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Crystallization under Nanoscopic Confinement: A Prescription for Controlling Crystal Polymorphism. University of Minnesota MRSEC graduate students Jeong-Myeong Ha and Johanna H. Wolf, with MRSEC investigators Marc Hillmyer and Michael Ward have discovered a unique route to regulating polymorphism - the ability of a material to adopt different crystal structures - a central challenge in the production of pharmaceutical solids and commercially important specialty materials. Decades of investigation, however, have failed to produce reliable and universal strategies for control of polymorphism during crystallization. Considerable effort and resources are expended by the pharmaceutical industry to discover and characterize polymorphs, largely because of their impact on bioavailability and shelf stability (against transformations to other polymorphs) of the product.Comprehensive profiling of polymorphism is mandated by new FDA regulations to ensure consistent manufacture of preferred crystal forms. Similar challenges exist for agrochemicals, for which the efficacy of delivery through leaf surfaces has economic and environmental consequences, and crystalline organic electronic materials, for which solid state properties hinge on crystal structure.

Figure 1. Scanning electron micrographs of (A) commercially available controlled porous glass (CPG) with a pore diameter (d) @ 55 nm, and (B) a platinum coated (ca. 2 nm thick) porous PCHE monolith with a hexagonal array of cylindrical pores (d @ 30 nm). Insets: Schematic representations of nanocrystals grown in the pores.

Any crystallization process involves the assembly of molecular growth units into nuclei, which become stable and grow into mature crystals upon achieving a critical size that is specific for a particular polymorph. By confining crystallization to nanopores with prescribed dimensions comparable with the critical sizes of the polymorphs (typically nanometer scale), Ha and co-workers achieved selective crystallization of certain polymorphs of anthranilic acid (AA) and 5-methyl-2-[(2-nitrophyenyl)amino]-3-thiophenecarbonitrile (ROY) - the latter an important intermediate in the production of the pharmaceutical olanzapine. The nanopores, which can be viewed as miniature crystallization reactors, were created by selective etching of glass beads and block copolymer monoliths through techniques that produced a variety of pore dimensions but with a high degree of uniformity. By dialing in a pore size that is smaller than the critical size of unwanted polymorphs, selective crystallization of desired forms with critical sizes less than the pore dimensions can be achieved. For example, polymorph III of AA crystallizes from the melt on nonporous glass beads or within larger pores, but metastable polymorph II crystallizes in pores with diameters < 23 nm. Of the six ROY polymorphs only the red form (R) crystallizes from the melt in 30 nm pores of porous poly(cyclohexylethylene). The ability to achieve polymorph selectivity in both glass and polymer matrices suggests wide-ranging compatibility with various organic crystalline solids, promising a new approach to controlling polymorphism and searching for unknown polymorphs. [Jeong-Myeong Ha, Johanna H. Wolf, Marc A. Hillmyer,and Michael D. Ward J. Am. Chem. Soc, 2004, 126, 3382]