Crystallization Of L-glutamic Acid Research Articles

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

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

Data-Driven Operation Modeling and Optimal Design for Batch Cooling Crystallization with a Case Study on β-LGA

In this paper, a data-driven modeling and optimization method is proposed for batch operation of the cooling crystallization process based on the design of experiments (DoE) in the operation ranges of cooling rate and initial solution supersaturation. The proposed model reflecting a mapping relationship between the manipulated variables of operating conditions and the product crystal size distribution (CSD) is established by two classes of basis functions, one is the wavelet basis function for reshaping the CSD and the other is the polynomial basis function for weighting the chosen wavelet basis functions to reflect the nonlinear relationship between the manipulated variables and the size distribution of product crystals. Meanwhile, a fractional factorial design of DoE is presented to reduce the number of experiments for the above modeling, in comparison with the classical full factorial design. The optimal operating conditions are designed by introducing a comprehensive objective function that combines the information entropy of the product CSD and the ratio of desired product yield with respect to the target crystal size. A particle swarm optimization algorithm with guaranteed convergence is given to solve the nonconvex optimization problem based on the established CSD prediction model. Simulation studies and experiments on the batch seeded β-form L-glutamic acid (LGA) crystallization process are conducted to demonstrate the effectiveness and advantage of the proposed method.

Crystallization by selective evaporation using membrane pervaporation: Application to l-glutamic acid to control polymorphism

Crystallization is an important unit operation in process industries, driven by supersaturation, i.e. the solute concentration difference between solution and equilibrium. Hence, to finely control the product qualities, controlling mass and/or heat transfer is crucial. Membrane pervaporation, based on a selective evaporation technique, appears as a process able to limit phase transition and control polymorphism. In this work, a semi-continuous system is developed for the crystallization of l-glutamic acid, which has two polymorphic forms. Hydrophilic HybSi® membranes are chosen. The influence of different operating parameters on process performance in terms of solvent separation, solute crystallization and control of polymorphism is investigated. Results validate the proof of concept and highlight the preferential crystallization of a polymorphic form over the other. Hence, the α-form is usually favoured except when the β-form is seeded, or at high temperature. Temperature appears as the parameter influencing mostly the membrane selectivity and the polymorph generated. However, concentration polarization and fouling, due to the deposit of l-glutamic acid crystals on the membrane surface, are reported and decrease the process performance. Both phenomena are caused by a high local supersaturation close to the membrane surface in addition to a local cooling due to the water evaporation during pervaporation.

Influence of Taylor Vortex Flow on the Crystallization ofl-Glutamic Acid as an Organic Model Compound

The mechanism of polymorph selection is still not fully understood in crystallization. This study demonstrates the impact of Taylor vortex flow on the crystallization and polymorph selection of l-glutamic acid as an organic model compound. Our results show that amorphous intermediates preceded the formation of a crystalline phase. The morphology of these amorphous precursors─ranging from spherical, oval, and ellipsoidal to irregular shapes─was governed by the velocity of the Taylor vortex flow. We attribute this observation to a transient liquidlike state of the amorphous precursor; simulations indeed corroborated this assumption as the morphology of droplets of a liquidlike precursor varies with the velocity of fluid motion accordingly. The phase selectivity depended on the intensity of the Taylor vortex flow. We found that the metastable α-form crystallized at low Taylor numbers, whereas the thermodynamically stable β-form was obtained at high Taylor numbers, suggesting an impact of Taylor vortex flow on the amorphous-to-crystalline rearrangement of the intermediates. Moreover, a critical value of the Taylor number as Ta ∼ 3636 was determined, which triggered the fast formation of the β-polymorph. We assume that the high shear rate and mass transfer of Taylor vortex flow facilitate the phase transformation from the α- to the β-polymorph.

Effect of ammonium chloride addition on crystal growth, structural, optical and biological applications of L-glutamic acid crystals

Effect of ammonium chloride addition on crystal growth, structural, optical and biological applications of L-glutamic acid crystals

Polymorphism control of l-Glutamic acid in a single-stage and a two-stage MSMPR crystallizer by different seeding strategies

Control of polymorphism in continuous crystallization processes has been investigated. Using population balance modeling, we found that the relative growth and birth kinetics of different polymorphs play a major role on the steady-state polymorph outcome in a mixed-suspension mixed-product removal (MSMPR) crystallizer. In this communication, we present the conditions to harvest the desirable polymorph of l-glutamic acid (LGA) by numerical simulation and experimental observation in a two-stage MSMPR and a single MSMPR with intermittent seeding. Different polymorphic outcomes of l-glutamic acid can be achieved at different operating temperatures of the MSMPR crystallizer. The interplay of growth and nucleation kinetic makes the stable β-form hard to secure at low operating temperatures. The design of a two-stage MSMSPR crystallizer configuration with different working temperatures realizes the continuous seeding of the stable β form from the first MSMPR to the production crystallizer (second stage).Another approach to ensure the production of the desired polymorph is the use of intermittent seeding with the desirable polymorph to a single-stage MSMPR. The feasibility of both continuous seeding (in a two-stage MSMPR) and intermittent seeding (in a single stage MSMPR) strategies is demonstrated in this paper. Based on the l-glutamic acid crystallization kinetics, numerical simulation is used to figure out the best inlet concentration, working temperature, and intermittent seeding frequency for producing the desired yield and polymorph.

Crystallization of l-glutamic acid under microfluidic conditions and levitation

To gain control over polymorph selection is a pivotal issue in the pharmaceutical, food, and fine chemical industry. However, the mechanisms which affect polymorph selectivity are still not fully chartered. In the present study, we demonstrated the complex crystallization behavior of l-glutamic acid under microfluidic conditions. Amorphous intermediates occur in the early stages of the experiment, which undergo a series of aging steps – such as aggregation/coalescence, growth, or shrinking – before the stable β-polymorph forms. Experiments indicated that the attachment of amorphous particles partly feds crystal growth. This complex mechanism, which was observed under laminar flow conditions, might lead to the preferential formation of a flower-like shape of β-l-glutamic acid. We accompanied these experiments, which were characterized by laminar flow-conditions, with experiments under acoustic levitation in which crystal formation takes place under constant but gentle convection in an evaporating droplet. In these experiments, a similar phenomenon was also observed. However, when crystallization was conducted in a conventional stirred-tank, a mixture of α-form and β-form was formed, characterized by a prism, needle- and plate-like morphologies instead of the distinct flower-like in earlier experiments. This demonstrates that gentle flow conditions, such as a laminar flow in a microfluidic device, preferentially leads to a complex flower-like shape than conventional approaches in a stirred tank.

Development of spin-contrast-variation neutron powder diffractometry for extracting the structure factor of hydrogen atoms

A spin-contrast-variation neutron powder diffractometry technique that extracts the structure factor of hydrogen atoms, i.e. the contribution of hydrogen atoms to a crystal's structure factor, has been developed. Crystals of L-glutamic acid were dispersed in a D-polystyrene matrix containing 4-methacryloyloxy-2,2,6,6,-tetramethyl-1-piperidinyloxy to polarize their proton spins dynamically. The intensities of the diffraction peaks of the sample changed according to the proton polarization, and the structure factor of the hydrogen atoms was extracted from the proton-polarization-dependent intensities. This technique is expected to enable analyses of the structures of hydrogen-containing materials that are difficult to determine with conventional powder diffractometry.

Size measurement and prediction for L-glutamic acid crystal growth during stirred crystallization based on imaging analysis.

In this paper, a crystal image analysis method is presented to measure and predict crystal sizes, based on cooling crystallization of β-form L-glutamic acid (LGA) by using an in-situ non-invasive imaging system. The proposed method consists of image restoration, image segmentation, crystal size measurement, and size prediction. To cope with the effects of noise pollution, uneven illumination and movement blurring, the image processing method is conducted for segmenting crystal images captured from the stirring reactor. Thus, the crystal size distribution for crystal population is obtained by using a probability density function. In addition, a short-term prediction method is given for crystal sizes. An experimental study on the cooling crystallization process of β-form LGA is shown to demonstrate the effectiveness of the proposed method.

In-situ Detection of Micro Crystals During Cooling Crystallization Based on Deep Image Super-Resolution Reconstruction

In this paper, a new image analysis method based on an in-situ microscopic imaging system is proposed for detecting micro crystals in cooling crystallization. Due to the limitation of measurement technology, it is a challenge to extract the evolutionary information of micro crystals, which are too small to be precisely analyzed by in-situ images, e.g. crystals at the initial crystallization stage. An improved deep-learning model is used to enhance the image resolution of micro crystals, thus more effectively obtaining the crystal shape and size information. In addition, a valid size calibration method by simulating particle motion is proposed. Consequently, image size measurement can be easily performed for crystals by using an axis-based algorithm. Experimental verifications on $\beta $ -form L-glutamic acid crystallization were performed to demonstrate the effectiveness of the proposed method for detecting micro crystal information.

Ultrasound-assisted intensified crystallization of L-glutamic acid: Crystal nucleation and polymorph transformation.

In this paper, the crystallization of L-glutamic acid with application of ultrasound was explored in detail, including the process of nucleation, polymorphic control and polymorphic transformation. The induction time and metastable zone widths (MSZWs) were measured with and without ultrasound during the nucleation process. The induction time and MSZWs were decreased by ultrasound and the induction time was further decreased by higher ultrasonic power. The calculated nucleation parameters (such as interfacial energy, critical nucleus size and critical Gibbs energy) showed an obvious decrease in the presence of ultrasound, indicating that the nucleation was enhanced with application of ultrasound. By adjusting the ultrasonic power in the quench cooling process, the difference in nucleation temperatures would determine the distribution of polymorphs. In further, the polymorphic transformation was investigated quantitatively, and to the best of our knowledge, it was the first time to study the transformation kinetics with ultrasound using Avrami-Erofeev model. In the transformation process, the crystallization mechanism of the stable form was modified by ultrasound. The ultrasound eliminated the nucleation element in the rate-limiting step and facilitated the crystal growth of stable form. Thus, the ultrasound has a profound influence on L-glutamic acid crystallization.

Crystal texture recognition system based on image analysis for the analysis of agglomerates

In the process of chemical production and biopharmaceutical, with the complex reaction, the products will overlap or adhere to each other. Effectively distinguishing the overlap and adhesion of crystals is of great significance for the statistics of different morphological characteristics such as the number and size of crystals. This paper proposes a crystal texture recognition system based on image analysis, which mainly includes image pre-processing, feature extraction and texture classification. Firstly, the crystal images are pre-processed to eliminate the influence of water droplets, particle shadows and uneven illumination. Secondly, the Improved-Basic Gray Level Aura matrix (I-BGLAM) is used to extract texture features of the crystals to determine the focus state of crystals. Finally, the texture features are classified by back propagation neural network (BPNN) to effectively distinguish agglomerates and pseudo-agglomerates. The case study and experimental results of cooling crystallization of l-glutamic acid show that the texture recognition system can effectively distinguish the adhesion and overlap of crystals, and effectively analyze the agglomerates, and has good experimental accuracy.

In Situ Measurement of 3D Crystal Size Distribution by Double-View Image Analysis with Case Study on l-Glutamic Acid Crystallization

An in situ measurement method is proposed for monitoring three-dimensional (3D) crystal size distribution (CSD) during a crystallization process, based on a binocular microvision system. The stereo particle shape is reconstructed from double-view images captured by two microscopic cameras fixed at different angles outside the crystallizer. To overcome the influence from solution turbulence and uneven illumination background involved with in situ imaging, a microscopic double-view image analysis method is established to identify the key corners of each particle shape in the captured images, including corner detection and corner matching. Two fast algorithms are therefore given for online detection of two typical crystal morphologies of prismatic and needle-like shapes, such as α- and β-forms of l-glutamic acid (LGA) crystals, respectively. On the basis of the identified key corners for different particle shapes, a 3D geometry model is established to approximately reconstruct the 3D shape for each imaged particle, such that 3D sizes of each particle could be quantitatively estimated, along with the particle volume. Experiments on the LGA cooling crystallization are performed to demonstrate the effectiveness of the proposed method.

Polymorph Selection and Process Intensification in a Continuous Crystallization–Milling Process: A Case Study on l-Glutamic Acid Crystallized from Water

The continuous crystallization of l-glutamic acid from water in a single-stage mixed-suspension mixed-product-removal crystallizer coupled to a milling loop is studied. We show that the stable β polymorph can be obtained in the presence of milling under operating conditions that would lead to the metastable α polymorph without milling. The effect is first shown through a series of experiments carried out at different residence times and feed concentrations in the absence or presence of milling. The experimental observations are rationalized through the use of a population balance equation model. We conclude that the observed effects result from fines generation and the corresponding increase in crystal surface area. Using the model, we obtain a map of polymorphic outcomes and process productivity in dependence on the operating conditions. It is shown that the combined crystallization–milling process exhibits higher productivity and an enlarged region of operating conditions where the stable polymorph of l...

Coupling of CFD and population balance modelling for a continuously seeded helical tubular crystallizer

A comprehensive model coupling the computational fluid dynamics with the population balance equation (CFD−PBE) for a continuous seeded mixed suspension mixed product removal (MSMPR)-helical tubular (HT) crystallizer assembly has been developed. The model accurately depicts the fluid dynamics, mass transfer, heat transfer and crystal size distribution (CSD) in the MSMPR-HT crystallizer. The crystallization system considered was to produce metastable α-form of L-glutamic acid. The PBE was discretized using a high-resolution central scheme and solved simultaneously with CFD equations in COMSOL Multiphysics® utilizing user-defined scalars. A good agreement was observed between the model and experimental data for the metastable α-form crystals of L-glutamic acid with uniform particles and a mean crystal size of 160 µm. The continuous crystallization under different stirrer speeds, saturated solution flow rates, inlet saturated solution concentrations and temperature was investigated. It was found the higher stirrer speeds, saturated solution flow rate and temperature lead to uniform distribution with smaller crystal size. Moreover, the mean crystal size becomes larger and the CSD wider when the saturated solution concentration increase.

Growth and characterization study of α and β polymorphs of l-glutamic acid single crystals in the presence of ammonium sulphate

In this work, l-glutamic acid polymorphs of β and α crystal were grown by the slow evaporation method by using additives of ammonium sulphate. The selective additive ammonium sulphate was added at different concentrations to study the l-glutamic acid polymorphs. It creates that at a level of 0.04 g/100 ml, the additive contributed to the crystallization of l-glutamic acid in α-form, and this additive exhibited an inhibitory action on the transition of α crystal to β crystals. The lower concentration of ammonium sulphate provides β polymorph whereas the higher concentration of ammonium sulphate provides α polymorph crystal. Structural confirmation of the grown polymorph was executed by powder X-ray diffraction study. UV–Vis-NIR spectral analysis the optical transparency of grown crystals. The powder second harmonic conversion efficiency of grown crystal was determined by using Kurtz and Perry powder technique and the efficiency compared to standard inorganic material potassium dihydrogen phosphate. The dielectric properties of dielectric constant and dielectric loss of grown crystal have been measured as a function of frequency and temperature. The photoconductivity study contributed its positive photo conducting nature. In vitro antimicrobial activity of grown crystals was analyzed against gram positive and negative bacteria’s carried out by disk diffusion process and created that the crystal proves superior inhibition against various bacteria’s strains.

Continuous crystallization of α-form L-glutamic acid in an MSMPR-Tubular crystallizer system

Continuous crystallization of active pharmaceutical ingredients is of prime significance. A continuous mixed suspension mixed product removal (MSMPR)-tubular crystallizer geometry is designed and optimized to produce the metastable α-form crystals of L-glutamic acid with uniform mean size of 130 µm. The MSMPR is used to produce well-tuned seed crystals that undergo further growth in a series of tubular crystallizers. The effects of the initial supersaturation, stirring speed, nucleation temperature and residence time were optimized in the MSMPR crystallizer to tune the supply of continuous seeds by using the principal component analysis and in-situ particle tracking measurement. The continuous seeds of the desired metastable polymorphic form with specific size ranging from 5.0 to 15.0 µm and number density ranging from 500 to 1500 counts, were transferred to a series of three coiled tubular crystallizers for further growth. In addition, the cooling strategy in the tubular crystallizers was utilized to further optimize the quality of the final crystal product. The crystal size distribution (CSD) in the MSMPR-tubular crystallizer system was compared with a single MSMPR with the same residence time and found to be superior. Finally, a potential scale up strategy of the MSMPR-tubular crystallizer system was proposed for further study.

In-situ particle segmentation approach based on average background modeling and graph-cut for the monitoring of l-glutamic acid crystallization

The crystal morphology often represents a critically important property for the reason that different morphological characteristics such as crystal shape and size distribution will directly affect crystal growth and the quality of final products. However, minor changes in reaction conditions can have a significant impact on crystal morphology. As a consequence, crystallization processes demand an on-line technique for real-time monitoring of crystal morphology. Image-based monitoring methods show a great potential for real-time monitoring, and performing particle segmentation accurately becomes a key issue in the particle image analysis. To avoid the influences of droplets and to eliminate the particle shadow of particle images obtained by invasive imaging system, an effective approach is proposed for particle segmentation based on combing the background difference method and the graph-cut based local threshold method. Through building the background model and performing subtraction between particle image and background model, droplets could be eliminated effectively. Then the local threshold method is performed further to eliminate the influences of particle shadow. Several particle images are used to demonstrate the efficiency and accuracy of the proposed method. In order to further evaluate the real-time performance of the proposed method, comparison experiments between the proposed method and other advanced or classic algorithms are presented. Experimental results show that the proposed method is efficient and has an impressive real-time performance.

Enhancement of electro-optic and structural properties of TGS single crystals on doping with l-glutamic acid

Single crystals of pure and l-glutamic acid (LG) doped Triglycine Sulfate (TGS) crystals were grown by slow evaporation solution technique at ambient conditions. Effect of doping on various properties of the grown crystals was investigated. Powder X-ray diffraction (PXRD) studies confirmed the monoclinic system of crystal structure with lattice parameter a = ~ 9.28 A, b = ~ 12.7 A, and c = ~ 5.73 A, and space group of P21. PXRD and Fourier-Transform Raman (FT-Raman) analysis confirmed that there is no new phase formation due to doping except a systematic variation in the intensity of the peaks in correlation with the morphology due to LG doping. The Raman bands obtained in the spectrum corresponds to NH3 vibrations, the stretching vibrations of COO−, carboxyl vibrations, and vibrational modes of SO42−. Ultraviolet–Visible Spectroscopy (UV-Vis-NIR) analysis was carried out to see the changes in the optical transparency of pure TGS crystals due to LG doping. Optical band gaps (5.24 eV for PRTGS, and 5.07 eV for LGTGS) were calculated and found to decrease due to doping. The photoluminescence excitation and emission were studied. The thermal behavior of the grown crystal was investigated by Thermogravimetric analysis/Differential thermal analysis. Second harmonic generation (SHG) efficiency measurement showed the enhancement in the nonlinear optical characteristics of the as-grown pure and doped TGS single crystals. In the present study, the researchers found the good and comparable SHG efficiency with KDP in TGS crystals by LG doping for the first time. The surface morphology of the grown TGS single crystals was analyzed by using Scanning Electron Microscope. The mechanical studies showed the Mayer’s index (n) greater than 1.6 and thus predicting a soft-material nature of the as-grown crystals. The values of fracture toughness (Kc), brittleness indices (Bi), and yield strength (σν) were estimated for the crystals. The dielectric constant and the dielectric loss decreased with an increase in the value of frequency. Hysteresis loop showed a negligible change in the doped TGS. The above studies reveal the effect of incorporation of LG into the lattice of TGS crystals.

Non-invasive 3D and 360\xb0 optical imaging of micro-particles

Scanning electron microscopy and X-ray microtomography are useful methods for high resolution shape imaging. Visible microscopy is also common, however, developing a low-cost and customizable system for surface and shape investigation of optically active particles is challenging. In this work, we demonstrate an assembly offering good light sensitivity, flexibility of illumination and contrasts from varying angles. The design was applied, together with recent programs for focus-stacking, to analyze crystals of taurine, L-glutamic acid, acetylsalicylic acid, and copper sulfate, along with digital 3D-360° modelling of phosphorescent [Ru(bpy)3]Cl2 and strontium aluminate particles. We further tested the approach for real time monitoring of size, shape and texture analysis of fat filled milk particles and acid whey powders. The findings show proof of concept for detailed feature imaging of particles directly from the process environment.