Determination of the Crystal Structure of a New Polymorph of Theophylline

• Published in: Chemistry : a European journal 2013-06, Vol.19 (24), p.7883-7888
• Main Authors: Eddleston, Mark D., Hejczyk, Katarzyna E., Bithell, Erica G., Day, Graeme M., Jones, William
• Format: Article
• Language: English
• Subjects: analytical methods; Chemistry; computational chemistry; Crystal structure; Crystallites; Electron diffraction; Electron microscopy; Electrons; Indexing; Mathematical analysis; Microscopy, Electron, Transmission - methods; Pharmaceuticals; polymorphism; structure elucidation; Theophylline; Theophylline - chemistry; Theophylline - pharmacology; Transmission electron microscopy
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201204369

A new approach to crystal structure determination, combining crystal structure prediction and transmission electron microscopy, was used to identify a potential new crystal phase of the pharmaceutical compound theophylline. The crystal structure was determined despite the new polymorph occurring as a minor component in a mixture with Form II of theophylline, at a concentration below the limits of detection of analytical methods routinely used for pharmaceutical characterisation. Detection and characterisation of crystallites of this new form were achieved with transmission electron microscopy, exploiting the combination of high magnification imaging and electron diffraction measurements. A plausible crystal structure was identified by indexing experimental electron‐diffraction patterns from a single crystallite of the new polymorph against a reference set of putative crystal structures of theophylline generated by global lattice energy minimisation calculations. Crystal structure of an organic picogram crystal: With a combination of electron diffraction and crystal structure prediction it was possible to propose the structure of a new crystal form of the pharmaceutical compound theophylline. This analysis was performed on a single crystallite (pictured), with a thickness of approximately 0.3 μm, present in a sample consisting predominantly of Form II of theophylline, a situation for which conventional X‐ray based approaches to crystal structure determination would not be applicable.