Continuous In Situ Seed Generation through the Integration of a Mixed Suspension Mixed Product Removal and an Oscillatory Baffled Crystallizer for the Control of Crystal Size Distribution and Polymorphic Form

Abstract

Fouling, encrustation, and lack of polymorphic form control are some of the major drawbacks of continuous oscillatory baffled crystallizers (COBCs), which can lead to clogging, undesired crystal form generation, and process failure. To counter these drawbacks, seeding with crystals is a methodology to not only control nucleation mechanism and crystal size distribution (CSD) but also provide polymorphic form control. Consistent manual preparation of seeds for continuous crystallization is labor-intensive and often economically infeasible. Furthermore, any fluctuations of seed quality can impact the startup dynamics. In this work, a proof-of-concept and the benefits of continuous in situ seed generation was demonstrated with an integration of a mixed suspension mixed product removal (MSMPR) crystallizer with a COBC via a continuous combined cooling antisolvent crystallization (CCAC). First, a CCAC solubility design space of metastable (form II) and stable forms (form I) of ortho-aminobenzoic acid was developed to identify operating regimes for selective polymorphic form generation. Second, the in situ form I seed generation experiments, with the COBC, prolonged steady-state generation of the crystal product for more than eight residence times. The crystal product generated from the combined system with segmented cooling had a higher mean size and narrower size distribution when compared to the product obtained from a single-stage MSMPR experiment. Polymorphic control coupled with continuous seed generation in the combined system generated a uniform crystal product with no seed wash out occurring. Lastly, the importance of the method of slurry transport for the combined system was highlighted in experiments utilizing mechanical pump transfer compared to gravimetric transfer. Overall, these proof-of-concept experiments demonstrated the feasibility and benefits of using the integrated MSMPR–COBC crystallization system, utilizing the MSMPR crystallizer for continuous in situ seed generation providing for the robust operation of the COBCs.

An Overview on Polymorph Preparation Methods of Active Pharmaceutical Ingredients

“…Photograph (right) and schematic diagram (left) of the experimental setup developed by Wu and colleagues. Reproduced from ref . Copyright 2021 American Chemical Society.…”

“…Recently, the concept of continuous in situ seed generation was proposed and executed by Wu and colleagues. 34 The experimental setup is illustrated in Figure 9. The selective crystallization of o-aminobenzoic acid polymorphs in the integration of a mixed suspension mixed product removal and an oscillatory baffled crystallizer showed the tremendous potential of continuous in situ seed generation in polymorph control.…”

“…The selective crystallization of o-aminobenzoic acid polymorphs in the integration of a mixed suspension mixed product removal and an oscillatory baffled crystallizer showed the tremendous potential of continuous in situ seed generation in polymorph control. 34 3.1.5. Additives.…”

“…However, the obtaining of high-quality seed crystals is difficult for some API, which limits the uses of seed crystals in polymorph control of API to some extent. Recently, the concept of continuous in situ seed generation was proposed and executed by Wu and colleagues . The experimental setup is illustrated in Figure .…”

A Continuous Process for Manufacturing Apremilast. Part II: Process Characterization to Establish a Parametric Control Strategy

“…This process begins with the reaction of ( S )-Aminosulfone and 3-Acetamidophthalic Anhydride (3-AA) in a plug flow reactor (PFR) to yield Apremilast in crude solution. The crude reaction solution is then collected in a surge tank prior to direct antisolvent crystallization of Apremilast executed using a series of continuous mixed-suspension mixed-product-removal (MSMPR) vessels. − Finally, semicontinuous isolation is achieved via the application of a dual centrifuge configuration in which the slurry is continuously fed and filtered, and then the isolated Apremilast cake is washed, spun down, and discharged in discrete batches.…”