Solid-state investigations of methyl group mobility in selected pharmaceutical derivatives and pseudopolymorphs
Abstract
The aim of this study is to test the hypothesis that the mobility of a molecule in the solid state can be calculated from its crystal structure. We are investigating the concept that solid-state thermal stability is related to the mobility of the reactant in the solid state. For the first time experimental and calculated methods for measuring solid-state mobility are compared in small pharmaceutical compounds. Solid-state NMR is used to measure $\sp{13}$C $T\sb1$ relaxation times for the $\alpha$-methyl group in ibuprofen and its derivatives flurbiprofen, ketoprofen, and naproxen. Molecular dynamics simulations are used to derive free energies and order parameters. Poor correlations are revealed when rank ordering these variables. In order to simplify the system, we decided to investigate the isostructural small-alcohol solvates of cholic acid, methyl cholate, and sodium cholate. Mobility of both the steroid and solvent molecules are examined. Since each series of solvates is isostructural, it is hypothesized that the solvent mobility will decrease as the size of the solvent molecule increases. The results indicate that the solvent mobility decreases as the solvent increases in size from methanol through ethanol to propanol. During the course of these steroid mobility studies, single crystal X-ray diffraction, X-ray powder diffraction, thermal analysis, and Karl Fischer titrimetry are used to examine the various pseudopolymorphic forms of cholamide, methyl cholate, and sodium cholate. The crystal structures of nine new cholamide solvates are reported. Unlike the small-alcohol solvates of cholic acid and methyl cholate, the small-alcohol solvates of cholamide are not isostructural. The first hydrated forms of the N-methylated cholamide derivatives are also reported. Preliminary hydration studies are presented for cholamide, N-methylcholamide, and N,N-dimethylcholamide. New pseudopolymorphic forms of methyl cholate and sodium cholate are investigated. X-ray crystal structures for four alcohol solvates are reported. Two new methyl cholate forms are examined and discussed. Powder diffraction studies reveal that the alcohol solvates of sodium cholate change form during air-drying. In conclusion, the results of the calculations on the isostructural pscudopolymorphs were promising for this simplest system. Subsequent studies on other systems are recommended.
Degree
Ph.D.
Advisors
Byrn, Purdue University.
Subject Area
Pharmacology|Analytical chemistry|Chemistry
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.