What is the difference between batch and continuous crystallization?

Batch and continuous crystallization are two different methods of producing solid materials, with batch crystallization being a discontinuous process that is controlled by adjusting various parameters and continuous crystallization being a continuous process that is controlled by adjusting feed rates and flow rates. Continuous crystallization is generally more efficient and produces more uniform crystals but requires specialized equipment. The main differences between batch and continuous crystallization are as follows: Process: Batch crystallization is a discontinuous process, meaning that the crystallization process is carried out in a single batch, starting with a liquid solution, then cooling or evaporating the solution to induce crystallization, and finally separating the crystals from the mother liquor. In contrast, continuous crystallization is a continuous process, meaning that the liquid solution is fed continuously into a crystallizer, and the crystals are continuously separated from the mother liquor. Control: In batch crystallization, the process is controlled by adjusting parameters such as temperature, concentration, and agitation, which can be difficult to maintain consistently from batch to batch. In contrast, continuous crystallization can be more easily controlled by adjusting the feed rate, flow rates, and residence time in the crystallizer, which can be monitored and adjusted in real time. Efficiency: Continuous crystallization is generally more efficient than batch crystallization because it can produce a higher yield of product in a shorter amount of time. Additionally, continuous crystallization can result in more uniform crystal sizes and shapes, which can be important for certain applications. Equipment: Batch crystallization typically requires larger vessels to accommodate the entire batch, while continuous crystallization can be performed in smaller vessels that can be scaled up or down as needed.

What is the difference between cooling and evaporative crystallization?

Cooling and evaporative crystallization are two common methods of separating solid materials from a liquid solution. Cooling crystallization involves cooling the solution to a temperature below the solute's saturation point, while evaporative crystallization involves heating the solution to evaporate the solvent and increase the solute concentration. The choice between the two methods depends on factors such as the solubility of the solute, the impurity content, and the required energy consumption. The main differences between cooling and evaporative crystallization are: Principle: Cooling crystallization is based on the principle that the solubility of a substance decreases as the temperature of the solution decreases. In this process, the liquid solution is cooled down to a point where the solute concentration exceeds its saturation point, leading to the formation of crystals. On the other hand, evaporative crystallization is based on the principle that the solubility of a substance decreases as the solvent's concentration decreases due to evaporation. In this process, the liquid solution is heated to evaporate the solvent, and, as the concentration of the solute in the solution increases, crystals start to form. Temperature: In cooling crystallization, the liquid solution is cooled to a temperature below the saturation point of the solute, which can be achieved by various cooling methods, such as heat exchangers or refrigeration systems. In contrast, in evaporative crystallization, the liquid solution is heated to increase the solute concentration until the solvent evaporates, leaving behind a concentrated solution that will eventually form crystals. Energy consumption: Cooling crystallization typically requires less energy than evaporative crystallization because the cooling process can be achieved using simple cooling methods. In contrast, evaporative crystallization requires more energy because the solvent must be evaporated, which requires additional heat input. Purity: Evaporative crystallization is generally more effective than cooling crystallization at separating impurities from the crystal product because the impurities are left behind in the concentrated solution that is removed during the evaporation process. In contrast, cooling crystallization is more likely to introduce impurities into the crystal product.

Which type of crystallizer is used most often in the pharmaceutical industry?

For pharmaceutical applications, MSMPR and plug flow reactors are used most often in order to achieve continuous manufacturing. Learn more about continuous flow chemistry. There are several other types of crystallizers besides MSMPR, some of which are: Continuous crystallizers : Operate in a continuous mode and are suitable for processes that require a large amount of product Batch crystallizers : Operate in a batch mode and are suitable for processes that require a small amount of product Cooling crystallizers: Rely on cooling to generate crystals and are used in processes where the product is highly soluble in the solvent Evaporative crystallizers: Rely on evaporation to generate crystals and are used in processes where the product is not highly soluble in the solvent Vacuum crystallizers: Operate under vacuum conditions and are used in processes where the product is heat-sensitive Swirl tube crystallizers: Use a rotating tube to create a swirling flow of supersaturated solution, which promotes crystal growth Draft tube baffle crystallizers: Use a draft tube and a series of baffles to control crystal growth and promote crystal size uniformity Fluidized bed crystallizers: Suspend the crystals in a fluidized bed to promote crystal growth and prevent agglomeration Spouted bed crystallizers: Use a spouted bed to promote crystal growth and prevent agglomeration

MSMPR Crystallizer

What Is an 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.

How Does an MSMPR Crystallizer Work?

The MSMPR crystallization process involves the suspension of seed crystals in a supersaturated solution, which is mixed continuously to maintain a homogeneous concentration of crystals throughout the reactor. The process also involves removing the crystals continuously from the reactor to prevent overgrowth and to maintain a narrow size distribution.

The basic working principle of an MSMPR crystallizer can be summarized as follows:

A supersaturated solution of the solute is prepared, usually by dissolving the solute in a solvent at a high temperature and then cooling the solution to a lower temperature to achieve supersaturation.
Seed crystals are added to the supersaturated solution to initiate crystal growth. The seed crystals act as nucleation sites onto which the solute can crystallize.
The mixture of the seed crystals and supersaturated solution is continuously agitated to prevent the formation of large crystals and to maintain a homogeneous concentration of crystals throughout the reactor.
The crystals are continuously removed from the reactor by a filter or a centrifuge to prevent overgrowth and to maintain a narrow size distribution. The removed crystals are then washed and dried to obtain the final product.

The key advantage of the MSMPR crystallizer is that it enables the production of high-purity crystals with a narrow size distribution. The continuous mixing and product removal make the processes based on time rather than volume, allowing for efficient production and scalability.

Key Features of MSMPR Crystallizers

The MSMPR crystallizer has several advantages compared to other crystallizers:

Continuous operation: The MSMPR crystallizer operates continuously and efficiently by maintaining a constant suspension of crystals in the liquid phase.
Mixed suspension: By maintaining a constant suspension of crystals, the MSMPR crystallizer promotes uniform crystal growth and prevents fouling and scaling.
Mixed product removal: Both the crystals and the mother liquor are continuously removed, filtered, and then returned to the crystallizer, reducing waste and energy consumption.
Precise control of crystal size and shape: The MSMPR crystallizer enables precise control of crystal size and shape, making it ideal for use in industries where the purity and uniformity of the final product are critical.
High yield and reduced production costs: The use of MSMPR crystallizers can result in higher yields and reduced production costs due to the efficient use of materials and the ability to produce crystals of a specific size and shape.

MSMPR Crystallizers

Automated Laboratory Reactors for Crystallization Studies

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.

Crystallization Kinetics from MSMPR Crystallizers

On-Demand Webinar

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.

MSMPR Crystallization Workstations

Monitoring, Modeling, and Control of Crystallization Processes

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:

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.
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.
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.
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.

Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

Featured Application

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.