Thermal analysis and FTIR spectral curve-fitting investigation of formation mechanism and stability of indomethacin-saccharin cocrystals via solid-state grinding process

The cocrystal formation of indomethacin (IMC) and saccharin (SAC) by mechanical cogrinding or thermal treatment was investigated. The formation mechanism and stability of IMC–SAC cocrystal prepared by cogrinding process were explored. Typical IMC–SAC cocrystal was also prepared by solvent evaporation method. All the samples were identified and characterized by using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) microspectroscopy with curve-fitting analysis. The physical stability of different IMC–SAC ground mixtures before and after storage for 7 months was examined. The results demonstrate that the stepwise measurements were carried out at specific intervals over a continuous cogrinding process showing a continuous growth in the cocrystal formation between IMC and SAC. The main IR spectral shifts from 3371 to 3,347 cm−1 and 1693 to 1682 cm−1 for IMC, as well as from 3094 to 3136 cm−1 and 1718 to 1735 cm−1 for SAC suggested that the OH and NH groups in both chemical structures were taken part in a hydrogen bonding, leading to the formation of IMC–SAC cocrystal. A melting at 184 °C for the 30-min IMC–SAC ground mixture was almost the same as the melting at 184 °C for the solvent-evaporated IMC–SAC cocrystal. The 30-min IMC–SAC ground mixture was also confirmed to have similar components and contents to that of the solvent-evaporated IMC–SAC cocrystal by using a curve-fitting analysis from IR spectra. The thermal-induced IMC–SAC cocrystal formation was also found to be dependent on the temperature treated. Different IMC–SAC ground mixtures after storage at 25 °C/40% RH condition for 7 months had an improved tendency of IMC–SAC cocrystallization.