Binding affinity of a small molecule to an amorphous polymer in a solvent

Abstract

Crystallization is a commonly used purification process in industrial practice. It usually begins with heterogeneous nucleation on a foreign surface. The complicated mechanism of heterogeneous nucleation is not well understood, but we hypothesize a possible correlation between binding affinity to a surface and nucleation enhancement. Amorphous polymers have been used in controlling crystallization. However, to our knowledge no attempt has been made to investigate the possibility of using binding affinity to help guide the selection of polymers promoting heterogeneous nucleation. This study investigated the possibility of using binding affinity of one molecule and many molecules to help guide the selection of these polymers. To measure the binding affinity of one molecule, we developed a two-step approach to compute the free energy of binding to a binding site, using a system of ethylene glycol, polyvinyl alcohol (PVA), and heavy water (D20). The first step of our approach uses Adsorption Locator to identify probable binding sites and molecular dynamics to screen for the best binding sites. The second step employs the Blue-Moon Ensemble method to compute the free energy of binding. We then applied our procedure to the systems of aspirin binding on the surfaces of four nonporous crosslinked polymers in ethanol-water 38 v%. These polymers are poly(4- acryloylmorpholine) (PAM), poly(2-carboxyethyl acrylate) (PCEA), poly(4-hydroxylbutyl acrylate) (PHBA), and polystyrene (PS), and they all are crosslinked with divinylbenzene (DVB). We developed an approach to construct these crosslinked polymers and built three independent surfaces for each polymer. We found the similarity between the trend of heterogeneous nucleation activity and that of the average free energies of binding to the best site of each polymer surface. To measure the binding affinity of many molecules, preferential interaction coefficient and the number of aspirin molecules associated with the area of the binding site was calculated. We found that there is also a similarity between the trend of heterogeneous nucleation activity and that of number of aspirin molecules associated with the area of the binding site (taken into account the effects of polar/apolar atom interactions between an aspirin and a polymer). These results suggest the possibility of using binding affinity, especially the free energy of binding to the best site and the number of nucleating molecule, to help guide the selection of polymers promoting heterogeneous nucleation.