Role of Molecular, Crystal, and Surface Chemistry in Directing the Crystallization of Entacapone Polymorphs on the Au(111) Template Surface

Abstract

The pharmaceutical compound entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide) is important in the treatment of Parkinson’s disease, exhibiting interesting polymorphic behavior upon crystallization from solution. It consistently produces its stable form A with a uniform crystal size distribution on the surface of an Au(111) template while concomitantly forming its metastable form D within the same bulk solution. Molecular modeling using empirical atomistic force-fields reveals more complex molecular and intermolecular structures for form D compared to form A, with the crystal chemistry of both polymorphs being dominated by van der Waals and π–π stacking interactions with lower contributions (ca. 20%) from hydrogen bonding and electrostatic interactions. Comparative lattice energies and convergence for the polymorphs are consistent with the observed concomitant polymorphic behavior. Synthon characterization reveals an elongated needle-like morphology for form D crystals in contrast to the more equant form A crystals with the surface chemistry of the latter exposing the molecules’ cyano groups on its {010} and {011} habit faces. Density functional theory modeling of surface adsorption reveals preferential interactions between Au and the synthon GA interactions of form A on the Au surface. Molecular dynamics modeling of the entacapone/gold interface reveals the entacapone molecular structure within the first adsorbed layer to show nearly identical interaction distances, for both the molecules within form A or D with respect to the Au surface, while in the second and third layers when entacapone molecule–molecule interactions overtake the interactions between those of molecule–Au, the intermolecular structures are found to be closer to the form A structure than form D. In these layers, synthon GA (form A) could be reproduced with just two small azimuthal rotations (5° and 15°) whereas the closest alignment to a form D synthon requires larger azimuthal rotations (15° and 40°). The cyano functional group interactions with the Au template dominate interfacial interactions with these groups being aligned parallel to the Au surface and with nearest neighbor distances to Au atoms more closely matching those in form A than form D. The overall polymorph direction pathway thus encompasses consideration of molecular, crystal, and surface chemistry factors.

Influence of Solvent Selection on the Crystallizability and Polymorphic Selectivity Associated with the Formation of the “Disappeared” Form I Polymorph of Ritonavir

“…In this, at the nucleation on-set point, the higher supersaturations would produce smaller critical cluster sizes, stabilizing the metastable form. 50 , 72 , 99 The PXRD analysis is supported by reference DSC data for forms I and II of ritonavir which are given in Figure S1 ( Supporting Information ) and reveal endothermic melting peaks at around 123 °C for form I and 126 °C for form II. 84 , 100 The observed melting points for the form I isolated from the four solvents were found to fluctuate slightly from 123 °C in toluene to 125 °C in acetone with their enthalpies of fusion calculated based on the DSC data increasing from 38.43 to 41.19 kJ mol –1 and the full widths at half-maximum decreasing from 3.45 to 2.21 °C [see Table S1 ( Supporting Information ) for further details], reflecting, perhaps, the different crystallinity and morphology of the associated solid forms.…”

“…In this, at the nucleation on-set point, the higher supersaturations would produce smaller critical cluster sizes, stabilizing the metastable form. 50,72,99 The PXRD analysis is supported by reference DSC S1 (Supporting Information) for further details], reflecting, perhaps, the different crystallinity and morphology of the associated solid forms.…”

“…In silico methods, such as molecular dynamics (MD) simulations, have been widely used to capture the dynamical behavior of the explicit intermolecular interactions within the solution phase both qualitatively and also quantitatively by developing an understanding of the molecular and intermolecular assembly behavior during the crystal nucleation process associated with crystallization from solutions (e.g., refs ,– ). Recently, some detailed methods have been developed to characterize the propensity of incipient bulk synthons within the solution state through the targeted analysis of the MD trajectory files. ,, …”

Influence of the crystallisation solution environment on the structural pathway from solute solvation to the polymorphic forms of tolfenamic acid

“…The development of computational molecular-scale modelling has contributed significantly to the understanding of the thermodynamic properties within the solution state, especially when integrated with experimental data. A variety of molecular-scale computation methods have been successfully applied to the characterisation of the solid state and solution chemistry, 2,5,16,24–41 such as ab initio quantum mechanics using density functional theory (DFT) and molecular dynamics (MD) and molecular mechanics (MM) simulations using parametrised empirical interatomic force fields. Although providing high accuracy, DFT calculations and MD simulations can make a significantly high demand on both computer power and calculation time.…”