Polymorph-Directing Seeding of Entacapone Crystallization in Aqueous/Acetone Solution Using a Self-Assembled Molecular Layer on Au (100)

Abstract

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.

Surface Adsorbed Templates for Directing the Crystal Growth of Entacapone as Monitored Using Process Analytical Techniques

“…The solubility of Entacapone in acetone solution was found to be several orders of magnitude higher than for the mixed aqueous/acetone solution studied previously 6 and close to the ideal predicted (Figure 3), revealing that solute/solute interactions are preferred for both solvents but that solute/solvent interactions in acetone is perhaps a bit stronger in the absence of water. Such wide MSZWs are not that uncommon for organic systems 25,26 .…”

“…Indeed, it is a common and anecdotal observation in industrial crystallization practice that the first crystallisation in a freshly cleaned reactor can be quite different in nature with respect to subsequent crystallisations (see e.g. reference 6 ). This is often related to surface effects, e.g.…”

“…Moreover, these ordered ad-layers have been shown to make a significant impact on the crystallisation process through inducing nucleation at significantly lower supersaturations and directing the solid-state properties of the resulting crystals resulting in the formation of the stable polymorphic form which is crystallised with a much narrower crystal size distribution and superior crystal perfection and morphology. In this study 6 the metastable zone width and nucleation kinetics were characterized with and without the presence of a nucleation (seeding) template. In this paper the work is extended using an ATR-UVvis spectroscopy and FBRM, to access the templates influence of crystal growth kinetics.…”

Fast real-time monitoring of entacapone crystallization and characterization of polymorphs via Raman spectroscopy, statistics and SWAXS

“…Full Surface-enhanced Raman spectroscopy (SERS) has been recently used for quantitative analysis of the two isomers in solution (30). It has also been demonstrated that the E-isomer crystallizes in six polymorphic forms, named A' (25), D (26), a, b, g and d (27), the first two being the most common in polar solvents (28). Furthermore, form A has been found to be the most stable phase thermodynamically.…”

“…Entacapone is clinically used as a therapy for Parkinson's disease (25), which is associated with a lack of dopamine. The solvents were chosen according to the solubility of entacapone and the fact that they were common solvents used in the production process (26)(27)(28).…”