title: Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization.
abstract: OBJECTIVE
  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.
  
  
  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 gamma-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-Hcdots, three dots, centeredO hydrogen bonds. The cocrystals were non-hygroscopic and were associated with a significantly faster dissolution rate than indomethacin (gamma-form).
authors: Department of Health Science, Luleå University of Technology, Luleå, S-971 87, Sweden.
authors: Srinivas
authors: S
authors: Basavoju
authors: Dan
authors: D
authors: Boström
authors: Sitaram P
authors: SP
authors: Velaga
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D007213:Indomethacin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D033362:Powder Diffraction; D012439:Saccharin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D014835:Volatilization
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D012439:Saccharin; D007213:Indomethacin
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