Search

This study employed solution crystallization in food engineering to prepare a high-purity vitamin intermediate, optimize its crystal morphology and regulate its particle size distribution. Model analysis was performed to investigate the quantitative correlations between the process variables and target parameters, indicating the substantial effect of temperature on separation performance. Under optimal conditions, the product purity exceeded 99.5%, which meets the requirement of the subsequent synthesis process. A high crystallization temperature reduced the agglomeration phenomenon and increased particle liquidity. Herein, we also proposed a temperature cycling strategy and a gassing crystallization routine to optimize the particle size. The results illustrated that the synergistic control of temperature and gassing crystallization could substantially improve the separation process. Overall, based on a high separation efficiency, this study combined model analysis and process intensification pathways to explore the process parameters on product properties such as purity, crystal morphology, and particle size distribution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The four-quadrant regimes of attainable polymorph crystallization (FQR-APC) plot was recently developed through numerical simulations of crystallization kinetics of a dipolymorphic system. Retraction in the polymorphic composition of the most stable form in crystallized samples was unveiled a characteristic indication of concomitant polymorphism. Comparisons were made with a recently developed concept, the Ostwald ratio (OR), in light of characterization of polymorphic formation. It was shown that both schemes display a good agreement in describing polymorphic outcomes, despite their distinct theoretical origins.

The effect of various controlling factors on the polymorphic outcome of sodium dehydroacetate crystallization was investigated in this study. Cooling crystallization experiments of sodium dehydroacetate in water were conducted at different concentrations. The results revealed that the rate of supersaturation generation played a key role in the formation of the hydrates. At a high supersaturation generation rate, a new sodium dehydroacetate dihydrate needle form was obtained; on the contrary, a sodium dehydroacetate plate monohydrate was formed at a low supersaturation generation rate. Furthermore, the characterization and transformation behavior of these two hydrated forms were investigated with the combined use of microscopy, powder X-ray diffraction (PXRD), Raman spectroscopy, Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and dynamic vapor sorption (DVS). It was found that the new needle crystals were dihydrated and hollow, and they eventually transformed into sodium dehydroacetate monohydrate. In addition, the mechanism of formation of sodium dehydroacetate hydrates was discussed, and a process growth model of hollow crystals in cooling crystallization was proposed.

A novel one‐pot deracemization method using a bifunctional chiral agent (BCA) is proposed for the first time to convert a racemate to the desired enantiomer. Specifically, chiral α, (α‐diphenyl‐2‐pyrrolidinemethanol) formed enantiospecific cocrystals with racemic dihydromyricetin, and used its own alkaline catalysis to catalyze the racemization between the (2R,3R)‐enantiomer and (2S,3S)‐enantiomer in solution, achieving a one‐pot spontaneous deracemization. This strategy was also successfully extended to the deracemization of three other racemic compound drugs: (R,S)‐carprofen, (R,S)‐indoprofen, and (R,S)‐indobufen. The one‐pot deracemization method based on the BCA strategy provides a feasible approach to address the incompatibility between cocrystallization and racemization reactions that are commonly encountered in the cocrystallization‐induced deracemization process and opens a new window to develop essential enantiomerically pure pharmaceutical products with atom economy. [ABSTRACT FROM AUTHOR]

Crystallization is an important unit operation in industry, and proteins are widely studied owing to their biological activity and multiple functions. Protein crystals can not only facilitate the elucidation of protein structural information but also have important prospects in biopharmaceuticals. However, owing to their high molecular weight and complex structure, most proteins are difficult to crystallize or the crystallization processes are difficult to control effectively. This paper aims to provide an overview of recent reinforcement techniques for protein crystallization. Several important additive applications and principles in protein crystallization are comprehensively reviewed, including ionic liquids (ILs), deep eutectic solvents (DESs), and molecularly imprinted polymers (MIPs). The mechanism of external fields, including magnetic, electric, ultrasonic, shear, and light fields, enhancing protein crystallization are described and summarized. Finally, the challenges and future research prospects of protein crystallization are proposed. This work is expected to guide the rational design of the protein crystallization process. [ABSTRACT FROM AUTHOR]

Based on the importance of polymorphic regulation, the molecular mechanism of nucleation has been widely concerned. This review begins by introducing the development and limitations of nucleation theory for organic small molecule crystals, followed by a summary of the general research mentality adopted by current researchers. Moreover, the progress of the molecular mechanism of polymorphic nucleation and its application to the regulation of crystal forms are discussed. In addition, the development of scientific tools for the study of the molecular mechanism of polymorphic nucleation is also summarized, including experimental characterization and computational simulation, providing reference for relevant researchers. Finally, according to the main defects of current research and research ideas, research models and development directions of prospects and recommendations are put forward. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In recent studies, the existence of mesoscale precursors has been confirmed in crystallization. Different from the classical crystallization theory, which only considers the sequential attachment of basic monomers (atoms, ions, or molecules), the nonclassical crystallization process involving precursors such as prenucleation clusters, nanoparticles, and mesocrystals is more complicated. The mesoscale structure is important for the quantitative description and directional regulation of the solution crystallization process. It is necessary to explore the mechanism by the mesoscale scientific research methods on the base of traditional chemical engineering and process system engineering research methods. Therefore, the paper reviews several representative nonclassical nucleation and growth theories, mainly including two-step nucleation theory, prenucleation clusters theory, particle agglomeration theory, amorphous precursor growth theory, particle attachment growth theory and mesocrystal growth theory. Then, the mesoscale structure and its spatiotemporal dynamic behavior are discussed, and the application of the EMMS model in the nucleation and growth process is analyzed. Finally, we put forward our views on the prospect of the paradigms and theoretical innovations of using mesoscale methods in crystal nucleation and growth. [ABSTRACT FROM AUTHOR]

The pathological mineralization of calcium oxalate monohydrate (COM) crystals in vivo inevitably brings renal injury wherein natural macromolecules play an indispensable role in regulating the process. However, the role of macromolecules in crystal growth is more complicated and less well understood. In this study, we innovatively propose two proteins extracted from earthworms, lumbrokinase (LRK) and earthworm protein (EP), as potent modifiers of calcium oxalate (CaOx) crystals. Our research shows that LRK and EP inhibit COM formation and initiate the calcium oxalate dihydrate (COD) phase, which is more easily excreted out of the body. Through a series of combined macroscopic and microscopic experimental techniques, we reveal the site-specific adsorption of inhibitors on the COM (121¯) and (021) surface, resulting in a reduction in the aspect ratio. In situ atomic force microscopy (AFM) measurements show that LRK and EP specifically inhibit the advancement of COM surface steps through more than one inhibition mode. In general, the discovery of natural macromolecules from earthworms as potent inhibitors of COM crystal formation provides some insights into the appropriate formulation of inhibitors, which could prevent the formation of undesired stones in the kidney. Our findings shed light on nature's remarkable mineralization capabilities and outline fabrication strategies for advanced materials. [ABSTRACT FROM AUTHOR]

Spherical agglomeration technology can produce high‐performance spherical particles in a single crystallization unit, although it is still challenging to control the particle size and shape. To solve this issue, a two‐step bridging (TSB) mechanism containing a preconditioning period, size period, and shape period is proposed. The dynamic balance among the forces of adhesion, dispersion, and capillary action in the multi‐liquid phases plays a key role. This is fully considered to establish the TSB‐based thermodynamic size model and particle design framework by weighting the force action regions in multi‐liquid phases with dynamic composition. The spherical agglomerates of benzoic acid, celecoxib, and salicylic acid with narrow particle size distributions and tunable particle size ranges of 2000–5000, 800–3500, and 1500–4500 μm, respectively, were designed and prepared successfully, showing good correlation with the calculation, which is superior to the reported methods and indicates that the mechanism has certain universality and guiding significance. [ABSTRACT FROM AUTHOR]

Ostwald's rule of stages is one of the most important empirical rules to understand the crystallization behavior of crystalline materials, however, it may not be always satisfied. Herein, we demonstrate that crystallization outcomes of citric acid (CA) in aqueous solutions violate this rule. The anhydrous phase was found to nucleate at the whole temperature range (below or above the transition point of the system), whereas, the monohydrate form only nucleated at high supersaturation below the transition point. The unexpected appearance of the anhydrous phase is shown to have been influenced by solution ionization and its crystallization kinetic advantage over the monohydrate form. [ABSTRACT FROM AUTHOR]

This article introduces the application of a novel supersaturation control (SSC) approach for the crystallization of heat‐sensitive materials. Traditional SSC implements parabolic temperature profile with slow initial cooling that maximizes growth over nucleation, however, which may also promote heat degradation. The proposed semibatch SSC fixes the crystallization temperature to a sufficiently low value to minimize thermal degradation, and manipulates the flow rate of a higher temperature feed stream to control the supersaturation. The high temperature feed is produced in a continuous dissolver before feeding, thus the solution spends considerably shorter time at high temperature than in the traditional batch cooling crystallization. This work demonstrates the effectiveness of the semibatch operation for the cooling crystallization of heat‐sensitive substances by thorough simulation study as well as experimental investigations. The experimental validation confirmed the simulation results, and both analyses revealed the superiority of semibatch SSC for the crystallization of heat‐sensitive materials. [ABSTRACT FROM AUTHOR]

Crystal engineering is aimed at controlling the crystal forms and desired properties from the view of molecular engineering, which is important for the production of high-value-added products. dl-Methionine (dl-met) usually crystallizes in a concomitant mixture with the known metastable α-form and stable β-form from a pure aqueous solution. In this contribution, we first applied molecular dynamics (MD) simulations to study the effects of the tailor-made additive and found that dl-leucine (dl-leu) might enable us to stabilize the metastable form. To validate our idea, we performed experiments including cooling crystallization with isothermal and non-isothermal methods, nucleation induction time measurements, solvent-mediated phase transformation and crystal growth rate measurements. It was found that on increasing the concentration of dl-leu, the nucleation of the β-form and the transformation of the α-form were hindered. When the concentration of dl-leu reached above 0.02 mol L−1, hexagonal crystals other than foliaceous crystals could be obtained. Hence, the metastable α-form of dl-met with fine crystal habits and high temporal stability was prepared. [ABSTRACT FROM AUTHOR]

Abstract: Clopidogrel hydrogen sulfate is a famous antiplatelet agent for vascular disease. Forms I and II can be used as medicine. However, both forms exhibit low density and flowability. In addition, form I shows low polymorph stability. To solve these problems, spherical crystallization technologies were developed for the two forms. For form I, the mechanism was studied and turned out to be 2D nucleation and spherulitic crystal growth. In case of form II, the spherical crystallization process was based on agglomeration. The influence of temperature, acid, and crystal seed were investigated. The optimized spherical forms I and II showed much higher density and flowability as well as high polymorph stability. [ABSTRACT FROM AUTHOR]

Abstract: The solvate and the solvent‐free form of sulfadiazine (SD) were investigated. SD was found to exist in one solvent‐free form and the N‐methylpyrrolidone (NMP) solvate form. The NMP solvate was shown to be a channel‐type compound. The intrinsic properties of the solvents were used to evaluate the effects of solubility on the phase transformation of SD and the NMP solvate. The SD phase could transform to the NMP solvate by NMP‐mediated phase transformation, which was governed by crystallization of the NMP solvate. The crystalline NMP solvate could transform to the solvent‐free solid state through solid‐solid transformation upon heating or water penetration‐mediated phase transformation. The rate of this water penetration‐mediated phase transformation of the NMP solvate to SD was unusually fast. It can be used to obtain SD aggregates of well‐defined shape and good powder properties. [ABSTRACT FROM AUTHOR]

Daidzein (DAID), known as a phytoestrogen, is an important bioactive flavonoid isolated from soybean and pueraria. However, its poor solubility and low dissolution rate limit its clinical application. With the aim of finding a form with fit-for-purpose physicochemical properties, a comprehensive solid-state screening experiment was performed. As a result, three polymorphs were discovered and the single crystal structure of stable form II was revealed for the first time. Form II was obtained in solvents with high β and π* values, while form III was produced under opposite conditions. To clarify this phenomenon, intermolecular interactions were investigated through single crystal structure analysis, solvent property analysis and computational methods. The results demonstrated that the compact arrangement of DAID and the solvents used played a critical role in solution crystallization. Moreover, the physicochemical properties of these three polymorphs were fully characterized, and the powder dissolution behavior was determined in pure water and pH 1.2 and pH 6.8 buffer solutions. The newly discovered form II exhibited better thermal stability, lower moisture sorption and faster dissolution rate compared with the other forms. [ABSTRACT FROM AUTHOR]

The slurry transformation of sodium dehydroacetate monohydrate with different compositions of water and methanol was investigated. The water content and temperature did not only affect the solubility but also the crystal form of the precipitated material. A new needle hydrate form of sodium dehydroacetate appeared on the surface of the anhydrate when the water content was between 2 % and the critical transformation values which varied with temperature. The results revealed that the needle hydrate was a new form of sodium dehydroacetate monohydrate. A possible explanation for these observations was found in the relationship between the change of water content, the interaction between solute and solvent, and the influence of supersaturation. [ABSTRACT FROM AUTHOR]

We report here a unique method for the preparation of aggregated crystals with well-defined shape and size using a solvent penetration-mediated phase transformation. An unusually fast phase transformation of sulfadiazine was observed. The aggregated sulfadiazine crystals are obtained through a water penetration mediated transformation of sulfadiazine N-methyl pyrrolidone solvate. The aggregated particles keep the same shape and size of the parent crystals. [ABSTRACT FROM AUTHOR]

The latest developments of industrial crystallization in China are reviewed. This includes the introduction of representative scientists and institutions promoting the progress of Chinese industrial crystallization. Additionally, primary application fields related to industrial crystallization are outlined to give an overview of the current research trends in China. National and international industrial crystallization meetings held in China are also presented. Finally, the expectations for the future research activities in the field of industrial crystallization in China are briefly described. [ABSTRACT FROM AUTHOR]

Atorvastatin calcium (AC) spherical crystals were prepared by spherical agglomeration. CH2Cl2 acting as bridging liquid was added together with the drug solution or after the antisolvent precipitation process. Polymorph transformation in antisolvent crystallization and agglomeration processes was observed by focused-beam reflectance measurement (FBRM). The results suggested the occurrence of an immediate agglomeration when CH2Cl2 was added together with the drug solution. Size-controllable AC spherical crystals with improved flowability and compressibility can be obtained by adjusting the amount of CH2Cl2 and the stirring speed. The improved compaction behavior of the AC particles can be applied for direct tableting. A higher stirring speed can reduce the amount of bridging liquid which is required for effective agglomeration. It was a prerequisite for fine particles to be wetted by the bridging liquid in the spherical agglomeration process. [ABSTRACT FROM AUTHOR]

Oiling‐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. [ABSTRACT FROM AUTHOR]

Crystallization is one of the important unit operations for the separation and purification of solid products in the chemical, pharmaceutical, and pesticide industries, especially for realizing high-end, high-value solid products. The precise control of the solution crystallization process determines the polymorph, crystal shape, size, and size distribution of the crystal product, which is of great significance to improve product quality and production efficiency. In order to develop the crystallization process in a scientific method that is based on process parameters and data, process analysis technology (PAT) has become an important enabling platform. In this paper, we review the development of PAT in the field of crystallization in recent years. Based on the current research status of drug crystallization process control, the monitoring methods and control strategies of feedback control in the crystallization process were systematically summarized. The focus is on the application of model-free feedback control strategies based on the solution and solid information collected by various online monitoring equipment in product engineering, including improving particle size distribution, achieving polymorphic control, and improving purity. In this paper, the challenges of feedback control strategy in the crystallization process are also discussed, and the development trend of the feedback control strategy has been prospected. [ABSTRACT FROM AUTHOR]

The reactive crystallization of lithium carbonate (Li2CO3) from lithium sulfate (Li2SO4) and sodium carbonate (Na2CO3) solutions is a key process in harvesting solid lithium, whether from ores, brines, or clays. However, the process kinetics and mechanism remain poorly understood and the modelling of the reactive crystallization of Li2CO3 is not available. Hence, this work aims to determine the kinetics and mechanisms of the nucleation and growth of Li2CO3 reactive crystallization by induction time measurements and to model and optimize the crystallization process using response surface methodology. Induction time measurements were carried out as functions of initial supersaturation and temperature using a laser method. It was found that the primary nucleation mechanism of Li2CO3 varies with solution supersaturations, in which, expectedly, the heterogenous nucleation mechanism dominates at low supersaturations while the homogeneous nucleation mode governs at high supersaturations. The transition point between heterogenous and homogenous nucleation was found to vary with temperatures. Growth modes of Li2CO3 crystals were investigated by relating induction time data with various growth mechanisms, revealing a two-dimensional nucleation-mediated growth mechanism. The modelling and optimization of a complex reactive crystallization were performed by response surface methodology (RSM), and the effects of various crystallization parameters on product and process performances were examined. Solution concentration was found to be the critical factor determining the yield of crystallization, while stirring speed was found to play a dominant role in the particle size of Li2CO3 crystals. Our findings may provide a better understanding of the reactive crystallization process of Li2CO3 and are critical in relation to the crystallization design and control of Li2CO3 production from lithium sulfate sources. [ABSTRACT FROM AUTHOR]

Melt crystallization is considered a sustainable method for chemical separation and purification. In comparison to static melt crystallization, suspension melt crystallization offers significant advantages in terms of continuous operation and scalability. Understanding the principles of subcooling and impurity inclusion is crucial for designing effective suspension melt crystallization processes. This review focuses on the advancements made in suspension melt crystallization techniques over the past two decades, specifically in process modeling, equipment development, and applications. The review places particular emphasis on kinetic modeling of crystallization and provides an overview of equipment advancements and process intensification strategies for suspension melt crystallization. Additionally, by comparing its applications in traditional chemical industries as well as water systems (such as food processing and water purification), this review discusses both the distinctions and connections between suspension melt crystallization technology with other separation and purification methods. Finally, future prospects for the development of suspension melt crystallization technology are presented. • The kinetic advantages of Suspension Melt Crystallization (SMC) are summarized. • Emphasis is placed on equipment integration for the development of SMC technology. • Process intensification is highlighted for the industrialization of SMC. • The coupling of SMC with various separation and refining technologies is discussed. [ABSTRACT FROM AUTHOR]

• The mechanism of the influence of dextran on trehalose crystal morphology was revealed through experiments and MD simulation. • The bulk trehalose crystals have excellent powder properties. • The Bulk trehalose products have better mixing uniformity and more stable starch protection. The residual dextran impurities in the upstream process significantly impact the crystallization of starch-based functional sugar and the related food properties. This study intends to reveal the mechanism of dextran's influence on trehalose crystallization, and build a relationship among the dextran in syrup and the physicochemical and functional properties of trehalose. Instead of incorporating into the crystal lattice, dextran changes the assembly rate of trehalose molecules on crystal surface. The different sensitivity and adsorption capacity of the crystal surface to the chain length of dextran determines the growth rate of crystal surfaces, resulting in different crystal morphology. The bulk trehalose crystals, which were obtained from syrups with short chain dextran, have excellent powder properties, including best flowability (35◦), highest crystal strength (2.7 N), lowest caking rate (62.22 %), and the most uniform mixing with other sweeteners (sucrose/xylitol) in food formulations, achieving more stable starch preservation. [ABSTRACT FROM AUTHOR]

• Edible sugar additives can alter the morphology of myo-inositol crystals. • d -glucose transforms myo-inositol from elongated lamellar to diamond-shaped lamellar. • Diamond-shaped products exhibit excellent sensory quality and solubility performance. • The products have better flowability, filtration and compression performance. Myo-inositol, referred to as vitamin B8, is an essential nutrient for maintaining human physiological functions. However, the morphology of myo-inositol products is predominantly powder or needle shaped, leading to poor food properties. In this work, three edible sugar additives, i.e. d -glucose, l -arabinose and d -fructose, are adopted in the crystallization of myo-inositol to improve its food properties. The results show that these additives change the morphology of myo-inositol crystals. d -glucose and l -arabinose reduced the aspect ratio of myo-inositol crystals, and d -glucose transformed elongated lamellar myo-inositol crystals into diamond-shaped lamellar crystals. The diamond-shaped lamellar myo-inositol products exhibited outstanding functional food properties. It offered a smoother texture and more pleasant mouthfeel when the products were added to infant formulas and nutraceuticals. When they were applied to functional beverages, the dissolution rate was increased by 35 %. This work provides a theoretical guidance for improving food properties through crystallization and possesses considerable potential for industrialization. [ABSTRACT FROM AUTHOR]

• The concentration calibration model is established to correlate the solubility. • Process intensification and control strategies are used to optimize the products. • Multi objectives optimization is achieved by the combination of techniques. This study explores the process intensification techniques and process control strategies on the product properties optimization. α-PABA, a long needle-like shape, can cause problems for the downstream processing. This study proposes ultrasound technique, supercooling control (SSC), and temperature cycling (TC) technologies to optimize the morphology and crystal size distribution of α-PABA. Firstly, the solubility and metastable zone of α-PABA in ethanol solvent are measured to determine the operational range. Next, the concentration calibration model is established to correlate the solubility with the ATR-FTIR intensity and temperature qualitatively. Furthermore, the process improvement techniques and control strategies are introduced to optimize the products. The ultrasound intensification contributes to produce the uniform crystal seeds. The SSC is benefit for the crystal growth, and can reduce the L/D ratio of the crystal product. While, TC is an efficient tool to eliminate the fine crystals. Moreover, the combination of ultrasound, SSC, and TC technology can show a significant improvement on the product particle aspects. The L/D ratio, crystal size, crystal morphology can show different degree of improvement under the combination techniques. At last, the outlook and perspectives on the process analytical technology are developed. [ABSTRACT FROM AUTHOR]

[Display omitted] • Struvite microspheres with outstanding morphological characteristics are fabricated. • Struvite microspheres have more excellent performances in multiple applications. • The dissolution rates of struvite microsphere both in water and soil decrease by 20%. • Mesoporous phosphate prepared by struvite microsphere has twice the loading capacity. Phosphorus (P) recovery from wastewater as struvite not only alleviates global P resource shortages but also prevents water eutrophication caused by wastewater discharge. This study presents a sodium dodecyl benzene sulfonate (SDBS)-assisted struvite crystallization method (SASC method) to recover P as the struvite crystalline microspheres with uniform particle size (27.51 ± 3.60 μm), high sphericity (roundness = 0.91 ± 0.04), and good dispersibility (no aggregation) under various operating conditions with different N/P/Mg molar ratios and magnesium sources. Mechanism of microsphere formation and the regulation of modifier type and process parameters (SDBS concentration, initial pH, and stirring rate) on microsphere formation are explored in detail to realize the controllable fabrication of microspheres. Compared with common struvite crystals, microspheres have more outstanding performance in multiple applications. Specifically, microspheres have improved powder properties including bulk density and fluidity, better slow-release fertilizer performance, that is, slower dissolution in water and soil, and the ability to prepare superior mesoporous phosphate materials with better macroscopic morphology and higher loading capacity. Thus, this study markedly improves the multiple application performance of struvite by designing and controlling the product morphology based on its simplicity and efficiency. These provide new insights into recovering P in the form of struvite with excellent quality, thereby enhancing the economic value of the recycled products of P recovery from wastewater. [ABSTRACT FROM AUTHOR]

• Layer melt crystallization is utilized to separate formic acid and water. • The product purity under optimal trajectory exceeds 99.7%. • Theoretical models are established to guide the crystallization optimization. • Correlations between sweating intensity and separation performance are revealed. The cost-effective separation of azeotropes poses a shared challenge. In this work, we utilized a green technique: layer melt crystallization (LMC), to separate the formic acid and water. Characterized by the lower energy consumption and high selectivity, LMC is welcome in high-purity production preparation. Firstly, we discussed the effects of temperature, cooling and heat rates, and time on the separation performance. We discovered that temperatures were important in the solute distribution and impurity migration. Then, the stirring technique is coupled to optimize the separation performance. Under the optimal trajectory, the product purity exceeds 99.7%. Next, to better understand the crystallization process, several theoretical models are established to clarify the intrinsic correlations of process variables and target parameters. Kinetic models are established to clarify the crystal layer growth, and sweating melt flow with the temperature difference-based driving force. Interfacial solute distribution factor and mass transfer coefficient are introduced to give the solute distribution rule and impurity migration mechanisms. At last, a dimensionless number is used to evaluate the sweating intensity, and we also correlated this coefficient with the separation performance of LMC qualitatively. In conclusion, LMC provides a viable approach for separating azeotropes, and the proposed theoretical models can offer valuable support for crystallization design. [ABSTRACT FROM AUTHOR]

The important intermediate thiothiamine for Vitamin B1 production is often challenged by issues related to mixed polymorphs and needle-shaped crystal morphology in industrial production. These challenges can be effectively addressed through crystal engineering strategies. In this study, the key factors affecting the crystal form were investigated in reactive crystallization. Subsequently, the reactive crystallization process was monitored online using in-situ ATR-FTIR and FBRM techniques. It was determined that crystallization process is the rate-limiting step throughout the reactive crystallization process. Various factors affecting the crystal morphology were identified. Through process control and optimization, a product was achieved with a filtration time reduced by over 60% and a moisture content reduction of >20%. Overall, this study provides valuable insights from a crystal engineering perspective to address the poor powder properties. [Display omitted] • Identified the thiothiamine crystal form I and II as enantiotropic polymorph. • The key factors affecting the crystal form were determined. • The high reaction temperature helps to optimize the crystal morphology. • The co-optimization of crystal morphology and crystal form was realized. [ABSTRACT FROM AUTHOR]

Process analytical technology (PAT) plays a crucial role in optimizing crystalline powder product qualities, improving process stability, and reducing experimental costs by enabling real-time monitoring and control of process variables during the crystallization process. In-situ process imaging and analysis have gained significant attention due to their capacity to provide abundant information through images, leading to remarkable advancements in image processing technology, particularly with the support of artificial intelligence. However, the performance suffers when processing high-density slurry images due to challenges such as defocusing, overlapping, background and crystal edges blurriness, and inconsistencies in crystal scales. To address these challenges and explore research strategies based on deep learning for segmenting and analyzing high slurry density images effectively, this study constructed a specific dataset that contains high-density slurry crystal images which is well-labeled, and introduced state-of-the-art neural networks including YOLOv8, U2-net, and Mask R-CNN combined with image and data enhancement strategies. Comparative analysis revealed that YOLOv8 outperformed Mask R-CNN and U2-net by capturing multi-dimensional information in high-density crystal slurry scenarios. Finally, based on the segmentation results of the practical taurine crystallization process using proposed strategy, 1D crystal size, aspect ratio along with 2D size distributions were extracted for further evaluation of crystallization kinetics and crystal properties accurately and quickly. [Display omitted] • In-situ crystal micrograph of high slurry density image database was conducted. • The state-of-the-art networks were introduced to high-density scenarios. • High-density images were segmented in higher accuracy. • Multi-dimensional information was extracted more accurately using proposed deep-learning strategy. [ABSTRACT FROM AUTHOR]

• Layer melt crystallization is used to purify the isomers. • Kinetic models are established to correlate the driving force and kinetic parameters. • Temperature and composition differences in the separation process are analyzed. • The optimized trajectory based on the models is given to guide crystallization. • Process intensification routes are introduced to improve separation efficiency. Layer melt crystallization (LMC) is deemed a green separation technique and is widely used in the purification of crude chemical products. This work optimizes the separation of LMC based on process design and model configurations. Firstly, we monitor the central temperature with the crystal layer growth, where the temperature change can be divided into two stages. The main heat exchange and crystal growth occur in stage 1. Then we establish two kinetics models based on the temperature and concentration difference, to describe the features of crystal layer growth. Both kinetic models can successfully correlate the driving force and kinetic parameters. Further, the temperature effect and composition of the feed mixture on the separation performance are analyzed. The proposed separation coefficients accurately figure out the underlying correlations of the technical variables and target products. The optimized operating trajectory based on the model analyses and experiments is given to guide the separation process. Finally, four process intensification strategies are proposed to improve separation efficiency, where the incorporation of the stirring operation into LMC is more suitable for industrial production. [ABSTRACT FROM AUTHOR]

Cefuroxime Sodium (CS) is a low-toxicity and highly effective antibiotic drug with a wide application market. Its polymorph form β has the advantage of thermal stability and resistance to degradation. However, poor powder properties cause filtration difficulties, severe electrostatic phenomena and difficulties in automated dispensing, which limit its application. In order to improve the powder properties and stability of CS from the source, we used a one-step crystallization method to prepare CS (form β) with high sphericity and uniform particle size. The spherulites of form β of CS (β spherulites) have excellent powder properties, with high flowability (32.8°), good sphericity (90.2%), low C.V. (45.6%), and adjustable particle size distribution. Thanks to improved powder properties, the β spherulites exhibits 40% higher thermal stability and maximum 41% faster dissolution rate in the compatible solutions, compared to commercially available products, which implies the β spherulites is more competitive in powder formulations. [Display omitted] • The spherulites of form β of CS are designed by one-step crystallization process. • Solvent systems are selected by solubility and product properties. • The formation and mechanism of polymorph form β are investigated. • The optimized product presents good powder properties and high stability. [ABSTRACT FROM AUTHOR]

[Display omitted] • The molecular mechanism of oiling-out phenomenon was proposed. • Solute dimers are emphasized to be the key factor in oiling-out. • A new prediction method was established for phase diagram of oiling-out. • The oiling-out curves and solvent systems of the five substances were predicted. • The purity of pyraclostrobin was significantly increased from 42.76% to 99.32%. Oiling-out is a unique liquid–liquid phase separation phenomenon in solution crystallization. The unknown microscopic mechanism of oiling-out makes it difficult to control and significantly reduces the separation efficiency. In this work, an adsorption–desorption mechanism of temperature-driven molecular clustering is proposed based on the configuration search and the transformation process monitoring of dimers. This mechanism indicates that the stable and sufficient solute dimers in the solvent is the key condition for inducing oiling-out, accompanied by the transformation among various dimer configurations. Based on this mechanism, a prediction method of oiling-out phase diagram has been established through configurational stability analysis and determination of the total energy-temperature curve. This prediction method has been successfully applied to five systems: pyraclostrobin, vanillin, ethyl vanillin, citric acid, and benzoic acid. Importantly, the purity of pyraclostrobin is increased from 42.76% to 99.32% with the assistance of the oiling-out phase diagram. These findings not only provide advanced insights into understanding and controlling oiling-out during crystallization, but also highlight the role that oiling-out plays in the molecular assembly process of crystal nucleation. [ABSTRACT FROM AUTHOR]

Caking of crystals leads to a great deal of negative impact on the quality of products leading to extra cost to restore the products to its original state before caking. It is therefore an undesired phenomenon that should be investigated and inhibited. This review considers particle issues (particle science and technology) in a crystallization view (crystallization science and engineering). 1. Characterization. Caking indices and the relevant characterization methods are classified. Their advantages and disadvantages are summarized. Particularly, potential novel characterization methods, e.g. image analysis technique and its application in analysis of caking ratio, are discussed. 2. Mechanisms. Caking process is organized into three stages: moisture sorption, then liquid bridge, and finally crystal bridge. The mechanisms are reconsidered with recent studies (e.g. mass transfer, adhesion effect of liquid bridge, kinetic of crystal caking) and crystallization science (e.g. nucleation and growth theory, polymorphism, and phase transition). 3. Prevention. Based on particle and crystal engineering, prevention of crystals caking is discussed through controlling ambient conditions (relative humidity, temperature, liquids screening, and pressure) and improving anticaking property of crystals (particles size, particles shape, impurity, and anticaking agent). A potential method of simulating crystal caking behavior based on discrete element method (DEM) and caking mechanisms is presented. With the aid of simulation, the enhanced design of particle and crystal engineering would be available, which could be a key to control these factors systematically. [ABSTRACT FROM AUTHOR]

Effects of polymeric additive and ultrasound on the morphology of ropivacaine crystals. [Display omitted] • The needle-like ropivacaine was modified as block-like crystals by adding little PVP in the crystallization system. • In ultrasound-assisted crystallization, the particles of ropivacaine precipitated at extended ultrasonic time exhibited plate-like crystals with shorter aspect ratio. • Combined using of polymeric additive and ultrasound led to rice-shaped crystals, which the average particle size was further decreased. • The mechanism for the morphological evolution of ropivacaine crystals assisted by PVP and ultrasound was proposed based on the experiments and molecular dynamics simulation. The objective of this research was to modify the crystal shape and size of poorly water-soluble drug ropivacaine, and to reveal the effects of polymeric additive and ultrasound on crystal nucleation and growth. Ropivacaine often grow as needle-like crystals extended along the a -axis and the shape was hardly controllable by altering solvent types and operating conditions for the crystallization process. We found that ropivacaine crystallized as block-like crystals when polyvinylpyrrolidone (PVP) was used. The control over crystal morphology by the additive was related to crystallization temperature, solute concentration, additive concentration, and molecular weight. SEM and AFM analyses were performed providing insights into crystal growth pattern and cavities on the surface induced by the polymeric additive. In ultrasound-assisted crystallization, the impacts of ultrasonic time, ultrasonic power, and additive concentration were investigated. The particles precipitated at extended ultrasonic time exhibited plate-like crystals with shorter aspect ratio. Combined use of polymeric additive and ultrasound led to rice-shaped crystals, which the average particle size was further decreased. The induction time measurement and single crystal growth experiments were carried out. The results suggested that PVP worked as strong nucleation and growth inhibitor. Molecular dynamics simulation was performed to explore the action mechanism of the polymer. The interaction energies between PVP and crystal faces were calculated, and mobility of the additive with different chain length in crystal-solution system was evaluated by mean square displacement. Based on the study, a possible mechanism for the morphological evolution of ropivacaine crystals assisted by PVP and ultrasound was proposed. [ABSTRACT FROM AUTHOR]

• Model-based design for anti-caking function of water-soluble crystals. • Development of the Caking-Size-Crystallization (CSC) model. • First model coupling between front-end crystallization and post-end caking process. • Model validation and optimal solution by case study of ammonium persulfate. • High efficiency and product quality with CSC model on comparison of model-free. Water-soluble crystals with anti-caking function have become high-end products, whereas they are prepared by trial and error due to the lack of quantitative correlation between particle size and caking tendency, as well as the absence of the models for global consideration between caking and crystallization. This work presents a coupled Caking-Size-Crystallization (CSC) model, which connects the front-end crystallization process and the post-end caking process to achieve the closed-loop design of the anti-caking function for the first time. The CSC model can directly generate the optimal cooling trajectory to crystallize the product free of caking. The introduction of the caking constant term, the mean particle size and the Mullin-Nyvlt's theory improve the design efficiency by an order of magnitude with the precision guaranteed. This model-based approach presents an opportunity to find optimal crystallization operating profiles with diverse crystal seed loading strategies that meet both product function and manufacturability demands. [ABSTRACT FROM AUTHOR]

Potassium chloride crystals are cubic, which often leads to caking and greatly limits their applications. This caking can be overcome by modifying the crystal shape toward sphericity. Spherical particles have a high anti-caking ability and flowability. In this work, spherical KCl particles were prepared using a simple cooling crystallization process designed to function without additives. Among the four main processes in the crystallization of spherical particles, i.e., nucleation, growth, agglomeration, and attrition, agglomeration is the greatest contributor to the formation of spherical KCl particles, which were prepared following the principle that the adhesion force must be larger than the dispersion force. The adhesion free energy between KCl particles and solvents (i.e., water, n -hexane, formamide, diazomethane, methanol, ethanol, ethyl acetate, ethylene glycol, and dimethyl sulfoxide) was calculated using the Lifshitz–van der Waals acid–base approach, and water was found to be the most appropriate solvent because of its attractive interaction with the crystals. According to the relationship between the adhesion force and dispersion forces, we found that the stirring rate should be lower than 1300 rpm. Additionally, the effects of stirring rate and cooling rate on the KCl products were investigated and optimized, and the optimal conditions were found to be 400–500 rpm and 10–15 min/ ° C, respectively. All of the spherical KCl products prepared under the optimal conditions show a better morphology, flowability, and anti-caking performance than the original crystals. [ABSTRACT FROM AUTHOR]

A method is presented for optimizing the cooling strategy and seed loading simultaneously. Focused beam reflectance measurement (FBRM) was used to determine the approximating optimal cooling profile. Using these results in conjunction with constant growth rate assumption, modified Mullin-Nyvlt trajectory could be calculated. This trajectory could suppress secondary nucleation and has the potential to control product’s polymorph distribution. Comparing with linear and two step cooling, modified Mullin-Nyvlt trajectory have a larger size distribution and a better morphology. Based on the calculating results, the optimized seed loading policy was also developed. This policy could be useful for guiding the batch crystallization process. [ABSTRACT FROM AUTHOR]

Nitroguanidine (NQ) is a commonly used explosive, which has been widely used for both civilian and military explosive applications. However, the weak flowability and mechanical performance limit its application. In this work, mechanical performance and thermodynamic stability of NQ crystals were improved by controlling crystal morphologies in the crystallization process. Typical NQ crystals with multiple morphologies and single crystal form were obtained in the presence of additives during the cooling crystallization. The morphology controlled NQ crystals showed higher density, unimodal crystal size distribution and enhanced flowability. The additives showed the inhibitory effect on the nucleation of NQ crystals by in-situ FBRM and PVM determination, and the mechanism was analyzed by means of morphological prediction and molecular simulation. Furthermore, the morphology controlled NQ crystals suggested higher thermodynamic stability according to the calculation of entropy, enthalpy, Gibbs free energy and apparent activation energy on the basis of DSC results. [ABSTRACT FROM AUTHOR]

Crystal engineering strategy was applied to develop new solid forms of lamotrigine. Two novel cocrystals of lamotrigine forming with 4,4′-bipyridine (2:1) and 2,2′-bipyridine cocrystal (1:1.5) were successfully obtained by neat grinding and liquid assisted grinding. The novel cocrystals were fully characterized and confirmed by X-ray diffraction, thermal and spectroscopic analysis. DXRxi Raman microscope was also used to identify the cocrystals. The factors such as solvent and the structure of coformers which influenced the cocrystal formation were discussed. Furthermore, the novel cocrystals were both obtained by slurry crystallization. Process analytical technologies including focused beam reflectance measurement and attenuated total reflectance Fourier Transform Infrared were applied to investigate the cocrystallization process and the mechanism. HPLC analysis showed that the dissolution rate and the solubility of the two novel cocrystals were both improved. [ABSTRACT FROM AUTHOR]

• Calcium citrate followed the second-category spherulitic growth mechanism. • A concentration-dependent spherulitic growth operating space was established. • Calcium citrate spherical products had better flowability and tabletability. • The micronized spherical products had great suspension stability. Calcium citrate, a high-end daily calcium supplement, whose irregular particle morphology leads to poor powder properties, limited food functions, and paste-like suspension problems. This study prepared the spherical calcium citrate by investigating four aspects of this reactive process: side reaction, crystallization, agglomeration, and fragmentation. Consequently, a concentration-dependent spherulitic growth operating space was established, in which reactive crystallization followed the second-category spherulitic growth mechanism depending on supersaturation. Besides, the temperature, stirring rate, and residence time were critical parameters for regulating the spherulite shape and size. These spherulites exhibited improved flowability and tabletability as calcium fortification ingredient, it also had a smoother and more pleasant texture. Furthermore, the micronized spherical powder showed high suspension stability as a calcium supplement during brewing. These spherical particles did not form paste-like suspension. Finally, the success of the scale-up experiments in semi-batch mode raised the possibility of industrialization of spherical calcium citrate. [ABSTRACT FROM AUTHOR]

The metastable crystal Form III of APZ was successfully produced using a continuous and controllable tubular cooling crystallization method with the assistance of ultrasound and air segmented slug flow process, while in batch crystallizers, the crystal form cannot be controlled due to uneven temperature and concentration distribution. [Display omitted] • Pure metastable Form III could be prepared consistently through tubular crystallization rather than batch crystallization. • Applying ultrasound and air segment solved the fouling problem in flow crystallization process. • The flow crystallization enabled a yield of 90.6% along with the desired polymorphic form. • The Fluent simulations revealed the uneven distribution of temperature and concentration in the batch crystallizer. 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. [ABSTRACT FROM AUTHOR]

• The effect of impurity sugars on the thermodynamics and kinetics of d -TAG crystallization has been studied. • Impurity sugars reduce the rate of d -TAG primary nucleation and crystal growth, but accelerate secondary nucleation rate. • The mechanism of the effect of impurity sugars on the nucleation and growth of d -TAG crystals was revealed by experiments and MD simulations. Impurity sugars produced in upstream process of functional sugars are significantly impacting the product quality. In this work, the effect of congeners (d -maltose (d -MAL), d -fructose (d -FRU), d -glucose (d -GLU)) on primary and secondary nucleation of d -tagatose (d -TAG) crystals was investigated. The impurity sugars showed an inhibition on primary nucleation of d -TAG crystals, while a promotion on the secondary nucleation of d -TAG. Interestingly, the impact of impurity sugars on d -TAG crystal growth was similar to that on primary nucleation. The diffusion ability, hydrogen bonding forming ability, interaction energy of d -TAG crystal surfaces and impurity sugars were evaluated by molecular dynamics (MD) simulations to reveal the nucleation and growth behavior. Based on the above findings, we designed the d -TAG crystallization experiments, and obtained d -TAG crystals with uniform particle size distribution and regular morphology. This study helps to understand the influence of impurity sugars on crystallization, guiding the industrial manufacturing of functional sugars. [ABSTRACT FROM AUTHOR]

[Display omitted] • Probability distribution method was used to study nucleation under ultrasound. • Ultrasound accelerates nucleation in all solvents, especially at low supersaturation. • The degree of enhancement on nucleation varies with the diffusion ability of solute. • Ultrasound does not change the order of nucleation difficulty in the three solvents. • The stronger the solvation of solvent on solute, the more difficult the nucleation. The nucleation rate significantly affects the separation and purification efficiency of crystallization. The proper choice of solvent combined with the intensification of ultrasound can further accelerate the nucleation. However, the difference in the ability of ultrasound to promote nucleation in different solvents needs to be considered. Here, the comparative study of crystal nucleation in various solvent environments under ultrasonic and non-ultrasonic conditions was explored. The probability distribution method was employed to better describe the randomness of nucleation events. Over 1500 nucleation induction time experiments of 3,5-dimethoxybenzoic acid in three solvents (ethanol, acetonitrile, acetone) were performed. The results showed that the enhancement on nucleation rate by ultrasound in different solvents ranged from 1% to 116%, which had obvious differences in different solvents. It is revealed that the enhancement degree is mainly affected by solute diffusion and solvation effect. On the one hand, mean square displacement (MSD) analysis of solute molecule demonstrates that, the weaker the diffusion ability of solute in a certain solvent, the more significant the enhancement effect of ultrasound on the nucleation in such solvent system. On the other hand, molecular dynamics (MD) simulation, density functional theory (DFT) calculation and spectroscopy method indicate that the solvation effect is the main factor determining the order of nucleation rate in the three solvents. The stronger the solvation of solvent on the solute, the more difficult the nucleation. So that in our system, the introduction of ultrasound enhances nucleation in each solvent but does not change the order of nucleation rate in the three solvents. [ABSTRACT FROM AUTHOR]

The cooling crystallization-spherical agglomeration (CCSA) technology proposed in this work overcomes the disadvantages of complex process and biohazardous solvents, which has broad application prospects in green and efficient granulation. CCSA selects oleic acid as a novel green and effective bridging liquid, and the results of droplet experiment and molecular simulation indicate that oleic acid presents the best wetting performance compared with the reported bridging liquids. Mechanistic studies demonstrate that oleic acid can induce spherical agglomeration during crystallization in a single solvent system, especially in water, reducing the dosage of organic solvent by about 90%, and fundamentally eliminating the toxicity of bridging liquid. The volume ratio of bridging liquid to solvent (RBS) and agitation are emphasized as the critical parameters tuning the particle size and sphericity. Further, the spherical agglomerates of benzoic acid, L-leucine and aspirin with controllable size and high sphericity were successfully prepared, which verifies the universality of CCSA. [Display omitted] • A green and efficient spherical crystallization technology (CCSA) was designed. • CCSA overcomes the disadvantages of complex process and biohazardous solvents. • A sharp decrease of about 90% of organic solvents, toxicity is eliminated. • The novel bridging liquid oleic acid was developed with wide application range. • Spherical agglomerates of benzoic acid, L-leucine and aspirin were prepared. [ABSTRACT FROM AUTHOR]

In this study, the liquid–liquid phase separation and crystallization of vanillin from 1-propanol/water solution were investigated. It was found that water could contribute to the improvement of vanillin solubility in 1-propanol/water solution, but the solubility of vanillin decreased with the increasing water/1-propanol ratios, when the water content was over 30 wt.%. High water fraction in 1-propanol/water solvents will result in the liquid–liquid phase separation in the crystallization process, and the liquid–liquid phase separation dominated the process before the nucleation of crystals during the crystallization of vanillin. A ternary phase diagram (vanillin/1-propanol/water) including the solubility curves and the liquid–liquid phase separation curves was measured and could, in certain cases, clearly illustrate the liquid–liquid phase separation and crystallization process of vanillin in 1-propanol/water solutions. As shown in the ternary phase diagram, liquid–liquid phase separation under high initial vanillin concentration results in low purity of vanillin crystals due to the inhibited crystallization process by liquid–liquid phase separation. Partial phase immiscibility was a function of temperature and the range of immiscibility decreased with increasing temperature. Moreover, nucleation and crystal growth of vanillin in the presence of liquid–liquid phase separation were investigated; process parameters such as the composition of solvent, cooling profiles and seeding were optimized to avoid liquid–liquid phase separation and thus increase the purity of crystallization products. [ABSTRACT FROM AUTHOR]