High-Pressure Studies of Pharmaceuticals: An Exploration of the Behavior of Piracetam Francesca P. A. Fabbiani,* ,² David R. Allan, ² William I. F. David, ‡ Alistair J. Davidson, ² Alistair R. Lennie, § Simon Parsons, ² Colin R. Pulham, ² and John E. Warren § School of Chemistry and Centre for Science at Extreme Conditions, The UniVersity of Edinburgh, King’s Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK, ISIS Neutron Facility, Rutherford Appleton Laboratory, Chilton, Didcot, OX11 0QX, UK, and CCLRC Daresbury Laboratory, Warrington, WA4 4AD, UK ReceiVed October 31, 2006; ReVised Manuscript ReceiVed March 14, 2007 ABSTRACT: The structural response of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) to both direct compression and high-pressure recrystallization from aqueous solution is reported. Crystals obtained by these methods have been characterized in situ by single-crystal X-ray diffraction. Compression of form II between pressures of 0.45-0.70 GPa caused a reversible, single- crystal to single-crystal transition to give a new polymorph, form V. Crystallization from a dilute aqueous solution of piracetam at a pressure of 0.6 GPa via crystallization of high-pressure ice-VI resulted in the formation of a previously unreported dihydrate. The molecular packing arrangements of these new structures are compared with the known polymorphs and hydrates of piracetam. This study highlights how the systematic variation of pressure is a powerful method for the exploration of polymorphism and solvate formation and has the potential to add a further dimension to polymorph screening of pharmaceuticals. Introduction The importance of polymorphism and solvate formation in the crystallization of organic compounds is widely recognized within the industrial and academic communities. 1 Within the pharmaceutical industry, the identification of polymorphic forms of drug compounds is of crucial importance. Polymorphs, hydrates, and solvates can be produced by a variety of standard pharmaceutical processes. 2 Two polymorphs of the same drug compound may have very different physical properties that affect bioavailability or processibility (e.g., tabletting), 3 and drug regulatory authorities demand detailed information about poly- morphism before granting licenses for product distribution. Intellectual property can also become an issue for the pharma- ceutical companies who develop and market new drug products, where challenges to patents have been made on the basis of the discovery of a new polymorph. The search for polymorphs is therefore an area of intense activity. Pharmaceutical companies deploy substantial effort and resources for the identification and characterization of polymorphs and solvates. These techniques typically involve recrystallizationsincreasingly via high- throughput robotic screeningsby varying parameters such as temperature, concentration, solvent, and relative humidity, with subsequent analysis by calorimetric, spectroscopic, and diffrac- tion techniques. 4 Almost all recrystallization studies in the pharmaceutical industry that seek to systematically screen for polymorphism and solvate formation are performed under ambient pressure. The only exceptions are a few processes that use supercritical fluidsssuch as carbon dioxidesas solvents, but the pressures rarely exceed 0.01 GPa and the pressure ranges are narrow. 5 Furthermore, the range of easily accessible super- critical solvent systems is limited to only a small number of solvents. Of more long-standing and growing interest is the effect of pressure on solid drugs during processing, since many solid drugs are subjected to mechanical action during various stages of drug manufacturing. 6,7 Typical processes include milling and grinding, both of which can cause localized increases in pressure and shear stress that can on occasion induce phase transitions. 8 The first high-pressure compression studies of pharmaceuticals date back to Bridgman. 9,10 More recently, a study of indomethacin has reported, using slurry techniques, how the relative stability of a polymorph can be modified by pressures up to 0.4 GPa. 11 This study also illustrated the importance of the solvent in mediating phase transitions since compression of γ-indomethacin in the absence of solvent did not result in a phase transition. The effects of pressure- transmitting fluids on pressure-induced transitions was also described for [Co(NH 3 ) 5 NO 2 ]I 2 . 12 Of notice are also the detailed compression studies of the polymorphs of paracetamol and fenacetine at hydrostatic conditions to 4.0 GPa 13 and of chlorpropamide A at quasihydrostatic pressure to 5.5. GPa. 14 It is well-known that the application of pressure to a wide range of materials (e.g., metals, alloys, minerals, and ices) is a very effective method for inducing phase transitions. Recent studies have demonstrated that high pressure is also effective at inducing phase transitions in a range of organic compounds such as alcohols, cyclic -diketoalkanes, carboxylic acids, and amino acids. 15-18 Comparative studies of different polymorphs of the same compound can provide a better understanding of intermolecular interactions. These interactions are important in understanding some of the properties of solid drugs, including crystallization, dissolution, and bioavailability, as well as for improving potentials used for structure and polymorph predic- * To whom the correspondence should be addressed. Present address: CCLRC Rutherford Appleton Laboratory, R3 2-24, Fermi Avenue, Chilton, OX11 0QX, UK. Tel: +44 (0)1235 445 137. Fax: +44 (0)1235 445 720. E-mail: Francescapaola@gmail.com. ² University of Edinburgh. ‡ Rutherford Appleton Laboratory. § CCLRC Daresbury Laboratory. Figure 1. Molecular structure of piracetam with numbering scheme. CRYSTAL GROWTH & DESIGN 2007 VOL. 7, NO. 6 1115 - 1124 10.1021/cg0607710 CCC: $37.00 © 2007 American Chemical Society Published on Web 05/12/2007