Preparation of Indomethacin Co-Crystals; Comparison of XRD, THz, and FT-IR Spectral Analyses; and Enhancement of Solubility

Background: The aqueous solubility of indomethacin, a poorly water-soluble anti-inflammatory drug, was enhanced by co-crystallization with co-formers. The co-crystals were characterized and compared by an X-ray diffraction (XRD) analysis, terahertz (THz) spectroscopy, and Fourier transform infrared (FT-IR) spectroscopy. Methods: Indomethacin co-crystals with either amides (saccharin, nicotine amide, and urea) or amino acids (lysine and histidine) as co-formers were prepared through the solvent evaporation method. The co-crystals were characterized by XRD, THz, and FT-IR analyses, followed by solubility tests to examine the solubility enhancement. Results: Both the XRD and THz analyses were capable of distinguishing co-crystals from physical mixtures; however, the THz spectra were relatively simpler and clearer than the XRD analysis. Furthermore, the solubility of indomethacin was successfully increased by two to three times that of pure indomethacin after co-crystallization with the above five co-formers. Conclusion: Five kinds of indomethacin co-crystals (with enhanced solubility) were successfully prepared and confirmed by the three spectroscopy techniques, XRD, THz, and FT-IR. The identification of co-crystals was achieved by a THz analysis, giving relatively simpler and clearer spectra with less noise. Hence, in addition to an XRD analysis, a THz analysis (a non-destructive, non-ionizing radiative, and relatively rapid measurement technique which is convenient and safe to use) is a good alternative method to characterize co-crystals.