RESEARCH ARTICLE Thermal, Spectroscopic, and Ab Initio Structural Characterization of Carprofen Polymorphs GIOVANNA BRUNI, 1 FABIA GOZZO, 2 DORETTA CAPSONI, 1 MARCELLA BINI, 1 PIERO MACCHI, 3 PETRA SIMONCIC, 2,3 VITTORIO BERBENNI, 1 CHIARA MILANESE, 1 ALESSANDRO GIRELLA, 1 STEFANIA FERRARI, 1 AMEDEO MARINI 1 1 C.S.G.I. Department of Physical Chemistry “M. Rolla”, Pavia 27100, Italy 2 Paul Scherrer Institut, Swiss Light Source, Villigen PSI 5232, Switzerland 3 Department of Chemistry and Biochemistry, University of Bern, Bern CH3012, Switzerland For thermal and spectroscopic investigations correspondence to: Giovanna Bruni (Telephone: +39-0382-987667; Fax: +39-0382-987670; E-mail: giovanna.bruni@unipv.it) Received 10 June 2010; revised 28 October 2010; accepted 7 December 2010 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.22470 ABSTRACT: Commercial and recrystallized polycrystalline samples of carprofen, a nons- teroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural tech- niques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the con- struction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P2 1 /c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I→II is isostructural. Poly- morphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci Keywords: ab initio structural determination; carprofen; FTIR; MDSC; polymorphism; thermal analysis; X-ray powder diffractometry; crystal structure INTRODUCTION Active principles are known to often exist under different polymorphic modifications. The search for polymorphs and the characterization of their physic- ochemical properties has become a topic of major interest. Different molecular arrangements in the crystal lattice lead to considerable differences in Additional Supporting Information may be found in the online version of this article. Supporting Information For structural investigations correspondence to: Fabia Gozzo (Telephone: +41-566-3103155; Fax: +41-56-3104551; E-mail: fabia.gozzo@psi.ch) Journal of Pharmaceutical Sciences © 2011 Wiley-Liss, Inc. and the American Pharmacists Association solubility, bioavailability, stability, and technological behavior. 1,2 Therefore, the knowledge of the polymor- phism of drugs is essential for the development of a successful pharmaceutical dosage form. Furthermore, regulatory agencies increasingly require detailed in- formation and evidence of full control on polymor- phism of drugs before allowing licensing and prod- uct distribution, making polymorphism screening of paramount importance during the formulation of a new drug. 1,3–4 Carprofen [(RS)-2-(6-chloro-9H-carbazol-2-yl)pro- panoic acid] (Fig. 1) is a nonsteroidal anti- inflammatory drug used in veterinary medicine in the treatment of patients with rheumatoid arthritis, os- teoarthritis, and acute gouty arthritis. 5–7 JOURNAL OF PHARMACEUTICAL SCIENCES 1