(301c) Free Energy of Binding of a Small Molecule to An Amorphous Polymer In a Solvent

Crystallization is a commonly used purification process in the pharmaceutical industry. Binding of a small molecule to a substrate is a first crucial step, leading to heterogeneous nucleation and crystallization. Amorphous polymeric substrates have been proven useful in controlling crystallization and discovering novel pharmaceutical polymorphs. However, no attempt has been made to calculate the free energy of binding of a small molecule to an amorphous polymer in a solvent, and to characterize the binding sites/conformations of this system in a molecular level. We developed a two-step approach using first Adsorption Locator to identify probable binding sites and molecular dynamics to screen for the best binding sites, and then using the Blue-Moon Ensemble method to compute the free energy of binding. A system of ethylene glycol, polyvinyl alcohol, and heavy water (D2O) was used as a model. Looking at four independently constructed surfaces, we found that ethylene glycol binds to an indentation on the surface or in a hole beneath the surface. We focused on the indentation binding sites because ethylene glycol does not have to overcome large free energy barriers to bind to these sites, and found that the free energy of binding of the three best binding sites are in reasonable agreement with the experimental value (within 0.4 ? 3.7 kcal/mol). Our approach offers a way to compute the free energy of binding, characterize the binding sites/conformations and is general enough to apply to other small molecule/amorphous polymer/solvent systems.