Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and L-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers.

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Active ingredients in most pharmaceutical products are complex organic molecules that require crystallization as a purification and isolation step that results in a pure product at a high process yield. Knowledge of the operating conditions required to obtain crystals with the desired crystal shape, polymorph, and morphology is critical during process development. This paper describes a two-stage mixed suspension mixed product removal (MSMPR) continuous reactive crystallization procedure developed for Aliskiren hemifumarate. This process was able to crystallize Aliskiren hemifumarate at both high purity (>99%) and high yield (>92%). A model of the crystallization was developed through the simultaneous solution of a population balance equation, kinetic expression for crystal growth and nucleation, and a mass balance. Experimental data were fit to the model to obtain kinetic parameters for crystal growth and nucleation. After including equilibrium distribution coefficient data, the model was used to optimize crystal purity and yield of the product by adjusting the operating temperature and residence time. This process has been integrated into an end-to-end continuous manufacturing system developed at MIT.

This paper describes a two-stage mixed-suspension, mixed-product removal (MSMPR) continuous crystallization developed for a pharmaceutical intermediate which uses anti-solvent and cooling to generate supersaturation. The results indicate that the stage in which anti-solvent is added has a significant influence on the final crystal properties, while purity and yield were nearly identical. The population balance model was employed to determine growth and nucleation kinetics through parameter estimation. With the incorporation of measured equilibrium distribution coefficients, the model was used to optimize crystal purity and yield of the product with respect to operating temperature and residence time.

The aim of this work is to provide a wide database of kinetic data for the most common biomass by thermogravimetric analysis (TGA) and differential thermogravimetry (DTG). Due to the characteristic parameters of DTG curves, a two-stage reaction model is proposed and the kinetic parameters obtained from model-based methods with energy activation values for first and second stages in the range 1.75·10(4)-1.55·10(5)J/mol and 1.62·10(4)-2.37·10(5)J/mol, respectively. However, it has been found that Flynn-Wall-Ozawa and Kissinger-Akahira-Sunose model-free methods are not suitable to determine the kinetic parameters of biomass combustion since the assumptions of these two methods were not accomplished in the full range of the combustion process.