Tubular 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.

Ultrasound-assisted continuous crystallization of metastable polymorphic pharmaceutical in a slug-flow tubular crystallizer

Metastable polymorphic pharmaceuticals have garnered significant attention in recent years due to their enhanced physicochemical properties, including solubility, bioavailability, and intellectual property considerations. However, the manufacturing of metastable form pharmaceuticals remains a formidable challenge. The stable preparation of metastable carvedilol (CVD) form Ⅱ crystals during CVD production is elusive, leading to substantial inconsistencies in product quality and regulatory compliance. In this study, we successfully prepared metastable CVD Form Ⅱ crystals using a continuous tubular crystallizer. Our findings demonstrate that the tubular crystallizer exhibits high efficiency and robustness for generating metastable crystal Form Ⅱ. We optimized the crystallization process by incorporating air bubble segments and employing ultrasonic irradiation strategies to overcome blockages and wall sticking issues encountered during operation. Ultimately, we developed an ultrasound-assisted continuous slug-flow tubular crystallization method and evaluated its performance. The results indicate that the CVD crystals produced through this process are resilient, sustainable, and uninterrupted products with promising potential for producing metastable polymorphic pharmaceuticals while effectively addressing encrustation problems associated with continuous tubular crystallization.

Cooling Crystallization of Paracetamol in a Slug-Flow Crystallizer with Silicone Oil as Continuous Phase

Continuous tubular crystallizers that can provide high yield and better control of crystal size would be of great interest to the industrial crystallization process. However, most continuous crystallizer designs face challenges either due to surface fouling or crystal breakage. In this paper, we explore the ability of slug-flow cooling crystallizers to continuously generate acetaminophen crystals using silicone oil as the continuous phase. Each slug acts as a crystallizer, and the crystals formed inside the dispersed phase avoid encrustation. Three crystallizer configurations were studied at a wide range of supersaturation and flow rates. It was found that a narrow crystal size distribution can be achieved at high flow rates and high supersaturation. Additionally, the average crystal size and the crystallization yield increased with supersaturation and residence time. The configuration of the tubular crystallizer was found to influence the crystallization yield by affecting the internal mixing in the slugs. With further studies, slug-flow cooling crystallizer can be developed for continuous crystallization of crystals with a narrow size distribution, polymorphic purity, and good yield.

Intensification design of green crystallization separation: Process optimization and technology coupling

This work designs different process intensification trajectories in the layer melt crystallization (LMC) to improve the separation efficiency. Parameters of distribution coefficient, interfacial solute distribution factor, and mass transfer coefficient are proposed to figure out the intrinsic correlations of technical variables and target parameters. The first proposal strategy is the optimization of the operating curve, divided into cooling process regulation and temperature cycling strategy. Both techniques can eliminate the fine crystals, thus favoring the crystal growth and reducing the impurities' adsorption. Next is the incorporation of the stirring intensification technique into the LMC. The problem of burst nucleation is restricted significantly through the suitable design of the stirring parameters. At last, a coupling technique that combines suspension and LMC is designed. The crystal seeds generated from the suspension melt can flow into the tubular crystallizer and act as the sites for crystal growth. This coupling technique exhibits excellent separation efficiency and huge potential in industrial production. The proposals for the further development of the LMC technique are given.

Taylor vortex-based protein crystal nucleation enhancement and growth evaluation in batchwise and slug flow crystallizers

The utilisation of nucleation seeds, coupling nucleation and growth during crystallization and realistic continuum are currently relatively robust, reliable and scalable methods for protein crystallization optimization. Here, we design a segmented crystallization method, in which combines the characteristics of the Taylor vortex enhanced lysozyme nucleation stage. Different crystallizer are used for the growth segment so that the nucleation segment and the growth segment are organically combined during lysozyme crystallization. During the crystal growth stage, the crystallization properties of the Couette-Taylor (CT) crystallizer, mixing Tank (MT) crystallizer and tubular crystallizer were evaluated. The experimental results emphasize the importance of shear rate, temperature, and fluid velocity in the design of segment crystallization methods to obtain products with complete crystal morphology and uniform size distribution. This strategy successfully expanded the lysozyme crystallization from the original 10 mL scale to 200 mL, realized the continuous process, and providing a promising strategy for the design and operation of continuous SFC to produce high value protein crystals in the future.

Temperature cycling-induced formation of crystalline coatings

The surface of particles is the hotspot of interaction with their environment and is therefore a major target for particle engineering. Particles with tailored coatings are greatly desired for a range of different applications. Amorphous coatings applied via film coating or microencapsulation have frequently been described in the pharmaceutical context and usually result in homogeneous surfaces. In the present study we have been exploring the feasibility of coating core particles with crystalline substances, a matter that has rarely been investigated. The expansion of the range of possible coating materials to include small organic molecules enables completely new product properties to be achieved. We present an approach based on temperature cycles performed in a tubular crystallizer to result in engineered crystalline coatings on excipient core particles. By manipulating the process settings and by the choice of coating substance we are able to tailor surface roughness, topography as well as surface chemistry.Benefits of our approach are demonstrated by using resulting particles as carriers in dry-powder-inhaler formulations. Depending on the resulting surface chemistry and surface roughness, coated carrier particles show varying fitness for delivering the model API salbutamol sulphate to the lung.

Controlled crystallization of metastable polymorphic pharmaceutical: Comparative study of batchwise and continuous tubular crystallizers

The deliberate and reproducible crystallization of metastable polymorphs of active pharmaceutical ingredients (APIs) from solution remains difficult and is still far from trivial. The main challenge is to prevent cross nucleation of the stable form. The traditional cooling experiments in a batch crystallizer cannot repeatably produce aripiprazole (APZ) metastable Form III within selected initial concentrations and cooling rates. The computational fluid dynamics simulations confirmed that fluctuations in temperature and solution concentration in the batch crystallizer would induce the nucleation of stable crystal forms and accelerate solvent-mediated phase transformation. This work presents, for the first time, ultrasonic- and slug-assisted tubular crystallizers for the continuous and controllable preparation of pure metastable crystal Form III of APZ. The ultrasound-assisted air segmented plug flow tubular crystallizer provides an efficient configuration to produce high purity metastable polymorphism pharmaceuticals, which also offers a facile approach for the continuous manufacturing of drug substances.

Control of crystal size distribution in batch protein crystallization by integrating a gapped Kenics static mixer to flexibly produce seed crystals

Seeding is often used in crystallization to control the quality of crystalline products. The conventional approach to obtaining seed crystals typically involves milling, which may not be suitable for protein crystallization due to possible protein denaturation. We propose a novel method for generating protein seed crystals by using a gapped Kenics tubular crystallizer (gKTC). Small and non-agglomerated seed crystals are generated in the gKTC for the model protein lysozyme. Different seeding policies can be implemented by adjusting the transfer of crystals from the gKTC to a batch crystallizer, which offers flexible control over the crystal size distribution (CSD) of the batch product. This flexibility is demonstrated through an open-loop control strategy in which an optimal seeding policy to obtain a flat-top CSD is derived from a model, which is then implemented experimentally. The obtained CSD is close to the specified one, which cannot be achieved well with conventional batch crystallization.

Implementation of sonicated continuous plug flow crystallization technology for processing of acetylsalicylic acid reaction mixture

An effective way to ensure proper mixing and thereby realize maintenance-free operation of the clogging-sensitive continuous tubular crystallizers is the utilization of ultrasound-irradiation. Considering this, our research aimed to develop an ultrasonicated plug flow crystallization process to separate and purify a multicomponent acetylsalicylic acid (ASA) flow reaction mixture with antisolvent and combined cooling-antisolvent method. The influence of process parameters – temperature, antisolvent to ASA solution ratio, mean residence time – on purity, yield, productivity, product size, and size distribution was investigated applying a 23 full factorial experimental design. In further analysis, the alteration of product quality and quantity was studied by reducing the ultrasonicated tubing length and increasing the feeding rate, which could be important for industrial applicability. It was found that ultrasonication results in robustness against process parameter modification regarding product quality producing purified, small (<50 μm), consistent quality product while enabling to reach 89% yield even with 30 s residence time.

Design and characterization of Kenics static mixer crystallizers

Tubular crystallizers are desirable for continuous operations because they can approach plug flow conditions, achieve higher throughputs, and can be easy to control. However, the possible limitations of tubular crystallizers may include settling of crystals, fouling and higher pressure drops at longer residence times. The performance of a tubular crystallizer with gaps between the Kenics type mixing elements is characterized and compared with a standard Kenics static mixer and a hollow tubular crystallizer for the crystallization of lysozyme from solution. The gapped Kenics static mixer crystallizer provides an attractive trade-off between the standard Kenics static mixer and the hollow tubular crystallizer in terms of mixing length, shear rate, residence time distribution, pressure drop and segregation or settling of crystals. Furthermore, the gapped Kenics static mixer crystallizer and the standard Kenics static mixer crystallizer exhibit a similar crystallization performance in terms of desupersaturation profile and mean crystal size at the outlet for different initial lysozyme concentrations and seed loadings. The advantages of the gapped Kenics static mixer crystallizer in terms of pressure drop and minimization of crystal settling allow for lower flow rates and longer residence times under plug flow conditions, which has important practical benefits for continuous crystallization.

Continuous Crystallization Using Ultrasound Assisted Nucleation, Cubic Cooling Profiles and Oscillatory Flow

Continuous tubular crystallizers have the potential to reduce manufacturing costs and increase product quality. However, designing tubular crystallizers is a complex and challenging task as crystallization is a complex, multiphase process with a propensity for fouling and clogging. While several designs have been proposed to overcome these issues, these designs are either unproven or poorly scalable and complex. In this work a continuous crystallizer is designed and evaluated to mitigate these issues. The tubular crystallizer combines a novel method to obtain a cubic cooling profile to control the supersaturation, ultrasound to induce nucleation and oscillatory flow to improve mixing and minimize fouling and sedimentation. The results show that the crystallizer was able to operate for more than 4 h without clogging, with high yields and a narrow particle size distribution. The design proposed here is therefore considered a viable approach for continuous crystallizers.

Open-source multi-purpose sensor for measurements in continuous capillary flow

Limited applicability and scarce availability of analytical equipment for micro- and millifluidic applications, which are of high interest in research and development, complicate process development, control, and monitoring. The low-cost sensor presented in this work is a modular, fast, non-invasive, multi-purpose, and easy to apply solution for detecting phase changes and concentrations of optically absorbing substances in single and multi-phase capillary flow. It aims at generating deeper insight into existing processes in fields of (bio-)chemical and reaction engineering. The scope of this work includes the application of the sensor to residence time measurements in a heat exchanger, a tubular reactor for concentration measurements, a tubular crystallizer for suspension detection, and a pipetting robot for flow automation purposes. In all presented applications either the level of automation has been increased or more information on the investigated system has been gained. Further applications are explained to be realized in the near future.Article highlights• An affordable multipurpose sensor for phase differentiation, concentration measurements, and process automation has been developed and characterized• The sensor is easily modified and can be applied to various tubular reaction/process units for analytical and automation purposes• Simple integration into existing process control systems is possibleGraphical abstract

Flow Map for Hydrodynamics and Suspension Behavior in a Continuous Archimedes Tube Crystallizer

The Archimedes Tube Crystallizer (ATC) is a small-scale coiled tubular crystallizer operated with air-segmented flow. As individual liquid segments are moved through the apparatus by rotation, the ATC operates as a pump. Thus, the ATC overcomes pressure drop limitations of other continuous crystallizers, allowing for longer residence times and crystal growth phases. Understanding continuous crystallizer phenomena is the basis for a well-designed crystallization process, especially for small-scale applications in the pharmaceutical and fine chemical industry. Hydrodynamics and suspension behavior, for example, affect agglomeration, breakage, attrition, and ultimately crystallizer blockage. In practice, however, it is time-consuming to investigate these phenomena experimentally for each new material system. In this contribution, a flow map is developed in five steps through a combination of experiments, CFD simulations, and dimensionless numbers. Accordingly, operating parameters can be specified depending on ATC design and material system used, where suspension behavior is suitable for high-quality crystalline products.

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Preparation of Aspirin Nanosuspension by Antisolvent Precipitation Method

Ultrasound in Continuous Tubular Crystallizers: Parameters Affecting the Nucleation Rate

Ultrasound has proven to be an important tool for controlling nucleation in continuous tubular crystallizers. However, insufficient information is available about the parameters controlling the nucleation rate in a continuous ultrasonic process. Previous research has studied parameters related to the nucleation rate, but has not measured the nucleation rate directly or continuously. In this work, the nucleation rate is measured continuously and inline to solve this problem and achieve a better process understanding. The results indicate that the ultrasound-assisted nucleation process is presumably dominated by secondary nucleation. Additionally, the supersaturation, residence time and flow rate have a strong influence on the nucleation rate. On the other hand, the influence of the ultrasonic power is crucial but levels off once a certain amount of power is reached. The static pressure in the system determines the effective ultrasonic power and is therefore also important for the nucleation rate. Finally, maintaining an equal power per unit of volume and an equal residence time by increasing the tubing diameter seems to be a good scale-up method. These results will improve understanding of ultrasonic tubular crystallizers and how to control them.

Quantification and evaluation of operating parameters’ effect on suspension behavior for slug flow crystallization

As small scale continuous crystallizers gain more attention, the challenge of suspension inside tubular crystallizers was recognized, which might be circumvented by using slug flow crystallization. In literature, the effects of operating conditions, like slug’s velocity, slug’s length, solid content, and crystal size are investigated qualitatively only. A quantitative method describing the suspension state under gravitational influence for tubular crystallizers is not established yet and developed in this study. Therefore, the goodness of suspension (GoS) is introduced describing the particles’ spread inside the slugs in horizontal and vertical direction. The GoS is systematically analyzed for different operating conditions using design of experiments. Results show that independent of the other operating conditions smaller slugs are favored for better GoS in horizontal direction only. The choice of slug’s velocity depends for vertical and horizontal direction on solid content and crystal size, whereby both of them are defined by crystalline product requirements.

Theoretical Feedback Control Scheme for the Ultrasound-Assisted Continuous Antisolvent Crystallization of Aspirin in a Tubular Crystallizer

Ultrasound-assisted crystallization is a promising process for the production of crystals within a size distribution width. Toward the direction of attaining high-quality crystals, this article pro...

Continuous enantioselective crystallization of chiral compounds in coupled fluidized beds

• Highly productive continuous enantioselective crystallization. • Exploitation of two coupled fluidized bed crystallizers. • Provision of narrow product crystal size distributions. • Validation of a reduced population balance model. • First results regarding high resolution CFD-DEM simulations. This review summarizes results of an interdisciplinary project devoted to improve the access to enantiopure components by applying an advanced continuous separation process exploiting the principle of kinetically controlled preferential crystallization within two coupled fluidized beds located in conically shaped tubular crystallizers. The process efficiently combines selective crystallization with integrated product classification. Along with summarizing the related literature, new original results are presented with respect to theoretical process description and experimental validation. Although only one chiral system is considered specifically, namely the separation of the enantiomers of a racemic mixture of asparagine monohydrate using water as solvent, general conclusions will be drawn to highlight the large potential of the process principle. The conceptual approaches presented are seen as useful tools for the development of productive continuously operating enantioselective crystallization processes. They are applicable to separate enantiomers of numerous chiral molecules.

Tunable protein crystal size distribution via continuous slug-flow crystallization with spatially varying temperature

Under appropriate buffer and pH conditions, the magnitude and dispersion of the product protein crystals were reproducibly manipulated by controlling the spatial temperature along the tube in a continuous tubular crystallizer.

Heat transfer and its effect on growth behaviors of crystal layers during static layer melt crystallization

The growth behaviors of crystal layers during static layer melt crystallization was studied from the perspectives of morphology structure, growth rates and temperature evolution. The temperature distributions of the melt and crystal layer were deduced. With these results, the heat transfer during crystallization was analyzed by considering the relative influences of natural convection, heat conduction in the melt and latent heat of crystallization. A model correlating growth rate with physical and experimental parameters was derived based on energy conservation. Effective thermal conductivity of crystal layers was evaluated. It was confirmed that the structure and density of the crystal layer can significantly affect the thermal conductivity. According to the temperature curves of melt, the static layer melt crystallization process in a tubular crystallizer can be divided into four stages as nucleation stage, fast growth stage, slow growth stage and steady state stage.