Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

Abstract

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous crystallizers, their engineering advantages/disadvantages, the introduction of the solid form structuring to continuously oriented chemical production, and the usage of the online process analytical technology (PAT) methodologies in interacting functional systems. Furthermore, mechanistic multiscale modeling, whose understanding is of decisive importance for further control application development, was thoroughly discussed as well. The multiscale modeling section also includes the simulation of processes and the optimization of crystallizers. In the last section, model-based predictive control (MPC) is considered, which also covers the intensification approach methods in the field of crystal formation and the introduction of new, highly potential continuous systems, e.g. the coiled flow inverter (CFI) crystallizer, in industry and academia. In the mentioned main sections, individual theme-related articles are collected, discussed, and compared; therefore, a reader can get acquainted with pieces of research, their found results, which have been developed until now, and various emerging perspectives. With regard to the importance of crystallization in the pharmaceutical industry, a reader can already find literature on continuous crystallization. However, due to the growing tendency toward the synthesis of products with specific properties which cannot be achieved with conventional approaches, more attention has been paid in the present work to the establishment of continuous systems for the production of specific fine chemicals. In addition, continuous crystallization could also enable more efficient and "on-demand" production, modeling for optimization, MPC, and intensification approaches. A review of the literature classifying studies according to the choice of a continuous system and their description was omitted in this study, as such reviews are already available in the literature.

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

“…Continuous crystallization is a promising operation mode for the small-scale production ( V ≤ 100 mL min −1 ) of active pharmaceutical ingredients (APIs) and fine chemicals [1][2][3][4]. Reaching the steady state in continuous operation is advantageous regarding the consistency of product quality, e.g., particle size and its distribution.…”

“…Reaching the steady state in continuous operation is advantageous regarding the consistency of product quality, e.g., particle size and its distribution. In addition, higher space-time yield than in batch operation is possible because smaller equipment sizes are required [2,4]. In order to utilize these advantages, however, the steady state must first be reached and then maintained [3].…”

Continuous Cooling Crystallization in a Coiled Flow Inverter Crystallizer Technology—Design, Characterization, and Hurdles

“…The Multistage Continuous Mixed-Suspension, Mixed-Product Removal (MSMPR) [4,[28][29][30][31][32][33], Taylor-Couette [32,34,35], or Draft Tube Baffle (DTB) [36,37] crystallizers belong to the stirred tank crystallizers. The oscillatory baffled crystallizers [32,38,39] and coiled tube crystallizers belong [40][41][42][43][44][45] to the plug flow crystallizers. Nice overviews of different crystallizer technologies are given in References [3,32,40].…”

“…The oscillatory baffled crystallizers [32,38,39] and coiled tube crystallizers belong [40][41][42][43][44][45] to the plug flow crystallizers. Nice overviews of different crystallizer technologies are given in References [3,32,40]. The crystallizer introduced in this work belongs to the coiled tube crystallizers.…”

Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

“…Having formed the key compound in a chemical or biotechnological reaction, crystallization is used to create a solid phase containing preferentially pure API in the crystal form desired. Crystallization directly influences the final product purity and should therefore be optimized to ensure both consistent purity and particle size distribution (PSD) [4,5]. Upcoming challenges are the solid-liquid separation as well as washing and drying steps to meet specific product specifications regarding residual moisture and preservation of PSD [6].…”