New Metastable Packing Polymorph of Donepezil Grown on Stable Polymorph Substrates

We obtained a new metastable packing polymorph of donepezil, designated as form K, epitaxially grown on substrate crystals of the more stable form F, or solely by increasing the concentration. Although donepezil is a highly flexible molecule, crystal structure analysis reveals that the molecular conformation is the same as in form F. Donepezil does not form hydrogen bonds and has no appreciable electrostatic interactions. Form K crystals can be grown homogeneously, i.e., without seeds, from highly supersaturated solutions (S > 12). However, in the presence of form F substrates, formation of form K is observed at supersaturations as low as S 2-3. This suggests form F can serve as a template to form K crystals. Both polymorphs share a structurally identical, common feature of inversion-related molecules. The structures differ in their translational symmetry; hence, they are packing polymorphs. By superimposing the structures and conducting structure fragment calculation using the XPac program, a common two-dimensional plane was identified, the (010) of form F and the (0 (1) over bar1) of form K. Using calculated BFDH morphologies, oriented in their superimposed orientations, epitaxial growth of form K on form F substrate crystals can be made plausible to occur in this fashion. The template effect can thus be understood as resulting from the 2D lattice match, resulting in a low interfacial energy, therefore leading to a low nucleation barrier.