Crystallization of the active pharmaceutical ingredient Entacapone, which exhibits strong polymorphic behavior in aqueous/acetone solutions, is examined with and without the presence of a self-assembled molecular layer of Entacapone (SALE) on an Au (100) surface. SALE characterization by electrochemical and spectroscopic tools confirms the existence of a well-ordered layer structure. These surfaces are found to act as nucleation catalysts providing polymorph-specific templates which enable secondary nucleation through provision of oriented adsorption and molecular recognition at the SALE/solution interface. In particular, crystallization of the stable prismatic polymorphic form A is observed from aqueous/acetone solutions in the presence of an SALE compared to needle-shaped crystals of the metastable form D which usually form. The quiescent crystallization of Entacapone from the same aqueous/acetone solutions in the presence of an Au (100) surface produces an assembly of single crystals form A epitaxially grown at the surface with concomitantly form D being produced in the bulk solution confirming the surface-sensitive nature of the crystallization process. The research reveals the possibility of switching nucleation from uncontrolled nucleation sites toward a more directed crystallization process, and hence more stable polymorphic form, through the selective choice of adsorbed species. The future potential of this concept and methodology for larger scale size processes is discussed.
The ability to direct the surface crystallisation of different polymorphs of entacapone by tuning the electrochemical potential of Au (100) (100) is negatively polarized (-150 mV), form D is still formed in the bulk solution but the metastable form is found to crystallise at the edges of the template. Both crystals of form A and were observed to grow epitaxially over the Au template surface. The electrochemical templating effect is consistent with the polarisation changing the structure of the initially adsorbed layers of supersaturated solution at the template surface which directs the nuclei formation and the subsequent crystal growth processes. This study demonstrates, for the first time, the direction of polymorphic form using a low field polarized nucleation template.
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