Tubular Crystallizer Research Articles

Low‐Cost Noninvasive Real‐Time Imaging for Tubular Continuous‐Flow Crystallization

AbstractA key design limitation to the effective monitoring and control of continuous crystallization processes is the ability to characterize crystals in real time. A low‐cost system composed of a basic stereomicroscope and video camera for the in situ imaging of sub‐millimeter crystals through curved walls of millifluidic tubular crystallizers is described. Real‐time videos taken for millimeter‐size slurry slugs are used to guide the experimental design for a recently developed multiphase‐flow crystallization process, including the improvement of the slug aspect ratio, visualization of crystal shapes, and observation of the extent of aggregation. Design considerations are also discussed for the use of multiple stereomicroscopes in other continuous‐flow tubular experiments.

Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Flow Baffled Crystallizer

Drug substance purification by crystallization is a key interface in going from drug substance synthesis to final formulation and can often be a bottleneck in process efficiency. There has been increased importance in the development of continuous crystallization systems of active pharmaceutical ingredients to produce crystals with targeted physical and biopharmaceutical properties. Continuous spherical crystallization (CSC) is a process intensification technique that can address many of the present flaws (e.g., size distribution, downstream processing efficiency) of traditional crystallization systems. In this study, a novel concept and method in the field of process intensification through continuous spherical crystallization is proposed. This study is based on performing crystallization/spherical agglomeration in an oscillatory flow baffled crystallizer (OFBC). OFBCs are comparable to plug flow crystallizers (PFCs) in that they are both tubular crystallizers; however, the OFBC has periodically spaced o...

Ultrasound Assisted Particle Size Control by Continuous Seed Generation and Batch Growth

Controlling particle size is essential for crystal quality in the chemical and pharmaceutical industry. Several articles illustrate the potential of ultrasound to tune this particle size during the crystallization process. This paper investigates how ultrasound can control the particle size distribution (PSD) of acetaminophen crystals by continuous seed generation in a tubular crystallizer followed by batch growth. It is demonstrated that the supersaturation ratio at which ultrasound starts seed generation has a substantial effect on the final PSD while the applied power is insignificant in the studied conditions. The higher the supersaturation ratio, the smaller the final crystals become up to a supersaturation ratio of 1.56. Furthermore, it was shown that ultrasound can also impact the final PSD when applied during the growth phase. Frequencies of 850 kHz or below reduce the final particle size; the lower the applied frequency, the smaller the crystals become. In conclusion, one could state that ultrasound is able to control the particle size during seed generation and subsequent growth until the final particle size.

Development of a Circulated Flow Mixing Method with a Tubular Crystallizer for Controlling Indomethacin Polymorphs

Development of a Circulated Flow Mixing Method with a Tubular Crystallizer for Controlling Indomethacin Polymorphs

Design of a Continuous Tubular Cooling Crystallizer for Process Development on Lab‐Scale

AbstractContinuous manufacturing of fine chemical, life science, and pharmaceutical products is under recent investigation in R&D. As cooling crystallization is an important unit operation for purification of products, continuously operated, scalable devices are required for process development on lab‐scale. A tubular crystallizer was developed, based on the coiled flow inverter design. Experimental characterization proved a narrow residence time distribution of the liquid phase close to ideal plug flow. Counter‐current air cooling allows for adjusting linear and curved temperature profiles. Unseeded operation with the L‐alanine (water) system demonstrated that nucleation has to be actively controlled to successfully apply intensified continuous cooling crystallization processes.

Continuous crystallization using a sonicated tubular system for controlling particle size in an API manufacturing process

A pH swing crystallization that was very sensitive toward scale-up and required specific equipment due to the non-Newtonian characteristics of the fluid, has been investigated using continuous crystallization (CC) as a means to improve particle size control, scalability and potentially reduce manufacturing cost. A sonicated tubular crystallizer was designed and shown to allow the pH swing crystallization to be operated robustly without blockage, to give a wide range of desired particle size. The results were compared with crystallization in a premixing semi-batch system and a simple addition semi-batch system under similar conditions. Interestingly, it was found that the sonicated tubular system was the only one of the three systems that gave the desired control for small particle size (1–7μm). Even though the productivity of the sonicated tubular crystallizer still needs to be increased to allow CC and numbering-up to become cost competitive with batch crystallization, we have demonstrated the potential of continuous tubular crystallization as a useful alternative method to conventional batch operation.

Mathematical Modeling, Design, and Optimization of a Multisegment Multiaddition Plug-Flow Crystallizer for Antisolvent Crystallizations

In the pharmaceutical industries, the requirements of rapid process development and scalable design have made the tubular crystallizer a promising platform for continuous manufacturing and crystallization processes, capable of replacing conventional capital- and labor-intensive batch operations. This paper takes a process systems engineering (PSE) approach to the optimal design of a continuous antisolvent addition crystallizer to deliver the most promising product qualities, such as the crystal size distribution. A multisegment multiaddition plug-flow crystallizer (MSMA-PFC) is considered as an example of a continuous antisolvent crystallization process, in which the total number, location, and distribution of antisolvent additions are to be optimized. First-principles dynamic and steady-state mathematical models for the MSMA-PFC are presented, based on example kinetic models for nucleation and growth of paracetamol crystallizing in acetone, with water as the antisolvent. The performances of different cry...

Crystal Size Control in a Continuous Tubular Crystallizer

This paper describes a simple model-free (i.e., empirical) control strategy for crystal size tuning in a continuously operated tubular crystallizer. The crystallizer is designed for a seeded cooling crystallization process and acetylsalicylic acid crystallization from an ethanol solution was used as model system. Using a crystal size distribution (CSD) analyzer and minor initial studies, we developed a feedback controller that accurately tuned the mean crystal size within the range of 90–140 μm. In addition, we created a cleaning concept for long-term runs based on a consistency study, which demonstrated that the CSD of the products remained robust when process settings were kept constant. Sufficiently small and uniform seed crystals were generated via ultrasound irradiation.

Continuous Crystallization of Proteins in a Tubular Plug-Flow Crystallizer.

Protein crystals have many important applications in many fields, including pharmaceutics. Being more stable than other formulations, and having a high degree of purity and bioavailability, they are especially promising in the area of drug delivery. In this contribution, the development of a continuously operated tubular crystallizer for the production of protein crystals has been described. Using the model enzyme lysozyme, we successfully generated product particles ranging between 15 and 40 μm in size. At the reactor inlet, a protein solution was mixed with a crystallization agent solution to create high supersaturations required for nucleation. Along the tube, supersaturation was controlled using water baths that divided the crystallizer into a nucleation zone and a growth zone. Low flow rates minimized the effect of shear forces that may impede crystal growth. Simultaneously, a slug flow was implemented to ensure crystal transport through the reactor and to reduce the residence time distribution.

Modelling and Simulation of Particle Size Distribution of Precipitates in Continuous Tubular Crystallizers

This paper presents a population balance model for describing the temporal evolution of the particle size distribution of a precipitate produced in a laboratory scale tubular crystallizer, including nucleation, growth and agglomeration of crystals. The quadrature method of moments is used to calculate the moments of the crystal size distribution. The gamma probability density function with the sixth order Laguerre polynomials are used to reproduce the particle size distribution from moments. A sensitivity analyses is carried out by simulation that can be helpful when designing a crystallizer. Influence of the design and process parameters on the particle size distribution of product is analysed.

Statistical Design of Experiment on Contact Secondary Nucleation as a Means of Creating Seed Crystals for Continuous Tubular Crystallizers

In the pharmaceutical industry, it is often desired to produce seed crystals with an appropriate narrow size distribution of the desired polymorph. This study describes a system that generates such crystals continuously in a small-scale tubular crystallizer at low supersaturation via contact secondary nucleation. A response surface model was constructed by conducting a statistical design of experiment that models the nucleation rate as a function of contact force, area, and frequency. This model reveals that within a certain range the nucleation rate is linearly related to all three factors in this system. A combination of in-line video analysis and off-line microscope image analysis was used to determine the particle size distribution of seed crystals obtained in this system, and the majority of the crystals were found to be under 20 μm. This seems to be a feature of contact secondary nuclei in general and does not vary significantly with contact force, area, and frequency. Furthermore, the seed crystals...

Modeling a seeded continuous crystallizer for the production of active pharmaceutical ingredients

The approximation of a well mixed reactor is prevalent when it comes to the modeling of a crystallization process. Since temperature, concentration, and mass content vary due to inhomogeneous mixing, this approximation is a very loose one. The continuously operated seeded tubular crystallizer system developed in our group overcomes obstacles like a slow response to changes in the outer parameters and inhomogeneous mixing. Therefore the applicable well mixed assumption facilitates detailed modeling of the crystallization process by means of population balance equations (PBE) coupled with mass and energy balances. Modeled results were validated by means of experiments. The amount of aggregation events during the crystallization could be quantified and it was proven that the growth of seeded crystals is almost exclusively responsible for solid mass uptake if the reactor is operated appropriately. The performed sensitivity analysis exposed which process settings should be maintained most accurately to avoid fluctuations in the product crystals’ quality attributes and to limit undesired nucleation events.

Contact Secondary Nucleation as a Means of Creating Seeds for Continuous Tubular Crystallizers

The control of crystal size of any crystallization process is especially important in the pharmaceutical industry where small sizes are often desired. Seeding is often used as a method of controlling crystal size and suppressing primary nucleation in batch processes. The continuous mixed suspension mixed product removal crystallizers are self-seeded; however, crystal attrition and contact secondary nucleation due to crystal interaction with the impeller influence the crystal size. In this study, a nuclei generation device (nucleator) employing contact secondary nucleation is described. The nucleator consists of a “crossed” flow tube with four openings. Two of the openings are the inlet of supersaturated solution and the outlet of crystal slurry, respectively. The other two openings are for contact nucleation, where the parent crystal comes into contact with a platform under an applied stress. The rate of nucleation and the size of the crystals generated can be controlled by supersaturation (S = c/cs) and ...

Continuous Sonocrystallization of Acetylsalicylic Acid (ASA): Control of Crystal Size

A continuous tubular crystallizer system with an inner diameter of 2.0 mm and an overall length of 27 m was used to generate acetylsalicylic acid seeds in situ from ethanolic solution via cooling and ultrasound irradiation and to grow the crystals in the tubing with a controlled temperature trajectory. In order to minimize the residence time distribution, air bubbles were introduced into the system to generate a segmented gas-slurry flow. The narrow residence time distribution and the tight temperature control in the small tubing due to the large surface to volume ratio resulted in relatively narrow crystal size distributions of the product. Generally, all experiments clearly demonstrated significant crystal growth for the product crystals in comparison to the seeds and yielded product masses on the g/min scale. Furthermore, it was demonstrated that the size of the product can be easily controlled via fines removal by dissolution due to rapid heating and varying the mass of seeds per mL of solution.

Production of Fine Organic Crystalline Particles by Using Milli Segmented Flow Crystallizer

In the pharmaceutical production field, it is required to produce organic fine crystalline particles having a monodispersed crystal size distribution (CSD). Anti-solvent crystallization is one method for producing crystal particles. In order to produce fine crystalline particles and/or crystals having a monodispersed CSD, several methods such as segmented flow in the tubular crystallizer, ultrasound irradiation, and modulated operation in batch cooling crystallization have been studied in previous studies. In this study, integrated operation of ultrasound irradiation and temperature modulation at a milli-sized segmented flow has been carried out to produce organic fine crystalline particles having a monodispersed CSD in the anti-solvent crystallization. Taurine (solute)–water (solvent)–EtOH (anti-solvent) system is employed. The effect of segmented flow on mixing solution has been observed with a high-speed microscope. Fine crystalline particles which have tens of microns average size are obtained with the integration of ultrasound irradiation and temperature modulation on a milli-sized segmented flow. Furthermore, crystals of 10 µm size are produced under controlled supersaturation condition. Additionally, it is suggested that the CSD could be improved by introducing temperature modulation after nucleation.

Seed loading effects on the mean crystal size of acetylsalicylic acid in a continuous‐flow crystallization device

AbstractThis study investigates the effects of seed loading on the mean crystal size of the model substance, acetylsalicylic acid, crystallized from ethanol in a continuously seeded tubular crystallizer. A hot, highly concentrated ethanolic acetylsalicylic acid solution was mixed with an acetylsalicylic acid‐ethanol seed suspension. Subsequent cooling of the slurry in the tubing promoted supersaturation and hence crystal growth. The tubular shape of the 15 m‐long crystallizer with an inner diameter of 2 mm enabled narrow residence time distributions of the crystals in the pipe and excellent temperature control in the radial direction and along the tubing. Crystals entering the crystallizer had both identical growth conditions in each section and about the same time for crystal growth. Narrow crystal size distributions were achieved with decreasing differences in the volume‐mean‐diameter sizes of the seed and product crystals as seed loadings increased. Decreasing the seed size had a similar effect as increasing the seed loading, since in that case the same amount of seed mass resulted in more individual seed particles. Altering the arrangement of the coiled crystallizer with respect to spatial directions (horizontal, vertical) did not lead to a significantly different outcome. All experiments produced considerably larger product crystals in comparison to the seeds despite relatively short crystallization times of less than 3 min. Moreover, product mass gains of a few hundred percent at a g/min‐scale were achieved. Similarities in product crystal samples taken at different times at the outlet of the crystallizer showed that steady‐state conditions were rapidly reached in the continuous flow crystallization device. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Continuously Seeded, Continuously Operated Tubular Crystallizer for the Production of Active Pharmaceutical Ingredients

A continuously operated tubular crystallizer system with an inner diameter of 2.0 mm has been successfully operated. It allows the crystallization of active pharmaceutical ingredients (APIs) under controlled conditions. Acetylsalicylic acid (ASA) which was crystallized from ethanol (EtOH) was used as the model substance. An ethanolic suspension of ASA-seeds was fed into the tubular crystallizer system, where it was mixed with a slightly undersaturated ASA−EtOH solution that was kept at an elevated temperature in its storage vessel. Supersaturation was created via cooling and the seeds grew to form the product crystals. This work mainly focuses on the proof-of-concept and on the impact of the flow rates on the product crystals and the crystal size distribution (CSD). All other parameters including concentrations, temperatures, and loading of seeds were kept constant. Higher flow velocities generally resulted in reduced number and volume mean diameters, due to reduced tendency of agglomeration and decreased...

Crystallization of APIs in a Continuously Seeded Tubular Crystallizer

Particle shape and size have an influence on the solubility of an API-particle and hence on the bioavailability of the substance. [...]

A Study on Nucleation for Protein Crystallization in Mixed Vessels

This study investigated mechanisms of secondary nucleation for the crystallization of the protein hen egg white lysozyme. A parametric study of the secondary nucleation of lysozyme in a stirred tank crystallizer was performed, testing the influence of stirrer speed, the size and volume of added seed crystals, solution temperature, supersaturation, and sodium chloride concentration on measured nucleation rates. The measured rates were highly variable, which made assessment of the influence of experimental parameters difficult. Only stirrer speed exhibited significant influence over experimental variability (10-fold increase in nucleation rates with a 50% increase in stirring speed). These results were interpreted by comparison with parameter influence that is commonly observed with secondary nucleation of nonproteins. A novel tubular crystallizer was used to assess the influence on secondary nucleation of fluid shear forces acting on lysozyme crystals. It was observed that fluid shear forces acting on mounted lysozyme crystals do not notably influence secondary nucleation. Overall, the results suggest that attrition is an important source of secondary nuclei in lysozyme crystallization and that secondary nucleation caused solely by fluid shear forces is not.

Crystallization of alpha-lactose monohydrate in a drop-based microfluidic crystallizer

A microfluidic process for producing crystals of controlled size by confining the crystallization within drops is demonstrated. The process consists of a drop producing stage which segments the mother liquor into monodisperse drops followed by crystallization in a temperature controlled tubular crystallizer. The process is implemented to produce lactose crystals with significantly narrower crystal size distribution (CSD) as compared with crystals produced in a stirred bulk crystallizer. By controlling the drop size and initial supersaturation the mean crystal size can be controlled. The distribution of the number of crystals per drop and the CSD are measured as a function of supersaturation at temperatures between 20 and 40 ∘ C for 150 and 300 μ m drops. In the case where drops contain only one crystal, a very narrow CSD is obtained with a coefficient of variation of crystal size as low as 7%. The crystallization of lactose in a microfluidic tubular crystallizer is modeled by treating nucleation in drops as a Poisson process with a nucleation rate based on classical nucleation theory. Experimental results are in good agreement with predictions from a Poisson process model over the range of temperatures, supersaturations and drop sizes tested.