Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 2. Antisolvent Crystallization

Abstract

The development of a continuous flow antisolvent crystallization protocol for a commercial active pharmaceutical ingredient, Brivaracetam, is described. To obtain increased nucleation kinetics of the desired crystalline form, solutions of Brivaracetam/isopropyl acetate are injected into micrometric tubing and mixed with a refrigerated antisolvent hexane. In this way very high supersaturation conditions are induced shortly after mixing. Residence times below 1 s after mixing in short tubular crystallizers are necessary for the desired, but thermodynamically unstable, crystals to grow. Arresting all crystal growth by immediate removal of the antisolvent containing mother liquors by continuous filtration or by casting the product onto filter paper prevents the formation of the thermodynamically stable pseudopolymorphundesired due to its needle shape and solvated nature. Sufficient solid material output can be generated in order to be implemented in actual processing conditions if combined with suited continuous filtration units.

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

“…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. The researchers then attempted to crystallize by antisolvent crystallization with brivaracetam/isopropyl acetate and frozen hexane solution . To achieve a high nucleation rate, the mixing process took place in a 500 μm inner diameter tube that ensured a residence time of less than 1 s after mixing.…”

“…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.…”

“…The researchers then attempted to crystallize by antisolvent crystallization with brivaracetam/isopropyl acetate and frozen hexane solution. 61 To achieve a high nucleation rate, the mixing process took place in a 500 μm inner diameter tube that ensured a residence time of less than 1 s after mixing. Under these conditions, the crystal could even grow to 20 μm.…”

Nucleation kinetics of lithium phosphate precipitation

“…The importance of crystal shape and stability to industrial processes and pharmaceutical products [1][2][3][4] prompted many research into the structural arrangement, physical and chemical properties, and medical activities of different crystals. The formation of crystalline materials through nucleation and growth is an intricate network in which a heterogeneous chemical reaction is coupled to various transport processes.…”

Modelling of the Polymorph Nucleation Based on Classical Nucleation Theory

“…Understanding the nucleation and growth mechanisms of polymorphism is crucial to better control of the desired forms during polymorph crystallization [14][15][16][17][18][19][20][21][22][23][24][25][26][27]. Although various nucleation theories for the single polymorphic system have been developed based on either the thermodynamics of the process [4,5] or the kinetics of the process [28][29][30], nucleation theory for the multiple polymorphic system is comparatively less studied in the literature.…”