Studies on the Crystallinity of a Pharmaceutical Development Drug Substance

The crystallinity and amorphous content of a micronized pharmaceutical development drug substance have been independently determined. An evaluation of different techniques for this purpose has been carried out, and it was found that solid-state nuclear magnetic resonance (ss NMR) and X-ray powder diffraction (XRPD) were suitable for the former and latter, respectively. The baseline intensities of X-ray powder diffractograms, associated with the amorphous component of the sample, have been used to detect levels of non-crystalline material greater than 5%w/w with an absolute accuracy of ±3%. ss NMR has been employed to quantify crystalline defects at levels of greater than 3%w/w with an estimated uncertainty of ±2%. It is proposed that such crystalline defects arise from molecular conformational differences that only have a small effect on crystal lattice parameters and, by implication, only have small effects on X-ray powder diffractograms. In both cases the techniques are shown to be highly reproducible and require minimal sample preparation. Excellent linearity is demonstrated for the determination of amorphous material using prepared standards. The present account describes the choice of analytical method, method validation and the results obtained for typical samples of drug substance. It is demonstrated that solid-state NMR should be used as a complementary technique with respect to XRPD for studying crystallinity. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association