Suspension Mixed Product Removal Research Articles

A continuous multi-stage mixed-suspension mixed-product-removal crystallization system with fines dissolution

This work demonstrates how crystal particle size is affected by the addition of fines dissolution in a mixed suspension mixed product removal (MSMPR) cascade system. The cooling crystallization of paracetamol in water was used as a case study. Two MSMPR cascade configurations were evaluated: (i) nucleation-growth (NG), and (ii) nucleation-dissolution-growth (NDG). Simulation results demonstrate that adding a dissolution step in the MSMPR cascade configuration increases the average product crystal size. Larger crystals and a narrower distribution were obtained due to the removal of fine crystals through the continuous process. However, a small decrease in the achievable yield was observed. Experimental results also showed a similar effect on the final mean size and CSD. The results demonstrate that a dissolution stage can be optimized to increase the final crystal size and CSD by varying the dissolution temperature to optimize the CSD with minimum effect on the achievable yield.

Calcium Lactate Pentahydrate Crystallization in the Presence of Pentanoic Acid

AbstractCalcium lactate crystallization was investigated in the presence of pentanoic acid in a mixed‐suspension mixed‐product removal (MSMPR)‐type crystallizer. Filtration rate measurements were carried out to define the effect of pentanoic acid on the filtration characteristics of calcium lactate pentahydrate crystals. The average particle size, length‐to‐width ratio, and morphologies of calcium lactate pentahydrate crystals were also determined and examined as a function of pentanoic acid concentrations. The zeta potential of calcium lactate pentahydrate crystals was measured. Thermogravimetric and differential thermal analysis (TGA‐DTA) as well as X‐ray diffraction (XRD) were performed and Coats and Redfern's method was used to verify the kinetic parameters in the dehydration steps observed in the TGA curves.

Effects of L‐Serine and L‐Proline on Crystallization Kinetics of Calcium Pyrophosphate Dihydrate

AbstractCalcium pyrophosphate dihydrate (CPPD) crystallization was investigated in a mixed‐suspension mixed‐product removal (MSMPR)‐type crystallizer in the presence of the amino acids L‐serine and L‐proline as additives. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and zeta potential analysis were applied for characterization of the crystals obtained. CPPD crystals obtained in pure media consisted of aggregated particles which included plate‐like structures and rod‐shaped crystals. However, it was observed that agglomeration and breakage tendency on CPPD crystals obtained in the presence of amino acids were remarkable. The population balance equation for CPPD crystals was resolved with numerical analysis considering aggregation and breakage steps. The predominant mechanism was the breakage for CPPD crystallization in the presence of amino acids.

Nucleation and Growth Kinetics for Combined Cooling and Antisolvent Crystallization in a Mixed-Suspension, Mixed-Product Removal System: Estimating Solvent Dependency

Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous mixed-suspension, mixed-product removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overp...

Control of a two-stage mixed suspension mixed product removal crystallizer

In this work, we consider the problem of controlling a two-stage cooling mixed suspension mixed product removal (MSMPR) crystallizer. For this process, the temperature in the first crystallizer is manipulated for controlling the average crystal dimension (d43), while it is desired to maintain the temperature of the second crystallizer at the minimum allowed value to guarantee maximum yield. Due to system nonlinearities and process delays, the performance of traditional PID controllers are poor. A control scheme is proposed to improve the closed loop performance and achieve desired control objectives. The control scheme is based on the coupling of a PI controller and a model-based nonlinear prediction block that serves as delay and disturbance compensator. The proposed scheme has been tested on the system in case of disturbances in the feed concentration, with and without measurement errors. It is observed that the proposed scheme outperforms the PI controller by reducing the output response settling time and overshoot.

Kinetic conditions of struvite continuous reaction crystallisation from wastewater in presence of aluminium(III) and iron(III) ions

Kinetic parameters of the continuous struvite reaction crystallisation process from aqueous solutions containing phosphate(V) ions with impurities: aluminium(III) or/and iron(III) ions were determined. A simplified kinetic model of ideal mixed suspension mixed product removal (MSMPR) crystalliser - size independent growth (SIG) was adopted. Nuclei population densities, nucleation rates and crystal linear growth rates were determined from product crystal size distributions. It was concluded that within the assumed process parameter ranges, the linear growth rate of struvite crystals in presence of aluminium(III) ions varied from 4.53 · 10‒9 to 1.89 · 10‒8 m/s, whereas in presence of iron(III) ions it was within the 4.59 · 10‒9 ‒ 1.62 · 10‒8 m/s range. Nucleation rate varied within the 3.8 · 107 ‒ 1.6 · 109 1/(sm3) and 4.5 · 107 ‒ 1.2 · 109 1/(sm3) ranges, correspondingly. These large differences show significant influence of impurities and technological parameters on the struvite reaction crystallisation kinetics, thus on the product quality. It was experimentally demonstrated that aluminium(III) ions affect struvite reaction crystallisation more advantageously than iron(III) ions.

A Comparative Study of Coupled Preferential Crystallizers for the Efficient Resolution of Conglomerate-Forming Enantiomers.

The separation of enantiomers is of great importance due to their possible differences in therapeutic properties. Preferential crystallization in various configurations of coupled batch crystallizers is used as an attractive means to separate the conglomerate-forming enantiomers from racemic mixtures. However, the productivity of such batch processes can be limited by the nucleation of the counter enantiomer and consumption of the supersaturation. In this work, a recently proposed process configuration, which uses coupled mixed suspension mixed product removal (MSMPR) with liquid phase exchange, is investigated by simulation studies. A detailed study on the effect of process parameters (e.g., feed flow rate, seed mass, and liquid phase exchange) on the productivity and yield of the coupled MSMPR has been presented. Moreover, a comparison of various coupled crystallizer configurations is carried out. It is shown through simulation studies that the productivity of the enantiomeric separation can be significantly improved compared to the previously proposed batch modes when the continuous configuration is used. The effect of nucleation kinetic parameters on the performances of various crystallizer configurations is studied as well. A set of coupled population balance equations (PBEs) was used to describe the evolution of the crystal phase of the both enantiomers in each vessel. These equations were solved numerically using the quadrature method of moments. The insights obtained in this study will be useful in the process design of coupled crystallizer systems.

Model-Based Evaluation of Direct Nucleation Control Approaches for the Continuous Cooling Crystallization of Paracetamol in a Mixed Suspension Mixed Product Removal System

Direct nucleation control (DNC) is a model-free feedback control approach based on the measurement of particle number in the crystallization process. The experimental implementation has demonstrated that this approach is efficient to produce large and uniform crystals in batch crystallization, or to reduce startup duration and suppress disturbance in continuous crystallization. In this work, five different DNC frameworks/strategies are proposed for a continuous mixed suspension mixed product removal (MSMPR) crystallization of paracetamol–water system and evaluated systematically using a model-based approach. It is found that the reverse DNC framework could provide the best control performance in terms of startup, set-point change, and disturbance suppression. In addition, an optimal heating/cooling rate of about 0.6 °C/min was determined. These observations are applicable for the model compound studied (paracetamol) and should be investigated for other systems. This study provides a general guidance of de...

Technoeconomic Evaluation of Multiple Mixed Suspension-Mixed Product Removal (MSMPR) Crystallizer Configurations for Continuous Cyclosporine Crystallization

Continuous crystallization using Mixed Suspension-Mixed Product Removal (MSMPR) crystallizers has been demonstrated as a feasible method for implementing continuous separations in pharmaceutical manufacturing processes. This work conducts a steady-state process modeling and simulation study of the continuous cooling crystallization of cyclosporine, comparing processes with and without solids recycle for their technoeconomic viability. The model describes population balance equations, crystallization kinetics, and process mass balances to compare attainable crystallization and plantwide yields of different process configurations. Total cost components using an established economic analysis methodology are compared for varying numbers of crystallizers, operating temperatures, total crystallizer cascade residence times and API feed concentrations. Economic analyses and the calculation of normalized cost components with respect to total crystallizer volumes identify the process without recycle as the most economically viable option, achieving the lowest total costs and low E-factors for pharmaceutical processes. The sensitivity of total costs to the selected total residence times for economic analyses highlights the need for rigorous comparison methodologies. This work identifies the need for technoeconomic optimization studies of continuous crystallization processes to establish the optimal design of manufacturing campaigns prior to further development.

Complexation-Assisted Continuous Crystallization of Isomeric Systems with Nanofiltration Recycle

In API-impurity systems consisting of structural isomers, the impurity has a strong affinity to incorporate into the host crystal owing to their identical molecular weight and similar structure. Conventional successive recrystallization turns out to be an unattractive purification strategy in such cases, since it can improve crystal purity only at the cost of yield. As an alternative, selective complexation of the impurity can sterically prevent its incorporation into the host lattice by increasing the apparent molecular weight and dimensions of the impurity. The increase in size of the impurity post complexation can be further exploited using a nanofiltration membrane to preferentially reject the complex in solution, while allowing the smaller molecules of uncrystallized API to permeate through. The crystallization yield can be enhanced by concentrating the permeate stream and recycling it back to the crystallizer. Thus, complexation-assisted nanofiltration recycle presents a strategy to improve both yield and crystal purity simultaneously in a continuous mode. In the present work, the application of this strategy is described for the continuous cooling crystallization of two isomeric systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer. The first system consists of 4-nitrophenol with 3-nitrophenol as an added impurity in an aqueous solvent, while the second one consists of the active pharmaceutical ingredient (API) acetaminophen with its isomer 3-acetamidophenol added as an impurity in a mixed solvent of 50:50 ethanol and water by volume. A working strategy for selecting the complexing agent and nanofiltration membrane is discussed. For both systems, the complexation-assisted continuous mode with nanofiltration recycle performed better than both the batch process as well as the unrecycled MSMPR process in terms of higher crystallization yield and lower impurity incorporation in crystals.

Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine

Continuous manufacturing (CM) is an emerging technology in the pharmaceutical manufacturing sector, and the understanding of the impact on product quality is currently evolving. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance 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, we focus on how to develop a continuous crystallization system, from the perspective of process engineering, and the related risk considerations on product quality. Specifically, we designed and built 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 microscopy, 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 as the three key risk areas for continuous crystallization process development. Our proof-of-concept continuous crystallization system uses feedback/feedforward controls to achieve constant levels in crystallizers, a centralized automation program coded in LabVIEW, and PAT monitoring for polymorphs and particle size distribution (Raman and FBRM). To the best of our knowledge, this is also the first study on continuous crystallization of carbamazepine for form III and its polymorphic transition (between form II and form III).

Determination of the Effects of Carboxylic Acids on Calcium Sulfate Dihydrate Crystallization

AbstractCalcium sulfate dihydrate crystallization was carried out using a mixed‐suspension mixed‐product removal (MSMPR)‐type crystallizer in pure media and in the presence of three different types of carboxylic acid: propionic acid, oxalic acid, and propane‐1,2,3‐tricarboxylic acid. The crystal size distributions and filtration rates of the calcium sulfate dihydrate crystals were measured, and the crystals obtained were analyzed using a thermogravimetric analyzer coupled with a Fourier transform infrared spectrometer and mass spectrometer (TGA‐FTIR‐MS). The average particle size, length‐to‐width ratio of the crystals, and the filtration rate of calcium sulfate dihydrate crystals were decreased in the presence of all three carboxylic acids when compared to the pure media. TGA‐FTIR‐MS indicated that all carboxylic acids adsorbed onto the calcium sulfate dihydrate crystals.

Two-Stage Crystallizer Design for High Loading of Poorly Water-Soluble Pharmaceuticals in Porous Silica Matrices

While porous silica supports have been previously studied as carriers for nanocrystalline forms of poorly water-soluble active pharmaceutical ingredients (APIs), increasing the loading of API in these matrices is of great importance if these carriers are to be used in drug formulations. A dual-stage mixed-suspension, mixed-product removal (MSMPR) crystallizer was designed in which the poorly soluble API fenofibrate was loaded into the porous matrices of pore sizes 35 nm–300 nm in the first stage, and then fed to a second stage in which the crystals were further grown in the pores. This resulted in high loadings of over 50 wt % while still producing nanocrystals confined to the pores without the formation of bulk-sized crystals on the surface of the porous silica. The principle was extended to another highly insoluble API, griseofulvin, to improve its loading in porous silica in a benchtop procedure. This work demonstrates a multi-step crystallization principle API in porous silica matrices with loadings high enough to produce final dosage forms of these poorly water-soluble APIs.

Continuous Membrane-Assisted Crystallization To Increase the Attainable Product Quality of Pharmaceuticals and Design Space for Operation

Continuous manufacturing is an important paradigm shift in pharmaceutical industries and has renewed the interest in continuous crystallization. The combination of crystallization and membranes is a promising hybrid technology for separation and purification of pharmaceuticals. The impact of membranes as an extension to conventional continuous crystallization processes on attainable product quality and design space is investigated systematically using model-based optimization. The proposed model is based on a full population balance such that all relevant crystallization phenomena can be included and is solved using a first-order discretization scheme with a hybrid grid. A case study involving continuous crystallization of paracetamol using a series of mixed suspension, mixed product removal (MSMPR) crystallizers is presented to illustrate the approach. The results show that the attainable size and design space can be enlarged significantly by extending conventional crystallization with membranes. In part...

Continuous Crystallization of Paracetamol (Acetaminophen) Form II: Selective Access to a Metastable Solid Form

The first continuous crystallization of a metastable polymorphic form of an active pharmaceutical ingredient is reported. Paracetamol form II, which displays enhanced solubility and compressibility in comparison to the stable form I, has been successfully crystallized in two continuous platforms: a continuous oscillatory baffled crystallizer and a mixed suspension mixed product removal (MSMPR) system, in the presence of the structurally similar molecule metacetamol as a template molecule. Samples from both crystallizers display high polymorphic purity and high solid phase purity, with the samples from the MSMPR in particular showing no evidence of the presence of a residual template molecule. The crystallization was found to be rapidly transferrable between the two continuous platforms. Samples produced display good stability with respect to the known form II to form I transition, reflecting the polymorphic selectivity achieved.

Design and optimization of production parameters for boric acid crystals with the crystallization process in an MSMPR crystallizer using FBRM® and PVM® technologies

In crystallization studies, newly developed technologies, such as Focused Beam Reflectance Measurement (FBRM) and Particle Vision and Measurement (PVM) are applied for determining on-line monitoring of a representation of the Chord Length Distribution (CLD) and observe the photographs of crystals respectively; moreover recently they are widely used. Properly installed, the FBRM ensures on-line determination of the CLD, which is statistically associated to the Crystal Size Distribution (CSD). In industrial crystallization, CSD and mean crystal size as well as external habit and internal structure are important characteristics for further use of the crystals. In this paper, the effect of residence time, stirring speed, feeding rate, supersaturation level and the polyelectrolytes such as anionic polyacrylamide (APAM) and non-ionic polyacrylamide (NPAM) on the CLD as well as the shape of boric acid crystals were investigated by using the FBRM G600 and the PVM V819 probes respectively in an MSMPR (Mixed Suspension Mixed Product Removal) crystallizer. The CSD and kinetic data were determined experimentally using continuous MSMPR crystallizer running at steady state. The population density of nuclei, the nucleation rate and the growth rate were determined from the experimental population balance distribution when the steady state was reached.

Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle

For crystal-impurity systems with similar structures and molecular weights, the impurity has a strong tendency to incorporate into the crystal lattice, making it difficult to obtain high purity with a single crystallization or even multiple crystallizations. In such cases, complexation of the impurity with an additive can be used to sterically prevent impurity incorporation in the host lattice. A nanofiltration membrane can be used to preferentially reject the higher molecular weight impurity complex in solution, while allowing the lower molecular weight API to permeate through. This permeate stream can be concentrated and recycled to operate the crystallization in a continuous mode with the aim of enhancing both yield and crystal purity simultaneously. In the present work, this strategy was applied to the continuous cooling crystallization of two systems in a mixed-suspension mixed-product removal (MSMPR) crystallizer from their solutions in 50:50 (by volume) water–ethanol mixed solvent. The first system...

Modelling geometrical and fluid-dynamic aspects of a continuous fluidized bed crystallizer for separation of enantiomers

Continuous selective crystallization using mixed suspension mixed product removal (MSMPR) crystallizers is an attractive method for separating enantiomers. Recent experimental results confirm the feasibility of the approach, but also indicate that the operation conditions for nominal operation lie in a rather small window. A systematic analysis and an optimal design are needed to exploit the full potential of the method. In this contribution, a mathematical process model based on population balance equations is presented. In contrast to other studies in literature, the considered crystallizer is not a stirred tank, but has a conical shape that requires a spatially distributed model formulation. Parameter studies identify the key operation and design parameters for maximizing the mass of the product crystals and for shaping their size distribution. The proposed model focuses on geometrical and fluid-dynamic aspects, but at the current stage does not include purity aspects.

Mathematical modelling and experimental validation of a novel periodic flow crystallization using MSMPR crystallizers

The challenges of insufficient residence time for crystal growing and transfer line blockage in conventional continuous mixed‐suspension mixed‐product removal (MSMPR) operations are still not well addressed. Periodic flow crystallization is a novel method whereby controlled periodic disruptions are applied to the inlet and outlet flows of an MSMPR crystallizer to increase its residence time. A dynamic model of residence time distribution in an MSMPR crystallizer was first developed to demonstrate the periodic flow operation. Besides, process models of periodic flow crystallizations were developed with an aim to provide a better understanding and improve the performance of the periodic flow operation, wherein the crystallization mechanisms and kinetics of the glycine‐water system were estimated from batch cooling crystallization experiments. Experiments of periodic flow crystallizations were also conducted in single‐/three‐stage MSMPR crystallizers to validate the process models and demonstrate the advantages of using periodic flow operation in MSMPR stages. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1313–1327, 2017

Evaluation of mixed suspension mixed product removal crystallization processes coupled with a continuous filtration system

As the pharmaceutical industry evolves and goes through the paradigm shift from batch to continuous manufacturing, innovative processes need to be developed to replace unit operations that have historically been batch operations. This requires innovation in the continuous crystallization field of study as well as innovation in downstream processes (e.g. filtration, drying, milling, and granulation). Herein a novel and commercially available continuous filter carousel (CFC) system was assessed for its feasibility of continuous filtration while coupled with a continuous mixed suspension mixed product removal (MSMPR) crystallizer. The filtration system was assessed using two different crystallization systems (i.e. cooling and antisolvent) with significantly different kinetics and morphologies to assess the robustness of the integrated platform. With proper optimization of the various filtration parameters for the different crystallization systems a controlled state of operation was achieved in each case. The crystal product from the CFC system shows good consistency with the crystals in the slurry in the MSMPR. Moisture content and productivity of the filtration system were reported and show dependency on crystal properties. The CFC system was equipped with solvent vessels that aided the continuous filtration by acting as a wash or a clean-in-place solvent, preventing or removing filter clogging, respectively.