Recent Progress in Continuous Crystallization of Pharmaceutical Products: Precise Preparation and Control

Abstract

Crystallization, as a solid−liquid separation process, is employed to purify and isolate a great diversity of crystalline pharmaceutical products. In recent years, continuous crystallization has attracted increasing attention because of the product and process robustness as well as higher productivity. In this work, we review the use of novel continuous crystallizers or modified conventional continuous crystallizers for the preparation of polymorphs, chiral enantiomers, solvates/hydrates, cocrystals, and spherical crystals. In addition, the theoretical framework and verification of the model-based control approaches are demonstrated. The application of process analytical technology tools in classical feedback loop control strategies in continuous crystallization is also discussed. Despite all this, the application of continuous crystallization still remains challenging because of the existence of drawbacks such as fouling and blockages. Therefore, a systematic discussion should be done before continuous crystallization is more widely applied.

Nucleation in continuous flow cooling sonocrystallization for coiled capillary crystallizers

“…The continuous operation of small-scale equipment is of utmost importance for accelerated process development [1][2][3][4]. It is not necessary to switch the operation mode from small scale batch to the continuous production of bigger quantities, smallest quantities can already be continuously produced, and similar equipment concepts can be transferred more easily to larger scales [5].…”

“…It is not necessary to switch the operation mode from small scale batch to the continuous production of bigger quantities, smallest quantities can already be continuously produced, and similar equipment concepts can be transferred more easily to larger scales [5]. Furthermore, the continuous mode has advantages, such as smaller hold-ups, higher product reproducibility, and space-time-yield [1,2,5,6].…”

Concomitant Polymorphism and Nucleation Control of DL‐Methionine Through Antisolvent Crystallization

“…Especially, it plays a vital role in separating the solutes from multicomponent solutions 9, 10. On the other hand, the drowning‐out agents can be solids, liquids (antisolvent), or gases solid drowning‐out agents) or miscible with it (liquid drowning‐out agents) and should not react with the solute to be precipitated 11, 12.…”

“…Amino acids are crucial in the case of health maintenance and are used widely in edible supplements and pharmaceutical industries. Especially, their solid‐state properties and structures have been thoroughly inspected under a variety of conditions 8–12. In general, the amino acid DL ‐methionine crystallizes from saturated aqueous solutions at room temperature conditions as a metastable α‐ form and stable β ‐form.…”

Enhancing continuous reactive crystallization of lithium carbonate in multistage mixed suspension mixed product removal crystallizers with pulsed ultrasound

“…Crystallization, a typical solid–liquid separation unit operation that can be employed to purify a great diversity of chemical compounds, is widely applied in the production of solid-state intermediates or final products [1] , [2] . Traditionally, for a simplification of crystallization equipment and manual operation, chemical enterprises predominantly conducted batch methods in industrial crystallization procedures.…”