Suspension Mixed Product Removal Research Articles

Development and integration of a continuous horizontal belt filter into drug production procedure

In the pharmaceutical industry, filtration is traditionally carried out in batch mode. However, with the spread of continuous technologies, there is an increasing demand for robust continuous filtration strategies suitable for processing suspensions produced in continuous crystallizers. Accordingly, this study aimed to investigate a lab-scale horizontal conveyor belt filtration approach for pharmaceutical separation purposes for the first time. The newly developed continuous horizontal belt filter (CHBF) was tested under different systems (microcrystalline cellulose (MCC)/water, lactose/ethanol and acetylsalicylic acid (ASA)/water) and diverse conditions. Filtration was robust using a well-defined unimodal particle size distribution MCC in water system, where the residual moisture content varied within narrow limits of 45–52% independently from the process conditions. Besides, the residual moisture content highly depended on the applied solvent and particle size. It could be reduced to below 2% by processing the suspensions of either a volatile solvent (lactose in ethanol) or an aqueous slurry of a large particle size ASA. Finally, the CHBF was connected to a mixed suspension mixed product removal (MSMPR) or a plug flow crystallizer (PFC). The residual moisture content of the CHBF-filtered ASA product and operation characteristics (onset of steady-state) were evaluated in both continuous crystallizer-filter systems. The MSMPR-CHBF system operated with a longer startup period. The size of the in situ-produced crystals was of a similar order magnitude in both systems, resulting in a similar residual moisture content (around 20%). Overall, the tested continuous filter was robust, did not modify the crystal morphology in the examined experimental range, and could be effectively integrated with continuous crystallizers.

Robust optimization of cascaded MSMPR crystallization unit using unsupervised machine learning

AbstractThe use of mixed suspension mixed product removal (MSMPR) system in the pharmaceutical industry to produce active pharmaceutical ingredients is well known. In industrial settings, the MSMPR system is subject to lot of process uncertainty which, if ignored, might result in poor product quality. In this work, the process uncertainty involved in MSMPR is targeted during the process optimization stage to find robust optimal operating conditions. The temperature and the residence time inside each cascaded MSMPR unit, altogether six, are considered as uncertain parameters. A sampled set of uncertain data points for such six different uncertain parameters are clustered using a novel support vector clustering (SVC) based algorithm. The uniqueness of this algorithm lies in its ability to fine‐tune the hyper‐parameters of SVC while intelligently clustering the uncertain data points into optimal number of clusters. Such identified clusters are helpful to generate more samples from the intended regions rather than generating them randomly to avoid proposing conservative solutions. Both best‐case and worst‐case scenarios for robust oOptimization (RO) are considered with , and samples. As the model has to be evaluated for a large number of samples and the MSMPR models are time‐consuming to evaluate, a surrogate model of the MSMPR process is developed to perform optimization under uncertainty. Performance metrics are used to quantitatively establish the superiority of the SVC based RO over the box‐sampling based RO.

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.

Recent Advancements in Continuous Crystallization of Proteins

AbstractRecently, there have been many studies and reports on various continuous protein crystallization processes. Due to the increasing demand for pharmaceutical proteins such as insulin and monoclonal antibodies, it has become essential to optimize the current industrial processes to meet these demands. There are various comparisons to be made between current batch crystallization processes and continuous processes for proteins. This review paper aims to review the recent advancements in continuous protein crystallization processes, such as slug flow crystallizers, oscillatory baffled crystallizers, and mixed suspension mixed product removal (MSMPR) crystallizers.

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.

Size-dependent growth kinetics model for potassium chloride from seeded chloride solution

Abstract It was widely known that crystallization kinetics are the basis for crystallization behavior and crystallizer scale-up design. Cooling crystallization of potassium chloride was an essential unit operation in recycling industry. Some researchers have proposed the strategy of adding seed crystals for the intermittent cooling crystallization process to control the particle size and distribution of the target product. This paper studied the complex function relation between particle size and growth rate of KCI in the crystallization process in a continuous mixed-suspension mixed-product-removal (MSMPR) crystallizer at a steady state. Using the crystallization kinetics data, the mathematical models of coupling crystallization were established based on the population balance equations and mass balance equations. Since population density distributions of products behave multiform under different conditions, based on diffusion theory. The growth rate was obtained by a least square method for the multivariate linear regression, and the reliability of the kinetics model was validated experimentally. Fitting results indicated that some classical models, including several size-independent growth models and size-dependent growth models, such as Bransom, C-R, MJ2, ASL, and MJ3, could not model the size-dependent growth accurately. Based on this situation, an exponential growth model was proposed and confirmed to describe the size-dependent growth behavior. It was found that the model parameters have definite meanings and were strongly related to particle size. Compared with the classical models, this model showed good pertinency and adaptability to experimental results when used to describe the population density distribution and the size-dependent growth rate of KCI. This research could provide a theoretical guide for optimizing the crystallization process and designing industrial crystallizers.

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.

New Discrete Formulation for Reduced Population Balance Equation: An Illustration to Crystallization

In this paper, we focus on providing a discrete formulation for a reduced aggregation population balance equation. The new formulation is simpler, easier to code, and adaptable to any type of grid. The presented method is extended to address a mixed-suspension mixed-product removal (MSMPR) system where aggregation and nucleation are the primary mechanisms that affect particle characteristics (or distributions). The performance of the proposed formulation is checked and verified against the cell average technique using both gelling and non gelling kernels. The testing is carried out on two benchmarking applications, namely batch and MSMPR systems. The new technique is shown to be computationally less expensive (approximately 40%) and predict numerical results with higher precision even on a coarser grid. Even with a revised grid, the new approach tends to outperform the cell average technique while requiring less computational effort. Thus the new approach can be easily adapted to model the crystallization process arising in pharmaceutical sciences and chemical engineering.

Influence of Aluminum on Morphologies and Crystallization Kinetics of Hemihydrate Calcium Sulfate in the Hemihydrate Process of Phosphoric Acid Production

The influence of aluminum on morphologies and crystallization kinetics of hemihydrate calcium sulfate (HH) in the hemihydrate process of phosphoric acid production was investigated. X-ray diffraction analyses showed that Al3+ ions can be adsorbed onto the crystal surface and incorporated into the crystal lattice. The crystal growth rate first increases and then decreases due to the dual role of Al3+ ions in a mixed suspension mixed product removal (MSMPR) crystallizer. For the first time, the effect of Al3+ ions on nucleation kinetics of HH at 93 °C was investigated by focused-beam reflectance measurement (FBRM). The results indicate that Al3+ ions retard the nucleation by increasing the interfacial tension values (γ).

Effects of Physicochemical Parameters on Struvite Crystallization Based on Kinetics

The precipitation of struvite (MgNH4PO4·6H2O) is considered to be a promising method for the recovery of phosphate from wastewater. In this review, the kinetic models, which are commonly used to explain the process of struvite crystallization, are described. The mixed-suspension mixed-product removal (MSMPR) model is based on the population balance equation (the size-dependent growth model and the size-independent growth model). Thereafter, the first-order kinetic fitting model that aligned with concentration changes in the substrate is summarized. Finally, the several physical and chemical factors that affected the efficiency of struvite crystallization are determined. The supersaturation ratio, which is seen as the driving force of struvite crystallization, is the main factor that influences crystallization; however, it cannot be used in practical applications of engineering because it is indirectly associated with the following factors: pH, the molar ratio of Mg:N:P, and the interference of foreign impurities. In this study, we present conclusions that should be used to guide further research studies, and encourage the engineering practice of wastewater treatment with struvite precipitation.

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.

Crystallization behavior of calcium silicate hydrate in highly alkaline system: Structure and kinetics

During utilization of high silicon solid wastes, a characteristic and complex desilication solution (DSS) generated, remains an important subject to be as precursor of calcium silicate hydrate (C–S–H) crystallization. By using the mixed suspension mixed product removal (MSMPR) crystallizer, the crystallization behavior of C–S–H in DSS was investigated. The effects of temperature, initial Ca/Si ratio, silicate concentrations, solvent alkalinity on the morphology and structure of synthesized C–S–H were investigated through X–ray diffraction, scanning electron microscopy, laser particle size analyzer, and 29Si magic angle spinning nuclear magnetic resonance. The crystallization growth rate and particle size of C–S–H were positively correlated with temperature. The elevation of Ca/Si molar ratio will lead to shortening of the silicate chain to form more monomers. The increase of silicate concentration and solvent alkalinity will result in the formation of shorter silicate chains. This work provides theoretical guidance for precise preparation and design of C–S–H synthesized by a causticization strategy.

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.

Influence of Hydrodynamic Conditions on Precipitation Kinetics of Barium Sulfate in a Multifunctional Reactor

In this paper, the influence of hydrodynamic conditions in Kenics static mixer, which acts as a multifunctional reactor, on precipitation kinetics of barium sulfate is investigated. The investigated range of the Reynolds number varied between 500 and 5000, which covered both laminar and turbulent flow regimes. In all experiments, the relative supersaturation was maintained at the constant level (σ = 205). The obtained precipitate was collected and used for crystal size distribution (CSD) determination. On that basis, the kinetic parameters of the process were calculated using the mixed suspension mixed product removal (MSMPR) mathematical model of the process. It was found that for the whole investigated range of Reynolds number, the mixing conditions were satisfactory. CSD analysis showed that in the laminar regime, a clear tendency in crystal behavior could not be noticed. However, during the analysis of the turbulent regime, the presence of a critical Reynolds number was noticed. Above this value, there is a change in the flow pattern, which results in a change of kinetic parameters (B, G), as well as manifests in a form of a decrease in the value of mean diameters of crystals. The flow pattern change is caused by the geometry of the reactor’s inserts.

Continuous lactose recovery from acid whey by mixed suspension mixed product removal (MSMPR) crystallizer in the presence of impurities

The continuous crystallization approach provides the opportunity to intensify production and improve the quality of crystals manufacturing. This study examined the effect of impurities on lactose crystallization in the continuous mixed suspension mixed product removal (MSMPR) crystallizer. Two impurities usually present in acid whey, protein and lactic acid, were examined. The continuous process was evaluated based on the time required to reach a steady state operation, particle size distribution (PSD), purity, and yield. Impurities increased the time for the continuous system to achieve a steady state condition. This effect was more pronounced in the presence of protein (>13 residence time). In the acidic environment, lactose crystals tended to promote caking and agglomeration during the filtration process, resulting in the formation of larger crystals and a wider PSD. The protein incorporation in the continuous process was 1.5 times higher than in the batch process due to the inefficiency of the filtration stage caused by the aggregated denatured protein particles, which entrapped the mother liquor between the void area of the agglomerated crystals. Understanding impurity effects on lactose crystals in continuous crystallization can be used as a fundamental study to intensify the process and improve the quality of the crystals.

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.