Continuous Crystallization Research Articles

Effects of Ultrasound on Reactive Crystallization and Particle Properties of an Aromatic Amine in Batch and Continuous modes

Ultrasound has shown its benefits in the manufacturing processes of many pharmaceuticals and fine chemicals. This study focused on the reactive crystallization system of an aromatic amine and explored the potential uses of ultrasound in both batch and continuous modes. In batch experiments, we studied the effects of different sonication conditions including power, duration, and starting point on final particle properties. Under ultrasound, the crystal form and crystal morphology remained well maintained. The results of particle size and size distribution suggested that ultrasound reduced the mean sizes by improving the nucleation process and breaking up large particles. Additionally, the presence of ultrasound in continuous experiments was capable of inducing nucleation and the crystal products collected had a suitable distribution. Integrating ultrasound into the beginning of the continuous crystallization process can be an alternative to the seeding technique. The increasing sonication power did not reduce the induction time substantially. This indicated that a rational sonication condition should balance the overall process efficiency and energy consumption. The findings from batch and continuous experiments indicate that ultrasound could intensify industrial crystallization of the aromatic amine. Incorporating energy-efficient ultrasound with the continuous process will potentially lead to increased production efficiency and a well-controlled product quality.

Residence Time Distribution Characterization and Proof-of-Concept of a Novel Stacked 7-Stage Continuous Crystallizer Cascade with Diaphragm-Driven Slurry Transfer

Residence Time Distribution Characterization and Proof-of-Concept of a Novel Stacked 7-Stage Continuous Crystallizer Cascade with Diaphragm-Driven Slurry Transfer

Continuous Isothermal Antisolvent Crystallization of Pyrazinamide in a Coiled Flow Inverter Device

Continuous Isothermal Antisolvent Crystallization of Pyrazinamide in a Coiled Flow Inverter Device

Thiourea Nucleation Behavior Investigation Based on Metastable Zone Width and Applied for Continuous Crystallization Designing

Thiourea Nucleation Behavior Investigation Based on Metastable Zone Width and Applied for Continuous Crystallization Designing

Surface morphology evolution, microstructural response and mechanical property variation of Au-ion irradiated CrNbZrMoV, TiCrZrMoV, TiNbCrMoV, TiNbZrCrV and TiNbZrMoCr high-entropy alloy coatings

In this work, the CrNbZrMoV, TiCrZrMoV, TiNbCrMoV, TiNbZrCrV and TiNbZrMoCr refractory high-entropy alloy (RHEA) coatings (1.67∼2.77 μm of thickness) were prepared by magnetron sputtering. Then, 6 MeV Au-ion irradiations with 2.5 × 1015 to 1.0 × 1016 ions/cm2 fluences were performed on these coatings at 473 K, and the surface morphology, microstructure and mechanical property were investigated. The peak damage of the CrNbZrMoV, TiCrZrMoV, TiNbCrMoV, TiNbZrCrV and TiNbZrMoCr coatings under 1.0 × 1016 ions/cm2 fluence are 48, 48, 44, 48 and 48 dpa, respectively. The peak Au concentration of the CrNbZrMoV, TiCrZrMoV, TiNbCrMoV, TiNbZrCrV and TiNbZrMoCr coatings under 1.0 × 1016 ions/cm2 fluence are 4.27 × 103, 4.12 × 103, 4.13 × 103, 4.16 × 103 and 4.37 × 103 appm, respectively. The surface morphology of the CrNbZrMoV, TiCrZrMoV, TiNbZrCrV and TiNbZrMoCr coatings were smoothed obviously. For BCC TiNbCrMoV coating, irradiation caused the growth of the nanocrystalline. For amorphous coatings, the crystallization occurred in the CrNbZrMoV, TiCrZrMoV and TiNbZrMoCr coatings after 2.5 × 1015 fluence irradiation (≥12 dpa), while the TiNbZrCrV coating remain mainly amorphous structure after all irradiation. It was found that irradiation induced continuous crystallization occurred not only at the surface but also in the peak damage zone of the coating, and then grew inside the irradiated region. Apparent irradiation hardening was observed in all the coatings except the TiNbZrCrV coating. The structural stability of these coatings under the current irradiation condition was discussed. Preliminary study shows that the great irradiation tolerance of amorphous TiNbZrCrV coating may be related to the lowest electronegativity difference (Δχ = 0.121) and large atomic size difference (δ = 9.042 %) that stabilize the structure and inhibit atomic diffusion, respectively. These findings provide the guidance for the development of high irradiation tolerance materials for future nuclear energy applications with great structural stability.

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.

PAT Aided Feasibility Study on Continuous Crystallization of Benzotriazole

PAT Aided Feasibility Study on Continuous Crystallization of Benzotriazole

A technique for continuous crystallization of high‐quality ammonium polyvanadate: Crystallization mechanism and simulation of deflector tube baffle crystallizer

A technique for continuous crystallization of high‐quality ammonium polyvanadate: Crystallization mechanism and simulation of deflector tube baffle crystallizer

Direct Solution Deposition of Large-Area Non-Solvated Fullerene Single-Crystal Films for High-Performance n-Type Field-Effect Transistors.

Fullerene (C60) crystals have attracted considerable attention in the field of optoelectronic devices owing to their excellent performance as n-type semiconductor material. However, a challenge still remains unbeaten as to the continuous crystallization of non-solvated C60 single-crystal films with high coverage and uniform alignment using low-cost solution techniques. Here, a facile bar coating method is used to prepare ribbon-shaped non-solvated C60 crystals with a large area (up to centimeters) and high coverage (>95%) by precisely controlling the crystallization process from specific solvents. Benefiting from the non-solvated crystalline structure, well-distributed thickness, uniform morphological alignment, and crystallographic orientation, organic field-effect transistors fabricated from the C60 single-crystal films exhibit a high average electron mobility of 2.28cm2V-1s-1, along with the coefficient of variance (CV) as small as 13.6%. This efficient manufacturing method will lay a strong foundation for C60 single-crystal films to fit into the future high-performance integrated optoelectronic application.

Development of Continuous Additive-Controlled MSMPR Crystallization by DoE-Based Batch Experiments.

Additive-controlled crystallization is a promising method to improve crystal morphology and produce solid drug particles with the desired technological and pharmacological properties. However, its adaptation to continuous operation is a hardly researched area. Accordingly, in this work, we aimed to come up with a methodology that provides the systematic and fast development of a continuous three-stage MSMPR cascade crystallizer. For that, a cooling crystallization of famotidine (FMT) from water, in the presence of a formulation additive, poly(vinylpyrrolidone) (PVP-K12), was developed. Process parameters with a significant impact on product quality and quantity were examined in batch mode through a 24-1 fractional factorial design for the implementation of additive-controlled continuous crystallization. These batch experiments represented one residence time of the continuous system. Based on the statistical analysis, the residence time (RT) had the highest effect on yield, while the polymer amount was critical from the product polymorphism, crystal size, and flowability points of view. The values of critical process parameters in continuous operation were fixed according to the batch results. Two continuous cooling crystallization experiments were carried out, one with 1.25 w/wFMT% PVP-K12 and one with no additive. A mixture of FMT polymorphs (Form A and Form B) crystallized without the additive through five residence times (>6.5 h) with 70.8% overall yield. On the other hand, the additive-controlled continuous experiment resulted pure and homogeneous Form A product with excellent flowability. The system could be operated for >6.5 h without clogging with a 71.1% overall yield and a 4-fold improvement in productivity compared to its batch equivalent.

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.

Automated Continuous Crystallization Platform with Real-Time Particle Size Analysis via Laser Diffraction.

The fourth industrial revolution is gaining momentum in the pharmaceutical industry. However, particulate processes and suspension handling remain big challenges for automation and the implementation of real-time particle size analysis. Moreover, the development of antisolvent crystallization processes is often limited by the associated time-intensive experimental screenings. This work demonstrates a fully automated modular crystallization platform that overcomes these bottlenecks. The system combines automated crystallization, sample preparation, and immediate crystal size analysis via online laser diffraction (LD) and provides a technology for rapidly screening crystallization process parameters and crystallizer design spaces with minimal experimental effort. During the LD measurements, to avoid multiple scattering events, crystal suspension samples are diluted automatically. Multiple software tools, i.e., LabVIEW, Python, and PharmaMV, and logic algorithms are integrated in the platform to facilitate automated control of all the sensors and equipment, enabling fully automated operation. A customized graphical user interface is provided to operate the crystallization platform automatically and to visualize the measured crystal size and the crystal size distribution of the suspension. Antisolvent crystallization of ibuprofen, with ethanol as solvent and water with Soluplus (an additive) as antisolvent, is used as a case study. The platform is demonstrated for antisolvent crystallization of small ibuprofen crystals in a confined impinging jet crystallizer, performing automated preplanned user-defined experiments with online LD analysis.

Shortcut model to evaluate the performance of continuous preferential crystallization for conglomerates forming chiral systems

The separation of two enantiomers of a chiral molecule is one of the most difficult tasks for separation technology. Among the available methods, Preferential Crystallization (PC) offers a relatively simple and efficient possibility to separate pairs of enantiomers of conglomerate forming chiral systems. To estimate the potential and to design PC processes, mathematical process models are required. Recently, a short-cut model (SCM) was developed which was found capable to predict the course of batch-wise operated PC until nucleation of the unseeded counter-enantiomer terminates the exploitable production period. In this paper the SCM is reformulated in a dimensionless way and extended to describe also more productive continuous operation of PC. Characteristic dimensionless numbers are demonstrated to be instructive to evaluate effects of system specific kinetic parameters and to identify suitable operating conditions. The sensitivity of the continuous PC process with respect to the most relevant model parameters is investigated based on simulation results. Finally, the role of the SCM in the workflow of designing continuous PC processes is summarized.

Amphibole fractionation as a key driver for oxidation of magmas in convergent margins

During the process of differentiation, the magmas in convergent margins undergo an increase of oxidized nature, accompanied by a decreased Fe content and concentration of heavy Fe isotopes. Garnet and amphibole are both Fe-rich minerals, which can be responsible for this phenomenon through fractional crystallization. One prevailing hypothesis suggests that Fe2+-rich garnet cumulates in the arc root as a "crustal redox filter." However, the stability of garnets is highly dependent on pressure conditions. In contrast, amphibole can crystallize under a broader range of temperature and pressure conditions and is a more common mineral phase in magmas. As such, the contribution of amphibole might have been underappreciated. Here, we conducted elemental composition, zircon trace element, and high-precision Fe isotope analyses on Miocene magmatic rocks from the Gangdese arc to trace the evolution of magmatic oxidation. The results indicate that the enrichment of heavy Fe isotopes in these magmas is primarily controlled by amphibole-dominated fractional crystallization rather than garnet. This also implies that amphibole fractional crystallization may play a role in enhancing the oxygen fugacity of the magmas. Taking a global perspective, we found a pervasive correlation between amphibole fractional crystallization and Fe isotope fractionation in magmatism at convergent plate margins, indicating its widely applicable influence on oxidation. The influence of garnet cannot be entirely neglected in some specific scenarios, such as within thickened continental arcs, but its impact is generally limited. Continuous amphibole fractional crystallization increases oxidation, facilitating the mobilization and concentration of Cu within the magma, thereby enhancing the potential for porphyry deposit formation. This impact is especially notable in spatiotemporally related magmatic events and could be decisive in determining the magmatic mineralization potential.

Real-time release testing of in vitro dissolution and blend uniformity in a continuous powder blending process by NIR spectroscopy and machine vision

Continuous manufacturing is gaining increasing interest in the pharmaceutical industry, also requiring real-time and non-destructive quality monitoring. Multiple studies have already addressed the possibility of surrogate in vitro dissolution testing, but the utilization has rarely been demonstrated in real-time. Therefore, in this work, the in-line applicability of an artificial intelligence-based dissolution surrogate model is developed the first time. NIR spectroscopy-based partial least squares regression and artificial neural networks were developed and tested in-line and at-line to assess the blend uniformity and dissolution of encapsulated acetylsalicylic acid (ASA) – microcrystalline cellulose (MCC) powder blends in a continuous blending process. The studied blend is related to a previously published end-to-end manufacturing line, where the varying size of the ASA crystals obtained from a continuous crystallization significantly affected the dissolution of the final product. The in-line monitoring was suitable for detecting the variations in the ASA content and dissolution caused by the feeding of ASA with different particle sizes, and the at-line predictions agreed well with the measured validation dissolution curves (f2 = 80.5). The results were further validated using machine vision-based particle size analysis. Consequently, this work could contribute to the advancement of RTRT in continuous end-to-end processes.

Integrated Continuous Crystallization–-Spherical Agglomeration (CCSA) Process for the Intensified Manufacturing of Atorvastatin Calcium

Integrated Continuous Crystallization–-Spherical Agglomeration (CCSA) Process for the Intensified Manufacturing of Atorvastatin Calcium

Recovery of nitrogen as struvite from swine wastewater: Comparison study of batch and continuous fluidized-bed crystallization process

The recovery of valuable compounds from waste supports the idea of a circular economy. Two systems were introduced in this study to recover nitrogen as struvite from swine wastewater, including batch stirred and fluidized-bed homogeneous crystallization (FBHC) systems. MgCl2 and NaH2PO4 were applied as precipitants to form struvite. In the batch stirred system, the removal efficiency of NH4+, Mg2+, and PO43− reached the optimum condition of 92.1 %, 75.6 %, and 91.1 %, respectively, under the operating conditions of pH 9 and an Mg/P molar ratio of 1.2. In the same operating conditions, the Crystallization ratio (CR) and Total Removal (TR) of the FBHC system reached 83.2 % and 89.1 %; 86.7 % and 90.6 %; 71.2 % and 76.1 % for NH4+, Mg2+, and PO43−, respectively. The XRD and FT-IR analyses confirmed the high purity and quality of the struvite solid product. However, the water content of the FBHC product is much lower than that of the batch-stirred system (5.8 % and 95.3 %, respectively). The great potential of swine wastewater as a nitrogen source for fertilizer production is evidenced by the high purity struvite product (>85.0 %).

Optimisation of thermal regime and consolidation properties of high-silica magnesium-containing pellets

An in-depth study on the preparation process of high-silica magnetite magnesium pellets based on a grate-rotary kiln process is of great significance for promoting the utilisation of low-grade magnetite resources. When the magnetic hematite ratio is 30% and the proportion of magnesia is 1.5%, the performance of green pellets is the best. The preparation of high-silica magnesium pellets requires two stages of grate preheating for additional heating, and the appropriate preheating system is 1150°C for 15 min. The suitable magnetic hematite mixture ratio of pellets should not exceed 30%, and the reasonable magnesia ratio should not exceed 1.5%. Otherwise, the preheating temperature should be further increased, or the preheating time should be extended. The suitable roasting temperature is low, only 1225°C for 15 min, and the pellet strength can reach more than 2365N. Magnetic hematite and added magnesium flux inhibited the continuous crystallisation consolidation property in the pellet. The high SiO2 content in the gangue of high-silica magnetite impedes the recrystallisation consolidation of Fe2O3 particles in the pellet. At the same time, the primary Fe2O3 in the magnetic hematite mixed ore is less reactive than the new Fe2O3 in the magnetite oxidation. With the roasting process, the magnesium ferrite content in the pellet increases, and the recrystallisation consolidation is inhibited, so the grate-rotary kiln process to produce high-silica magnesium-containing pellets is suitable to use a higher preheating temperature to meet the requirements of grate-rotary kiln pellet strength.

Investigation on tribological properties of high-velocity air fuel spraying WC–Cr3C2–Ni coating on the surface of continuous casting crystallization rollers

To overcome the wear problem of the substrate of thin-strip continuous casting crystallization rollers and improve economic efficiency, high-velocity air fuel (HVAF) technology was used to deposit WC–Cr3C2–Ni wear-resistant coatings on the surface of the crystallization rollers. The existing performance and wear condition of curved WC–Cr3C2–Ni coatings during continuous casting were investigated by the ring-block wear system. The experimental results showed that the WC–Cr3C2–Ni coating with a thickness of 300 μm effectively reduced the coefficient of friction (by 16.4 %) and the wear rate (by 82.5 %) on the surface of the crystallization roller and significantly reduced the roughness of the wear interface (by 71.2 %), which provided reliable protection for the substrate. The results of high-temperature (200 °C) wear tests showed that the WC–Cr3C2–Ni coating deposited via HVAF protected the substrate in actual long-cycle production and exhibited an excellent resistance to the emergence and expansion of failure cracks. This study provided a theoretical basis for the selection and preparation of surface coatings for thin strip continuous casting crystallization rollers.

Design and Characterization of a Novel Continuous Annular Gap Crystallizer

Design and Characterization of a Novel Continuous Annular Gap Crystallizer