the current approaches rely on empiricism or searching for crystal structure with lowest lattice energy. Former approach, although reliable, is time consuming and uses valuable resources and the latter approach fails to properly capture the mechanism of crystallization process. To overcome this issue, we propose a multiscale model based on the kinetics of crystallization. Fundamentally, mechanism of crystallization involves attachment and detachment of molecules at different time scales. With the help of molecular dynamics simulations, the potential energy profiles of solvated and partially de-solvated molecules can be superimposed to find the energy of attachment. The information obtained from molecular dynamics simulation can then further be used to simulate the motion of the solute molecule molecule in a solvent using stochastic simulations. Proper choice of simulation technique results in obtaining most probable polymorph at certain operating conditions. The ability of this multiscale model to capture the mechanics of crystallization at different time scales will be exemplified with the help of a system containing glutamic acid molecule in aqueous environment.