Effects of additives on crystallization, polymorphic transformation, and solubility
Abstract
This thesis describes the effects of additives on crystallization processes, solid-state polymorphic transformations, dissolution/solubility, and polymorph selection of pharmaceutical compounds. Model drugs were (1) flufenamic acid and (2) mefenamic acid. A structurally related compound, mefenamic acid, stabilizes the metastable form of flufenamic acid against solid state polymorphic transformation. It was shown that mefenamic acid attached on the (100) face of flufenamic acid crystals or was incorporated into flufenamic acid crystals. Stabilization could be achieved by inhibiting nucleation of the new phase and by decreasing the difference in free energy between two polymorphs. In sublimation study, it was shown that mefenamic acid Form I crystals grew on the (100) faces of flufenamic acid Form I and Form III with different affinity and orientations. Differences in affinity and orientations can be explained by comparing lattice matching pattern, hydrogen bonding patterns and conformational similarities of mefenamic acid to those of flufenamic acid polymorphs. Solubility study of flufenamic acid and mefenamic acid was conducted with solvent having different polarity. From this study, it was shown that (a) the behaviors between flufenamic acid and mefenamic acid were similar in solvent with high polarity but different in solvents with low polarity and that (b) the solubility of mefenamic acid could be increased as many as seven times in some solvents when flufenamic acid is present. The interactions between the solute and the solvent and between two different solutes seem to be the key to determining the solubility of each compound and increase in mefenamic acid solubility in the presence of flufenamic acid. Effect of additives on crystallization behavior of mefenamic acid was investigated using flufenamic acid as an additive. In this study, metastable single crystal of mefenamic acid could be obtained when flufenamic acid was added in a crystallization solvent. The metastable polymorph of mefenamic acid can be obtained by inhibiting the nucleation of the stable form in the presence of flufenamic acid. Effect of salt additives on polymorph selection of flufenamic acid was studied. In this study, the metastable Form V of FFA was induced and stabilized by using ammonium chloride as an additive.
Degree
Ph.D.
Advisors
Byrn, Purdue University.
Subject Area
Pharmacology
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