Use of sublimation catalysis and polycrystalline powder templates for polymorph control of gas phase crystallization

Abstract

In pursuit of a solvent-free green alternative to solution-based processes, we have applied the combined use of catalytic additives and polycrystalline powder templates for polymorph control of gas phase crystallization to a range of pharmaceuticals and related compounds. Complementary volatile additives have been found that can catalyze the sublimation of a range of typical active pharmaceutical ingredients (APIs). Sublimation temperatures are typically reduced by up to 20 °C, and the process is accelerated. The use of polycrystalline powder templates for polymorph control has also been successfully applied in several cases. Temperature control at the sites of both sublimation and desublimation is often required. The absence of even traces of solvent in the polymorphs produced appears to give the samples higher stability than samples obtained by crystallization from solution. Complete polymorph control was achieved with the following APIs, carbamazepine (five polymorphs), metaxalone (two polymorphs), mefenamic acid (two polymorphs), paracetamol (two polymorphs), and ortho-, meta-, and para-amino benzoic acids (one, four, and two polymorphs respectively).