Transmission Electron Microscopy of Pharmaceutical Materials

Transmission electron microscopy (TEM) and its facility for electron diffraction has long been a key technique in materials science. Its use for characterization of pharmaceutical samples has, however, been very limited, largely due to the difficulties associated with the preparation of appropriately thin samples, as well as issues with sample damage caused by the electron beam. In this overview, we describe straightforward approaches for overcoming these issues which have enabled us to characterize a variety of pharmaceutical compounds, including theophylline, paracetamol and aspirin, and also pharmaceutical salts and cocrystals. A range of relevant information about these compounds is derived including morphology, polymorph identification, mapping of crystal habit to crystal structure and crystal defect characterization. With theophylline, we identify crystals of "impurity" polymorphic phases in samples that appear from powder X-ray diffraction to be monophasic, and observe that crystal growth behavior of samples prepared from nitromethane is significantly different to that of samples prepared from methanol. The existence of imperfections, such as dislocations, is also established and these are shown to be likely sites at which fracturing occurs when the crystals are stressed. The results demonstrate that various issues associated with pharmaceutical form development might usefully be addressed using TEM. (C) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4072-4083, 2010