Real-time monitoring of cocrystallization processes by solvent evaporation: A near infrared study

Abstract

This work aims at pinpointing some of the events that can be detected during a solvent evaporation cocrystallization process by near infrared spectroscopy, highlighting the importance of the real-time monitoring strategy of these processes. Small differences in process parameters such as temperature or composition can lead to substantial differences in the polymorphic form or in the purity of the cocrystal. To demonstrate this, a solvent evaporation type cocrystallization process involving furosemide and p-aminobenzoic acid was selected. Initial components were dissolved in a mixture of methanol and water (8:1 v/v) and the cocrystallization process was monitored in-line by near infrared spectroscopy using a diffuse reflectance probe set 1cm above the cocrystallization medium. All batches were run at room temperature under agitation until complete solvent evaporation (approximately 16h). Acquired near infrared spectra were analyzed by principal component analysis. The final cocrystallization product was characterized using near infrared spectroscopy, differential scanning calorimetry and X-ray powder diffraction. Results show that small variations on the temperature (±3°C) lead to the appearance of a mixture of the initial components and the cocrystal in varying proportions emphasising the importance of a careful control of the cocrystallization parameters as well the importance of the real-time monitoring.