Designs of continuous-flow pharmaceutical crystallizers: developments and practice

Abstract

This review of recent research advances in continuous-flow crystallization includes a five-step general design procedure, generally applicable process intensification strategies, and practical insights.

Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow

“…Continuous crystallization has received increasing research interests in both academia and industry for controlling crystal qualities, including polymorphic form, size, and morphology [1][2][3][4][5][6][7][8][9][10][11][12][13]. Many types of continuous crystallizers have been designed to meet different product quality requirements, with representative examples: (a) multi-stage mixed-suspension mixed-product removal (MSMPR) crystallizers [14][15][16][17]; (b) fluidized bed crystallizers [18][19][20][21][22]; (c) oscillatory baffled crystallizers [23][24][25]; (d) unbaffled crystallizers with an interior tubing mixing enhancer [8] (such as static mixers [11,26,27]); and (e) segmented/slug-flow crystallizers [3,[26][27][28][29].…”

“…Besides, compared to tube/pipe-based crystallizers (b-e), transferring the concept from a batch/semi-batch experiment into a stirred-tank crystallizer is easier in general. Correspondingly, tubular crystallizers have a short residence time, a narrow crystal size distribution (CSD), low shear force, and rapid heat transfer [10].…”

“…Various types of crystallization have been demonstrated in slug flow [10], including reactive precipitation [27,[41][42][43][44][45][46], cooling crystallization [3,39,40,47,48], and anti-solvent crystallization [49,50]. Several compounds (e.g., L asparagine monohydrate [3], acetylsalicylic acid [39], and succinic acid [27]) were crystallized into uniform crystals of up to a few hundred microns in millifluidic slugs.…”

Global uncertainty-sensitivity analysis on mechanistic kinetic models: From model assessment to theory-driven design of nanoparticles

“…Previously, Wu et al synthesized C-S-H (of lower Ca:Si ratios) with specific surface areas ranging between 100 and 500 m 2 /g, obtained by varying the synthesis conditions [7]. Our results show that there is room for further improvement by increasing the addition flow rate of silicate solution although one has to optimize the design of the synthesis reactor for maximal mixing [77]. This can be reinforced by the synergistic effect of lowering the cohesion energy (that is, lowering / ; Figure 9(b)) which can be induced either by increasing the relative concentration of monovalent ions (e.g., adding a sodium salt to the mixture) or by working at lower pH values [42,78].…”

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

“…To better understand crystallization processes, more reproducible methods are required to control these processes over multiple length scales. Because of the inhomogeneity and irreproducibility of batch crystallizers, flow technologies have recently emerged as a highly effective means of achieving this goal . Continuous flow platforms that can simultaneously provide direct scale-out routes, narrow time resolution, representative sampling, and high-throughput materials synthesis up to production-scale rates are particularly attractive .…”