Solution Crystallization Processes Research Articles

Control of Liquid–Liquid Phase Separation, Nucleation, and Growth of L‐Menthol Single Crystals from Water–Ethanol Solvent Mixtures

AbstractL‐Menthol is a commonly used material in food production for flavor enhancement and fragrances, as well as in pharmaceuticals. However, during the solution crystallization process of L‐menthol, there is a major issue of oiling out or liquid–liquid phase separation (LLPS) in most organic solvents and their mixtures. The objective of the current work is to prevent the LLPS phenomenon and grow high‐quality single crystals of L‐menthol. A water–ethanol mixed solvent with nine different mixing ratios is used, ranging from 0.99W:0.01E to 0.91W:0.09E, through the conventional slow evaporation process. The findings indicate that the mixing composition of the solvent plays a significant role in the variation of solubility, refractive index, LLPS, nucleation, and crystallization. This is clearly demonstrated in the phase diagram. The occurrence of LLPS phenomenon, nucleation, growth behavior, and morphology of L‐menthol single crystals through optical microscopy is identified. Additionally, the internal structure and thermal stability of the grown polymorphs using PXRD, SCXRD, and DSC analyses are confirmed.

Nucleation control and separation of ethyl maltol polymorphs under different growth conditions through solution crystallization process in selected solvent environments

Nucleation control, separation and growth of Form-I, II & III polymorphs of ethyl maltol were achieved through solution crystallization processes. Morphology, unit cell structure and polymorphic phase transformations were revealed for the first time.

Development of a Calibration Model for Real-Time Solute Concentration Monitoring during Crystallization of Ceritinib Using Raman Spectroscopy and In-Line Process Microscopy

Raman spectroscopy is a useful tool for polymorphic form-monitoring during the crystallization process. However, its application to solute concentration estimation in two-phase systems like crystallization is rare, as the Raman signal is influenced by various changing factors in the crystallization process. The development of a robust calibration model that covers all variations is complex and represents a major challenge for the implementation of Raman spectroscopy for in-line monitoring and control of the solution crystallization process. This paper describes the development of a Raman-based calibration model for estimating the solute concentration of the active pharmaceutical ingredient ceritinib. Several different calibration approaches were tested, which included both temperature and spectra of clear solutions and slurries/suspensions. It was found that the concentration of the ceritinib solution could not be accurately predicted when suspended crystals were present. To overcome this challenge, the approach was enhanced by including additional variables related to crystal size and solid concentration obtained via in-line process microscopy (chord-length distribution percentiles D10, D50 and D90) and turbidity. Partial least squares regression (PLSR) and artificial neural network (ANN) models were developed and compared based on root mean square error (RMSE). ANN models estimated the solute concentration with high accuracy, with the prediction error not exceeding 1% of the nominal solute concentration.

Revealing the mechanism of polymer inhibition of 2,4-dichlorophenoxyacetic acid Polymorphs phase transition by experimental and molecular dynamics simulation

It is well-established that the occurrence of solution-mediated phase transformation makes the precise preparation of pure metastable forms of drugs by solution crystallization methods extremely challenging. This paper demonstrates that the polyvinylpyrrolidone (PVP) and N-vinyl-2-pyrrolidone and vinylacetate (PVPVA) polymers can effectively prevent crystal form transformation of the 2,4-dichlorophenoxyacetic acid (2,4-D) in the solution. We performed the induction time and crystal growth rate experiments at different supersaturation levels. The results showed that the polymer additives can significantly prolong the induction time and have an inhibition effect on crystal nucleation. The PVP and PVPVA almost completely inhibited the crystal growth in both the length and width directions. Molecular dynamics simulations reveal that the interaction energy between the polymer and crystal face determines the magnitude of the inhibition effect on the crystal growth of stable polymorph Form I. These results suggest that polymorph control during the solution crystallization process can be achieved by adding polymer additives.

Deep‐learning based in situ image monitoring crystal polymorph and size distribution: Modeling and validation

AbstractIn situ monitoring and closed‐loop control of the solution crystallization process are the modern trends for pharmaceutical development, in which the critical process parameters (CPPs) as well as the product critical quality attributes (CQAs) can be regulated and guaranteed during the manufacturing process. In this study, an in situ image monitoring methodology based on a state‐of‐the‐art deep‐learning model was developed to track the CQAs such as polymorph ratio, two‐dimensional crystal size, and crystal shape in a solvent‐mediated polymorphic transformation (SMPT) process. Coupled with the multidimensional process information, a 2D population balance model (PBM) was developed and validated using the results of the in situ image‐based CQAs analysis. The 2D‐PBM was solved using a high‐resolution finite volume method (HR‐FVM) which could provide a high dimensional particle‐size distribution. Through the validation between the process image analysis and the 2D‐PBM, the accuracy of image analysis was discussed, and the potential and challenges of in situ image analysis were proposed. This work aims to integrate the crystal polymorphism and two‐dimensional crystal size distribution (2D‐CSD) information in the SMPT process using intelligent microscopic image analysis and then to validate the results of neural network processing by solving the numerical solution of the multidimensional PBM.

Glutaric acid purification by coupled solution crystallization and melt crystallization

The mixed dibasic acids (DBA) is a by-product during adipic acid (ADA) production by oxidation of cyclohexanol or cyclohexanone, which contains large amount of glutaric acid (GA) with ADA and succinic acid (SA). In this work, we have explored the feasibility of the coupled solution crystallization and melt crystallization for the purification of GA. To obtain fundamental thermodynamic properties for the process design, the gravimetric method was used to measure the solubility of the three dibasic acids in water from 293.15 K to 345.15 K at atmospheric pressure. The results showed that GA was the most soluble component while all solubility increased with increasing temperature. Therefore, it is reasonable to concentrate GA in the liquid phase by cooling crystallization. Similarly, the ternary solid-liquid melt equilibrium phase diagram was constructed based on the experimental data of the three binary subsystems (GA-ADA, GA-SA, ADA-SA). It was found that the concentrated GA after solvent evaporation could be purified by melt crystallization efficiently. Thus a coupled solution crystallization and melt crystallization process was designed. With the operated operating parameters, the purity of GA could reach 99.06% by secondary melt crystallization. Overall, the coupled solution crystallization and melt crystallization method to separate DBA has proven to be effective.

Study on polycyclic macromolecular drug solid stability: A case exploration of methylcobalamin

As one of derivatives of Vitamin B12, methylcobalamin (MeCbl) is an indispensable “Life Element” and plays an essential role in maintaining human normal physiology function and clinical medicine application. Because of the intricate molecular structure, strong hygroscopicity and optical instability, maintaining its solid stability is a great challenge in pharmaceutical preparation. Based on the structure features of MeCbl hydrates, this study explored the drug solid stability by designing solid-solid phase transformation (SSPT) experiments. Three hydrate powders of MeCbl that had special structure with isolated site and channel water molecules were discovered. It was found that drying condition and surrounding humidity were controlling factors influencing the final solid form. The inter-conversion relations relevant to heating-induced and humidity-induced structure changes were established among the three hydrate powders. Powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, high performance liquid chromatography and dynamic vapor sorption were used to characterize the differences and related properties of stably prepared MeCbl hydrate powders. The particle size of product could be regulated and controlled by optimizing operating conditions of crystallization process, where ultrasound-assisted and seeding-introduced were applied as promising strategies to enhance solution crystallization process. This study opens up the possibility for the stable preparation and large-scale production of polycyclic macromolecular bulk drugs like methylcobalamin.

Highly Efficient Production of Desired Solid Forms of Drugs with Improved Mechanical Properties via an Organic Solvent-Free Sublimation Process

The pharmaceutical industry is required to constantly broaden its development areas and accelerate technical transformation because of the continued global rise in medicine consumption. However, the usage of organic solvents in pharmaceutical production results in up to 20 million tons annually of chemical waste, causing a serious environmental problem. Here, we proposed a solvent-free sustainable chemical technology, sublimation crystallization, for highly efficient screening and preparation of pharmaceutical solid forms (i.e., polymorphs), which eliminates the wastes associated with solvent use from the source. By adjusting the parameters of sublimation crystallization, we have obtained multiple polymorphs of several important drugs, including the antituberculosis drug pyrazinamide (PZA) and nonsteroidal anti-inflammatory drugs (NSAIDs), flufenamic acid (FFA) and mefenamic acid, particularly γ form of PZA and polymorphs IV and VII of FFA, which are difficult to produce from conventional solution crystallization methods. Mechanical property measurements from both powder and single crystal tests reveal that the γ form of PZA readily prepared by sublimation crystallization has the most excellent tabletability properties. In situ crystal growth observations indicate a direct vapor-to-crystal growth mechanism for the sublimation crystallization process consistent with conventional vapor phase deposition. Furthermore, the governing factors and growth mechanisms of sublimation and solution crystallization processes were analyzed and discussed, and it was found that the rate-limiting step of crystal growth is the surface-integration process in solution crystallization, whereas it becomes the surface diffusion process in sublimation crystallization. Overall, our developed sublimation crystallization provides a promising green technology for the development and production of (new) drugs, broadening the thinking behind the development of sustainable chemicals.

Direct Imaging of the Kinetic Crystallization Pathway: Simulation and Liquid-Phase Transmission Electron Microscopy Observations.

The crystallization of materials from a suspension determines the structure and function of the final product, and numerous pieces of evidence have pointed out that the classical crystallization pathway may not capture the whole picture of the crystallization pathways. However, visualizing the initial nucleation and further growth of a crystal at the nanoscale has been challenging due to the difficulties of imaging individual atoms or nanoparticles during the crystallization process in solution. Recent progress in nanoscale microscopy had tackled this problem by monitoring the dynamic structural evolution of crystallization in a liquid environment. In this review, we summarized several crystallization pathways captured by the liquid-phase transmission electron microscopy technique and compared the observations with computer simulation. Apart from the classical nucleation pathway, we highlight three nonclassical pathways that are both observed in experiments and computer simulations: formation of an amorphous cluster below the critical nucleus size, nucleation of the crystalline phase from an amorphous intermediate, and transition between multiple crystalline structures before achieving the final product. Among these pathways, we also highlight the similarities and differences between the experimental results of the crystallization of single nanocrystals from atoms and the assembly of a colloidal superlattice from a large number of colloidal nanoparticles. By comparing the experimental results with computer simulations, we point out the importance of theory and simulation in developing a mechanistic approach to facilitate the understanding of the crystallization pathway in experimental systems. We also discuss the challenges and future perspectives for investigating the crystallization pathways at the nanoscale with the development of in situ nanoscale imaging techniques and potential applications to the understanding of biomineralization and protein self-assembly.

A Workflow for Crystallization Process Design with Simultaneous Process Optimization and Solvent Selection based on the Perturbed‐Chain Statistical Associating Fluid Theory

AbstractSolvent selection is a critical part of crystallization process design and is inherently intertwined with optimization of the operating conditions. Computer‐aided tools can greatly assist in solving these two problems simultaneously. However, the integration of predictive thermodynamic models and process optimization tools is often complicated, which may hamper industry adoption. This work presents a workflow for simultaneous solvent selection and process optimization for solution crystallization processes based on the perturbed‐chain statistical associating fluid theory (PC‐SAFT) equation of state. The workflow is provided with readily executable computational tools and aims to strike a balance between the resources needed to obtain experimental input data and good prediction performance. The use of the workflow is demonstrated through a case study involving aspirin crystallization, which shows that the workflow can provide suitable solvents and operating conditions for the crystallization process based on either cooling, antisolvent, or evaporative crystallization.

Research on Mesoscale Nucleation and Growth Processes in Solution Crystallization: A Review

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.

Exploration of the Nucleation-Growth Effect of Cetyltrimethylammonium Bromide for High β-Poly(Vinylidene Fluoride) Crystallization

Poly(vinylidene fluoride) (PVDF, β-phase) exhibits excellent electrical properties because of its all-trans conformation in the crystalline phase, which has attracted much attention in electronic device applications. This paper describes our studies of the cetyltrimethylammonium bromide (CTAB)-induced PVDF crystallization in PVDF thin films via solution crystallization and melt crystallization by compression molding. In the solution crystallization process the relative crystal content of the polar crystals phase of PVDF reached 90% due to the solvent effect and low crystallization temperature. During the melt crystallization process the polar crystal nucleation effect of CTAB (powders) was pronounced. The strong "ion-dipole" interaction between the positive charges on the surface of CTAB and the -CF2 of PVDF promoted the formation of polar crystals. The incorporation of 1 wt% CTAB in PVDF led to the nucleation of polar crystallites up to 97.6%. Additionally, the tensile strength and elongation at break reached 39.8 MPa and 172.5%. The crystallinity of the PVDF increased with an increase in the content of CTAB. The electrostatic interaction between CTAB and the PVDF molecular chains induced and stabilized the all-trans conformation of the PVDF crystals, resulting in PVDF films with high polar phase content, which are expected to be applicable to industrially produced piezoelectric films.

Solubility Measurement and Thermodynamic Correlation of Diacetone Acrylamide in 15 Pure Solvents from 272.05 to 323.65 K

For the design, optimization, and control of the solution crystallization process of diacetone acrylamide (DAAM), solid–liquid equilibrium data in various solvents are critical. In this work, the solubility of DAAM in 15 pure solvents, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 1-hexanol, isobutanol, n-pentanol, isopentanol, 2-butanone, acetone, ethyl acetate, 2-pentanone, acetonitrile, methyl acetate, and ethyl formate, is analyzed by a gravimetric method under ambient pressure and temperatures ranging from 272.05 to 323.65 K. The solubility values in all of the solvents are positively correlated with temperature. The solubility of DAAM can be satisfactorily correlated by the Apelblat equation, λh equation, nonrandom two-liquid (NRTL) model, and Wilson model, and the calculated solubility agrees well with the measured results. The obtained maximum relative average deviation (RAD) and root-mean-square deviation (RMSD) are 2.44 × 10–2 (n-propanol, NRTL model) and 2.40 × 10–2 (methanol, λh equation), respectively. The most suitable model is the Apelblat equation.

Integrated membrane emulsification and solution cooling crystallization to obtain a narrow and predictable crystal size distribution

• A novel concept integrating membrane emulsification and solution crystallization. • Membrane emulsification enabled the confinement of solution crystallization. • Different droplet size distributions showed different yield and crystal quality. • A narrow crystal size distribution was achieved through monodisperse droplets. • The crystal number density was affected both by supersaturation and droplet size. Solution crystallization processes are challenged by the need to control crystal quality attributes such as the crystal size distribution (CSD). Emulsion crystallization is an attractive process intensification strategy to control crystal quality attributes through miniaturization. Droplets of an emulsion can act as tiny crystallizers by confining crystals so that crystal nucleation and growth are limited by the droplet size with available supersaturation. This work presents a novel process concept based on the integration of membrane emulsification and solution crystallization. A water-in-oil emulsion is created through membrane emulsification and glycine is crystallized inside droplets by cooling. The process is characterized in terms of the droplet size distribution, crystal number density, and CSD as a function of the emulsification method and supersaturation. Large and monodisperse droplets obtained from membrane emulsification can achieve a narrow and predictable CSD with higher productivity compared to a mechanical emulsification method. The crystal number density is strongly affected by the initial supersaturation when using membrane emulsification but not the final CSD. In contrast, the CSD changes with supersaturation when applying a mechanical emulsification method. The CSD obtained from a conventional bulk crystallization process is broader and lacks the control imposed by the uniform droplets from membrane emulsification.

Thermodynamic modelling for solubility of methyl 2-sulfamoylbenzoate in sixteen organic solvents from T (272.15–324.15 K) and dissolution properties

The solubility and solution thermodynamics of methyl 2-sulfamoylbenzoate (MeSAB) in different solvents are essential for the design, optimization and control of its solution crystallization process. In this study, the solubility of MeSAB in sixteen mono solvents including methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, 2-butanone, acetone, ethyl acetate, 2-pentanone, acetonitrile, methyl acetate, ethyl formate and cyclopentanone was obtained through a gravimetric method within the temperature range from 272.15 to 324.15 K under ambient pressure. The highest and lowest solubility of MeSAB was observed in ketones and alcohols, respectively. At fixed temperatures, the solubility data rank as cyclopentanone > acetone > 2-butanone > acetonitrile > 2-pentanone ≈ methyl acetate > ethyl acetate > ethyl formate > methanol > ethanol > n-propanol > isopropanol > n-butanol > n-pentanol > isopentanol ≈ isobutanol. The experimental solubility can be well correlated using the Apelblat equation, λh equation, non-random two-liquid (NRTL) model and the Wilson model. The obtained maximum relative average deviation (RAD) and root-mean-square deviation (RMSD) were 6.74 × 10−3 and 5.61 × 10−4 respectively. Besides, the dissolution enthalpy, entropy, and Gibbs free energy were calculated on the basis of thermodynamic relations and the Wilson model, which revealed that the dissolution of MeSAB was a spontaneous and endothermic process.

Deep learning-based oriented object detection for in situ image monitoring and analysis: A process analytical technology (PAT) application for taurine crystallization

Image analysis enables the estimation of critical process properties such as crystal size, morphology, and crystallization kinetics. Despite the rich image information, the lack of a robust image analysis technique has been an obstacle to promote its applications. In this work, an automated image analysis technique that combines the state-of-the-art oriented object detection model, S2A-Net, was developed for in situ estimation of the two-dimensional crystal size distribution (CSD) and the crystal counts. The model was trained to detect and classify both crystals and clusters to enable quantification of the extent of agglomeration and exclude unreliable detections. The effectiveness and robustness of extracting size and aspect ratio at various image complexities were verified by comparing with the focused beam reflective measurement (FBRM) and manually analyzed images in the experimental studies for taurine batch cooling crystallization with different seed loadings. An on-line calibration strategy for solute concentration measurement with Raman spectroscopy was introduced to eliminate the dedicated calibration experiments. The secondary nucleation and growth rate kinetics were evaluated from the on-line measurements and validated by numerical simulation. The proposed method provides a novel PAT strategy that enables accurate two-dimensional size measurement and shape characterization for online monitoring and control of a solution crystallization process.

Discontinuous solid solutions of anthracene–phenanthrene: Thermodynamics and crystallization kinetics

We explored such issues as the formation mechanism, structure and propriety of the solid solutions of anthracene (ANT)–phenanthrene (PHE). Solution crystallization and solid-state grinding were employed to prepare solid solutions under different conditions. The thermal behavior and PXRD scanning results revealed the formation of discontinuous solid solutions, whose melting points and crystal lattices varied linearly with mixed ratio. Combing with Materials Studio, the formation possibility of solid solutions were investigated by evaluating the change of the energy. The crystal morphology of the solid solutions have a positive correlation with the change of the major part. Finally, the solution crystallization process of solid solution were studied using the population balance model.

Application of PAT-Based Feedback Control Approaches in Pharmaceutical Crystallization

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.

Catalytically Active Copper Phosphate–Dextran Sulfate Microparticle Coatings for Bioanalyte Sensing

AbstractEngineering reactive and functional nanostructured surfaces is important for enhancing the sensitivity and versatility of biosensors and microreactors. For example, the assembly of hybrid inorganic–organic porous microparticles on surfaces may provide a catalytic microenvironment for a wide range of reactions. Herein, the synthesis of catalytically active porous dextran sulfate–copper phosphate hybrid microparticles by a facile and rapid crystallization process in aqueous solution is reported. The sulfated polysaccharide enables control over the size and hierarchical morphology of the hybrid microparticles, as well as their assembly into stable macroporous coatings. The engineered microparticle coatings display intrinsic nonenzymatic peroxidase‐like catalytic activity when employed as a platform for the detection of hydrogen peroxide. Pairing of the microparticle coating with glucose oxidase affords a hybrid platform that is employed as a glucose sensor for monitoring physiological concentrations of a given analyte via a hybrid enzymatic/nonenzymatic cascade reaction. This work presents a strategy for the assembly of hybrid porous microparticles into enzyme‐mimicking surfaces for copper‐based catalysis and biochemical analyte sensing.

Seeding Techniques and Optimization of Solution Crystallization Processes

Over the past few decades, seeding strategies for solution crystallization processes have been developed for various applications, and significant improvements in crystal quality and process robust...