Continuous Reaction Crystallization Research Articles

Continuous Reactive Crystallization in a Mesoscale Oscillatory Baffled Reactor

AbstractContinuous reactive crystallization was carried out in a mesoscale oscillatory baffled reactor (meso‐OBR), using calcium carbonate as a case study to demonstrate the ability of high solid loadings and to examine the fouling potential in continuous processes. Plug flow behavior was easily achieved in reactive solid‐liquid phase reaction systems, as evidenced by the rapid establishment of a steady state. Effects of the operating conditions (reactant concentration, mixing conditions, and temperature) on the yield, particle size, and particle size distribution were studied. Increasing the reactant concentration and oscillation conditions reduced the particle size whereas increasing the operating temperature led to a large particle size. The meso‐OBR produced uniformly shaped spherical crystals, with a 35 % reduction in average particle size and high purity compared to conventional stirred tanks. The meso‐OBR could be used continuously for up to 6 h with less than 1 wt % of fouling (product loss).

L-Glutamic acid crystals of pure α form and uniform size distribution from continuous non-seeded reaction crystallization in slug flow

Desired goals of crystal synthesis include high crystal quality (e.g., pure solid forms and uniform size distribution) and high process efficiency and reproducibility.

Periodic wet milling as a solution to size-based separation of crystal products from biocatalyst for continuous reactive crystallization

Combining the synthesis and crystallization of a compound into a single step may be beneficial for certain processes. Motivations range from process intensification to improving reaction network yield by shifting an equilibrium limited reaction or protecting an intermediate, as is the case in the biocatalytic synthesis of beta-lactam antibiotics. Adapting such a reactive crystallization process to continuous manufacturing faces a challenge: the continuous separation of crystals from biocatalyst carriers. In this study, a size-based method for this separation problem is proposed. Separation is performed using a filter placed on the reactive crystallization vessel outlet. The primary factors for filter design are carrier and crystal size dictated by the separation condition Lcrystal<Lfilter<Lcarrier. Enzymatic assays confirmed an increasing loss of activity and selectivity for the biocatalyst, Penicillin G Acylase, when large carrier sizes are used for immobilization, limiting the maximum Lcarrier that can be used in the process. Intermittent wet milling, however, is shown to be effective in reducing the crystal size and allowing the use of sufficiently small carriers while still satisfying the criterion for solid–solid separation. Slurry transfer tests were performed to check the possibility of isokinetic withdrawal when the separator filter was used. Filter size of 300μm, a carrier size of 300–425μm, and intermittent wet milling of 2–3 reactor volumes per residence time at 5000RPM were found to provide an almost complete separation, acceptable biocatalyst kinetics, and an isokinetic crystal product withdrawal.

Synthesis of a dipeptide by integrating a continuous flow reaction and continuous crystallization

This paper describes a case study on integrating a continuous flow reaction and continuous crystallization. For the synthesis of Fmoc-l-Phe-l-Phe-OMe, we previously reported that this coupling reaction via acid chloride could be completed in approximately 1 min under continuous conditions. However, the crystals of Fmoc-l-Phe-l-Phe-OMe were obtained by batch crystallization. The quenched solution was unstable and rapid transfer to the crystallization step was desirable. Under such circumstances, continuous crystallization was considered to be the most reliable strategy for a robust scalable synthesis methodology. For this, we tested a mixed-suspension mixed-product-removal (MSMPR) crystallizer that allows for rapid crystallization without seeding and clogging. The steady state for the continuous crystallization could be monitored by particle size distribution using in-line monitoring. As a result, the integration of a continuous flow reaction and continuous crystallization worked smoothly for 2 h, which showed the feasibility of manufacturing using this integration system.

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.

マイクロ空間を利用した高温高圧水中におけるスピネル型酸化物ナノ粒子の連続反応晶析

マイクロ空間を利用した高温高圧水中におけるスピネル型酸化物ナノ粒子の連続反応晶析

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.

High-throughput on demand access of single enantiomers by a continuous flow crystallization process

A novel continuous flow reactive crystallization process for the in situ on-demand access of single enantiomer crystals is reported and exemplified for a chiral pharmaceutical intermediate that crystallizes as a racemic conglomerate.

Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs

The influence of PFR on crystal size distribution, reaction and crystallization yields, and supersaturation level was investigated.

Recovery of phosphates(V) from wastewaters of different chemical composition

AbstractPhosphate(V) ions were recovered from wastewaters of different chemical compositions in a continuous reaction crystallization of struvite. Two real wastewaters were represented by an effluent sample from the phosphorus mineral fertilizer industry and by liquid manure derived from a cattle-breeding farm. Two other wastewaters were prepared under laboratory conditions. Impurities present in the wastewaters caused the precipitation of solid products of distinctly different quality. The mean size of struvite crystals varied from ca. 18 to ca. 40 μm. Homogeneity within their populations, quantified by the coefficient of variation CV, varied from satisfactory (CV ca. 75%) to unfavorable (CV ca. 100%), which resulted in the elongation of necessary filtration time. Calcium ions in wastewater precipitated as amorphous hydrated calcium phosphates ACP. Their content in the products varied from 33.4 up to 73.1 mass %. Also 28.32 – 32.74 mass % of P2O5, 6.35 – 14.12 mass % of MgO and 4.35 – 16.94 mass % of CaO were confirmed in the products, together with hydroxides of some metals and salts of other impurities. Based on the chemical composition of the products derived from the investigated wastewaters, their application in agriculture as valuable mineral fertilizers is recommended.

Continuous reactive crystallization of β-lactam antibiotics catalyzed by penicillin G acylase. Part II: Case study on ampicillin and product purity

Continuous reactive crystallization of β-lactam antibiotics can ease shortage and contamination concerns for an important class of medicines. With a model of continuous reactive crystallization catalyzed by penicillin G acylase (PGA), a process is developed to ensure purity of the antibiotic product. Guaranteeing the solid-phase purity of ampicillin and cephalexin is important because PGA produces a slightly soluble byproduct, phenylglycine, which can contaminate the antibiotic crystals. In a single well-mixed reactive crystallizer, productivity is optimized and nearly two-fold greater than the non-crystallizing maximum productivity. Process robustness is essential because multiple steady states, only one of which produces pure ampicillin crystals, exist in the well-mixed reactive crystallizer. By combining well-mixed and plug-flow reactive crystallizers in series, crystallization of phenylglycine can be suppressed while high yield and comparable productivity are still achieved. The reactive crystallizer series demonstrates high purity with uncertainty in model parameter values and variability in operating conditions.

Continuous reactive crystallization of β-lactam antibiotics catalyzed by penicillin G acylase. Part I: Model development

A model is developed for simulating continuous manufacturing of β-lactam antibiotics by enzymatic reactive crystallization. An amoxicillin case study using the unified model of reaction and crystallization kinetics in different reactor designs is presented. Attainable regions are constructed for conversion of amoxicillin precursors and mean crystal size. Attainable regions for conversion show that, with a 2:1 molar ratio of precursors, 98% conversion of the limiting reactant is possible with reactive crystallization while only 72% conversion can be achieved without crystallization. A well-mixed reactive crystallizer is shown to have higher productivity than a plug-flow reactive crystallizer, which is uncommon for positive-order processes like enzyme reactions and crystallization. A Pareto optimal surface is drawn for conversion, productivity, and fractional yield to inform the design of an optimal process. Additional means of optimizing production of amoxicillin, including classified crystal fines removal, are discussed to further enhance crystal size and productivity.

Struvite nucleation and crystal growth kinetics from cattle liquid manure

Cattle liquid manure (CLM) in future may become excellent raw material for the solid mineral fertilizers production. Phosphates(V) recovery from CLM can be done, e.g. through reaction crystallization of sparingly soluble salts: magnesium and ammonium phosphate(V) hexahydrate MgNH4PO4·6H2O (MAP, struvite) or/and calcium phosphates(V). The original kinetic calculations based on experimental test results concerning continuous reaction crystallization of sparingly soluble phosphates(V) from cattle liquid manure in a continuous laboratory DT MSMPR (Draft Tube, Mixed Suspension Mixed Product Removal) crystallizer with internal circulation of suspension driven by propeller stirrer are presented. Two kinetic models of continuous mass crystallization in MSMPR crystallizer: SIG (Size Independent Growth) and RE SDG (Rojkowski Exponential Size Dependent Growth) were adopted. Advantageous effects of: low pH (8.5), elongated mean residence time of suspension in a crystallizer (3600 s) and magnesium ions excess in relation to phosphate(V) ions concentration (1.2:1) on the process results were observed. Under the considered process conditions linear crystal growth rates of struvite were: G from 4.11 × 10−3 to 1.01 × 10−2 µm s−1 and G∞ from 5.30 × 10−3 to 1.02 × 10−2 µm s−1.

Development of an automated multi-stage continuous reactive crystallization system with in-line PATs for high viscosity process

Lower E-factor was obtained in an automated multi-stage continuous reactive-crystallization system.

Continuous reactive crystallization of pharmaceuticals using impinging jet mixers

For reactive crystallization of pharmaceuticals that show a rapid reaction rate, low solubility of active pharmaceutical ingredient and hence a large supersaturation, it was found in a recent study that a process design which integrates an impinging jet mixer and batch stirred tank produces high quality crystals. The current investigation examines if the short processing time of reactive crystallization permits the impinging jet mixer—stirred tank design to be modified to operate in a continuous mode. The new design combines an impinging jet mixer for feed introduction and reaction with a continuous stirred tank reactor (CSTR) and tubular reactor for crystal growth. A study of reactive crystallization of sodium cefuroxime (an antibiotic), using first a 1L CSTR then scaling to a 50L CSTR, found that the new design produces crystals of higher crystallinity, narrower particle size, and improved product stability, than batch crystallizers. © 2016 American Institute of Chemical Engineers AIChE J, 63: 967–974, 2017

EFFECT OF CONTINUOUS CRYSTALLIZER PERFORMANCE ON STRUVITE CRYSTALS PRODUCED IN REACTION CRYSTALLIZATION FROM SOLUTIONS CONTAINING PHOSPHATE(V) AND ZINC(II) IONS

Continuous reaction crystallization of struvite from aqueous solutions containing phosphate(V) (1.0 mass %) and zinc(II) ions (from 0.1 to 2.0 mg kg-1) in a continuous DT MSMPR crystallizer was investigated. The influence of pH (9 - 11) and mean residence time (900 - 3600 s) on the product characteristics and its chemical composition was tested. Struvite crystals of mean size 22-41 µm were produced. An increase in Zn2+ concentration decreased the mean crystal size and homogeneity. An elevation of the pH also decreased the struvite crystal size. Augmenting the mean residence time influenced product quality advantageously. Coexistence of struvite and Zn(OH)2 in the product was confirmed analytically.

Dynamics and control of continuous reactive crystallization processes

Control of two continuous reactive crystallization processes, one for the production of barium sulfate and one for the production of L-glutamic acid, is investigated. In both processes, the crystal mass production rate and the volume mean size of the product are controlled by manipulating the reactant inlet volumetric flow rates and the holdup in the crystallizer. The reactant inlet concentration, nucleation rate, and temperature of the crystallizer are considered as disturbances. The control structures provide good performance for 10% changes in disturbance variables and setpoint changes. Furthermore, stability analysis is performed for both processes and operating regions where continuous oscillations in solute concentration and crystal size distribution can occur are identified.

Recovery of Struvite from Synthetic Animal Wastewater by Continuous Reaction Crystallization Process

Recovery of Struvite from Synthetic Animal Wastewater by Continuous Reaction Crystallization Process

Gypsum Crystallization during Phosphoric Acid Production: Modeling and Experiments Using the Mixed-Solvent-Electrolyte Thermodynamic Model

The size distributions of calcium sulfate dihydrate crystals formed during the industrial phosphoric acid production process are critical to the acid filtration efficiency. In this work, a thermodynamically consistent definition of supersaturation is derived and modeled using the mixed-solvent-electrolyte framework in OLI software for gypsum in an acid mixture. Continuous reactive crystallization experiments are carried out to estimate the gypsum growth and nucleation kinetics at different temperatures. A population balance model is implemented using the method of characteristics and integrated with the thermodynamic model platform to accurately simulate the dynamic propagation of the solution concentration and particle size distribution. The experimentally fitted kinetic parameters are verified through a comparison with the predicted crystal size distribution (CSD) and supersaturation. The comparison shows a good agreement between the predicted and measured CSD and supersaturation at a temperature range ...

Application of Continuous Crystallization in an Integrated Continuous Pharmaceutical Pilot Plant

Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated continuous manufacturing (ICM) of pharmaceuticals. However, appropriate selection of PAT tools is challenging, and the design and operation of automated control loops for continuous crystallization within a continuous pharmaceutical process brings forward important questions. This paper discusses the process design and operation of a continuous reactive crystallization of aliskiren hemifumarate as part of an ICM pilot plant. Several PAT tools were used within automated control loops to satisfy specifications on the critical materials attributes of the crystallization process. The operational performance of the process was maintained for periods of time over 100 h. The purity of the targeted product exceeded 99%, and the process yield reached 91.4%.