Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

Abstract

A key design limitation to the effective monitoring and control of continuous crystallization processes is the ability to characterize crystals in real time. A lowcost system composed of a basic stereomicroscope and video camera for the in situ imaging of sub-millimeter crystals through curved walls of millifluidic tubular crystallizers is described. Real-time videos taken for millimeter-size slurry slugs are used to guide the experimental design for a recently developed multiphaseflow crystallization process, including the improvement of the slug aspect ratio, visualization of crystal shapes, and observation of the extent of aggregation. Design considerations are also discussed for the use of multiple stereomicroscopes in other continuous-flow tubular experiments.

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

“…Small glycine crystals (about 0.11 mm) generated under Condition 4 (the dark particles in Figure 8d) were circulated in the whole slug geometry. This behavior was consistent with the past observation that particles of a few hundred microns were able to circulate evenly inside the slurry slug of an aspect ratio of ~1 [9,58]. However, millimeter-sized glycine crystals performed differently in the slugs whose dimension was on the same length scale (e.g., the tubing ID was less than four-times larger than the average crystal size).…”

“…The front is protruding more than the tail end[57]. Larger liquid flow rate and smaller air flow rate would reduce the length of the slurry slug[58]. Scale bar: 0.5 mm.…”

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

“…Jiang et al used an imaging method based on a stereomicroscope and a video camera for suspension quality evaluation [18]. Later, they refined this method as a real-time imaging method [20]. Due to the microscope placed in top view, however, the influence of gravity on the growing crystals was not taken into account.…”

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

“…The image analysis probe gave results similar to those of the FBRM measurements. Moreover, Jiang and Braatz described a low-cost system with effective monitoring and controlling ability for continuous crystallization processes. It was composed of a basic stereo microscope and video camera for imaging and characterization of l -asparagine monohydrate crystals in real time.…”

“…The authors claimed that each of the above three systems had been experimentally validated, and all were consistent with their polymorph selection design principle. However, because of the uncontrollability of the nucleation process, the existence of back-mixing in the MSMPR crystallizer and the nonideal 43 cyclosporin, 23,42 isothiocyanate, 44,45 prexasertib monolactate monohydrate, 46 L-alanine, 21 aliskiren hemifumarate, 47 carbamazepine, 48 D-/L-threonine, 49 albuterol, 50 azithromycin, 50 melitracen hydrochloride 51,52 continuous plug flow crystallizer benzoic acid, 26,53 acetaminophen, 54 triacylglycerol, 55−58 griseofulvin, 59 brivaracetam, 60,61 ketoconazole, 62 paracetamol, 63 acetylsalicylic acid, 64 flufenamic acid 62 continuous oscillatory baffled crystallizer L-glutamic acid, 28 biuret, 65 paracetamol, 66 melamine, 67 butyl paraben, 68 urea, 65 adipic acid, 69 α-lactose monohydrate, 70 salicylic acid, 71 aspirin 72 continuous segmented flow crystallizer L-asparagine monohydrate, 32,73,74 60 conducted a series of studies on brivaracetam in continuous-flow tubular crystallization, applying two crystallization strategies. With the cooling crystallization strategy, the extreme cooling condition of 20 °C/s was implemented, and high supersaturation was generated to obtain the desired crystal form.…”