Crystallization at production scale (>10 kg) is typically a poorly understood unit operation with limited application of first-principles understanding of crystallization to routine design, optimization, and control. In this study, a systematic approach has been established to transfer an existing batch process enabling the implementation of a continuous process in an oscillatory baffled crystallizer (OBC) using ultrasound. Process analytical technology (PAT) was used to understand and monitor the process. Kinetic and thermodynamic parameters have been investigated for lactose sonocrystallization using focused beam reflectance measurement (FBRM) (Mettler Toledo) and mid-infrared spectroscopy (mid-IR) (ABB) in a multiorifice batch oscillatory baffled crystallizer (Batch-OBC). This platform provides an ideal mimic of the mixing, hydrodynamics and operating conditions of the continuous oscillatory flow crystallizer (COBC) while requiring only limited material. Full characterization of the hydrodynamics of the COBC was carried out to identify conditions that deliver plugflow behavior with residence times of 1−5 h. The results show that continuous crystallization offers significant advantages in terms of process outcomes and operability, including particle size distribution (mean particle size <1500 μm) of alpha lactose monohydrate (LMH), as well as reduced cycle time (4 h compared to the 13−20 h in a batch process). Continuous sonocrystallization was performed for the first time at a throughput of 356 g•h −1 for 12−16 h. During the run at near plug flow, with supersaturation and controlled nucleation using sonication, no issues with fouling or agglomeration were observed. This approach has demonstrated the capability to provide close control of particle attributes at an industrially relevant scale. 50 principle of OBC has been described elsewhere. 4,5 The basic 51 design comprises a tubular network containing periodically 52 spaced orifice baffles superimposed with oscillatory motion of a 53 fluid. Oscillatory flow mixing has been developed and 54 investigated as a process intensification technology to achieve 55 efficient and controlled mixing in tubular crystallizers. Unlike 56 conventional tubular crystallizers in which the mixing is caused 57 by the turbulent net flow, the mixing achieved in an OBC is 58 mainly obtained by fluid oscillations and thereby the residence 59 time distribution within the device can be adjusted by the 60 oscillatory conditions and net flow rate allowing longer 61 residence times in short reactors and hence is more suitable 62 for slower processes like crystallization. 7−12 Previous studies 63 have shown that processing in an OBC resulted a greater 64 regularity of crystal shape with fewer defects and better control 65 over the crystallization process. A recent review provides a 66 detailed description of OBCs for crystallization as well as 67 summarizing the relevant literature. 63 These are attributed to 68 the uniform mixing when compared to a batch stirred tank 69 system. 3 Batch to ...
The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.
Experimental data on the effects that different antisolvents and antisolvent addition strategies have on nucleation behavior in antisolvent crystallization is very limited, and our understanding of these effects is sparse. In this work we measured the metastable zone width for the isothermal antisolvent crystallization of glycine from water utilizing methanol, ethanol, and dimethylformamide as antisolvents. We then investigated induction times for glycine crystallization across these metastable zones using the same three antisolvents. Supersaturated solutions were prepared by mixing of an antisolvent with undersaturated aqueous glycine solutions, either by batch rapid addition or using a continuous static mixer. Induction times were then recorded under agitated isothermal conditions in small vials with the use of webcam imaging and vary from apparently instant to thousands of seconds over a range of compositions and different mixing modes. Well-defined induction times were detected across most of the metastable zone, which shows that primary nucleation is significant at supersaturations much lower than those identified in conventional metastable zone width measurements. As supersaturation increases toward the metastable zone limit, crystal growth and secondary nucleation are likely to become rate-limiting factors in the observed induction times for antisolvent crystallization. Furthermore, the observed induction times were strongly dependent on the mode of mixing (batch rapid addition vs continuous static mixing), which demonstrates an interplay of antisolvent effects on nucleation with their effects on mixing, leading to crossover of mixing and nucleation time scales. This shows that appropriate mixing strategies are crucial for the rational development of robust scalable antisolvent crystallization processes.
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