UBC Theses and Dissertations

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UBC Theses and Dissertations

Crystallinity changes and phase transitions of selected pharmaceutical solids with processing Wong, Marion W. Y.


The solid state properties of drugs and pharmaceutical excipients can be significantly affected by processing (e.g. grinding, tabletting, heating and additive incorporation) and reflect structural changes within a solid. Such changes may involve alterations in both the chemical and physical nature of the crystal structure (e.g. hydrates), complete rearrangements of the same chemical components in three-dimensional space (e.g. polymorphs), or more subtle changes which involve neither the chemical composition nor the space lattice. These more subtle changes do not involve phase changes and are referred to as changes in the degree of crystallinity, X. Metronidazole (MTZ), acetylsalicylic acid (ASA), diphenylhydantoin (DPH) and chiorpromazine hydrochloride (CPZ) were selected to illustrate these various changes. Many of the empirical methods which have been proposed for studying crystallinity were initially used to assess the X of MTZ before and after processing. Although a reduction and subsequent increase in X was indicated, the observed changes could not be adequately explained. The results were inconclusive and a more direct measure of X was necessary. X-ray powder diffractograms reflect the crystal structure, and when used in conjunction with the Rietveld structure refinement method, the processes which cause changes in X (i.e. crystallite size and lattice distortion) can be directly quantified. Tabletting reduced the peak intensities of ground MTZ and this was accompanied by an increase in the full width at half maximum height (FWHM). Since the unit cell dimensions were not significantly altered, reductions in crystallite size were thought to be primarily responsible for the reduction in the X of MTZ. This was confirmed using the Voigt profile function. Though the Gaussian component was slightly affected (indicating some lattice strain), it was the FWHM of the Lorentzian component of the diffractograms which showed dramatic increases with processing and subsequent reductions with time at 25°, 54°, 700 and 10000. From the Lorentzian profile, a mean crystallite size for MTZ can be obtained. Tabletting the mechanically ground MTZ further reduced the mean crystallite size. With storage at elevated temperatures, a subsequent increase in crystallite size was observed, where the rate and extent of recovery was dependent on the storage temperature (i.e. recovery at 100°C was greater than recovery at 700, 54° or 25°C). Complete recovery was not observed. The extent to which the peak intensities of ASA were reduced with processing was similar to MTZ, but the underlying structural changes were different. Significant lattice distortion was observed with a 0.5% reduction in the b dimension on tabletting. No significant recovery was found on storage at elevated temperatures. Contrary to previous workers who suggested that the incorporation of DPH with 3-propanoyloxymethyl-5,5-diphenylhydantoin (PMDPH) caused significant “lattice disorder or disruption”, no significant changes in the lattice dimensions were detected. Analysis of bond lengths suggested that the incorporation of PMDPH into the crystal lattice was unlikely. CPZ illustrated a complete change in both the chemical and physical nature of the crystal lattice with processing. Wet granulation completely converted CPZ from a room temperature metastable form to a hemihydrate of the room temperature stable polymorph. Significant differences in the tablettability of each form were shown.

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