(13b) Crystal Form Generation of Pharmaceutical Materials Using Nano-Engineered Substrates

Crystals of a chemical compound can exist in more than one structure, which is known as polymorphism. Polymorph screening, in which discovering and characterizing all possible solid forms that a target compound can have, is required in the early stage of the drug development process. In this work, a novel technology for generating different crystal forms concomitantly is described. Arrays of small solution droplets on the nano- and pico liter scale are generated using patterned substrates of SAM's¹. As the solvent evaporates from the droplets, the crystals are formed within each droplet. The solid state form of each crystal produced is characterized using Raman and optical microscopy. With mefenamic acid and sulfathiazole as model drug compounds, two and four different polymorphic forms of mefenamic acid and sulfathiazole, respectively, were observed under identical conditions. Furthermore, it is established the polymorphic distribution of crystals obtained is highly dependent on the evaporation rate of solvent and the concentration of solution. These results imply that the different polymorphic forms competitively nucleate in a solution, and the probability of each polymorph form nucleating is strongly dependent on the supersaturation of the solution. This technology complements current approaches, in that very small amount of drug substance and short times are required and large numbers of experiments can be conducted.

1. Lee, A.Y., Lee, I. S., Dette, S. S., Boerner, J. and Myerson, A. S. ?Crystallization on Confined Engineered Surfaces: A Method to Control Crystal Size and Generate Different Polymorphs,? Journal of the American Chemical Society, Vol. 127, pp 14982?14983, 2005.