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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

Abstract

Purpose

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.

Results

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.

Conclusions

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 

Notes

Acknowledgements

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)

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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

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