Solid -state phase transformation of polymorphic organics: Kinetics and mechanism

Hui Li, Purdue University

Abstract

The structure adopted by a given compound when it is crystallized normally exerts a profound effect on the solid-state properties of that system. Of pharmaceutical concern is that different polymorphic forms may give different dissolution rates and different degrees of biological absorption. Phase transformation in the solid-state can affect the physical stability, chemical stability, and mechanical processing of a formulation. The complete study of phase transformation, both kinetics and mechanism, helps in the design of a robust formulation which will prevent an unwanted phase transformation during manufacture, especially at later stages, and storage. This study was carried out to test the hypothesis that the rate of phase transformation in the solid-state is correlated to the density/activity of the defects carried by the crystals: the higher the crystal density/activity, the higher the phase transformation rate. The model compounds used in this study were 5-methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile (4′-Me) and flufenamic acid. For both systems, it was shown that larger particles transform faster than smaller ones crystallized from the same batch. Atomic force microscopy studies show that larger crystals developed more defects than smaller ones during crystal growth. Another compound, 2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (5-Nor-Me), was synthesized and the thermodynamic stability of its polymorphs was studied for the purpose of comparing phase transformation kinetics with 4′-Me. The results indicate that the former compound transforms much slower than the latter one, even though the free energy difference between polymorph pairs is very similar. Various factors, such as temperature, relative humidity, seeding and grinding, accelerate the rate of phase transformation. The dramatic effect of relative humidity on the physical stability of hydrophobic compounds indicates that RH should be strictly controlled during processing for every system. The acceleration effect of seeding on phase transformation shows the importance of crystallizing pure polymorphs.

Degree

Ph.D.

Advisors

Byrn, Purdue University.

Subject Area

Pharmaceuticals

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