Increasing the Batch Size of a QESD Crystallization by Using a MSMPR Crystallizer

Abstract

Quasi-emulsion solvent diffusion (QESD) crystallizations can improve the micromeritic properties of drugs and excipients. A solution is dispersed in a miscible antisolvent as a transient emulsion. Using this technique, substances that normally crystallize in the form of e.g., needles, agglomerate into spherical, hollow particles. A disadvantage of QESD crystallizations is that the particle size of the agglomerates decreases with an increased solvent fraction of the mother liquor. Therefore, in batch production, many consecutive runs have to be performed, which is a time- and material-intensive process. The aim of this study was to convert a previously used lab-scale batch crystallizer into a mixed-suspension, mixed-product removal (MSMPR) crystallizer, since the batch size could be simply increased by increasing the run time of the system. The mean residence time (MRT) and solvent fraction in the system was predicted and verified using actual measurement curves. The experiments showed that >50 g QESD metformin hydrochloride could be crystallized in a single run, without observing a large shift in the particle size, while maintaining good flowability. Observations regarding the effect of the MRT on the particle size distribution could be verified for the production on a larger scale than previously described.

Particle Design of Drugs via Spherical Crystallization: A Review from Fundamental Aspects to Technology Development

“…The solvent recycle system successfully overcomes the disadvantage of conventional SC whereby a large volume of organic solvent should be utilized. Hansen et al 148 demonstrated that CSC in a MSMPR crystallizer can increase the production capacity in a single run while maintaining the ASD.…”

Process Intensification via End-to-End Continuous Manufacturing of Atorvastatin Calcium Using an Integrated, Modular Reaction-Crystallization-Spherical Agglomeration-Filtration-Drying Process

“…Unlike peristaltic pumps, which can cause mechanical stress on crystals, resulting in fragmentation and size reduction, vacuumdriven transfers are gentler, maintaining the uniformity of the crystalline particles. 74 This careful treatment ensures that the crystals retain their desired qualities, which is vital in procedures where particle size and morphology affect product performance and quality. Thus, using vacuum-driven transfer systems can result in more efficient and effective crystallization procedures, improving the overall quality of the finished product.…”

Continuous Spherical Crystallization of Escitalopram Oxalate without Additives

“…10 Instead, if particles have intrinsically optimal flow properties, these additional steps can be avoided, and the crystals can undergo direct tableting, granting conspicuous savings in operation costs. 14 Particle engineering techniques that can solve such issues directly during the crystallization step are known as ammonia diffusion (AD), 15 quasi-emulsion solvent diffusion (QESD), 16 and spherical agglomeration (SA). 17 In the AD and QESD methods, quasi-emulsion droplets are formed by the addition of an antisolvent, forcing the counterdiffusion of solvent and antisolvent in and out of the droplets, creating supersaturation within them.…”

“…Instead, if particles have intrinsically optimal flow properties, these additional steps can be avoided, and the crystals can undergo direct tableting, granting conspicuous savings in operation costs . Particle engineering techniques that can solve such issues directly during the crystallization step are known as ammonia diffusion (AD), quasi-emulsion solvent diffusion (QESD), and spherical agglomeration (SA) …”