Atomic mobility of selected pharmaceutical compounds

Pascal Henri Toma, Purdue University

Abstract

The long range goal of this research is to investigate the applicability of X-ray crystallography and solid state NMR to studies of atomic mobility in compounds of pharmaceutical importance. The general approach for the X-ray studies involves determining accurate anisotropic displacement parameters (ADP). Using single crystal X-ray diffraction, data were collected on a crystal at various temperatures to determine the change in the ADPs of the atoms with temperature. The crystal structure of hexyl p-aminobenzoate has been studied at five different temperatures between 98 and 298 K. The ADPs of each atom were determined and plotted versus temperature; a linear relationship was observed. The resulting slopes are inversely proportional to an energy barrier related to the motion of the atoms. Thus selected pharmaceutical compounds containing at least two unequivalent methyl carbons were chosen to determine a relative mobility for similar groups. The X-ray temperature studies were performed on Ibuprofen, Indomethacin, and Phenacetin. The slopes of the ADPs versus temperature were calculated for all the atoms and correlated with relative atomic mobility. Using solid-state NMR, the spin-lattice relaxation times (T$\sbsp{1}{c}$'s) of methyl carbon atoms were measured at temperatures between 203 and 293 K from which activation energies associated with methyl spinning were calculated. The solid-state NMR studies of the p-aminobenzoate derivatives, Ibuprofen, Indomethacin and Phenacetin were performed to calculate the activation energies of the different methyl carbon atoms. A correlation between the results of the X-ray and the solid state NMR studies was hypothesized, and related to the relative atomic mobility in the crystal lattice. The two techniques agreed for all three compounds, yielding similar relative activation energies for methyl rotation. The effect of water on Cefazolin sodium (CEZ) was also investigated using X-ray diffraction and solid-state NMR. Using low-temperature crystallography, a more accurate structure of Cefazolin sodium pentahydrate was redetermined. Using solid-state NMR, the spectra of the different forms (amorphous, monohydrate, and pentahydrate) of CEZ were compared. The T$\sbsp{1}{c}$'s of the methyl carbon were investigated as the amount of water in the sample was altered.

Degree

Ph.D.

Advisors

Byrn, Purdue University.

Subject Area

Pharmacology|Analytical chemistry

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