Solid-state NMR study of polymorphism in pharmaceuticals

Abstract

This thesis is concerned with attempts to establish solid-state NMR as a complementary technique to X-ray crystallography for providing information on crystal structure, i.e. information regarding conformation, packing and inter- or intra-molecular interactions. Methods of assigning the solid-state NMR spectrum have been used which rely upon (^1)H-(^13)C dipolar interactions and upon the shielding anisotropy experienced by the nuclei. Single pulse experiments have also been used to identify solvate molecules. Of particular importance, the anisotropy and asymmetry have been found for a number of steroids, and the values used to assign the high frequency region of the spectrum. This has enabled chemical shifts to be linked to the hydrogen bonds that are present. Thus, the mode of hydrogen bonding can be predicted in forms of cortisone acetate for which the crystal structure is not available. Chemical shifts have also been linked with the conformation of the D ring. In this way, important crystallographic information has been gleaned from the solid-state NMR spectrum. The effect of the formation of hydrogen bonds upon the shielding tensor components of carbonyl and ester carbons has been studied, and found to cause a high frequency shift in δ22, which is probably oriented along the C=0 bonds. This leads to a high frequency shift in the isotropic chemical shift. The effect of the spinning speed upon the centreband intensity of a peak as the anisotropy and asymmetry are varied has been investigated. It has been found that at low spiiming speeds, the centreband intensity does not vary in a simple fashion. Thus it is recommended that full shielding tensor analysis is performed. The effect of the spinning speed on the sample temperature has also been studied. Results show that at low spinning speeds (up to 2 kHz) there is sample cooling as the spinning speed increases (attributed to the Joule -Thompson effect). But at higher spinning speeds (above 2 kHz) then there is sample heating as the spinning speed increases. The importance of this result is discussed. The effect of quadrupolar nuclei (35C1 and (^14)N) upon the spectrum of a spin-(^1)(_2) nucleus ((^13)C) has been studied. In favourable cases, the anisotropy in the spin-spin coupling constant has been found, whilst in other cases, the sign and magnitude of the quadrupolar coupling constant have been obtained. The broadening of resonances of carbon atoms adjacent to quadrupolar nuclei has been valuable in assigning the solid-state NMR spectra. The broadening effect has also been observed at more distant sites. It has not been possible to distinguish the effects of (^37)C1 and (^35)C1 on the carbon spectra of chlorine containing steroids.