Novel Impinging Jet and Continuous Crystallizer Design for Rapid Reactive Crystallization of Pharmaceuticals

Abstract

Reactive crystallization is an important operation in the pharmaceutical industry for the production of the active pharmaceutical ingredients (APIs), but has not been as widely studied as cooling or anti-solvent crystallization. Reactive crystallization has many unique features that make them different from cooling or anti-solvent crystallization, even leading to some concepts and methods not directly applicable to the former. Literature survey reveals that previous research on reactive crystallization has mainly been conducted for inorganic materials which are known to be simpler than crystallization of organic molecules. The focus of this research project was to carry out research on the process design and optimization of organic reactive crystallization. The objective was to research on novel crystallizer designs that suit and take advantages of the features of reactive crystallization, and on advanced modeling and optimization techniques with the aim of manufacturing high quality products. Process analytical technology was used as a supporting tool to achieve the above stated objectives. The results showed that by using novel impinging jet design, the product had uniform size distribution and superior crystallinity. In addition, continuous process design can achieve a greater amount of product handling and reduce the batch-to-batch variation.

Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

“…However, tubular crystallizers are more prone to have crystal fouling, clogging, settling issues, and poor mixing, which are all hurdles for industrial implementation . In addition to these two common setups, there are several novel crystallization approaches that potentially can be used for continuous crystallization, such as microfluidics, impinging jet, film crystallization, electro-spraying, nanospraying, and crystallization within porous media. − …”

Loop-Configuration for Plug Flow Crystallization Process Development

“…CFICs have been used, among others, , to intensify the continuous antisolvent crystallization of flufenamic acid . Impinging jets on the other hand, consisting of two equal diameter fluid jet nozzles that collide within a small chamber before entering the plug flow crystallizer, have been shown beneficial in achieving fast mixing. , However, the small scale of the device has high risk of clogging, and its scale up is cumbersome . Static mixers are a simpler easier-to-scale-up alternative, offering significant practical advantage, similar to the COBC, of lower flow rates and longer residence times under plug flow conditions, mitigating the material consumption during early process development. − …”

“…Therefore, to obtain representative kinetics for the system, there is a significant advantage in using the final PFC configuration. However, given the lack of intensive mechanical agitation in tubular crystallizers, rapid mixing is hard to achieve, which, particularly under conditions of high supersaturation, can lead to crystallization prior complete mixing, negatively affecting the product’s CSD, morphology, and purity, manufactured under partial segregation conditions. − Examples of alternative designs and systems enhancing mixing in PFCs while attaining nearly plug flow behavior are the continuous oscillatory baffled crystallizer (COBC), the segmented/slug flow crystallizer, , and the continuous coiled flow inverter crystallizer (CFIC). , Also, impinging jets or fitting static mixers inside the pipeline allows fast homogenization of the reacting streams. , COBCs allow the attainment of turbulent flow regime by either periodic motion of intrinsic elements (moving baffles) within the pipe, or by the periodic motion of the fluid against the internal static elements . As such, mixing is provided by the generation and cessation of eddies when flow interacts with the restrictions (baffles).…”

Magnetic separation of immobilized biocatalyst enables continuous manufacturing with a solids-forming reaction

“…19 Generally, reactive crystallization can be useful for process intensification, 20 overcoming unfavorable reaction equilibria, 18 and for isolation of desired intermediates as in the case of PGA-catalyzed β-lactam synthesis. 10,15,18,[20][21][22][23][24][25][26][27][28][29][30][31] The formation of solid product directly from solution-phase reactants provides increased selectivity in β-lactam production.…”