Continuous Crystallization Research Articles

Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous crystallizers, their engineering advantages/disadvantages, the introduction of the solid form structuring to continuously oriented chemical production, and the usage of the online process analytical technology (PAT) methodologies in interacting functional systems. Furthermore, mechanistic multiscale modeling, whose understanding is of decisive importance for further control application development, was thoroughly discussed as well. The multiscale modeling section also includes the simulation of processes and the optimization of crystallizers. In the last section, model-based predictive control (MPC) is considered, which also covers the intensification approach methods in the field of crystal formation and the introduction of new, highly potential continuous systems, e.g. the coiled flow inverter (CFI) crystallizer, in industry and academia. In the mentioned main sections, individual theme-related articles are collected, discussed, and compared; therefore, a reader can get acquainted with pieces of research, their found results, which have been developed until now, and various emerging perspectives. With regard to the importance of crystallization in the pharmaceutical industry, a reader can already find literature on continuous crystallization. However, due to the growing tendency toward the synthesis of products with specific properties which cannot be achieved with conventional approaches, more attention has been paid in the present work to the establishment of continuous systems for the production of specific fine chemicals. In addition, continuous crystallization could also enable more efficient and “on-demand” production, modeling for optimization, MPC, and intensification approaches. A review of the literature classifying studies according to the choice of a continuous system and their description was omitted in this study, as such reviews are already available in the literature.

Data-Driven Control of Infinite Dimensional Systems: Application to a Continuous Crystallizer

Controlling infinite dimensional models remains a challenging task for many practitioners since they are not suitable for traditional control design techniques or will result in a high-order controller too complex for implementation. Therefore, the model or the controller need to be reduced to an acceptable dimension, which is time-consuming, requires some expertise and may introduce numerical error. This letter tackles the control of such a system, namely a continuous crystallizer, and compares two different data-driven strategies: the first one is a structured robust technique while the other one, called L-DDC, is based on the Loewner interpolatory framework.

Integrated Continuous Crystallization and Spray Drying of Insulin for Pulmonary Drug Delivery

Pulmonary delivery of insulin in the form of a dry powder is an attractive alternative in comparison to conventional subcutaneous delivery. Insulin crystals have potential advantages such as sustained release and higher stability in comparison to amorphous particles. However, the design of crystallization processes that can reliably produce insulin crystals in a suitable size range for pulmonary delivery is challenging. A continuous process involving the integration of a tubular crystallizer and a spray dryer is characterized for the production of inhalable insulin. Supersaturation is created via cooling and a pH shift at the inlet of the crystallizer, aiming at a high nucleation rate. The recovery of insulin in the crystallizer exceeds 90%, and the insulin particles appear crystalline under most of the tested conditions. Integration with a spray dryer produces a dry powder with favorable properties for pulmonary drug delivery. The emitted fraction of insulin from a capsule in a commercial inhaler is in the range of 84.3–93.1%, which shows good powder dispersibility. Furthermore, the fine particle fraction of the insulin crystals ranges from 22.0% to 36.4%, which indicates a good potential for pulmonary delivery.

Biotite composition as a tool for exploration: An example from Sn-W-Mo-bearing Mount Douglas Granite, New Brunswick, Canada

The Mount Douglas Granite (MDG) in southwestern New Brunswick (Canada) consists of three geochemically different intrusive phases, from earlier to late, changing from barren coarse-grained granite (Dmd1) to more fractionated medium- to fine-grained fertile granites (Dmd2 and Dmd3). This provides a unique geological setting to apply different techniques in order to constrain petrogenesis and metallogeny of the system. This study uses biotite chemistry to test its applicability as a mineral exploration tool to discriminate the least evolved non-mineralized Dmd1 from more highly evolved mineralized Dmd2 and Dmd3. Chemical composition of magmatic biotite was determined by EPMA and in situ laser ablation ICP-MS for different phases within the MDG. Applying the reconstruction of trace element contents accompanied with determined minerals-melt partition coefficients, we were able to further constrain the genetic relationship between the Dmd1, Dmd2, and Dmd3 from the composition of biotite. Biotite trace element contents follow a differentiation trend from the least to most evolved phases, indicative of a continuous magmatic evolutionary series. The fact that high degrees of fractional crystallization produced units Dmd2 and Dmd3 associated with endogranitic Sn, W (Mo), Bi, Zn and U mineralization is reflected in the composition of biotite from mineralized units. Remarkably, the biotite from the Dmd2 and Dmd3 is enriched in Zn (≤ 879 ppm), Pb (≤ 248 ppm), Sn (≤ 164 ppm), Ta (≤ 163 ppm), Ga (≤ 113 ppm), Cu (≤ 44 ppm), W (≤ 14 ppm), and U (≤ 6 ppm); it is also rich in incompatible elements, such as Li, Cs, Rb, Ta, and Nb, as well as substantial contents of F (≤ 2.87 wt%) and Cl (≤ 0.71 wt%). The geochemical compositions of biotite not only demonstrate a continuous fractional crystallization of magmas, but also can be used as a fertility indicator.

A Novel Robust Digital Design of a Network of Industrial Continuous Cooling Crystallizers of Dextrose Monohydrate: From Laboratory Experiments to Industrial Application

This paper presents the first-ever industrial application of the digital design of a complex, large-scale industrial continuous crystallization network. The aim of the work is to optimize a large-s...

Risk-Based Operation of a Continuous Mixed-Suspension-Mixed-Product-Removal Antisolvent Crystallization Process for Polymorphic Control

Innovations in the continuous crystallization field are required for the pharmaceutical industry to go through the paradigm shift from batch to continuous processing. To do so, different risks associated with the continuous crystallization have to be identified and discussed. In this work, a continuous antisolvent crystallization of the model compound indomethacin (IMC) from a ternary solvent system in a mixed-suspension-mixed-product-removal (MSMPR) to produce the desired polymorphic γ-form is evaluated, and potential risks for process failure are identified. One of the main risks identified with the continuous crystallization is gaining a balance between the inlet and outlet flows. Two novel and different level controls are proposed in this work to overcome this risk, an ultrasonic sensor and image analysis based on a video recording of the level. These two methods demonstrate improved process robustness upon implementation. Additionally, different process parameters were investigated and showed that the seed load has a significant effect on maintaining the desired polymorph and avoiding process failure. To the best of our knowledge, this is the first study on continuous crystallization of IMC for the polymorphic control of γ-IMC.

Generation of Calc-Alkaline Magmas during Crystallization at High Oxygen Fugacity: An Experimental and Petrologic Study of Tephras from Buldir Volcano, Western Aleutian Arc, Alaska, USA

Abstract Despite agreement that calc-alkaline volcanism occurs at subduction zones and is responsible for the genesis of continental landmasses, there is no consensus on the source of the Fe-depleted signature hallmark to calc-alkaline volcanism. In this study, we utilize mafic tephras collected from Buldir Volcano to address the genesis of strongly calc-alkaline volcanic rocks (those with a low Tholeiitic Index; ≤0·7) in a segment of the western Aleutian Arc to determine if the eruptions are plausibly part of a liquid line of descent, if they are mixtures of crustal melts and parental magmas, or if they are mixtures of melts of the mantle and the subducting slab. We conducted a series of H2O-saturated phase equilibrium experiments (1175–1000°C; 100 MPa) in a rapid-quench cold-seal (MHC) apparatus on the most primitive natural lava from Buldir (9·34 wt % MgO) at oxidizing conditions near the Re–ReO2 buffer. We confirmed that all experiments equilibrated 0·3 ± 0·23 log units above the Re–ReO2 buffer (ΔQFM ∼ +2·8) using X-ray Absorption Near Edge Structure (XANES) spectroscopy. Chromite is the liquidus phase, followed by olivine, then plagioclase, then clinopyroxene, and finally hornblende. Once clinopyroxene saturates, spinel composition shifts to magnetite. We compared our experimental results to the major element geochemistry and petrology of six tephras (51·9–54·8 wt % SiO2) from Buldir collected during the 2015 field season of the GeoPRISMS shared platform. Tephras contain olivine + plagioclase + clinopyroxene + spinel ± hornblende; plagioclase comprises most of the crystalline volume, followed by either olivine or hornblende. Spinel is ubiquitous; with Cr-rich spinel inclusions in olivine and hornblende, and magnetite in the groundmass. Variations in phenocryst assemblages and compositions between samples can be attributed to differences in pre-eruptive temperatures, where hotter samples are devoid of hornblende, and contain Fo-rich olivine and plagioclase with lower An-contents, owing to the position of the mineral-in curves at fluid-saturated conditions. Experimental glasses match the depletion in FeOT observed in the tephra whole rock compositions. The continuous depletion in FeOT is attributable to saturation of spinel as a liquidus phase (initially as chromite) and continuous crystallization through the experimental series (changing to magnetite at colder temperatures). In contrast to the natural samples, the experiments show enrichment in TiO2 with decreasing MgO, suggesting that differentiation did not occur at 100 MPa on Buldir. The TiO2 depletion in volcanic rocks from Buldir can be accounted for if hornblende crystallization occurs close to the liquidus of a parental magma; a condition that is met at higher pressures and hydrous conditions. The emerging picture for Buldir Island is that (1) oxidizing conditions are required to drive the observed depletions in FeOT via crystallization of spinel, and (2) elevated H2O contents and high pressures are required to saturate hornblende close to the liquidus to reproduce the entire suite of major elements. Our study provides a mechanism to generate the calc-alkaline trends observed at Buldir without requiring mixing of slab and mantle melts. We conclude that calc-alkaline volcanic rocks with extremely low Tholeiitic Indices (0·7), like those from Buldir, cannot be generated in absence of high oxygen fugacity, even at high pressure and/or elevated water pressures.

Mineral and whole-rock chemistry of the Chating porphyry Cu--Au deposit related intrusions in the Middle-Lower Yangtze River Belt, Eastern China: Implications for magma evolution and mineralization

The Chating deposit is the largest Cu--Au porphyry deposit in the Xuancheng district of the Middle-Lower Yangtze River Metallogenic Belt. It is associated with three intrusive phases, an amphibole diorite porphyry, an ore-bearing quartz diorite porphyry and a late diorite porphyry. The amphibole diorite porphyry and quartz diorite porphyry are characterized by large ion lithophile element enrichment, depleted high field strength elements, low Yb/Lu and Y/Yb ratios, low εHf(t) (−8.29 to −12.02), εNd(t) (−6.93 to −7.42), and high 87Sr/86Sr(i) (0.705723 to 0.705802), suggesting a source comprised of both subduction-modified mantle- and crust-derived materials. The zircon U--Pb ages of the amphibole diorite porphyry (138.8 ± 3.0 Ma) and quartz diorite porphyry (137.6 ± 3.0 Ma) are consistent with their cross-cutting relationships and within error of the average molybdenite Re--Os age of 136.0 ± 1.3 Ma, suggesting that the Chating porphyry mineralization belongs to the early metallogenic event in the Middle-Lower Yangtze River Metallogenic Belt. Both the amphibole diorite porphyry and quartz diorite porphyry contain high and low Al amphiboles. The high Al amphiboles from the two intrusions show similar ranges of calculated temperatures (842 to 908 °C), pressures (143 to 229 MPa; corresponding to depths of 5.2 to 8.6 km), melt H2O contents (2 to 4 wt%), ΔNNO values (0.12 to 0.99), and Mg# (57 to 65), suggesting coeval crystallization in the same magma chamber. The low Al amphiboles with higher Mg# (68 to 75) formed at lower temperatures (711 to 812 °C) and pressures (49 to 89.3 MPa; corresponding depth of 1.9 to 3.4 km). The core-rim textures and abrupt compositional changes of amphibole and plagioclase from the amphibole diorite porphyry suggest that mafic magma was repeatedly injected into the magma chamber. In contrast, the patchy amphiboles and oscillatory zoned plagioclases in the quartz diorite porphyry may result from continuous fractional crystallization of biotite, amphibole, and plagioclase which would have increased the metal content and fO2 of the residual magma, and resulted in the exsolution of ore-forming fluids.

Modeling of pharmaceutical filtration and continuous integrated crystallization-filtration processes

As continuous manufacturing is evolving in the pharmaceutical industry, continuous filtration has emerged as a bottleneck for connecting the crystallization of the active pharmaceutical ingredient with the formulation of the final drug product. This work aims the modeling of filtration to improve the understanding of the process, to support the development of continuous filtration methodologies, and to aid the integration of crystallization and filtration. The presented model utilizes the generalized form of Darcy’s law together with the calculation of the cake porosity and specific cake resistance based on the full crystal size distribution (CSD) of the slurry, without the need for experimental filtration data. The model is applied the first time for the dynamic simulation of an automated batch- type continuous filtration, which is also integrated with a population balance model of crystallization. The effect of the slurry properties (solid concentration, CSD) and the crystallization and filtration process parameters (crystallization temperature, flow rates, filter pressure difference, carousel rotation time) on the specific cake resistance, filtration time and residual moisture content are determined. It is concluded that continuous filtration facilitates the filtration of slurries with bad filterability through the modification of the rotation time and provides an opportunity to control the filtration when connected to a continuous crystallization. The simulation results show good agreement with real integrated continuous crystallization and filtration experiments of acetylsalicylic acid. The presented methodology could be used for both batch Nutsche filtration and continuous filtration to predict filterability and for optimization, risk analysis and control purposes.

Theoretical Study of the Scalability of a Sonicated Continuous Crystallizer for the Production of Aspirin

Ultrasound is frequently applied in crystallization to enhance nucleation and achieve crystal sizes within a narrow range. In this work, a mathematical model is developed, which couples the acousti...

Linear Analysis of a Continuous Crystallization Process for Enantiomer Separation

Continuous preferential crystallization is an innovative approach to the separation of chiral substances. The process considered in this work takes place in a gently agitated fluidized bed located in a tubular crystallizer. The feasibility of the process has been shown in previous work, but it also turned out that choosing suitable operation conditions is quite delicate. Hence, a model based process design is desirable. Existing models of the process are rather complicated and require long computational times. In this work, a simple linear dynamic model is suggested, which captures the main properties of the process. The model is distributed in space and in a property coordinate. Using the method of characteristics, a semi-analytical solution of the linear model is derived. As a challenge to the solution, there is a recycle loop in the process that causes a feedback and couples the boundary conditions at different boundaries of the computational domain. In order to deal with this, a numerical scheme is suggested. The semi-analytical solution provides a deeper insight into the process dynamics. A comparison with a more detailed mathematical model of the process and with experiments shows strengths and limitations of the linear model.

Determination and modelling of density, viscosity and solubility of (R)-(-)-phenylephrine hydrochloride in methanol + ethyl acetate at (278.15–323.15) K and 0.1 MPa

For further optimizing the pipeline design of continuous crystallizer, in this research work, density, viscosity and solid-liquid equilibria (SLE) solubility of (R)-(-)-phenylephrine hydrochloride (R-PEC) in binary solvent of “methanol (MtOH) + ethyl acetate (EtAC)” were investigated at temperature T = (278.15–323.15) K under pressure p = 0.1 MPa. The results showed that experimental density and viscosity values were negatively related with temperature while the SLE solubility data had positive correlation with the experimental temperature. Moreover, density and viscosity profiles increased with the incremental molarity of R-PEC, similarly, solubility of R-PEC raised along with the mass fraction of MtOH in binary solvents. Hansen solubility parameter (HSP) was applied to investigate the solubility behavior of R-PEC in MtOH+EtAC, four selected solubility parameters could give a logical explanation on R-PEC solubility. By using Mathcad software (Version: 15), the Vogel-Tammann-Fulcher (VTF) equation was employed for the description of density as well as viscosity values. Values of average relative deviation (ARD), multi-correlation coefficient (R2) and root-mean square deviation (RMSD) between experimental data and predicted data showed that VTF equation could provide satisfactory correlations with the experimental data. Besides, solubility values of R-PEHC in selected binary solvent were correlated with three activity coefficient models including Wilson, NRTL (Non-Random Two Liquids) and UNIQUAC (Universal Quasi–Chemical) model by using Mathcad software, the UNIQUAC model were more suitable for correlation with experimental solubility than others in terms of ARD and RMSD. Furthermore, based on the experimental solubility results and regression parameters of UNIQUAC model, thermodynamic properties of mixing and dissolution process were discussed in this work, the results showed that the both processes of R-PEHC in MtOH+EtAC were always spontaneous and entropy driven, the mixing process and part of dissolution process (R-PEHC in MtOH + EtAC at T ≤ 303.15 K) were exothermic. Experimental densities, viscosities, solubility as well as selected models would be very helpful for optimizing the pipeline design (including material selection, size calculation and so on) of continuous crystallizer.

Identifying the Polymorphic Outcome of Hypothetical Polymorphs in Batch and Continuous Crystallizers by Numerical Simulation

Polymorphism is one of the most important challenges in pharmaceutical manufacturing. However, the strategy to crystallize the desired polymorph has not been extensively investigated, especially in...

Scalable Reaction-spinning of Rigid-rod Upilex-S® Type Polyimide Fiber with an Ultrahigh Tg

In the family of polyimide (PI) materials, Upilex-S® film has been a shining star through the research PI materials due to its appealing merits. Unfortunately, the wholly rigid-rod backbone and easily formed skin-core micromorphology and microvoids of Upilex-S® type PI lead to the high difficulty in melt- and wet-spinning fabrication. Herein, we propose a facile and scalable method, reaction-spinning, to fabricate the Upilex-S® type PI fiber, in which the rapid solidification of spinning dope and partial imidization take place simultaneously. Thus, the stability and mechanical strength of as-spun fibers can be improved, and the microvoids in fibers can be greatly reduced in relative to the wet-spun fibers. The resultant Upilex-S® type PI fiber shows higher tensile strength and modulus than most commercial thermal-oxidative polymeric fibers with an ultrahigh glass transition temperature Tg of 478 °C. Moreover, the WAXS and SAXS results indicate that orthorhombic crystals are formed for Upilex-S® type PI fiber in the post hot-drawing process. Increasing the hot-drawing temperature results in a continuous crystallization and high orientation of PI chains in amorphous phase and perfects the existing lamellar structure, which make a great contribution to the improved mechanical property.

Effect of Process Conditions on Particle Size and Shape in Continuous Antisolvent Crystallisation of Lovastatin

Lovastatin crystals often exhibit an undesirable needle-like morphology. Several studies have shown how a needle-like morphology can be modified in antisolvent crystallisation with the use of additives, but there is much less experimental work demonstrating crystal shape modification without the use of additives. In this study, a series of unseeded continuous antisolvent crystallisation experiments were conducted with the process conditions of supersaturation, total flow rate, and ultrasound level being varied to determine their effects on crystal size and shape. This experimental work involved identifying acetone/water as the most suitable solvent/antisolvent system, assessing lovastatin nucleation behaviour by means of induction time measurements, and then designing and implementing the continuous antisolvent crystallisation experiments. It was found that in order to produce the smallest and least needle-like particles, the maximum total flow rate and supersaturation had to be combined with the application of ultrasound. These results should aid development of pharmaceutical manufacturing processes where the ability to control particle size and shape would allow for optimisation of crystal isolation and more efficient downstream processing.

Improving the reproducibility of size distribution of protein crystals produced in continuous slug flow crystallizer operated at short residence time

Continuous crystallization of proteins at short residence time and high supersaturation level is attractive in terms of the space-time yield and production efficiency. Nevertheless, it is rarely pursued due to its less-than-desirable crystal size distribution (CSD) characterized by the abundance of small crystals due to high nucleation rate. The small crystals were prone to random agglomeration, resulting in poor crystals’ residence time distribution, hence low CSD’s reproducibility. Herein we developed a segmented slug flow crystallizer (SFC) design operated at short residence time (<30 min) comprising a short nucleation segment and a growth segment operated at different temperature and fluid velocity. The SFC design improved the CSD’s reproducibility by limiting small crystals and large-sized agglomerates formations as evidenced by the small coefficient-of-variations between replicates (<10%). Lysozyme crystals having size of roughly 13–14 µm with well-preserved bioactivity were produced at yield and space-time yield of approximately 67% (w/w) and 93 g/L·h, respectively.

Overview of Secondary Nucleation: From Fundamentals to Application

Secondary nucleation can bring the crystallization process into a more easily controlled state, and it is playing an important role in controlling crystal size distribution, polymorphism, and chirality of the crystal products, no matter whether in a batch or continuous crystallizer. Therefore, in this review, we revisit the research of secondary nucleation in the past 30 years to understand the fundamentals and application of secondary nucleation. First, we summarize the sources of secondary nuclei, that is, how secondary nucleation occurs. Then, we discuss the secondary nucleation threshold from the perspective of the metastable zone widths which are associated with the nucleation mechanism. Furthermore, we discuss how to employ secondary nucleation to regulate the properties of crystalline products (particle size distribution, crystal polymorphism, chirality, etc.). More importantly, we also discuss how polymorphism and chirality can act as a probe to explore the origin of secondary nucleation. Finally, we give conclusions and outlooks, mainly on the molecular nucleation mechanism and crystal growth dead zone of the current topic of secondary nucleation.

Experimental analysis and compartmental modeling of the residence time distribution in DN6 and DN15 continuous oscillatory baffled crystallizer (COBC) systems

Compartment models (CMs) are widely used to capture typical hydrodynamic features of systems, generally having low computational cost. The main building blocks of the CMs are the continuous stirred tank reactor and plug flow reactor models. In this study, the hydrodynamics of two laboratory scale continuously oscillated baffled crystallizer systems were investigated: the commercially available DN15 and a scaled down version known as the DN6. CM structures were identified based on residence time distribution (RTD) measurements by direct fitting method for both the DN6 and DN15 systems, which showed superior performance compared to the traditional tank in series CM structure determination. To attain a more accurate CM calibration, the piston and pump flowrates obtained by the typical peristaltic pump configurations were thoroughly analyzed.The investigations revealed that the behavior of the systems varies based on the oscillation amplitudes and frequencies, so the number of compartments required for an adequate model was identified based on measurement with different amplitudes and frequencies. It is shown that adaptive tank in series CMs are needed to capture the measured RTD characteristics over a broad piston operation range. Not only the RTD curves but the calculated compartment numbers follow similar trends in DN6 and DN15. This enabled the generalization of the CM structure for the DN6 and DN15 systems.

Concurrent Antisolvent Electrospraying: A Novel Continuous Crystallization Technique

Pharmaceutical co-crystals (CCs) are multicomponent materials that enable the development of novel therapeutic products by enhancing the properties of active pharmaceutical ingredients, such as solubility, permeability and bioavailability. Currently, CCs are a commercial reality; nonetheless, their industrial production remains a challenge due to problems related to scale up, control and mode of preparation, which usually relies on batch production rather than continuous. This paper describes the implementation of a concurrent coaxial antisolvent electrospray (Co-E), as a new manufacturing technique, for the synthesis of CCs in a rapid, continuous and controlled manner. The features of Co-E were sized against other co-crystallization methods such as antisolvent crystallization, neat and liquid assisted grinding. Three pairs of amino acids were used as model compounds to demonstrate the features of this new system. The Co-E displayed exclusive product characteristics, including spherical particle morphology and enhanced CC formation. This technique exhibited robustness against process disturbances, displaying consistent product characteristics. Co-E represents a new alternative for the reliable production of CCs and other pharmaceutical products.

Residence Time Characteristics of the Novel Archimedean Screw Crystallizer/Reactor

AbstractThis work presents a novel design of a continuous crystallizer, the Archimedean screw crystallizer reactor (ASKR) with integrated Archimedean screw as conveying element. By the screw, the axial motion of the product solution is initiated, and an undesired axial mixing is restricted. This structure results in a narrow residence time distribution and, thus, promotes a defined product quality. In order to quantitatively assess the flow characteristics of the crystallizer and to highlight the influence of variable operating parameters such as rotational speed and volumetric flow, investigations of the residence time behavior with variation of the operating parameters are reported.