Indomethacin-saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization.
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).
Basavoju
Srinivas
S
Department of Health Science, Luleå University of Technology, Luleå, S-971 87, Sweden.
Boström
Dan
D
Velaga
Sitaram P
SP
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
D000894:Anti-Inflammatory Agents, Non-Steroidal; D012439:Saccharin; D007213:Indomethacin
J Am Chem Soc. 2004 Oct 20;126(41):13335-42
15479089
Eur J Pharm Sci. 2001 Dec;14(4):301-11
11684404
Angew Chem Int Ed Engl. 2006 Nov 20;45(45):7546-50
17051633
Mol Pharm. 2006 May-Jun;3(3):362-7
16749868
Pharm Res. 2006 Aug;23 (8):1888-97
16832611
Pharm Res. 2006 Oct;23(10):2381-92
16988890
Pharm Res. 1999 Nov;16(11):1722-8
10571278
J Pharm Sci. 2006 Mar;95(3):499-516
16444755
Chem Commun (Camb). 2003 Jan 21;(2):186-7
12585383
Crit Rev Ther Drug Carrier Syst. 2004;21(3):133-93
15248808
J Pharm Sci. 1999 Oct;88(10):1058-66
10514356
Int J Pharm. 2006 Aug 31;320(1-2):114-23
16769188
Chem Commun (Camb). 2004 Sep 7;(17):1889-96
15340589
Pharm Res. 1994 Apr;11(4):471-7
8058600
J Pharm Sci. 1994 Dec;83(12 ):1700-5
7891297
Eur J Pharm Sci. 2004 Oct;23(2):159-68
15451004
J Pharm Sci. 2002 Feb;91(2):492-507
11835208
J Pharm Sci. 1977 Jan;66(1):1-19
833720
J Am Chem Soc. 2002 Dec 18;124(50):15012-9
12475345