Indomethacin–Saccharin Cocrystal: Design, Synthesis and Preliminary Pharmaceutical Characterization
- 4k Downloads
To design and prepare cocrystals of indomethacin using crystal engineering approaches, with the ultimate objective of improving the physical properties of indomethacin, especially solubility and dissolution rate.
Materials and Methods
Various cocrystal formers, including saccharin, were used in endeavours to obtain indomethacin cocrystals by slow evaporation from a series of solvents. The melting point of crystalline phases was determined. The potential cocrystalline phase was characterized by DSC, IR, Raman and PXRD techniques. The indomethacin–saccharin cocrystal (hereafter IND–SAC cocrystal) structure was determined from single crystal X-ray diffraction data. Pharmaceutically relevant properties such as the dissolution rate and dynamic vapour sorption (DVS) of the IND–SAC cocrystal were evaluated. Solid state and liquid-assisted (solvent-drop) cogrinding methods were also applied to indomethacin and saccharin.
The IND–SAC cocrystals were obtained from ethyl acetate. Physical characterization showed that the IND–SAC cocrystal is unique vis-à-vis thermal, spectroscopic and X-ray diffraction properties. The cocrystals were obtained in a 1:1 ratio with a carboxylic acid and imide dimer synthons. The dissolution rate of IND–SAC cocrystal system was considerably faster than that of the stable indomethacin γ-form. DVS studies indicated that the cocrystals gained less than 0.05% in weight at 98%RH. IND–SAC cocrystal was also obtained by solid state and liquid-assisted cogrinding methods.
The IND–SAC cocrystal was formed with a unique and interesting carboxylic acid and imide dimer synthons interconnected by weak N−H⋯O hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (γ-form).
Key wordscrystal engineering dissolution rate indomethacin pharmaceutical cocrystals poorly soluble drugs
We acknowledge ‘Norbottensforskningsråd’ and ‘Kempestiftelserna’ for the project grant (NoFo 05-011) and instrumental grant respectively. We thank Surface Measurement Systems, UK, for the DVS studies. We wish to thank Mr. Amjad Alhalaweh for his laboratory assistance with the dissolution studies.
- 1.H. Brittain. Polymorphism in pharmaceutical solids. Marcel Dekker, New York, 1999, p. 95.Google Scholar
- 3.S. R. Byrn, R. P. Pfeiffer, and J. G. Stowell. Solid State Chemistry of Drugs, SSCI Inc, West Lafayete, IN, 1999.Google Scholar
- 5.P. H. Stahl and C. G. Wermuth. Handbook of pharmaceutical salts, Verlag Helvetica Chimica Acta; Zurich and Wiley-VCH, Weinheim, 2002.Google Scholar
- 8.C. B. Aakeröy and D. J. Salmon. Building co-crystals with molecular sense and supramolecular sensibility. Cryst. Eng. Comm. 7:439–448 (2005).Google Scholar
- 9.Ö. Almarsson and M. J. Zaworotko. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem. Commun. (Camb.) 1889–1896 (2004).Google Scholar
- 10.M. C. Etter. Hydrogen bonds as design elements in organic chemistry. J. Phys. Chem. 95:4601–4610 (1990).Google Scholar
- 11.M. C. Etter. Hydrogen bond directed cocrystallization and molecular recognition properties of acyclic imides. J. Am. Chem. Soc. 113 (1991).Google Scholar
- 15.S. L. Childs, L. J. Chyall, J. T. Dunlap, V. N. Smolenskaya, B. C. Stahly, and G. P. Stahly. Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids. J. Am. Chem. Soc. 126:13335–13342 (2004).PubMedCrossRefGoogle Scholar
- 16.J. R. Dipalma. Basic Pharmacology in Medicine, McGraw-Hill, New York, 1976.Google Scholar
- 21.R. D. B. Walsh, M. W. Bradner, S. Fleischman, L. A. Morales, B. Moulton, N. Rodriguez-Hornedo, and M. J. Zaworotko. Crystal engineering of the composition of pharmaceutical phases. Chem. Commun. 186–187 (2003).Google Scholar
- 24.G. M. Sheldrick. SHELX-97: Program for the Solution and refinement of Crystal Structures, University of Göttingen, Germany, 1997.Google Scholar
- 26.P. J. Cox and P. L. Manson. Indomethacin tert-butanol solvate at 120 K. Acta Crystallogr. E59:o1189–o1191 (2003).Google Scholar
- 28.J. G. Stowell, S. R. Byrn, G. Zografi, and M. Yoshioka. Private Communication (2002).Google Scholar
- 29.J. L. Wardell, J. N. Low, and C. Glidewell. Saccharin, redetermined at 120 K: a three-dimensional hydrogen-bonded framework. Acta Crystallogr. E61:o1944–o1946 (2005).Google Scholar
- 30.S. G. Fleischman, S. S. Kuduva, J. A. McMahon, B. Moulton, R. D. B. Walsh, N. Rodriguez-Hornedo, and M. J. Zaworotko. Crystal engineering of the composition of pharmaceutical phases: multiple-component crystalline solids involving carbamazepine. Cryst. Growth Des. 3:909–919 (2003).CrossRefGoogle Scholar
- 31.The refcodes of the crystal structures with acid-dimer and imide-dimer or amide dimer synthons in the CSD: Acid-Imide: XUNHIX, XUNHUJ, GUGCUG, PAXNIL, YEJMOP. Acid-Amide: LORRIT, NUHYEU, TORQIA, TORQOG, WARXIW.Google Scholar
- 32.M. O’Brien, J. McCauley, and E. Cohen. Indomethacin. Anal. Profiles Drug Subst. 13:211–238 (1984).Google Scholar
- 33.G. Jovanovski. Metal saccharinates and their complexes with N-donor ligands. CCACAA 73:843–868 (2000)Google Scholar
- 37.Simulated PXRD pattern from single crystal X-ray diffraction obtained from CSD (Ref code: SCCHRN02).Google Scholar