Pharmaceutical Research

, Volume 25, Issue 3, pp 530–541 | Cite as

Indomethacin–Saccharin Cocrystal: Design, Synthesis and Preliminary Pharmaceutical Characterization

  • Srinivas Basavoju
  • Dan Boström
  • Sitaram P. VelagaEmail author
Research Paper



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 words

crystal 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.

Supplementary material

11095_2007_9394_MOESM1_ESM.doc (6.9 mb)
Supplementary Information (DOC 6.87 MB)


  1. 1.
    H. Brittain. Polymorphism in pharmaceutical solids. Marcel Dekker, New York, 1999, p. 95.Google Scholar
  2. 2.
    S. M. Berge, L. D. Bighley, and D. C. Monkhouse. Pharmaceutical salts. J. Pharm. Sci. 66:1–19 (1977).PubMedCrossRefGoogle Scholar
  3. 3.
    S. R. Byrn, R. P. Pfeiffer, and J. G. Stowell. Solid State Chemistry of Drugs, SSCI Inc, West Lafayete, IN, 1999.Google Scholar
  4. 4.
    A. T. M. Serajuddin. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J. Pharm. Sci. 88:1058–1066 (1999).PubMedCrossRefGoogle Scholar
  5. 5.
    P. H. Stahl and C. G. Wermuth. Handbook of pharmaceutical salts, Verlag Helvetica Chimica Acta; Zurich and Wiley-VCH, Weinheim, 2002.Google Scholar
  6. 6.
    A. M. Kaushal, P. Gupta, and A. K. Bansal. Amorphous drug delivery systems: Molecular aspects, design and performance. Crit. Rev. in Ther. Drug Carrier Syst. 21:133–193 (2004).CrossRefGoogle Scholar
  7. 7.
    D. P. McNamara, S. L. Childs, J. Giordano, A. Iarriccio, J. Cassidy, M. S. Shet, R. Mannion, E. O’Donnell, and A. Park. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm. Res. 23:1888–1897 (2006).PubMedCrossRefGoogle Scholar
  8. 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. 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. 10.
    M. C. Etter. Hydrogen bonds as design elements in organic chemistry. J. Phys. Chem. 95:4601–4610 (1990).Google Scholar
  11. 11.
    M. C. Etter. Hydrogen bond directed cocrystallization and molecular recognition properties of acyclic imides. J. Am. Chem. Soc. 113 (1991).Google Scholar
  12. 12.
    G. R. Desiraju. Supramolecular synthons in crystal engineering—a new organic synthesis. Angew. Chem., Int. Ed. Engl. 34:2311–2327 (1995).CrossRefGoogle Scholar
  13. 13.
    P. Vishweshwar, J. A. McMahon, J. A. Bis, and M. J. Zaworotko. Pharmaceutical co-crystals. J. Pharm. Sci. 95:499–516 (2006).PubMedCrossRefGoogle Scholar
  14. 14.
    A. V. Trask, W. D. Motherwell, and W. Jones. Physical stability enhancement of theophylline via cocrystallization. Int. J. Pharm. 320:114–123 (2006).PubMedCrossRefGoogle Scholar
  15. 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. 16.
    J. R. Dipalma. Basic Pharmacology in Medicine, McGraw-Hill, New York, 1976.Google Scholar
  17. 17.
    P. A. Slavina, D. B. Sheena, E. E. A. Shepherda, J. N. Sherwooda, N. Feederb, R. Dochertyb, and S. Milojevic. Morphological evaluation of the γ-polymorph of indomethacin. J. Cryst. Growth 237–239:300–305 (2002).CrossRefGoogle Scholar
  18. 18.
    T. Matsumoto and G. Zografi. Physical properties of solid molecular dispersions of indomethacin with poly(vinylpyrrolidone) and poly(vinylpyrrolidone-co-vinyl-acetate) in relation to indomethacin crystallization. Pharm. Res. 16:1722–1728 (1999).PubMedCrossRefGoogle Scholar
  19. 19.
    N. Bandi, W. Wei, C. B. Roberts, L. P. Kotra, and U. B. Kompella. Preparation of budesonide and indomethacin hydroxypropyl-beta-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur. J. Pharm. Sci. 23:159–168 (2004).PubMedCrossRefGoogle Scholar
  20. 20.
    M. Yoshioka, B. C. Hancock, and G. Zografi. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J. Pharm. Sci. 83:1700–1705 (1994).PubMedCrossRefGoogle Scholar
  21. 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
  22. 22.
    R. Banerjee, P. M. Bhatt, N. V. Ravindra, and G. R. Desiraju. Saccharin salts of active pharmaceutical ingredients, their crystal structures, and increased water solubilities. Cryst. Growth Des. 5:2299–2309 (2005).CrossRefGoogle Scholar
  23. 23.
    T. Friščić, A. V. Trask, W. Jones, and W. D. S. Motherwell. Screening for inclusion compounds and systematic construction of three-component solids by liquid-assisted grinding. Angew. Chem. Int. Ed. 45:7546–7550 (2006).CrossRefGoogle Scholar
  24. 24.
    G. M. Sheldrick. SHELX-97: Program for the Solution and refinement of Crystal Structures, University of Göttingen, Germany, 1997.Google Scholar
  25. 25.
    S. Hess, U. Teubert, J. Ortwein, and K. Eger. Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance. Eur. J. Pharm. Sci. 14:301–311 (2001).PubMedCrossRefGoogle Scholar
  26. 26.
    P. J. Cox and P. L. Manson. Indomethacin tert-butanol solvate at 120 K. Acta Crystallogr. E59:o1189–o1191 (2003).Google Scholar
  27. 27.
    X. Chen, K. R. Morris, J. J. Griesser, S. R. Byrn, and J. G. Stowell. Reactivity differences of indomethacin solid forms with ammonia gas. J. Am. Chem. Soc. 124:15012–15019 (2002).PubMedCrossRefGoogle Scholar
  28. 28.
    J. G. Stowell, S. R. Byrn, G. Zografi, and M. Yoshioka. Private Communication (2002).Google Scholar
  29. 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. 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. 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. 32.
    M. O’Brien, J. McCauley, and E. Cohen. Indomethacin. Anal. Profiles Drug Subst. 13:211–238 (1984).Google Scholar
  33. 33.
    G. Jovanovski. Metal saccharinates and their complexes with N-donor ligands. CCACAA 73:843–868 (2000)Google Scholar
  34. 34.
    Y. Hase. The infrared and raman spectra of phthalimide, N-d-phthalimide and potassium phthalimide. J. Mol. Struct. 48:33–42 (2005).CrossRefGoogle Scholar
  35. 35.
    G. Jovanovski. The SO2 stretching vibrations in some metal saccharinates: spectra-structure correlations. Spectrosc. Lett. 28:1095–1109 (1995).CrossRefGoogle Scholar
  36. 36.
    M. A. R. Matos, M. S. Miranda, V. M. F. Morais, and J. F. Liebman. Saccharin: a combined experimental and computational thermochemical investigation of a sweetener and sulfonamide. Mol. Phys. 103:221–228 (2005).CrossRefGoogle Scholar
  37. 37.
    Simulated PXRD pattern from single crystal X-ray diffraction obtained from CSD (Ref code: SCCHRN02).Google Scholar
  38. 38.
    S. J. Nehm, B. R. Spong, and N. R. Hornedo. Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation. Cryst. Growth Des. 6:592–600 (2006).CrossRefGoogle Scholar
  39. 39.
    N. R. Hornedo, S. J. Nehm, K. F. Seefeldt, Y. P. Torres, and C. J. Falkiewicz. Reaction crystallization of pharmaceutical molecular complexes. Mol. Pharm. 3:362–367 (2006).CrossRefGoogle Scholar
  40. 40.
    K. J. Crowley and G. Zografi. Cryogenic griding of indomethaci polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability. J. Pharm. Sci. 91:492–507 (2002).PubMedCrossRefGoogle Scholar
  41. 41.
    B. C. Hancock and G. Zografi. The relationship between the glass transition temperature and water content of amorphous pharmaceutical solids. Pharm. Res. 11:471–477 (1994).PubMedCrossRefGoogle Scholar
  42. 42.
    A. Jayasankar, A. somwangthanaroj, Z. J. Shao, and N. R. Hornedo. Cocrystal formation during cogrinding and storage is mediated by amorphous phase. Pharm. Res. 23:2381–2392 (2006).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Srinivas Basavoju
    • 1
  • Dan Boström
    • 2
  • Sitaram P. Velaga
    • 1
    Email author
  1. 1.Department of Health ScienceLuleå University of TechnologyLuleåSweden
  2. 2.Energy Technology and Thermal Process ChemistryUmeå UniversityUmeåSweden

Personalised recommendations