Suspension Mixed Product Removal Crystallizer Research Articles

In-situ wet milling for particle size control in continuous crystallization: Expanding the attainable region

Continuous mixed-suspension mixed-product removal crystallizer cascades are robust and proven options for continuous manufacturing. However, when applied to a late-stage drug substance the desired particle size could not be achieved due to rapid crystal growth and slow secondary nucleation kinetics. This necessitated a batch terminal milling operation to achieve particle size control (Johnson et al., 2021). To overcome this and to intensify the process, an in-situ high-shear wet mill was integrated into the continuous equipment train to achieve the target physical properties of the drug substance that met the quality and manufacturability criteria needed for the drug product. This article describes the workflow used to optimize the equipment set and operational parameters. Incorporation of a high-shear wet mill operated intermittently in the continuous drug substance process greatly expanded the attainable particle size region, improved product quality, reduced cycle time, and simplified process development and scale-up compared to the process of batch milling after continuous crystallization. Small scale batch milling experiments were used to characterize milling performance at lab and production scales and inform operational space. Several lab-scale continuous runs were then used to define the process operating space and validate the process parameters necessary to meet the particle specifications of the product. Scale-up of the equipment set for in-situ milling was also demonstrated. This approach was tested at lab-scale on representative material operating for 70 h while changing the particle size of the product in real time. This illustrated the potential of intermittent milling for model-free particle size control.

The effect on the crystallization of calcium sulfate hemihydrate with the addition of magnesium in an MSMPR crystallizer

The effect of Mg2+ ions on the purity of calcium sulfate hemihydrate (HH) in concentrated phosphoric acid solution (wt% P2O5 39) was studied, using a continuously mixed suspension mixed product removal (MSMPR) crystallizer. Impurity distribution into crystals in the MSMPR crystallizer was considered by the population balance equation. The presence of Mg2+ ions make the crystals needle-like and agglomerated in large quantities, leading to more three-dimensional defects formation. This effect on crystals increases the uptake ratio (U) of phosphate and reduces HH purity and phosphorus yield. Through the scanning electron microscopy (SEM) and the focused beam reflectance measurement (FBRM), the effect of Mg2+ ions in inhibiting the radial growth of crystals and increasing the critical nuclear radius (rcrit) of crystals in solution was discovered. The influence of Mg2+ ions is crucial for the preparation of HH in the phosphoric acid hemihydrate process.

Improvement of drug processability in a connected continuous crystallizer system using formulation additive

Continuous crystallization in the presence of polymer additives is a promising method to omit some drug formulation steps by improving the technological and also pharmacological properties of crystalline active ingredients. Accordingly, this study focuses on developing an additive-assisted continuous crystallization process using polyvinylpyrrolidone in a connected ultrasonicated plug flow crystallizer and an overflow mixed suspension mixed product removal (MSMPR) crystallizer system. We aimed to improve the flowability characteristics of small, columnar primary plug flow crystallizer-produced acetylsalicylic acid crystals as a model drug by promoting their agglomeration in MSMPR crystallizer with polyvinylpyrrolidone. The impact of the cooling antisolvent crystallization process parameters (temperature, polymer amount, total flow rate) on product quality and quantity was investigated. Finally, a spatially segmented antisolvent dosing method was also evaluated. The developed technology enabled the manufacture of purified, constant quality products in a short startup period, even with an 85% yield. We found that a higher polymer amount (7.5–14%) could facilitate agglomeration resulting in “good” flowability without altering the favorable dissolution characteristics of the primary particles.

Continuous crystallization and its potential use in drug substance Manufacture: A review

Interest in the continuous manufacturing in the pharmaceutical industry for the production of Active Pharmaceutical Ingredients (API’s) has greatly increased in recent years. This has led to a variety of studies on continuous processing including a large number of studies in the area of continuous crystallization. While various potential crystallizer configurations exist, the vast majority of work in this area has focused around the Mixed Suspension Mixed Product Removal (MSMPR) crystallizer. In this review, MSMPR crystallizers will be described along with their use in continuous API manufacture.

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

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.

Design and Optimization of the Single-Stage Continuous Mixed Suspension-Mixed Product Removal Crystallization of 2-Chloro-N-(4-methylphenyl)propenamide.

A continuously operated single-stage mixed suspension–mixed product removal (MSMPR) crystallizer was developed for the continuous cooling crystallization of 2-chloro-N-(4-methylphenyl)propanamide (CNMP) in toluene from 25 to 0 °C. The conversion of the previous batch to a continuous process was key to developing a methodology linking the synthesis and purification unit operations of CNMP and gave further insight in the development of continuous process trains for active pharmaceutical ingredient materials. By monitoring how parameters such as cooling and agitation rates influence particle size and the yield, two batch start-up strategies were compared. The second part of the study focused on developing and optimizing the continuous cooling crystallization of CNMP in the MSMPR crystallizer in relation to the yield by determining the effects of varying the residence time and the agitation rates. During the MSMPR operation, the plot of the focused beam reflectance measurement total counts versus time oscillates and reaches an unusual state of control. Despite the oscillations, the dissolved concentration was constant. The yield and production rate from the system were constant after two residence times, as supported by FTIR data. The overall productivity was higher at shorter residence times (τ), and a productivity of 69.51 g/h for τ = 20 min was achieved for the isolation of CNMP.

Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process

The development of an impurity and form controlling continuous crystallization process to deliver the JAK1 inhibitor GDC-4379 is described. Explored as a next generation process for the two-step batch recrystallization procedure used in production, the translation of the impurity control step to a continuous mixed suspension, mixed product removal (MSMPR) crystallizer enabled superior kinetic rejection of a key regioisomer impurity (97.9%) versus the batch process (32.4%). By operating the MSMPR crystallizer at sufficient water content and temperature it was verified that the target hydrate form A of GDC-4379 for the active pharmaceutical ingredient (API) could be selectively crystallized from the DMSO/MeOH solvent system of the purification step. This demonstration provided proof of concept for a telescoped continuous crystallization process for GDC-4379 to replace the separate batch impurity and form control recrystallizations carried out in production.

Solid-State Deracemization via Temperature Cycles in Continuous Operation: Model-Based Process Design.

Solid-state deracemization via temperature cycles converts a racemic crystal mixture into an enantiopure product by periodic cycling of the temperature in the presence of a racemization catalyst. A continuous counterpart of this conventional batch-operated process is proposed that can be performed in mixed suspension mixed product removal crystallizers (MSMPRCs). More specifically, three different configurations are described to perform periodic forcing via temperature cycles, which differ from each other in the type of the feed and in the withdrawal system. We have developed a model by extending our recent population balance equation model of batch solid-state deracemization via temperature cycles, and we exploit this tool to analyze the start-up and periodic steady-state behavior. Moreover, we compare the performance of the different configurations based on the selected key performance indicators, namely, average periodic steady-state enantiomeric excess and productivity. The process with solution feed yields pure enantiomers, while the solid and suspension-fed process alternatives result in highly enantiomerically enriched crystals. We further design an MSMPRC cascade to overcome this purity limitation. This work discusses guidelines on how to transform the batch process of temperature cycles into a continuous operation, which enables stable, unattended operation and chiral crystal production with consistent product quality.

Optimal start-up strategies of a combined cooling and antisolvent multistage continuous crystallization process

A model-based optimization methodology was developed to systematically address all possible optimal start-up scenarios of a multistage combined cooling and antisolvent continuous MSMPR (mixed-suspension, mixed-product removal) crystallizer. The crystallization of aspirin (acetylsalicylic acid, ASA) in ethanol (solvent) and water (antisolvent) was used as a case study. A steady state optimization was firstly conducted to optimize the crystallizer design and operating conditions and set-up the reference trajectories. The discretised profiles of the jacket temperatures, antisolvent flowrates and seeding policies, which includes the seed flowrates, loading and mean size, were used as decision vectors for the dynamic optimization problem. Scenarios with single and combined decision vectors were addressed and analysed in start-up situations involving prefilled or empty vessels. The impact of simplified optimization and operating procedures or refined discretization schemes were also addressed. It was shown that several options may provide comparable performance and the start-up time can be improved by nearly 80% in the case of combined decision vectors involving all possible decision vectors.

Real-Time Monitoring of Continuous Pharmaceutical Mixed Suspension Mixed Product Removal Crystallization Using Image Analysis

In this work, we developed an in-line image analysis system for the monitoring of the continuous crystallization of an active pharmaceutical ingredient. Acetylsalicylic acid was crystallized in a mixed suspension mixed product removal crystallizer, which was equipped with overflow tubing as an outlet. A steep glass plate was placed under the outlet onto which the slurry dripped on its surface. The glass plate spread and guided the droplets toward the product collection filter. A high-speed process camera was mounted above the glass plate to capture images of the crystals. Several light sources were tested in various positions to find the appropriate experimental setup for the optimal image quality. Samples were taken during continuous operation for off-line particle size analysis in order to compare to the crystal size distributions calculated from the images. The results were in good agreement, and the trends of the process could be followed well using the images. As a next step, image analysis was operated throughout the entire continuous crystallization experiment, and a huge quantity of information was collected from the process. The crystal size distribution of the product was calculated every 30 s, which provided a thorough and detailed insight into the crystallization process.

Frequency response analysis for MSMPR crystallizer with modulated feed flow rate: A method for studying secondary nucleation mechanism

In industrial crystallization, understanding the effect of individual secondary nucleation mechanisms is difficult. This paper presents frequency response of a mixed suspension mixed product removal (MSMPR) crystallizer to a periodic modulation in feed rate. This will help in roughly understanding the effect of magma density or thick solute layer adsorbed on crystals, on the formation of secondary nucleation, which are otherwise practically impossible to understand through stirrer speed modulation (V. Bal and B. Peters, Cryst. Groth Des., 21 (2021) 227–234). Feed rate modulation drives the oscillation in magma density, which in turn drives the supersaturation. Combined effect of magma density and supersaturation controls the oscillation in nucleation rate and hence, damped oscillation in number density. In the intermediate frequency limit, strong oscillation in either amplitude or phase shift can be exploited to study the different secondary nucleation mechanisms. There is a narrow range of frequency and amplitude of feed rate modulation over which the crystallizer should be operated for detectable response.

Utilization of FBRM and PVM to analyze the effects of different additives on the crystallization of ammonium dihydrogen phosphate

The purpose of this study is to determine the effect of feeding rate, supersaturation level, stirring speed and the additives such as potassium nitrate (KNO3) and a new chelating agent (NCA) on the chord length distribution (CLD) as well as the crystal form of ammonium dihydrogen phosphate (MAP). The MAP crystals’ growth is investigated by using the FBRM G400 and the PVM V19 probes respectively in an MSMPR (Mixed Suspension Mixed Product Removal) crystallizer. Herein, the FBRM ensures an on-line determination of the CLD, which is expressed as the cumulative undersize square-weight percentage distribution of MAP crystals. CLD is statistically proportional to crystal size distribution. The PVM ensures the real-time monitoring of crystal morphology. In addition, an optical microscope is used to characterize the shapes of the crystals obtained in the MSMPR crystallizer. The chemical structures of the crystals are characterized by Fourier transform infrared (FT-IR) analysis. The population density of the nuclei, the nucleation rate, and the growth rate of the MAP crystals are also calculated. Industrial problems encountered in the production of MAP crystals, such as filtration and small crystal size, are eliminated especially in the presence of KNO3 and 1% NCA, which is proved by FBRM, PVM and number density theory application.

Enhancing continuous reactive crystallization of lithium carbonate in multistage mixed suspension mixed product removal crystallizers with pulsed ultrasound

In this work, pulsed ultrasound was used to facilitate steady-state reactive crystallization and increase the final yield and productivity of lithium carbonate in continuously operated single and multistage mixed suspension mixed product removal (MSMPR) crystallizers. Experimental analyses of the stirred tank MSMPR cascade were performed to investigate the effects of ultrasound field, residence time and temperature which contributed to the steady-state yield, crystal size distribution and crystal morphology. The results show that pulsed ultrasound can not only significantly enhance the reaction rate, but also help to improve the particle size distribution and the crystal habit. Subsequently, a population balance model was developed and applied to estimate the final yield of the continuous process of the lithium bicarbonate thermal decomposition reaction coupling lithium carbonate crystallization. The consistency of the final yield between the experiments and the simulations proved the reliability of the established model. Through the experimental and simulation analyses, it is demonstrated that the use of pulsed ultrasound, higher final stage temperature, MSMPR cascade design and appropriate residence time help to achieve higher yield and productivity. Furtherly, based on the conclusion drawn, pulsed ultrasound enhanced three-stage MSMPR cascaded lithium carbonate continuous crystallization processes were designed, and the maximum productivity of 44.0 g/h was obtained experimentally.

Model-based design of pressure-driven product removal from stirred suspensions

Achieving “mixed-product removal” in a mixed-suspension mixed-product removal crystallizer (MSMPRC), operating with a pressure-driven suspension transfer, is challenging. In this work, single and multiphase computational fluid dynamics (CFD) simulations were used to guide the choice of a suitable withdrawal position, which was found to be that of an immersed tube close to the vessel wall. The chosen withdrawal position was then tested and compared to other withdrawal positions experimentally. It performed as predicted, whereas for the other positions, the degree of dilution (size-independent classification) and of sieving (size-dependent classification) of the product removed increased. Furthermore, the influence of a non-representative withdrawal on an MSMPRC steady-state was investigated using a population balance equation (PBE) model.

API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing

Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early research scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.

Polymorphism control of l-Glutamic acid in a single-stage and a two-stage MSMPR crystallizer by different seeding strategies

Control of polymorphism in continuous crystallization processes has been investigated. Using population balance modeling, we found that the relative growth and birth kinetics of different polymorphs play a major role on the steady-state polymorph outcome in a mixed-suspension mixed-product removal (MSMPR) crystallizer. In this communication, we present the conditions to harvest the desirable polymorph of l-glutamic acid (LGA) by numerical simulation and experimental observation in a two-stage MSMPR and a single MSMPR with intermittent seeding. Different polymorphic outcomes of l-glutamic acid can be achieved at different operating temperatures of the MSMPR crystallizer. The interplay of growth and nucleation kinetic makes the stable β-form hard to secure at low operating temperatures. The design of a two-stage MSMSPR crystallizer configuration with different working temperatures realizes the continuous seeding of the stable β form from the first MSMPR to the production crystallizer (second stage).Another approach to ensure the production of the desired polymorph is the use of intermittent seeding with the desirable polymorph to a single-stage MSMPR. The feasibility of both continuous seeding (in a two-stage MSMPR) and intermittent seeding (in a single stage MSMPR) strategies is demonstrated in this paper. Based on the l-glutamic acid crystallization kinetics, numerical simulation is used to figure out the best inlet concentration, working temperature, and intermittent seeding frequency for producing the desired yield and polymorph.

Continuous Protein Crystallization in Mixed-Suspension Mixed-Product-Removal Crystallizers

The metastable needlelike form of lysozyme can be obtained from continuous crystallization in mixed-suspension mixed-product-removal (MSMPR) crystallizers for conditions at which the stable tetragonal form is obtained from batch crystallization. A 3D-printed airlift crystallizer and stirred tank crystallizer are used, which both approximate an MSMPR crystallizer well. The influence of residence time, precipitant concentration, and agitation mechanism on the attainable solid-state form is presented. The needlelike crystals appear after nucleation of the tetragonal form. An earlier transition from the tetragonal form to the needlelike form is observed in an airlift crystallizer compared to a conventional stirred crystallizer, which is possibly caused by reduced attrition and the presence of a gas–liquid interface in the airlift crystallizer. Furthermore, a long residence time and high precipitant concentration favor the formation of the needlelike crystals. This work demonstrates how the mode of operation of well-mixed crystallizers affects the attainable solid-state form of a model protein. The results generally show the importance of obtaining a quantitative understanding of the dynamic interplay between stochastic primary nucleation processes and deterministic growth and secondary nucleation processes so that future continuous MSMPR crystallizers can be designed and operated robustly to produce protein crystals of a desired solid-state form.

Direct Processing of a Flow Reaction Mixture Using Continuous Mixed Suspension Mixed Product Removal Crystallizer

Crystallization as the most widespread purification, separation, and morphology-determining method is a critical technology that could be made safer and more economical by using continuous crystall...

Size-dependent growth kinetics of struvite crystals in wastewater with calcium ions

AbstractKinetic parameters describing continuous reaction crystallization of struvite from aqueous solutions containing also calcium ions (from 100 to 2000 mg Ca2+/kg) were estimated. Test results were compared with kinetic data of struvite manufactured from real cattle liquid manure. Kinetic model for ideal MSMPR (Mixed Suspension Mixed Product Removal) crystallizer was used assuming dependence of crystal growth rate G on its size L (size-dependent growth, SDG MSMPR model). Based on nonlinear regression and statistical analysis, one from within five considered G(L) models was selected – Rojkowski exponential (RE) model – rendering the experimental population density distributions the best. It was concluded, that calcium ions influenced all components of struvite manufacturing process disadvantageously. A rise of Ca2+ concentration in a feed from 100 to 2000 mg/kg increased nucleation rate ca. 160-time, whereas growth rate of nuclei up to macroscopic size G0 decreased more than 10-time. Linear (larger) crystal growth rate G¥ was nearly two-times smaller: 1.71·10–8 m/s (100 mg Ca2+/kg) – 9.10·10–9 m/s (2000 mg Ca2+/kg). Resulting in a product with deteriorated quality. Mean size of the crystals decreased nearly two-times (to 18.4 μm), non-homogeneity within product population enlarged and calcium fraction in the product increased. The product, beside struvite MgNH4PO4·6H2O, also contained hydrated amorphous calcium phosphate(V) Ca3(PO4)2·nH2O (ACP). It was observed, that 5-times smaller concentration of phosphate(V) ions in a feed and magnesium ions excess in relation to phosphate(V) and ammonium ions (1.2 : 1 : 1) influenced all kinetic parameters of continuous struvite reaction crystallization advantageously.

End-to-end continuous manufacturing of conventional compressed tablets: From flow synthesis to tableting through integrated crystallization and filtration.

An end-to-end continuous pharmaceutical manufacturing process was developed for the production of conventional direct compressed tablets on a proof-of-concept level for the first time. The output reaction mixture of the flow synthesis of acetylsalicylic acid was crystallized continuously in a mixed suspension mixed product removal crystallizer. The crystallizer was directly connected to a continuous filtration carousel device, thus the crystallization, filtration and drying of acetylsalicylic acid (ASA) was carried out in an integrated 2-step process. Steady state was reached during longer operations and the interaction of process parameters was evaluated in a series of experiments. The filtered crystals were ready for further processing in a following continuous blending and tableting experiment due to the good flowability of the material. The ASA collected during the crystallization-filtration experiments was fed into a continuous twin-screw blender along with microcrystalline cellulose as tableting excipient. After continuous blending Near-Infrared spectroscopy was applied to in-line analyze the drug content of the powder mixture. A belt conveyor carried the mixture towards an eccentric lab-scale tablet press, which continuously produced 500mg ASA-loaded compressed tablets of 100mg dose strength. Thus, starting from raw materials, the final drug product was obtained by continuous manufacturing steps with appropriate quality.