Thermodynamic and kinetic control of the crystallization of polymorphs
Abstract
The purpose of the present study is to control the crystallization of polymorphs through a thermodynamic and kinetic approach. The first project involves a thermodynamic control of crystallization of polymorphs. The model compound has four energetically similar polymorphs. The thermodynamic relationships of these four forms were obtained by a variety of solid-state techniques, and an energy-temperature diagram was constructed based on the characterization studies. The energy-temperature diagram provides insights into how to control the crystallization of all the polymorphs. The second project demonstrates a kinetic approach for controlling the crystallization of polymorphs. The model compound has three colored polymorphs. To stabilize the metastable form A, two iso-structural additives 4-chloro-2-nitroacetanilide (4Cl) and 4-trifluoromethyl-2-nitroacetanilide (4CF3) were synthesized. It was found that the incorporation efficiency of both 4Cl and 4CF3 into A is much higher than that into polymorphs W and Y. Once the incorporation level exceeds a certain threshold, both additives kinetically stabilize the metastable A. To understand why the additives stabilize A, Cerius2 was used to study the molecular interaction between additives and WAY. It was found that the distances between F/Cl and O atoms are significantly shorter in W than in A. Thus, 4Cl and 4CF 3 may cause stronger electrostatic repulsion in W, and are more disruptive to the W lattice than the A lattice.
Degree
Ph.D.
Advisors
Byrn, Purdue University.
Subject Area
Pharmaceuticals
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