Application of Wet Milling-Based Automated Direct Nucleation Control in Continuous Cooling Crystallization Processes

Abstract

A novel wet milling-based automated direct nucleation control (WMADNC) concept is proposed and implemented in two continuous cooling crystallization processes in this work. In process 1, WMADNC is implemented upstream to provide closed-loop controlled primary nucleation kinetics and produce seed crystals in situ for continuous mixed suspension mixed product removal crystallizer (MSMPRC). In process 2, WMADNC is applied downstream to achieve closed-loop controlled secondary nucleation kinetics and reduce particle size for crystals in the MSMPRC through recycling. For both processes, a focused beam reflectance measurement (FBRM)-based closed-loop control approach is successfully implemented to control the nucleation kinetics inside the wet mill therefore to control the final chord length distribution (CLD). In the proposed WMADNC approach, the process critical quality attributes (CQA) (e.g., particle number or size) can be directly controlled by the automated closed-loop control framework, which on one hand is aligned with the quality-by-design (QbD) concept, and on the other hand also applies the new quality-by-control (QbC) framework in continuous crystallization processes. Although the proposed WMADNC approach was not able to improve startup dynamics, it can provide high quality control of CLD and automated and effective disturbance rejection for continuous cooling crystallization processes.

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

“…They used an inline rotor-stator mixer to generate seeds for an MSMPR during the continuous cooling crystallization of paracetamol, and found that this could significantly decrease the time to reach steady state. They also found that an increasing tip speed resulted in a decreasing particle size due to increasing primary nucleation [20][21][22].…”

“…However, they are not often used during crystallization; rather, they are used during post-processing in the form of a wet mill to reduce the particle size. To our best knowledge, only Yang et al previously used rotor-stator mixers to control nucleation [20,21]. They used an inline rotor-stator mixer to generate seeds for an MSMPR during the continuous cooling crystallization of paracetamol, and found that this could significantly decrease the time to reach steady state.…”

Designs of continuous-flow pharmaceutical crystallizers: developments and practice

“…Linear velocities 7,42 (or flow rates 29 ) Reynolds number 105,[108][109][110] Damkohler number, 108,110 jet geometry (jet angle and internozzle spacing), 28,42,105,108,110 seed load 9,29 Amplitude (energy, intensity), 14,114,120,140,141 sonic exposure time 12 (flow rate), frequency 13 Tip/rotational speed, 54,122,124 turn over (or cycle) number and/per residence time 55,124,126 Residence time, 10,104 T range and ramp, 10,104 T cycle number 104 Recycle ratio, nanoparticles and/or nanocrystals. [19][20][21][22][23][24][25][26] The slug flow tubular crystallizer also maintains useful operational properties of both batch (e.g., less clogging) and continuous crystallizers (e.g., scale up 27 ), and improves crystal qualities in flow.…”

“…4,5,16 In each MSMPR, feed solution/slurry is continuously pumped into a stirrer-agitated vessel, 5 with product slurry nominally being continuously withdrawn at the same composition as in the vessel. [50][51][52][53][54][55][56][57] Usually multiple MSMPRs are used to maximize the overall yield. Single-stage MSMPR has also been investigated in research studies: (1) the single-stage yield and/or purity has been improved by combining with continuous recycling of mother liquor or crystals after treatment [58][59][60][61][62][63][64] (details in seeding strategy section and Table 2), (2) the polymorphic ratio has been controlled by varying the temperature and residence time, 65 and (3) singlestage MSMPR experiments have been used to provide information for the design of multi-stage MSMPRs.…”

“…50 Startup modes are also suggested to quickly achieve steady state and reduce fouling, including beginning with the crystallizer filled with solution or slurry, instead of a dry crystallizer; 68 higher temperature in the feed line; 12 and adopting dynamic operational profile and process control strategies. [50][51][52][53][54][55][56][57] Fluidized bed crystallizers Fluidized bed crystallizers (FBCs, Fig. 2f) have been used to make large crystals, 45,46 and/or for isomeric separation, 46,48,69 mainly via cooling crystallization.…”