Industrial Crystallization Research Articles

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

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

Particle formation: Promise and challenges

Particle formation establishes fundamental particle attributes at the initiation of an overall particle production process. These attributes include particle size distribution, particle morphology, crystal form, and defect level. These fundamental properties, in turn, affect downstream particle processing and product performance properties, including rate of drying, filterability, flowability, caking tendency, rate of dissolution, and for biologically active products bioavailability. Almost always, the goal is that the properties established at formation will provide excellent performance all the way through downstream processing, product formulation, and ultimate use of the product. However, meeting this goal is often not possible for a variety of reasons. First, it may be difficult, prohibitively expensive, or even impossible to achieve the desired properties during formation. Second, there are often conflicting requirements at different stages of production and use. For example, large equant particles may be desired for good filterability and flowability through downstream process steps, but very small particles may be required in the ultimate product application. Examples from the chemical and pharmaceutical industries are presented: both cases successfully producing particles with properties meeting the needs throughout the chain of downstream processing and final application, as well as cases where it was impossible to meet those requirements. For the latter, the additional processing or adaptations required for the product to succeed are outlined. The focus here is on additive particle formation, e.g. crystallization and precipitation from solution, and not subtractive particle formation, e.g. milling. Legacy of Reg DaviesI was fortunate enough, as a budding industrial crystallization engineer, to be invited by Reg to join the newly formed PARticle Science And Technology PARSAT group at DuPont. Reg recognized and documented the importance of particle technology to a large, diverse chemical and materials company like DuPont and PARSAT was to become a leading industrial particle technology group. Reg's vision was to combine the fundamental particle unit operations into a unified, comprehensive technology organization that would address the formation and processing of particles from process concept through end use.This paper describes the first step in many particle processes: particle formation. Reg's legacy vis a vis particle formation is the recognition that particle formation is a critical, foundational process in an overall process train that ultimately produces useful particulate products and intermediates, but that particle formation is nonetheless but one part of the overall process. It may be able to produce particles exactly as needed for end use performance, or additional processes may be needed to tailor particles for their ultimate use. In addition, intermediate processes may be required to preserve useful properties developed during formation but subject to degradation in subsequent operations.Finally, Reg served as inspiration and mentor for everyone in his orbit, and we are far better scientists and engineers for it.

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.

Online monitoring of solubility of Li2CO3 in the NaCl–KCl–Na2SO4 system

ABSTRACT The solubility and thermodynamics of lithium carbonate (Li2CO3) play an important role in industrial crystal production. The solubility of Li2CO3 in H2O, NaCl, KCl, Na2SO4 and mixed NaCl–KCl–Na2SO4 solutions is measured, respectively, at temperatures ranging from 293.15 K to 368.15 K using the gravimetric method and immersion infra-red probe. The results suggested that the solubility of Li2CO3 exhibits a decreasing trend with increasing temperature. The impurity composition such as NaCl, Na2SO4 and NaCl–KCl–Na2SO4 can significantly affect the solubility of Li2CO3. It is higher than that in pure water, and the addition of KCl decreases its solubility in the temperature ranging from 293.15 K to 313.15 K. The Van’t Hoff and modified Apelblat models are further employed to correlate the solubility data of Li2CO3 in different systems. In addition, the thermodynamic data of Li2CO3 are calculated, which shows a non-spontaneous exothermal process and entropy reduction.

Oiling‐Out in Industrial Crystallization of Organic Small Molecules: Mechanisms, Characterization, Regulation, and Applications

AbstractOiling‐out is a common phenomenon in industrial crystallization processes that not only prolongs the total operating time but also leads to undesirable crystal morphology, making it challenging to control crystallization paths. This review provides a comprehensive overview of the oiling‐out phenomenon in organic small molecule crystallization. First, the formation mechanisms of oiling‐out are summarized from both thermodynamic and dynamic perspectives, providing the theoretical foundation for understanding the phenomenon. Then, the universal characterization methods for studying the oiling‐out phenomenon of organic small molecules are introduced in detail, covering both offline and online analytical tools. Moreover, the regulation strategy for oiling‐out, including solvents, impurities, seeding, temperature, and mixing methods are discussed. This paper also focuses on the application of oiling‐out in co‐assembly and crystal shape modulation. Finally, future opportunities and challenges are presented to address the current shortcomings and application bottlenecks in the study of organic small molecule oiling‐out phenomena. This review aims to provide valuable insights and guidance for researchers working on the crystallization of organic small molecules, particularly in the pharmaceutical industry, to better understand, control, and utilize the oiling‐out phenomenon.

Optimization design analysis on sodium chloride solution evaporative crystallization system driven by high-temperature heat pump

Industrial crystallization is an essential procedure for food, chemistry, and seawater desalination, whereas it accompanies with considerable energy consumption. Although the mechanical vapor recompression serves as an effective tool for heat recovery, it cannot adapt to the lower evaporation temperatures of crystallization process (45–90 °C). To address the above issues, this paper proposed a composited system consisting of high-temperature heat pump and draft tube baffle evaporative crystallizer, which can achieve higher energy efficiency. The coupling mathematical model is solved through the Newton iterative method. The optimized input parameter is determined based on thermal analysis, and the coefficient of performance can reach 5.85. Moreover, the system employs R1234ze as the working medium, achieving the minimum total heat exchange area of 19.27 m2. Simultaneously, this system with different evaporation capacities exhibit similar cycle rates, approximately 58.3. After the system is constructed, the energy-saving and economic evaluation is performed. The result indicates that the system demonstrates an annual carbon dioxide emission reduction about 550 tons, an annual cost reduction of 221,718 CNY, and a dynamic payback period of only 0.89 years, presenting significant economic advantages. By this study, it provides some theoretical guidance for practical engineering applications.

Monitoring of industrial crystallization processes through image sequence segmentation and characterization

Monitoring of industrial crystallization processes through image sequence segmentation and characterization

Solid-liquid equilibrium of in some pure solvents and binary solvents from 293.15 K to 318.15 K

The solubility of nicotinohydrazide in two binary solvents were determined by a static weight method from 293.15 to 318.15 K. It found that the solubility of nicotinohydrazide was influenced by temperature, solvent polarity, and solvent composition. Meanwhile, the TG-DSC analysis was used to obtain the weight change and thermal effect of nicotinohydrazide. The XRD analysis indicated that the crystal morphology of nicotinohydrazide was coincident in five different solvents. Furthermore, the models including modified Apelblat equation, Van’t Hoff equation, Jouyban-Acree model, and CNIBS/R-K model were used to fit the experimental data. It was concluded that the four models were reliable in fitting the experimental data. Then the dissolution apparent thermodynamic was obtained, which explained well the dissolution of nicotinohydrazide. This study could help optimize and control the industrial crystallization of nicotinohydrazide.

Unknown crystal-like phases formed in an imidazolium ionic liquid: A metadynamics simulation study.

Crystal polymorphism of complex liquids plays a crucial role in industrial crystallization, food technology, pharmaceuticals, and materials engineering. However, the experimental identification of unknown crystal structures can be challenging, particularly for high-viscosity complex liquids, such as ionic liquids (ILs). In this study, we performed a molecular dynamics simulation coupled with metadynamics to investigate an imidazolium IL (1-alkyl-3-methylimidazolium hexafluorophosphates). The simulation employed two distinct radial-distribution functions, represented by Gaussian window functions as collective variables, and revealed at least two crystal-like phases distinct from the known α and β crystal phases typically formed by this IL. Additionally, the simulation unveiled a unique phase characterized by the ordered spatial arrangement of anion aggregations. These crystal-like and unique phases emerged regardless of the potential used. The simulation methodology presented here is broadly applicable for exploring unknown phases in complex systems and contributes to the design of functional materials, such as porous ILs for gas molecule capture and separation.

Solubility measurement, thermodynamic modeling, and molecular dynamic simulation of glycylglycine in five binary solvents

Glycylglycine (Gly–Gly) is a crucial biochemical reagent widely used in cosmetics, food additives, and medicine. Using the equilibrium method, the solubility data of Gly–Gly in four binary solvents (ethanol/isopropanol/ethanediol/acetone + water) were investigated at temperatures over a range of 288.15–328.15 K under 101.3 kPa, as well as in the binary solvent of acetic acid + water from 293.15 to 333.15 K. The solubility data were correlated by Apelblat-Jouyban Acree, Van’t Hoff-Jouyban Acree, and CNIBS/Redlich-Kister models. Additionally, the radial distribution function was obtained through molecular dynamic simulation. It presented the unusual dissolution behavior of Gly–Gly in acetic acid and water mixture. The apparent thermodynamic properties, including standard enthalpy, Gibbs free energy, and entropy change of dissolution, were obtained accordingly. This article could help the industrial crystallization of Gly–Gly.

Automated Growth Rate Measurement of the Facet Surfaces of Single Crystals of the β-Form of l-Glutamic Acid Using Machine Learning Image Processing.

Precision measurement of the growth rate of individual single crystal facets (hkl) represents an important component in the design of industrial crystallization processes. Current approaches for crystal growth measurement using optical microscopy are labor intensive and prone to error. An automated process using state-of-the-art computer vision and machine learning to segment and measure the crystal images is presented. The accuracies and efficiencies of the new crystal sizing approach are evaluated against existing manual and semi-automatic methods, demonstrating equivalent accuracy but over a much shorter time, thereby enabling a more complete kinematic analysis of the overall crystallization process. This is applied to measure in situ the crystal growth rates and through this determining the associated kinetic mechanisms for the crystallization of β-form l-glutamic acid from the solution phase. Growth on the {101} capping faces is consistent with a Birth and Spread mechanism, in agreement with the literature, while the growth rate of the {021} prismatic faces, previously not available in the literature, is consistent with a Burton-Cabrera-Frank screw dislocation mechanism. At a typical supersaturation of σ = 0.78, the growth rate of the {101} capping faces (3.2 × 10-8 m s-1) is found to be 17 times that of the {021} prismatic faces (1.9 × 10-9 m s-1). Both capping and prismatic faces are found to have dead zones in their growth kinetic profiles, with the capping faces (σc = 0.23) being about half that of the prismatic faces (σc = 0.46). The importance of this overall approach as an integral component of the digital design of industrial crystallization processes is highlighted.

Data‐driven identification of crystallization kinetics

AbstractA novel data‐driven methodology is presented for developing mathematical models for crystallization processes. The data‐driven approach is based on the sparse identification of nonlinear dynamics (SINDy) method, which iterates between a partial least‐squares fit and a sparsity‐promoting step leading to the discovery of sparse interpretable models. The performance of the SINDy methodology is characterized for the identification of crystallization kinetics in a mixed tank operated in a continuous mode, the isothermal crystallization of lysozyme in a batch stirred tank and cooling crystallization of paracetamol. The SINDy method is robust against noise. Good agreement is obtained between the data‐driven model and the data obtained from crystallization experiments. The presented data‐driven approach can be attractive for modeling industrial crystallization processes where process analytical technology tools are available for the measurement of process variables but functional forms of kinetic expressions are unknown.

The elementary reactions for incorporation into crystals

The growth rates of crystals are largely dictated by the chemical reaction between solute and kinks, in which a solute molecule severs its bonds with the solvent and establishes new bonds with the kink. Details on this sequence of bond breaking and rebuilding remain poorly understood. To elucidate the reaction at the kinks we employ four solvents with distinct functionalities as reporters on the microscopic structures and their dynamics along the pathway into a kink. We combine time-resolved in situ atomic force microscopy and x-ray and optical methods with molecular dynamics simulations. We demonstrate that in all four solvents the solute, etioporphyrin I, molecules reach the steps directly from the solution; this finding identifies the measured rate constant for step growth as the rate constant of the reaction between a solute molecule and a kink. We show that the binding of a solute molecule to a kink divides into two elementary reactions. First, the incoming solute molecule sheds a fraction of its solvent shell and attaches to molecules from the kink by bonds distinct from those in its fully incorporated state. In the second step, the solute breaks these initial bonds and relocates to the kink. The strength of the preliminary bonds with the kink determines the free energy barrier for incorporation into a kink. The presence of an intermediate state, whose stability is controlled by solvents and additives, may illuminate how minor solution components guide the construction of elaborate crystal architectures in nature and the search for solution compositions that suppress undesirable or accelerate favored crystallization in industry.

Unraveling the concomitant polymorphism phenomenon in crystallization process: A case study on risperidone in ethyl acetate

Concomitant polymorphism is a widespread occurrence in industrial crystallization processes. A thorough understanding of this phenomenon is essential to prevent the emergence of undesirable polymorphs and ensure the production of high-quality products. In this study, the induction time method was employed to investigate the concomitant polymorphism phenomenon of risperidone in ethyl acetate. The impact of crystallization temperature and stirring rate on the concomitant polymorphism region was explored. Additionally, an analysis of the nucleation tendencies of risperidone form I and form II was conducted from both thermodynamic and kinetic perspectives. Based on the induction time theory, the nucleation parameters of form I and form II were calculated. Through an examination of the change in these nucleation parameters with supersaturation, a comprehensive explanation was provided for the reasons behind the occurrence of concomitant polymorphism and the nucleation behavior of form I and form II under varying degrees of supersaturation. Moreover, the concomitant polymorphism phenomenon during the slow-cooling crystallization process was investigated, and the relationship between operational conditions and the concomitant polymorphism region was discussed.

The Effect of Solvents on the Crystal Morphology of Isosorbide Mononitrate and Its Molecular Mechanisms.

In this work, the modified attachment energy model was used to predict the crystal morphology of isosorbide mononitrate (ISMN) in the dichloromethane (CH2Cl2) solvent system and dichloromethane-n-hexane (CH2Cl2-C6H14) mixed solvent system. The solvent effect can significantly affect the crystal morphology, which can profoundly impact both the drug's physicochemical properties and the subsequent technological treatment process. In addition, the interactions between solvent molecules and crystal faces were investigated using molecular dynamics simulation, and radial distribution function (RDF) analysis was performed to determine the types of interactions. The structural parameter S was introduced to characterize the roughness of each crystal surface; the change in the CH2Cl2 diffusion coefficient before and after the addition of C6H14 was analyzed using mean square displacement (MSD). The calculation results of the modified attachment energy from the two solvent systems revealed that C6H14 could accelerate crystal growth, while the crystal morphology was not greatly affected, which is of some significance as a guide for the industrial crystallization process.

Recent Advances in Lipid Crystallization in the Food Industry.

This review discusses fundamental concepts of fat crystallization and how various processing conditions such as crystallization temperature, cooling rate, and shear or agitation affect this process. Traditional methods used to process fats, such as the use of scraped surface heat exchangers, fractionation, and interesterification, are described. Parameters that affect fat crystallization in these systems, such as shear, crystallization temperature, type of fat, and type of process, are discussed. In addition, the use of minor components to induce or delay fat crystallization based on their chemical composition is presented. The use of novel technologies, such as high-intensity ultrasound, oleogelation, and high-pressure crystallization is also reviewed. In these cases, acoustic and high-pressure process parameters, the various types of oleogels, and the use of oleogelators of differing chemical compositions are discussed. The combination of all these techniques and future trends is also presented.

Size-Independent Nucleation and Growth Model of Potassium Sulfate from Supersaturated Solution Produced by Stirred Crystallization.

This paper explores the kinetics of the crystallization of potassium sulfate in a stirred bed crystallizer through experimental investigation. Employing classical nucleation theory, the homogeneous and heterogeneous nucleation mechanisms of potassium sulfate were investigated. The induction time and critical nucleation parameters, including the surface tension (γ), critical nucleation radius (r*), critical nucleation free energy (ΔG*), and critical nucleation molecule number (i*), were meticulously determined under varying temperatures and supersaturation ratios. The experimental findings revealed that as the temperature and supersaturation ratio increased, the induction time, critical nucleation free energy, critical nucleation radius, and critical molecule number decreased whereas the nucleation rate increased. The crystalline shape remains relatively unaltered with respect to temperature and supersaturation ratio, yet the particle size (D10, D50, D90) increases as the supersaturation and temperature increase. The variations in the measured nucleation parameters align well with the predictions of classical nucleation theory. Furthermore, the kinetic equations of crystal nucleation and the growth rate in a stirred crystallization system were fitted using population balance equations. The results demonstrate that the growth rate increases with increasing supersaturation and stirring rates. Additionally, the effects of the parameters in the nucleation rate equation suggested that the suspension density exerted the greatest influence, followed by the supersaturation ratio and stirring rate. This extensive research provides invaluable theoretical guidance for optimizing the crystallization process and designing industrial crystallizers.

A model-based supersaturation estimator (inferential or soft-sensor) for industrial sugar crystallization process

The degree of supersaturation of the mother liquor is a key factor in improving the monitoring and control of the final stage of industrial sugar crystallization. However, the difficulty of obtaining online supersaturation measurements is one of the challenges associated with monitoring and controlling sugar crystallization. There is no direct method or single instrument for measuring supersaturation. It can only be calculated or inferred from other measurements. In the literature, estimators of mother liquor supersaturation are reported, typically focused on the first stage of crystallization. The SeedMaster series transmitters are the sole industrial instruments that provide online supersaturation information by calculating it from external measurements. The purpose of this study is to design a first-principles model-based soft-sensor as a practical alternative to obtain real-time information about supersaturation in the last stage of sugar crystallization. The proposed estimator relies on two models: a supersaturation model and a second simplified model of the last stage of crystallization. The parameters of both models were estimated based on real industrial data. The estimation is performed in three steps: 1. An Unscented Kalman Filter estimates the states of the crystallization model and their variance. 2. The estimated supersaturation value is obtained by substituting the estimated states into the supersaturation model. 3. The estimator’s bias, and variance are calculated to establish error bounds. The main characteristics of the obtained estimator are: practical unbiasedness, nearly minimum variance and robustness. The performance and behavior of the supersaturation estimator are contrasted using real data from an industrial crystallization plant (Urbano Noris factory, Holguín, Cuba). Regardless of its initial conditions, the estimator converges to the three standard deviation error band in less than three minutes. The exact time may vary depending on how much the estimator’s initial conditions deviate from those of the process. After this time (Reach Time), the estimates remain within the calculated error limits of three standard deviations. The maximum absolute errors obtained were less than 0.019 units, corresponding to a maximum relative error of less than 1.5%. These values are favorable since they are well below critical values (0.125 units of absolute error). Moreover, the error bands are much smaller than the operating zone width (approximately 0.25 units), which is a necessary condition for any supersaturation estimator to be useful. Finally, it should be noted that the errors have been reduced compared to the values reported in previous research focused on the sugar industry using other techniques.

Research Progress in the Industrial Crystallization of Citrate—A Review

The citrate industry has a wide range of applications in food, pharmaceutical, and other fields. As a common class of food additives and functional supplements with tremendous development potential and strong core competitiveness, particles with good powder characteristics and functionalization are becoming one of the primary directions in the evolution of citrate into the high-end market. This article reviews the primary citrate crystallization techniques and examines the fundamental citrate crystallization mechanisms by describing citrate nucleation and growth during the industrial crystallization process. A variety of citrate hydrates are also summarized. The primary control conditions of the three essential product indices of purity, particle size, and grain shape are established. The need to take into account the density, fluidity, caking resistance, dissolution rate, suspension, bioavailability, and other indices of products is highlighted, along with applications for products that meet the purity and particle size requirements. While summarizing industrial citrate crystallization equipment, this paper also discusses the beneficial effect of continuous crystallization in achieving industrialization. Finally, the future development of citrate crystals is anticipated, and it is suggested that the combination of basic research and application research should be strengthened to explore the new application field of citrate crystals, and the automation and intelligence of the crystal preparation process should be realized as far as possible.

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.