Stirred Tank Crystallizer Research Articles

Novel twisted hexagonal tubular crystallizer used for thiourea cooling crystallization: Improving crystal qualities

The stirred-tank crystallizer (STC) is the widely used apparatus in industrial crystallization. However, it presents notable challenges, including a broad crystal size distribution (CSD) and fouling. Herein, the twisted hexagonal tube (THT) was employed for thiourea cooling crystallization. The THT exhibited superior heat transfer performance compared to the circular tube (CT) under identical conditions. Furthermore, the THT exhibited longer induction times and wider metastable zone width compared to STC and CT, indicating that the THT can effectively mitigate the nucleation rate. Crystals formed in the THT exhibited elliptical shapes, with a purity of 99.3 % and a target-product (425 μm) proportion of 78 wt%. Thiourea crystallized using the THT met the first-class in China standard HG/T 3454–2013, whereas those crystallized using STC and CT met the second-class standard. Consequently, the THT, as a novel tubular crystallizer, demonstrated considerable potential.

Nucleation and Growth Kinetics of Potassium Dihydrogen Phosphate Crystal in Stirred Tank Crystallizer

Nucleation and Growth Kinetics of Potassium Dihydrogen Phosphate Crystal in Stirred Tank Crystallizer

The Role of Operating Conditions in the Precipitation of Magnesium Hydroxide Hexagonal Platelets Using NaOH Solutions.

Magnesium hydroxide, Mg(OH)2, is an inorganic compound extensively employed in several industrial sectors. Nowadays, it is mostly produced from magnesium-rich minerals. Nevertheless, magnesium-rich solutions, such as natural and industrial brines, could prove to be a great treasure. In this work, synthetic magnesium chloride and sodium hydroxide (NaOH) solutions were used to recover Mg(OH)2 by reactive crystallization. A detailed experimental campaign was conducted aiming at producing grown Mg(OH)2 hexagonal platelets. Experiments were carried out in a stirred tank crystallizer operated in single- and double-feed configurations. In the single-feed configuration, globular and nanoflakes primary particles were obtained, as always reported in the literature when NaOH is used as a precipitant. However, these products are not complying with flame-retardant applications that require large hexagonal Mg(OH)2 platelets. This work suggests an effective precipitation strategy to favor crystal growth while, at the same time, limiting the nucleation mechanism. The double-feed configuration allowed the synthesis of grown Mg(OH)2 hexagonal platelets. The influence of reactant flow rates, reactant concentrations, and reaction temperature was analyzed. Scanning electron microscopy (SEM) pictures were also taken to investigate the morphology of Mg(OH)2 crystals. The proposed precipitation strategy paves the road to satisfy flame-retardant market requirements.

Process Performance and Operational Challenges in Continuous Crystallization: A Study of the Polymorphs of L-Glutamic Acid.

The crystallization of the two polymorphs of l-glutamic acid (LGA) is carried out in a continuous crystallization process, and its performance according to different criteria is evaluated. The study aims at identifying suitable operating conditions for producing either αLGA or βLGA with a high polymorphic purity. To this end, we investigate the process both from a theoretical perspective and through experiments using either a single stirred-tank crystallizer or a cascade of two stirred-tank crystallizers in series. In terms of theory, we extend the MSMPR-based steady-state stability analysis of Farmer et al. (Farmer, T. C. et al. AIChE J.2016, 62, 3505-3514) by accounting for the possibility of a nonrepresentative withdrawal of the solid phase from the crystallizer. Additionally, the process is simulated using population balance equations, thereby investigating the effect of operating conditions on polymorphic purity, yield, and productivity. Guided by the model-based conclusions, we identified suitable operating conditions and experimentally tested them. The experimental campaign has demonstrated that βLGA could be successfully and continuously produced in both process configurations according to the theory with performance as expected, whereas that was not possible for αLGA. The difference between the two stems from different operational challenges, whose consequence is that steady-state operation is attained in the case of βLGA but not in that of αLGA. In the former case, the needle-like βLGA crystals, which exhibit no agglomeration, tend to be only slightly oversampled; in the latter case, the prismatic αLGA crystals undergo major agglomeration and hence are very difficult to suspend and effectively withdraw from the crystallizer.

Application of a Fiber Optic Refractometric Sensor to Measure the Concentration of Paracetamol in Crystallization Experiments

A refractometric sensor was applied to measure in real-time the concentration of Active Pharmaceutical Ingredients (APIs) in crystallization experiments. Paracetamol was used as a model system due to the extensive literature available for this API. The refractometric sensor was fabricated by a simple and inexpensive method that consisted in splicing a short section of a multimode fiber to a single mode fiber. The compact geometry of this sensor, with an external diameter of just 125 μm, allowed it to measure the concentration of paracetamol, both in a stirred tank crystallizer operating in batch and in an oscillatory flow crystallizer operating continuously. The proposed technique shows the potential to monitor the concentration of APIs in crystallizers of different sizes and geometries as an alternative to more expensive and complex analysis equipment.

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.

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.

Investigation of Nucleation under High-Shear Conditions for a Pharmaceutical Compound in an Unseeded System

The effect of in situ high energy mixing on primary nucleation of an active pharmaceutical compound (ABT-089) has been investigated by measuring the induction time for 1, 5, and 140 mL scales via different shear-inducing mechanisms, namely, magnetic stirrer, Couette device, and high-shear rotor–stator mixer known as wet-mill in pharmaceutical industry. Experiments performed on previously untested scale and equipment show that the onset time of nucleation decreases with an increase in average energy input per unit volume of the solution (i.e., specific energy input) as previously reported (Liu, J.; Svard, M.; Rasmuson, Å.C. Influence of Agitation on Primary Nucleation in Stirred Tank Crystallizers, Cryst. Growth Des. 2015, 15, 4177–4184). The variability in the induction time is found to decrease with an increase in volume and specific energy input. Studies at different scales are compared using the Rasmuson (Liu, J.; Svard, M.; Rasmuson, ÅC. Influence of Agitation on Primary Nucleation in Stirred Tank Crystallizers, Cryst. Growth Des. 2015, 15, 4177–4184) approach based on the classical nucleation theory. It is shown that the effect of specific energy input can be adequately described by the kinetic term “A” or pre-exponential factor within the classical nucleation theory framework because the critical free-energy term appears to be constant for the same scale. A semiempirical correlation specific to ABT-089 is proposed between the energy input to a system and the average onset of primary nucleation for each of the means of shear induction. The generic approach presented in this work can be used as part of the overall development strategy to scale-up and scale-down crystallization experiments by estimating the specific energy input or the corresponding tip speed requirement to induce primary nucleation within a specified time range. However, given the practical limitations on the amount of data that can be generated and used to develop such correlations, appropriate caution is necessary in defining the scope of their applicability.

An Airlift Crystallizer for Protein Crystallization

Crystallization is an attractive separation and purification technique for proteins. However, protein crystallization often suffers from long batch times due to slow crystallization kinetics. Furthermore, brittle protein crystals may be subject to attrition in conventional crystallizers. An airlift crystallizer is fabricated using three-dimensional (3D) printing and characterized for crystallization of lysozyme. The desupersaturation profile is substantially shorter in the airlift crystallizer compared to a conventional stirred tank crystallizer for all tested conditions. Furthermore, the crystals from the airlift crystallizer are larger and less agglomerated. Finally, the biological activity of the product indicates that the airlift crystallizer preserves the functionality of the protein well. The increased throughput and larger crystals with reduced agglomeration demonstrate that an airlift crystallizer is well suitable for crystallization of a protein. This work also demonstrates how 3D printing can be used to fabricate innovative crystallizers rapidly and at a lower cost, which is especially important for early learning during process development.

A comparative study of continuous operation between a dynamic baffle crystallizer and a stirred tank crystallizer

Crystallization, often as the final isolation and purification step in drug substance manufacturing, has substantial impact on downstream efficiency and final drug product quality. It is a critical but challenging step in developing end-to-end continuous manufacturing, which has been identified as an emerging technology in the pharmaceutical manufacturing sector by the U.S. Food and Drug Administration (FDA). A traditional stirred tank crystallizer (STC) operated as a mixed-suspension-mixed-product-removal (MSMPR) system is a popular choice for continuous crystallization for its utilization of existing knowledge and equipment. However, there are disadvantages associated with agitational systems like the STC, such as poor local mixing and high shear rate. A commercial dynamic baffle crystallizer (DBC) was studied here as an alternative unit operation. The DBC in this study consists of a jacketed glass vessel with dynamic ‘donut’ shaped baffles to provide oscillatory mixing to improve heat and mass transfer while exerting less shear. Our goal is to compare continuous operation performances in the DBC with the STC as MSMPR systems. First, residence time distribution (RTD) studies of both systems were performed considering single phase (liquid only) and two-phase (solid-liquid) operation. The RTD gives good insights into the mixing dynamics without computationally heavy fluid dynamic simulations. Continuous cooling crystallization of paracetamol was performed in the DBC and the STC. The DBC showed good potential to be used as an MSMPR system producing more uniform RTDs as well as higher quality crystallization products compared to a traditional STC.

Determination of protein crystallization kinetics by a through-flow small-angle X-ray scattering method

The kinetics of protein crystallization was analyzed using a modified Small-Angle X-ray Scattering (SAXS) setup that was operated in a flow-through mode. The model protein for the study was lysozyme, which was crystallized from supersaturated aqueous solutions of ammonium sulfate. A small amount of the protein solution was forced to recirculate within the SAXS setup. The SAXS intensity curves were measured at different time intervals and converted into kinetic profiles using a calibration factor. The diffraction images of the sample taken at the end of the kinetic experiments were recorded to confirm the presence of the crystalline phase. A population balance model was used to describe the course of the crystallization process. The results of the measurements and numerical simulations were compared to those obtained from a typical stirred-tank crystallizer (STC), where seeded and unseeded crystallization was performed. The kinetic data acquired from the SAXS and STC setups followed similar trends regarding kinetic dependencies on the salt concentration and the supersaturation degree. Moreover, the hydrodynamic conditions in the SAXS setup were determined, for which a quantitative agreement between the kinetic data acquired from both systems was achieved. Then, the same kinetic equations could be used to describe the course of crystallization in both systems. Hence, the modified SAXS technique can potentially substitute the STC-based method in quantification of crystallization kinetics.

Characterization of a Multistage Continuous MSMPR Crystallization Process Assisted by Image Analysis of Elongated Crystals

This work demonstrates how quantitative image analysis can assist in the characterization of continuous crystallization processes and in the proper selection of mathematical models for the early assessment of crystal quality. An active pharmaceutical ingredient presenting an elongated crystal habit was crystallized using two stirred tank crystallizers in series. With image analysis of the crystallization magma, the sources of crystal breakage in the crystallization cascade were identified, and the impact on crystal habit was evaluated quantitatively. As it is expected for particles presenting high aspect ratios, crystal breakage preferentially occurs in the smallest plane, perpendicular to the largest dimension. This phenomenon is hardly avoidable in downstream production, but it can be accounted for with a design approach based on the real crystal dimensions. The kinetic rate equations for nucleation and crystal growth were determined based on crystal width, from which a model for the accurate prediction...

Methane gas hydrate kinetics with mixtures of sodium dodecyl sulphate and tetrabutylammonium bromide

The effect of combining a thermodynamic promoter, tetrabutylammonium bromide (TBAB), with a kinetic promoter, sodium dodecyl sulphate (SDS), to a methane clathrate system was investigated. Kinetic growth experiments were conducted in a semi‐batch stirred tank crystallizer at driving forces of 1500 kPa using a range of 100 to 1500 ppm SDS and 200 to 200 000 ppm TBAB. Solutions containing low concentrations of TBAB in water reduced methane hydrate growth rates up to 55 % for 1250 ppm TBAB compared to pure water. Solutions containing 900 ppm SDS in water enhanced the growth rate by 880 % compared to pure water. Solutions were then tested combining both promoters. The gradual addition of SDS from concentrations between 100 to 1250 ppm to low‐concentration TBAB systems between 200 to 1250 ppm was initially found to reduce growth kinetics, but eventually increased the growth rates once a threshold SDS concentration was reached. In all cases, the promoting effect of the SDS was more pronounced in the absence of the TBAB. The growth kinetics of systems containing 5 and 20 wt% TBAB also followed a similar inhibition‐promotion trend with the SDS concentration. An increase of 177 % in the gas consumption rate was observed when 1500 ppm SDS was added to the 20 wt% TBAB clathrate system. This work demonstrates that SDS can be added to a TBAB‐water‐methane system to enhance gas consumption rates, but care must be taken to ensure that the concentration of the additives places the system in a promotion regime.

Development of Couette-Taylor Crystallizer in Cooling Crystallization: Promotion of Size Distribution of L-lysine

The Couette-Taylor (CT) crystallizer was developed to promote the size distribution of L-Lysine crystal product in cooling crystallization. When using the CT crystallizer, the size distribution of crystal product was much narrower than that of the conventional Stirred tank (ST) crystallizer. Here, the coefficient size distribution (n) in CT crystallizer was quite large as 3.43, while it was only 2.17 in ST crystallizer at the same 360 rpm of agitation or rotation speed. This result indicated that the CT crystallizer was much more effective than the ST crystallizer in terms of the size distribution of L-lysine crystal products in cooling crystallization. The advantage of CT crystallizer over the ST crystallizer was explained in terms of the high energy dissipation of Taylor vortices flow, where it was 7.6 times higher than that of random fluid motion in conventional ST crystallizer. As such, the supersaturation profile in the CT crystallizer was much more homogeneous than that in the ST crystallizer, which resulted in promotion of size distribution L-lysine crystal product.

Couette-Taylor crystallizer: Effective control of crystal size distribution and recovery of l-lysine in cooling crystallization

A Couette-Taylor crystallizer is developed to enhance the l-Lysine crystal size distribution and recovery in the case of continuous cooling crystallization. When using the proposed Couette-Taylor (CT) crystallizer, the size distribution and crystal product recovery were much narrower and higher, respectively, than those from a conventional stirred tank (ST) crystallizer. Here, the coefficient of the size distribution for the crystal product from the CT crystallizer was only 0.45, while it was 0.78 in the case of the conventional ST crystallizer at an agitation speed of 700rpm, mean residence time of 20min, and feed concentration of 900(g/L). Furthermore, when using the CT crystallizer, the crystal product recovery was remarkably enhanced up to 100%wt with a mean residence time of only 20min, while it required a mean residence time of at least 60min when using the conventional ST crystallizer. This result indicates that the CT crystallizer was much more effective than the conventional ST crystallizer in terms of controlling a narrower size distribution and achieving a 100%wt l-lysine crystal product recovery from continuous cooling crystallization. The advantage of the CT crystallizer over the conventional ST crystallizer was explained based on the higher energy dissipation of the Taylor vortex flow and larger surface area for heat transfer of the CT crystallizer. Here, the energy dissipation of the Taylor vortex flow in the CT crystallizer was 13.6 times higher than that of the random fluid motion in the conventional ST crystallizer, while the surface area per unit volume for heat transfer of the CT crystallizer was 8.0 times higher than that of the conventional ST crystallizer. As a result, the mixing condition and heat transfer of the CT crystallizer were much more effective than those of the conventional ST crystallizer for the cooling crystallization of l-lysine, thereby enhancing the l-lysine crystal size distribution and product recovery.

Reaction rate constant of CO2–Tetra‐n‐butylammounium bromide semi‐clathrate formation

Semi‐clathrate growth experiments were performed using a carbon dioxide‐water‐tetra‐n‐butyl ammonium bromide system. Experiments were conducted in a semi‐batch stirred tank crystallizer at temperatures of 287, 288, and 289 K with a 3‐K subcooling at each temperature. Gas consumption, temperature, hydrate former mole fraction, and particle size were measured throughout growth. Significant differences in gas consumption and heat effects were observed with these systems compared with pure clathrate systems. A kinetic growth model was applied to estimate the intrinsic rate constant. Rate constants did not show a clear trend with temperature at the conditions studied. Intrinsic reaction rate constant values ranged from 7.6 × 10−6 m/s to 13.8 × 10−6 m/s.

Pharmaceutical crystallization in Couette-Taylor crystallizer: A case study of polymorphism of amino acid L-glutamic acid

The influence of intensity Taylor vortex flow in Couette-Taylor crystallizer on the crystallization of polymorphic amino acid L-glutamic acid was investigated in cooling crystallization. Here, the L-glutamic acid was chosen as the model crystal product, where it has two kinds of polymorphism including the unstable phase α-form and stable phase β-form crystal. In cooling crystallization, the α-form crystal transformed to the β-form crystal corresponding to the phase transformation of α-form to β-form crystal. The present study found that the selective polymorphism of α-form and β-form crystal as well as the phase transformation significantly depended on the intensity of turbulent Taylor vortex flow in Couette-Taylor crystallizer. Here, the selective β-form nucleation and phase transformation were remarkably promoted as increasing the rotation speed of inner cylinder in Couette-Taylor crystallizer. By comparison with the conventional stirred tank (ST) crystallizer, the Couette-Taylor (CT) crystallizer was at least 2.0 times more effective as regards the selective β-form polymorphism and phase transformation time. The advantage of CT crystallizer over the conventional ST crystallizer was explained in terms of the high shear stress and mass transfer of turbulent Taylor vortex flow in CT crystallizer. Here, the shear stress of Taylor vortex flow in CT crystallizer was at least 23.0 times higher than that of fluid motion in conventional ST crystallizer, whereas the mass transfer of Taylor vortex flow in CT crystallizer was at least 1.2 times higher than that of fluid motion in conventional ST crystallizer. As such, the high turbulent shear stress of Taylor vortex flow was expected to promote the β-form nucleation via the effective molecules alignment, whereas the high mass transfer of Taylor vortex flow facilitated the dissolution rate of α-form and growth rate of β-form crystal, resulting in an acceleration of phase transformation rate.

An Investigation into Parameters Affecting Crystal Purity of Urea in a Stirred Tank and an Oscillatory Baffled Crystallizer

Confidential industrial trials showed that higher purity crystals were produced in an oscillatory baffled crystallizer (OBC) compared to a stirred tank crystallizer (STC) when operating at similar conditions. This trend is verified in this work using urea as the test compound that is different from that was employed in industrial tests. We have observed that a higher supersaturation level at nucleation coupled with a lower nucleation temperature was measured in the STC at all investigated conditions compared to that in the OBC. This led to a higher nucleation rate in the STC, consequently producing smaller crystals. Crystal size distributions and imaging analyses suggest that these smaller crystals were more likely to form agglomerates in the STC, trapping either mother liquor or impurity or both and leading to the lower purity observed when compared to that in the OBC.

On the effect of added impurity on crystal purity of urea in an oscillatory baffled crystallizer and a stirred tank crystallizer

Previous work has indicated that crystals produced in oscillatory baffled crystallisers (OBC) from a relatively ‘pure’ starting environment gave statistically higher purities than that in stirred tank crystallisers (STC) under comparable conditions. In this work, a known amount of biuret (the impurity) was added to the ‘pure’ urea system and the results show that the OBC still produced higher purity crystals than the STC, although these purity values were statistically lower than from the ‘pure’ environment in both vessels. By evaluating crystallisation rates of both urea and biuret, we noticed that these rates are higher in the STC than in the OBC, which would have led to small crystals in the former vessel. The CSD data however gave the opposite result where the CSD is wider with more, large crystals in the STC than in the OBC, in particular in the presence of added impurity. These larger crystals are likely formed due to agglomeration coupled with incorporation of impurity, which leads to a lower purity.

Influence of Agitation on Primary Nucleation in Stirred Tank Crystallizers

The influence of agitation on nucleation of butyl paraben and m-hydroxybenzoic acid polymorphs has been investigated through 330 cooling crystallization experiments. The induction time has been measured at different supersaturations and temperatures in three parallel jacketed vessels equipped with different overhead stirring agitators. In each case, the nucleating polymorph of m-hydroxybenzoic acid has been identified by infrared spectroscopy. The influences of agitation rate, impeller type, impeller diameter, impeller to bottom clearance, and the use of baffles have been investigated. A general trend in all of the experiments is that the induction time decreases with increasing agitation rate. Across all experiments with different fluid mechanics for the butyl paraben system, the induction time is correlated to the average energy dissipation rate raised to the power −0.3. It is shown that this dependence is consistent with a turbulent flow enhanced cluster coalescence mechanism. In experiments with m-hyd...