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Tiotropium Fumarate: An Interesting Pharmaceutical Co-Crystal

MIHAELA POP,1 PETER SIEGER,2 PETER W. CAINS1

1 2

Avantium Technologies BV, Zekeringstraat 29, 1014 BV Amsterdam, The Netherlands Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany

Received 28 April 2008; accepted 9 July 2008 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21531

ABSTRACT: A new salt–co-crystal of tiotropium fumarate with fumaric acid has been discovered, and found to be the most stable solid form of tiotropium fumarate. This type of structure consists of matched cations and anions (a salt) together with a nonionized free acid moiety as the co-former (co-crystal), and is unique amongst the large number of tiotropium salts that have been prepared and characterized. The stoichiometry cation/ anion/co-former of 2:1:1 corresponds to a simple polymorph of the 1:1 salt, and its identity as a co-crystal has been established by single-crystal X-ray diffraction with some corroborating evidence from the Raman and infrared spectra. A detailed investigation of the bonding and geometry of the three crystalline forms of the fumarate indicates that the hydrogen bonding motifs are very similar, and that conformational differences arising from the packing of the two thiophene rings into the crystal structure is probably important in determining their relative stabilities. A comparison with the structures of other tiotropium salts indicates that there is a correlation of the dihedral angle between the two tiotropium thiophene rings with the stability of the crystal forms. ß 2008 WileyLiss, Inc. and the American Pharmacists Association J Pharm Sci

Keywords: co-crystals; crystal structure; crystallization; crystals; high throughput technologies; materials science; polymorphism; spectroscopy; crystallography

INTRODUCTION

The use of co-crystals as a new class of solid forms for the consolidation of...