MSMPR Crystallizer

The Mixed-Suspension, Mixed-Product-Removal (MSMPR) crystallizer is favored for continuous crystallization, as its use can result in higher yields, reduced production costs, and improved product quality. Its importance lies in its ability to maintain a constant suspension of crystals in the liquid phase, which promotes uniform crystal growth and prevents fouling and scaling.

The MSMPR crystallizer continuously removes crystals and the mother liquor from the crystallizer, which is filtered and returned to the crystallizer. The MSMPR crystallizer enables the production of crystals with a specific size and shape, making it ideal for use in the pharmaceutical, chemical, and food industries where the purity of the final product is critical. 

EasyMax™ and OptiMax™  automated lab reactors can be configured to be used as batch, continuous, or MSMPR crystallizers, enabling researchers to get the most out of their equipment and offering flexibility for different applications. 

These easy-to-use platforms accurately execute recipes and precisely control reaction parameters, resulting in highly reproducible reactions. Experimental procedures can be run unattended around the clock, automatically recording data so it’s ready for instant sharing.

Martha Grover of the Georgia Institute of Technology presents a process model of a pilot plant that included an MSMPR reactor-crystallizer by coupling relevant reaction and crystallization kinetic models, informed by in-situ process analytical technologies (PAT). Process simulations were then used to assess the interaction between different process attributes. In the next step, a pilot plant with feed reservoirs, an MSMPR reactor-crystallizer, a separator, and a filtration unit was constructed for the continuous production of beta-lactam antibiotic crystals.

METTLER TOLEDO is a leading provider of precision instruments and equipment, including laboratory-scale MSMPR crystallizers. Along with various configurable MSMPR crystallizers and reactors, real-time PAT tools can be integrated to facilitate continuous crystallization studies:

1. Particle Size Analyzers: Inline particle characterization is essential for successful crystallization process development as it can continuously monitor particle size, shape, and count in situ, providing immediate process understanding, and directly link process parameters to particle mechanisms to avoid process risks and produce better particles faster. The interoperability of MSMPR crystallizers with probe-based particle size analyzers such as EasyViewer™ and ParticleTrack™ allows scientists to establish feedback control loops for managing particle size or count-controlled cooling. This system also enables the regulation of antisolvent dosing rates to reduce the unwanted formation of particles, such as excess fines.
2. FTIR and Raman Spectrometers: MSMPR crystallizers can be paired with in-situ spectroscopy instruments such as ReactIR™ and ReactRaman™ to provide real-time solution concentration, supersaturation, and crystal form information during crystallization processes. This technology enables researchers to gain a deeper understanding of the underlying mechanisms of MSMPR crystallization, leading to improved process performance and crystal quality.
3. Chemical Reaction Sampling: Automated and unattended sampling delivers high-quality samples day and night for standard offline analysis, such as HPLC. EasySampler™ with EasyFrit allows for selective sampling of the solution phase despite the presence of suspended particles.
4. Modeling Software: Achieving essential quality attributes in crystallizations requires proper design as numerous factors interact to affect crystal size, particle size distribution, polymorphism, and other properties. Dynochem® modeling software uses data from offline and in-situ analytical measurements to characterize the solubility and kinetics of crystallization that can be applied to predict continuous crystallization in multistage MSMPRs, permit more effective design and operation of crystallizers, and facilitate the optimization of seeding and scaling up.

METTLER TOLEDO's contributions to the field of MSMPR crystallization have led to improved process control, faster process development, and better crystal quality, making essential technologies for a wide range of applications in various industries.

Yang, X., Acevedo, D., Mohammad, A., Pavurala, N., Wu, H., Brayton, A. L., Shaw, R. A., Goldman, M. J., He, F., Li, S., Fisher, R. J., O’Connor, T. F., & Cruz, C. N. (2017). Risk considerations on developing a continuous crystallization system for carbamazepine. Organic Process Research & Development, 21(7), 1021–1033. https://doi.org/10.1021/acs.oprd.7b00130

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and an understanding of the impact on product quality is evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substances and is considered a critical process step in achieving the continuous manufacturing of drug substances. Although many publications previously focused on various innovative techniques to continuously make crystals with desired properties, engineering difficulties such as system design, automation, and integration with process analytical technology (PAT) tools have not been thoroughly discussed. Here, researchers focus on how to develop a continuous crystallization system, from the perspective of process engineering and the related risk considerations on product quality.

Specifically, they describe an automated two-stage mixed-suspension, mixed-product removal (MSMPR) crystallization platform for a model compound (carbamazepine, CBZ) that exhibits multiple polymorphs. The crystallization process includes the integration of PAT tools (online Raman microscopy and Focused Beam Reflectance Measurement-FBRM) for real-time monitoring.

A series of case studies were done to evaluate the performance of the continuous system and PAT tools. Specifically, the drawing schemes, slurry transport, and variations on process variables are considered the three key risk areas for continuous crystallization process development. The proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM).

This research scale system can be used to evaluate concepts of control strategy development and process risks. Currently, the system is successfully demonstrated to perform two-stage cooling crystallization of CBZ. Preliminary studies indicate that a level control system with bottom-draw suspension removal configuration and alternating filtration setup can provide a basis of operation.