Pharmaceutical cocrystals are a novel drug form with the potential to enhance pharmaceutical properties, including the solubility and dissolution behavior for BCS class II drug substances such as indomethacin (IMC). Recently, we reported that pure indomethacin–saccharin (IMC–SAC) cocrystals were prepared via anti-solvent crystallization. In this study, we investigated the solubility behavior of IMC–SAC cocrystals and individual components in methanol–water cosolvent. Also, the phase solubility diagram (PSD) of the cocrystal was determined to increase our understanding of cocrystallization. The criterion for pure IMC–SAC cocrystal formation was proposed and verified through supporting experiments performed with different concentrations. We also found that S cocrystal and S cocrystal/S drug are critical factors for the design of the cocrystallization process via anti-solvent addition. Real-time monitoring of the cocrystallization process was performed using an in-line near-infrared (NIR) system. Principal component analysis (PCA) was applied to NIR spectral analysis. Based on the PCA results, distinct differences were observed in the pathways of IMC–SAC cocrystal formation depending on the initial concentrations.

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In situ monitoring techniques are essential for the control and optimization of the cocrystallization process. In our previous study, we successfully monitored indomethacin−saccharin (IMC−SAC) cocrystallization by antisolvent addition using a method based on near-infrared principal component analysis (NIR−PCA). In this study, a calibration model was developed to predict the solute concentration of the two components. Several samples withdrawn from five sets of experiments were used to develop the calibration model. The actual concentrations of the two components were determined using UV−vis spectroscopy and high performance liquid chromatography (HPLC). The amount of solid-phase material in suspension was calculated from these solute concentration data. Correlations between NIR spectra and solid concentrations were evaluated using partial least-squares (PLS) regression analyses. Reasonably good calibration models with determination coefficients (R 2 ) higher than 0.979 were obtained. Process monitoring was performed using in situ NIR and Raman spectroscopies to predict the concentrations of both IMC and SAC in solution and to identify the solid-phase materials, respectively. The calibration models were deemed suitable, with reasonable accuracy and precision, for in situ concentration monitoring of the antisolvent crystallization of IMC− SAC cocrystals. This combination of NIR and Raman spectroscopies was able to detect the formation and phase transition of the resulting cocrystal.

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