Continuous Crystallization Research Articles

Continuous Crystallization Kinetics of Cefradine in a Mixed Suspension Mixed Product Removal System

Continuous Crystallization Kinetics of Cefradine in a Mixed Suspension Mixed Product Removal System

Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Impurity Profiling for a Scalable Continuous Synthesis and Crystallization of Carbamazepine Drug Substance

Single and Multiobjective Shutdown Optimization of a Multistage Continuous Crystallizer.

This study presents the first model-based optimal shutdown procedure of a multistage continuous crystallization process which aims at the maximization of on-spec production and minimization of the shutdown time. The cooling antisolvent crystallization of Aspirin (acetylsalicylic acid) in a three-stage continuous crystallizer was used as a case study. To address the optimal shutdown problem, several single optimization scenarios were considered to assess the impact of the degrees of freedom, discretization schemes, and optimization settings such as the constraints. The proposed optimal shutdown procedures showed that significant amounts of on-spec crystals can be produced both at fixed and variable shutdown times. Most importantly, the optimal shutdown procedures can match the steady-state productivity, based on the shutdown to steady-state productivity ratio (STSPR) which can easily reach 100%. Moreover, the residual shutdown material, considered as waste, can be dramatically reduced by >80% compared to the current standard shutdown procedures. Given the conflicting nature of the maximization of on-spec production and minimization of the shutdown time, multiobjective optimization of the shutdown operation was also addressed to identify the set of Pareto optimal solutions. Finally, a multicriteria decision-aiding method, based on multiattribute utility theory, was proposed to rank the Pareto optimal solutions to support the decision-making and help identify a suitable and feasible single optimal shutdown solution.

Exploiting Domain Partition in Response Function-Based Dynamic Surrogate Modeling: A Continuous Crystallizer Study

Given the exponential rise in the amount of data requiring processing in all engineering fields, phenomenological models have become computationally cumbersome. For this reason, more efficient data-driven models have been recently used with the purpose of substantially reducing simulation computational times. However, especially in process engineering, the majority of the proposed surrogate models address steady-state problems, while poor studies refer to dynamic simulation modeling. For this reason, using a response function-based approach, a crystallization unit case study was set up in order to derive a dynamic data-driven model for crystal growth whose characteristic differential parameters are derived via Response Surface Methodology. In particular, multiple independent variables were considered, and a well-established sampling technique was exploited for sample generation. Then, different sample sizes were tested and compared in terms of accuracy indicators. Finally, the domain partition strategy was exploited in order to show its relevant impact on the final model accuracy. In conclusion, the outcome of this study proved that the proposed procedure is a suitable methodology for dynamic system metamodeling, as it shows good compliance and relevant improvement in terms of computational time. In terms of future research perspectives, testing the proposed procedure on different systems and in other research fields would allow for greater improvement and would, eventually, extend its validity.

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations.

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions' quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1-10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale.

Hydrate-based technique for natural gas processing: Experimental study of pressure-dropping and continuous modes

Gas hydrate crystallization is perspective and energy-efficient technology for gas mixtures processing, including natural gas. There were compared pressure-dropping and continuous gas hydrate crystallization methods for separation of gas mixture closed to natural gas. The studied mixture has been chosen similar to the natural gas composition: CH4 (75.68 mol.%) - С2H6 (7.41 mol.%) - C3H8 (4.53 mol.%) - н-C4H10 (2.47 mol.%) - CO2 (5.40 mol.%) - H2S (1.39 mol.%) - N2 (3.01 mol.%) - Xe (0.11 mol.%). Experiments were provided in the 4 L high pressure reactor, using water solution of SDS (0.20 wt.%). The experiment conditions were 280.15 K and pressure of 4.25 MPa. The components separation factors and recovery for two modes have been researched and compared for choosing more effective options. After comparing these characteristics, it was concluded that continuous process is more productive than pressure-dropping mode. At the stage cut (θ) of 0.9, the gas components total recovery (R) for the continuous mode have exceeded the total recovery for the pressure-dropping mode by 8.15 %, and at θ = 0.8, exceeded by 6.11 %. The recovery and separation factors have the highest values for H2S, C3H8, Xe in the continuous mode: 97.62 %, 94.90 %, 84.98 % and 8.7, 10.53, 6.36, respectively. Thus, the choosing of the more effective stage cut depends on the aim of the process: the highest purity or the largest recovery.

Coupled U–Pb and 40Ar/39Ar chronology of late‐stage intrusions at Elba Island (Italy) supports late Miocene long‐lived magma reservoirs in the Tyrrhenian upper crust

AbstractThe late Miocene Monte Capanne and Porto Azzurro plutons are investigated by means of coupled U–Pb zircon and 40Ar/39Ar white mica dating to test the occurrence of long‐lived magmatic systems in the upper crust. Zircon crystallized for >1 Ma in both plutonic systems, with supersolidus conditions overlapping for ~220 ka indicating previously unrecognized co‐existence of the two reservoirs. The development of the Porto Azzurro high T‐aureole is post‐dated by continuous igneous zircon crystallization until ~6.0 Ma. By linking crystallization to post‐emplacement cooling of late‐stage pulses in both western and eastern Elba we constrain long‐lived sizeable reservoirs (possibly the same reservoir) in the Tyrrhenian upper crust between ~8 and 6 Ma.

Cotreatment strategy for hazardous arsenic-calcium residue and siderite tailings via arsenic fixation as scorodite

Siderite tailings is a potentially cost-free iron (Fe) source for arsenic (As) fixation in hazardous arsenic-calcium residues (ACR) as stable scorodite. In this study, a pure siderite reagent was employed to investigate the mechanism and optimal conditions for As fixation in ACR via scorodite formation, while the waste siderite tailings were used to further demonstrate the cotreatment method. The cotreatment method starts with an introduction of sulfuric acid to the ACR for As extraction and gypsum precipitation, and is followed by the addition of H2O2 to oxidize As(III) in the extraction solutions and finalized by adding siderite with continuous air injection for scorodite formation. The dissolution-oxidation of siderite can slowly produce Fe(III) to control aqueous As(V)-Fe(III) precipitation supersaturation for continuous scorodite crystallization. Chemical analyses show that the extraction efficiency of As from the ACR reaches 94.55%, while the precipitation yield of extracted As via scorodite formation arrives at 99.63% and 99.47%, leading to fixation efficiency of 94.20% and 94.04% in terms of the total As in the ACR by using siderite reagent and tailings, respectively. The final solid products show desirable TCLP stability and long-term stability, meeting the requirement for safe storage (GB 5085.3–2007). XRD, FTIR, and TEM results reveal that such high stability is attributable to the formation of scorodite and the surface adsorption of As on the raw siderite and secondary maghemite. This innovative and economical application of siderite tailings for the treatment of hazardous ACR can be extended to the management of hydrometallurgical wastes.

Continuous Spherical Crystallization of Escitalopram Oxalate without Additives

Continuous Spherical Crystallization of Escitalopram Oxalate without Additives

General stability analysis of the steady states in the continuous mixed-suspension crystallizer

We report new mathematical tools to analyze the continuous mixed suspension crystallizer, which is widely used across industries, as it enables the manufacture of crystalline materials under well-controlled conditions. In particular, we develop a general framework to assess the stability of its steady states based on the birth rate ν, which denotes how many secondary nuclei a crystal forms throughout its lifetime in the crystallizer. A stable steady state is defined as follows: (i) ν(css)=1, the birth rate at the steady state concentration must equal one. (ii) dν/dc>0, the derivative of the birth rate must be positive. (iii) c0>css, the steady state must maintain a positive suspension density. These conditions enable the steady state analysis under general conditions, i.e., for arbitrary rate expressions of crystal growth and secondary nucleation, for size-dependent crystal growth and withdrawal, and for growth rate dispersion.The application of this theory to compounds with multiple solid forms, i.e., polymorphic and chiral compounds, is of particular interest. The analysis of the polymorphic steady states agrees with and generalizes the existing approaches. Concerning chiral compounds, enantiopure steady states are found to be unstable with respect to the racemic steady state, hence explaining the experimental challenges in the enantiopure crystallization of chiral compounds.

Tangential flow filtration for continuous processing of crystallized proteins

Protein crystallization has the potential to provide nearly pure protein products in a single processing step. Most previous studies of protein crystallization have used centrifugation for dewatering and washing the crystallized solids, but this approach would be difficult to adopt in continuous bioprocessing operations. This study provides the first demonstration that crystallized proteins can be successfully filtered using hollow fiber tangential flow filtration (TFF) modules. Experiments were performed with human serum albumin (HSA) crystallized by the addition of trivalent CeCl3, both with and without polyethylene glycol (PEG). Greater than 85 % protein yield was achieved using 4.5 mM CeCl3 in the presence of 3 wt% PEG with the crystallization occurring in less than 20 s, which is ideal for continuous processing. The addition of PEG had minimal effect on the crystallization yield, but it did lead to the formation of larger and denser crystals and a corresponding increase in the critical flux, which is the maximum value of the flux that causes minimal increase in the transmembrane pressure (i.e., minimal fouling). Filtration experiments performed at optimal conditions were successfully run for 24 h with the transmembrane pressure remaining below 5 kPa, demonstrating the feasibility of using continuous crystallization with tangential flow filtration for the purification of high value protein products.

Computational fluid dynamics simulation of a jet crystallizer for continuous crystallization of lovastatin

Continuous crystallization of lovastatin from a lovastatin-methanol solution and water as the anti-solvent in an impinging jet crystallizer is investigated using a computational fluid dynamics model. To capture the important phenomena, the model is coupled with micro-mixing, population balance, and related energy balance equations. It is implemented in OpenFOAM and validated against experimental data, where a fairly good agreement is found. The effects of key process parameters on the crystallization performance are also studied using the validated model. The results show that increasing the inlet jet velocity from 1 to 4 m/s yields a much narrower size distribution and 70% reduction in the mean crystal size. The four-fold increase in the inlet jet velocity also reduces the crystal production rate by one order of magnitude. Also, it is found that increasing the inlet supersaturation ratio from 6.8 to 8.8 nearly doubles the mean crystal size. Moreover, it results in a wider size distribution and a six-fold increase in the crystal production rate. The simulations also confirm that lower solution to anti-solvent mass flow ratios yield a wider size distribution, a larger mean crystal size and a higher crystal production rate. Increasing this ratio from 0.5 to 2 reduces the production rate by two orders of magnitude.

Continuous flow synthesis and crystallization of modafinil: a novel approach for integrated manufacturing

This study reports efforts toward the integrated advanced manufacturing of the anti-narcoleptic drug modafinil via flow chemistry and continuous crystallization.

Industrial Data Modeling With Low-Dimensional Inputs and High-Dimensional Outputs

Data-driven modeling will be complicated for a process if the output quality indices are defined in a high-dimensional space, e.g., a quality distribution. In this work, a novel probabilistic modeling method is proposed for industrial processes with low-dimensional inputs and high-dimensional outputs. First, based on a limited sample set, the variational autoencoder (VAE) is applied to extract features of the high-dimensional outputs. Next, a Gaussian Process (GP) model is established on the sub-manifold space defined by the low-dimensional features, and the high-dimensional predictions can be obtained through the VAE reverse procedure. Finally, a deep composing kernel strategy is developed to capture the nonlinearity and correlation hidden in the features. It can significantly improve the generalization performance of the GP model. The effectiveness of the proposed modeling algorithm is demonstrated by applications in a continuous crystallizer system and an ethylene homo-polymerization system.

Automated self-optimization of continuous crystallization of nirmatrelvir API

Automated self-optimization platform for the continuous crystallization of APIs.

Population balance model enabled digital design and uncertainty analysis framework for continuous crystallization of pharmaceuticals using an automated platform with full recycle and minimal material use

A systematic digital design framework for the development of a digital twin of a continuous crystallization process was presented using the model compound, diphenhydramine hydrochloride (DPH). The key features of the framework include operating space investigations, kinetic parameter estimation using population balance modeling, and systematic batch-to-continuous crystallization translation of the estimated parameters. An approach that compares experimental uncertainties with model-prediction uncertainties was used to justify the robustness of the parameter estimation procedure. For continuous crystallization development, a continuous configuration with full recycle and dissolution was developed, which enabled rapid process design with minimal material use. The results demonstrated successful model development for both batch and mixed-suspension-mixed-product-removal (MSMPR) crystallization configurations. This experimentally validated model, along with quantified uncertainty space of the kinetic parameters, serves as a digital twin of the process, which was later used to optimize the multistage MSMPR process to produce larger crystals with narrower distributions.

CAST HOLLOW BILLET STRUCTURE SIMULATION MODELING FOR OIL GRADE PIPES

Simulation modeling of hollow billet casting processes for the production of seamless oil grade pipes was performed. The aim of the work was to study the influence of geometric shape on the quality and properties of a continuously cast pipe billet. Modeling parameters, initial and boundary conditions were selected taking into account the conditions of the current production. The object of the study was a pipe billet with a diameter of 210 mm. When modeling the process of casting and solidification of billets, low-alloy structural chromium-molybdenum steel was used. For the simulation processes, three-dimensional models of billets were created, as well as models of shapes. Several factors were taken into account when modeling continuous casting and crystallization of a hollow billet: casting speed, chemical composition of the alloy being poured; casting temperature; geometric dimensions of the billet section. Modeling of hollow billet casting in the «LVM Flow» software package predicted the non-shrinking structure formation a decrease in microporosity (more than 0.85 according to the Niyama criterion) of the billet. As a result of simulation modeling, the improvement of the structure is theoretically confirmed when using a hollow steel billet as a starting point for the production of seamless hot-rolled pipes. There were no signs of shrinkage and microporosity on the hollow billet exceeding the permissible value according to the Niyama criterion. Keywords: hollow billet, steel, modeling, pipe, 25CrMoV.

Mineralogical constraints on pegmatite genesis and rare metal mineralization in the Mufushan batholith, South China

Pegmatites are commonly associated with or strongly influenced by the crystallization of magmatic volatile phases (MVP) as ascending magmas undergo differentiation. The mechanism of fractional crystallization, liquid immiscibility, and water–rock interactions that influence the rare metals concentration in pegmatites are still unclear. We analyzed the mineralogy (incl. monazite, garnet, zircon, and muscovite) from pegmatites to unravel the timing and magmatic-hydrothermal processes for the giant Renli-Chuanziyuan pegmatite Li-Nb-Ta mineralization in the Mufushan region (South China). Five types of pegmatites have been identified at Mufushan, i.e., those containing mainly orthoclase (O-pegmatite), microcline (M-pegmatite), albite-orthoclase (AO-pegmatite), microcline-albite (MA-pegmatite), and spodumene-albite (S-pegmatite).Monazites from the Renli high-Th Li-mica pegmatite exhibit magmatic affinity. The ∼140 Ma age of monazite U-Pb suggests a temporal relationship between the Li-rich pegmatite and its muscovite granite host. Garnet from these pegmatites is magmatic and belongs to the almandine-spessartite series, and contains feldspar and apatite inclusions. Continuous fractional crystallization likely controlled the pegmatite development, as the garnet spessartite content increases with distance from the Mufushan batholith. Garnet in the spodumene-albite pegmatites has very low REE content, and it represents a late stage of crystallization related to magmatic-hydrothermal fluids. Compositional variation in muscovite from all of the pegmatites is negligible. The K/Rb ratio (a proxy for the degree of fractionation) increases gradually from the O- to S-pegmatite, whilst the muscovite F content correlates positively with the degree of magma fractionation. The transformation of muscovite to lepidolite in pegmatites can occur through magmatic-hydrothermal crystallization or metasomatism. Zircon in pegmatites generally occurs as metasomatic remnants, with uneven zoning shown in cathodoluminescence (CL) images. Hydrothermal zircon U-Pb ages are concentrated in the 140–134 Ma range, consistent with the garnet leucogranite ages. This suggests that pegamtites and the garnet leucogranite were formed in the same magmatic-hydrothermal activity. The accumulated MVP and incompatible elements may have migrated from deeper, more crystal-rich zones under medium degree of fractionation. The MVP may contain abundant dissolved melt components as single-phase hydrous silicate liquids, forming typical quartz-/feldspar-dominated pegmatite and the diversity of rare-metal deposits.

End-to-End Continuous Small-Scale Drug Substance Manufacturing: From a Continuous In Situ Nucleator to Free-Flowing Crystalline Particles

In the evolving landscape of pharmaceutical manufacturing, a comprehensive continuous production process is being crafted for the small-scale production of active pharmaceutical ingredients. This study focuses on continuous crystallization with separate nucleation and crystal growth units, as well as continuous downstream processing, encompassing filtration, washing, and drying until the formation of free-flowing particles. We introduce a novel continuous nucleator designed based on solubility data and produced via 3D printing, enabling the fast and precise small-scale manufacturing of a nucleator meeting the requirements for nucleation and further growth processes. The nucleator is evaluated with regard to its suitability for continuous long-term operation across various coupled crystallizers. As a practical application example, it is connected to a slug flow crystallizer to enable high-quality continuous crystallization. Additionally, the full integration of downstream processes using a continuous vacuum screw filter to achieve free-flowing product particles is realized. Even under non-optimized process conditions, with the help of the in situ generation of nuclei, free-flowing product particles are successfully obtained. This is particularly useful during drug development when no material is available for seed addition and to quickly obtain products for further characterization.

Magma storage conditions over the past 4 Ma on Martinique Island, Lesser Antilles

We constrain, for the first time, the storage conditions beneath recent (<5 Ma) volcanic edifices in Martinique Island, combining petrography, geochemistry, and thermobarometry. Specifically, we investigate Morne Jacob volcano (5.2–1.5 Ma), Pitons du Carbet complex (998 ka – 322 ka), Trois Îlets Volcanic field (2.35 Ma – 346 ka), and Mt. Conil – Mt. Pelée system (<550 ka). Lava samples range in composition from basalt to dacite, and in age from 4.1 Ma (Morne Jacob) to 1929 CE (Mount Pelée). For the last ∼5 Ma, the volcanoes in Martinique were fed by andesitic to dacitic magma stored in the upper 6 km of the crust, at temperatures between 900 and 1100 °C. These shallow reservoirs were frequently replenished and remobilized by basaltic and basaltic-andesite magmas originating from the lower crust with temperatures as high as 1200 °C. Erupted products contain simple to more complex mineral assemblages, and plagioclase phenocrysts exhibit textures and compositional profiles typical of antecrysts, identified as (1) normal, (2) oscillatory, (3) sieved, (4) resorbed core, and (5) resorbed rim. All complexes also show a crystallization gap in the middle crust (10–18 km). Trois Îlets, a distributed volcanic field, is the only complex that shows continuous crystallization through the entire crust, distinct magma batches and storage regions for each individual volcano. More importantly, we see drastic changes in terms of rock composition, storage conditions, and crystal populations in pre - and post – collapse lavas. Large flank collapse (> 5 km3) can induce decompression as large as 5 MPa in the upper crust and as low as 0.1 MPa down to 10–12 km. Such decompression magnitudes might be sufficient to enhance ascent of basaltic magma from depth, initiate dike intrusions in the mid to upper crust, and remobilize shallow silicic reservoirs. Such events are likely to initiate magma mixing in shallow reservoirs. This noteworthy eruption-triggering mechanism may lead to the incorporation of distinct crystal populations and subsequently contribute to heightened rates of eruption. In summary, the magma storage conditions and plumbing system architecture for the recent volcanoes in Martinique closely resemble those observed in other volcanoes within the Lesser Antilles Island Arc, such as Soufriere Hills Volcano or La Soufriere de Guadeloupe. These newly established correlations offer valuable insights that can aid in the assessment of potential future volcanic eruptions.