The aim of this study was to develop a new, easily performable feedback control of crystallization based on the exact polymorphic concentration (mass ratio of polymorph/solvent). The efficiency of the developed process control, utilizing combined signals of inline Raman and attenuated total reflectance ultraviolet visible sensors, was tested in a cooling crystallization of carvedilol. The solution concentration was determined according to multivariate calibration results of UV/vis spectroscopic detection, while the evaluation of the composition of the solid phase was performed by means of Raman spectroscopy assisted by the classical leastsquare method resulting in spectral concentrations. Polymorphic concentrations were obtained by calculating the current solid phase concentration from UV/vis data, and then this value was proportionated to the Raman spectral concentrations of different polymorphs. The real-time parallel evaluation of Raman and UV spectra was performed with the assistance of a Matlab program. The calculated polymorphic concentrations governed the control of cooling and reheating cycles of the crystallization using a programmable logic controller. The developed control approach was successfully adapted for the production of both pure polymorphic forms such as the kinetically preferred Form II or thermodynamically stable Form I.
Crystallization as the most widespread purification, separation, and morphology-determining method is a critical technology that could be made safer and more economical by using continuous crystallization alternatives. Accordingly, this study aims to develop the continuous crystallization method for direct processing of a flow reaction mixture of acetylsalicylic acid (ASA) and to provide pure, homogeneous crystalline products for further formulation steps. The solid−liquid separation and the purification of the acetylsalicylic acid from the multicomponent mixture were accomplished in a single stage mixed suspension mixed product removal (MSMPR) continuous crystallizer equipped with an overflow and an inner buffer element to ensure the representative withdrawal of the product suspension. The effect of process parameters such as the operating temperature and the length of residence time (RT) on product quality and quantity were studied at two and three levels, respectively. Investigating these parameters, we found that higher operating temperatures (25 °C) and longer residence time (47 min) favor appropriate purity (>99.5%), and narrow crystal size distribution. By reducing the operating temperature (2.5 °C), the yield improved slightly (approximately 77%) and polydisperse products were characterized. The developed crystallization process can link the flow synthesis with the continuous formulation, and consequently serves a further step toward end-to-end production.
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