Stable polymorphs crystallized directly under thermodynamic control in three-dimensional nanoconfinement: A generic methodology

Thermodynamic control of crystallization has been achieved to produce stable polymorphs directly by using three-dimensional (3D) nanoconfinement in microemulsions. The theoretical basis for thermodynamic control of crystallization using 3D nanoconfinement is outlined. Our approach leap-frogs the usual metastable polymorph pathway because crystallization becomes governed by the ability to form stable nuclei, rather than critical nuclei. The generality of this approach is demonstrated by crystallizing the stable polymorph of three "problem" compounds from microemulsions under conditions yielding metastable forms in bulk solution. The polymorphic compounds are mefenamic acid (2-[(2,3-(dimethylphenyl)amino] benzoic acid), glycine (aminoethanoic acid), and the highly polymorphic 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile, commonly known as ROY because of its red, orange, and yellow polymorphs. Application of this methodology should prevent another Ritonavir-type disaster, whereby a marketed drug transforms into a more stable form, reducing its bioavailability and effectiveness. The lowest energy nuclei selectively grow in our approach. Consequently, this also provides a generic method for producing higher crystallinity materials, which may prove beneficial for crystallizing proteins and inorganic nanocrystals.