Crystallization Of L-glutamic Acid Research Articles

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.

Chiral separation ofdl-glutamic acid by ultrasonic field

In this communication, pure D- or L-glutamic acid crystals can be obtained from a racemic solution by controllable addition of chiral seed crystals and ultrasonic-assisted recrystallization. In contrast, only racemic compounds were yielded under identical conditions in bulk solutions in the absence of an ultrasonic field.

Comparative study on ATR-FTIR calibration models for monitoring solution concentration in cooling crystallization

In this paper calibration model building based on using an ATR-FTIR spectroscopy is investigated for in-situ measurement of the solution concentration during a cooling crystallization process. The cooling crystallization of L-glutamic Acid (LGA) as a case is studied here. It was found that using the metastable zone (MSZ) data for model calibration can guarantee the prediction accuracy for monitoring the operating window of cooling crystallization, compared to the usage of undersaturated zone (USZ) spectra for model building as traditionally practiced. Calibration experiments were made for LGA solution under different concentrations. Four candidate calibration models were established using different zone data for comparison, by using a multivariate partial least-squares (PLS) regression algorithm for the collected spectra together with the corresponding temperature values. Experiments under different process conditions including the changes of solution concentration and operating temperature were conducted. The results indicate that using the MSZ spectra for model calibration can give more accurate prediction of the solution concentration during the crystallization process, while maintaining accuracy in changing the operating temperature. The primary reason of prediction error was clarified as spectral nonlinearity for in-situ measurement between USZ and MSZ. In addition, an LGA cooling crystallization experiment was performed to verify the sensitivity of these calibration models for monitoring the crystal growth process.

Pharmaceutical crystallization in Couette-Taylor crystallizer: A case study of polymorphism of amino acid L-glutamic acid

The influence of intensity Taylor vortex flow in Couette-Taylor crystallizer on the crystallization of polymorphic amino acid L-glutamic acid was investigated in cooling crystallization. Here, the L-glutamic acid was chosen as the model crystal product, where it has two kinds of polymorphism including the unstable phase α-form and stable phase β-form crystal. In cooling crystallization, the α-form crystal transformed to the β-form crystal corresponding to the phase transformation of α-form to β-form crystal. The present study found that the selective polymorphism of α-form and β-form crystal as well as the phase transformation significantly depended on the intensity of turbulent Taylor vortex flow in Couette-Taylor crystallizer. Here, the selective β-form nucleation and phase transformation were remarkably promoted as increasing the rotation speed of inner cylinder in Couette-Taylor crystallizer. By comparison with the conventional stirred tank (ST) crystallizer, the Couette-Taylor (CT) crystallizer was at least 2.0 times more effective as regards the selective β-form polymorphism and phase transformation time. The advantage of CT crystallizer over the conventional ST crystallizer was explained in terms of the high shear stress and mass transfer of turbulent Taylor vortex flow in CT crystallizer. Here, the shear stress of Taylor vortex flow in CT crystallizer was at least 23.0 times higher than that of fluid motion in conventional ST crystallizer, whereas the mass transfer of Taylor vortex flow in CT crystallizer was at least 1.2 times higher than that of fluid motion in conventional ST crystallizer. As such, the high turbulent shear stress of Taylor vortex flow was expected to promote the β-form nucleation via the effective molecules alignment, whereas the high mass transfer of Taylor vortex flow facilitated the dissolution rate of α-form and growth rate of β-form crystal, resulting in an acceleration of phase transformation rate.

Sparsity-based image monitoring of crystal size distribution during crystallization

To facilitate monitoring crystal size distribution (CSD) during a crystallization process by using an in-situ imaging system, a sparsity-based image analysis method is proposed for real-time implementation. To cope with image degradation arising from in-situ measurement subject to particle motion, solution turbulence, and uneven illumination background in the crystallizer, sparse representation of a real-time captured crystal image is developed based on using an in-situ image dictionary established in advance, such that the noise components in the captured image can be efficiently removed. Subsequently, the edges of a crystal shape in a captured image are determined in terms of the salience information defined from the denoised crystal images. These edges are used to derive a blur kernel for reconstruction of a denoised image. A non-blind deconvolution algorithm is given for the real-time reconstruction. Consequently, image segmentation can be easily performed for evaluation of CSD. The crystal image dictionary and blur kernels are timely updated in terms of the imaging conditions to improve the restoration efficiency. An experimental study on the cooling crystallization of α-type l-glutamic acid (LGA) is shown to demonstrate the effectiveness and merit of the proposed method.

A novel backlight fiber optical probe and image algorithms for real time size-shape analysis during crystallization

Process analytical technology requires not only process suitable sensors, but also novel data processing approaches in order to make real time analysis feasible. In this paper, a novel in-line probe was designed, fabricated and tested for crystallization monitoring. The design benefits from state of the art optics and camera, fiber backlight illumination, and an optimized depth of focus and field of view. Image analysis steps to study both crystal size and shape are presented. These image analysis algorithms do not require manual-thresholding of individual images or time zero image subtraction, due to the use of a ‘rolling ball’ self-adapting background correction step. The approach is tolerant to blank images, noise, blurriness, out of focus objects, and common spatial or intensity variations. The method developed should help in the identification of changes in size and shape in crystal populations. Examples are presented for glass sphere standards, the crystallization of d-mannitol and l-glutamic acid, as well as an engineered needle-sphere mixture. A data binning strategy useful for future studies is also reported. The ultimate goal is control of crystallization under the Process Analytical Technology framework.

In-situ crystal morphology identification using imaging analysis with application to the L-glutamic acid crystallization

A synthetic image analysis strategy is proposed for in-situ crystal size measurement and shape identification for monitoring crystallization processes, based on using a real-time imaging system. The proposed method consists of image processing, feature analysis, particle sieving, crystal size measurement, and crystal shape identification. Fundamental image features of crystals are selected for efficient classification. In particular, a novel shape feature, referred to as inner distance descriptor, is introduced to quantitatively describe different crystal shapes, which is relatively independent of the crystal size and its geometric direction in an image captured for analysis. Moreover, a pixel equivalent calibration method based on subpixel edge detection and circle fitting is proposed to measure crystal sizes from the captured images. In addition, a kernel function based method is given to deal with nonlinear correlations between multiple features of crystals, facilitating computation efficiency for real-time shape identification. Case study and experimental results from the cooling crystallization of l-glutamic acid demonstrate that the proposed image analysis method can be effectively used for in-situ crystal size measurement and shape identification with good accuracy.

Investigation of the l-Glutamic acid polymorphism: Comparison between stirred and stagnant conditions

This work highlights the effect of the stirring, the temperature and the supersaturation on the cooling crystallization of l-Glutamic acid (LGlu) polymorphs. First, solubility measurements of the metastable polymorph α and the stable polymorph β were performed. Then, crystallization experiments were carried out in stirred vessel and in stagnant cell. All these experiments were monitored by in situ devices. The effect of the temperature on the LGlu polymorphs was found to be more relevant than the supersaturation in the stirred crystallizer. In the stagnant cell, only the stable form β crystallized regardless of the operating conditions. Moreover, an unexpected and new habit of the β form was discovered and confirmed. These results suggest that the temperature and the stirring can strongly affect the nucleation and the growth kinetics of polymorphic forms.

Two dimensional population balance modelling of crystal growth behaviour under the influence of impurities

This short communication investigates the impact of impurity on crystal growth behaviour in terms of crystal shape distribution. A two dimensional population balance model is applied to study the crystal shape changing behaviour in cooling crystallisation producing β-form L-glutamic acid crystals, in the presence and without the presence of an additive, L-phenylalanine. The simulation results were verified in experiments using a 1-litre crystalliser for crystallisation of L-glutamic acid.

JITL-based concentration control for semi-batch pH-shift reactive crystallization of l-glutamic acid

Although concentration control (C-control) strategy has been shown to give effective and robust control performance for batch cooling and semi-batch antisolvent crystallizations in recent years, no research work was reported concerning the potential application of conventional C-control for the more challenging semi-batch pH-shift reactive crystallization that is common in the process industries. To this end, this paper presents detailed analysis to find out that it is not feasible to apply the C-control to semi-batch pH-shift reactive crystallization. To circumvent this problem, a variant of C-control strategy by incorporating the Just-in-Time Learning (JITL) method to cope with strong process nonlinearity inherent in the pH-shift reactive crystallization is developed in this paper. Simulation results are presented to illustrate the proposed design and a comparison with conventional optimal control is made.

Optimization of temperature swing strategy for selective cooling crystallization of α-form l-glutamic acid crystals

l-glutamic acid can be crystallized as metastable α-form and stable β-form crystal. The α-form is desired because of its prismatic shape. Production of α-form of l-glutamic acid by cooling crystallization is not well-defined and α-form solid is commercially not available. In this study, an optimal cooling strategy to selectively produce large and narrowly distributed α-crystals is found by modeling and optimizing the crystallization and polymorphic transformation of l-glutamic acid. The optimal temperature profile is found to be cooling-heating-cooling concept where short nucleation period is followed by growth period in metastable zone. The obtained α-form of L-glutamic acid by optimal strategy had improved mean size, distribution, and purity compared to constant cooling.

Polymorphism stabilization by crystal adsorption on a self-assembled monolayer

The control over crystal polymorphism is a well-established subject in crystallization and materials chemistry. In recent years, self-assembled monolayers (SAMs) with different functionalized groups have been used as a new chemical approach to control crystal nucleation and polymorphism. In this paper, we focus on a study of the different mechanisms involved in polymorphism control by crystallization onto SAMs. We study the crystallization of L-glutamic acid on SAMs with various functionalized end groups: R–OH, R–CH3 and R–COOH. Furthermore, in this work we select crystallization conditions in which we can identify different mechanisms of polymorphism stabilization and show that functionalized SAMs can be used to stabilize crystal polymorphism by means of crystal adsorption from the crystallization solution onto SAMs, and not merely by nucleation and crystal growth onto the SAMs.

Concentration Control for Semi-batch pH-shift Reactive Crystallization of L-glutamic Acid

While major advances have been made in the control of cooling and antisolvent crystallizations, very little progress has been made for the much more challenging pH-shift reactive crystallizations that are also quite common in industry. This paper extends the concentration control strategy developed for cooling and antisolvent crystallization to pH-shift reactive crystallization of L-glutamic acid. The straightforward extension to semi-batch pH-shift reactive crystallization is not applicable, which motivates a variant that incorporates data-based models so as to better cope with process nonlinearity. Further analysis motivates the development of control strategies that directly incorporate measurements of the key product quality attributes.

Closed-loop control of crystal shape in cooling crystallization of l-glutamic acid

Recent simulation research has proved the principle that it is possible to exercise closed-loop control over the particle shape of the crystals produced from cooling crystallisation processes through tracking an optimum temperature or supersaturation profile which can be obtained through optimisation using a morphological population balance (M-PB) model. Here, attention is given to experimentally designing a closed-loop control system on a real crystallisation process to produce the desired shape for rod-like crystals. An optimization algorithm was applied to an M-PB model developed for l-glutamic acid crystallisation to find the optimal profiles of cooling temperature and supersaturation that lead to the desired shape of β-form rod-like product crystals. A closed-loop feedback control system was designed to control the solution temperature or concentration to track the optimum trajectory. On a 1-l crystalliser, it was demonstrated that crystals of different shape can be obtained using the developed closed-loop control methodology. Both supersaturation control and temperature control are compared with each other, and also with constant supersaturation strategy in performance in achieving the final product shape.

L-Glutamic Acid Polymorph Control Using Amino Acid Additives

Additive is an effective factor in controlling crystallization of polymorph. l-Tryptophan, l-leucine, l-threonine, l-histidine, l-alanine, and l-valine, as additives during l-glutamic acid crystallization, were investigated for probing their effects on the polymorphic transformation. l-Tryptophan was then chosen as a representative case to evaluate the effect of addition concentration on the morphology, nucleation, and polymorphic transformation rate of l-glutamic acid. It is shown that all these additives have a certain influence on the polymorphic transformation and the presence of a bulky side chain (phenyl) in l-tryptophan and l-histidine is identified as an essential feature in achieving stabilization of the α-polymorph. When the concentration of l-tryptophan reaches above 0.008 M, the elongation of crystals occur. Increasing l-tryptophan concentration, the transformation time and nucleation rate of l-glutamic acid are retarded. The inclusion behavior of additive molecules in l-Glu crystals was investigated, and the results show that the effect of additive molecule on the polymorphic transformation may be through incorporating into crystal structures by adsorption.

Model identification of crystal facet growth kinetics in morphological population balance modeling of l-glutamic acid crystallization and experimental validation

Morphological population balance (PB) modeling of crystallization processes predicts the dynamic evolution of shape distribution of crystals grown from solution. It requires growth kinetics of individual facets of crystals. This paper investigates model identification techniques for deriving size-dependent facet growth kinetics models as functions of supersaturation and size of the crystal. Cooling crystallizations experiments were carried out with solution concentration and temperature recorded. The seeds and obtained product crystals were characterized for shape and size distributions using an integrated particle dispersion–imaging system. The models obtained were tested using experimental data of crystallization of the same chemical under different cooling conditions. During all experiments an on-line imaging instrument was applied to obtaining real-time images for the purpose of qualitative comparison with model predicted shape distribution.

Unsteady-state inhibition of crystal growth caused by solution impurities

The competitive adsorption model under unsteady state conditions (CAMUS) is presented and validated against experimental results of crystal growth inhibition in the presence of impurities. Particular emphasis is given to peculiar growth rate trends documented in the literature that are unexpected by the existing theories. These behaviours include intermittent crystal growth, increasing growth rates with time, and inverted U-shaped growth curves, which have been reported to occur in very diverse systems such as sucrose–sugarcane impurities (P. M. Martins, A. Ferreira, S. Polanco, F. Rocha, A. M. Damas and P. Rein, J. Cryst. Growth, 2009, 311, 3841–3848), barite crystals grown in the presence of carbonate ion (N. Sanchez-Pastor, C. M. Pina, L. Fernandez-Diaz and J. M. Astilleros, Surf. Sci., 2006, 600, 1369–1381) or L-glutamic acid crystals grown in the presence of L-phenylalanine (M. Kitamura and T. Ishizu, J. Cryst. Growth, 1998, 192, 225–235). The CAMUS adequately describes the experimental observations as a result of dynamic equilibrium between impurity and solute molecules, with the impurity being adsorbed first at the crystal surface and then being gradually replaced by the crystallizing solute until the steady state is reached. The set of CAMUS parameters that best fit the experimental results were determined for each case analyzed in this study.

Continuous Plug Flow Crystallization of Pharmaceutical Compounds

Crystallization processes in the pharmaceutical industry are usually designed to obtain crystals with controlled size, shape, purity, and polymorphic form. Knowledge of the process conditions required to fabricate crystals with controlled characteristics is critical during process development. In this work, continuous crystallization of ketoconazole, flufenamic acid, and l-glutamic acid in a nonconventional plug flow crystallizer was investigated. Kenics type static mixers were used to promote homogeneous mixing of active pharmaceutical ingredient solution and antisolvent. A strategy of multiple points of addition of antisolvent along the crystallizer was evaluated to control the size of the crystals. Interestingly, it was found that crystal size can be increased or decreased with an increased number of antisolvent addition points, depending on the kinetics of the system. It was also found that smaller crystals with a narrower size distribution can be obtained with the static mixers. A model to describe the continuous crystallization process was developed through the simultaneous solution of a population balance equation, kinetics expressions for crystal growth and nucleation, and a mass balance. The comparison of experimental and calculated values for crystal size distribution revealed that a growth rate dispersion model could describe accurately the continuous crystallization process. Collision of crystals with each other and with mixing elements inside the crystallizer may be the source of random fluctuation of the growth rate in the nonconventional plug flow crystallizer with static mixers.

Effects of mixing, seeding, material of baffles and final temperature on solution crystallization of l-glutamic acid in an oscillatory baffled crystallizer

Abstract In this paper, we report the effects of mixing intensity, seeding, composition of baffle material and final temperature on meta-stable zone width (MSZW) and crystal polymorph in solution crystallization of an industrially important compound, l -glutamic acid, in an oscillatory baffled crystallizer (OBC). The results show that the MSZW decreases with increasing of mixing; meta-stable α crystals are transformed into stable β crystals with enhanced mixing intensity. Seeding meta-stable α crystals in operational conditions that promote β crystals leads to the formation of α crystals allowing co-existence of both forms; while seeding stable β crystals in conditions that favour α form allow β crystals prevailing in all conditions. Smoother surface of baffle material in OBC exhibits larger MSZW and favours meta-stable crystals, while rougher surface has smaller MSZW with stable crystals dominating. The meta-stable crystals gradually change into the stable form when final cooling temperature is closer to its nucleation temperature. The outcomes from this work indicate that by controlling process parameters desirable crystal polymorph can be obtained in the OBC.

Measurement of 3D particle size distributions by stereoscopic imaging

In this work a method is presented to acquire 3D size information on particles in suspension. An experimental setup capable of acquiring two images from the same particle at different angles is presented. These images are then processed to yield a 4D measurement called axis length distribution (ALD). Using a measurement model and a restoration algorithm, the 3D particle size distribution (PSD) is reconstructed. The technique is applied to characterize the 3D PSD of ascorbic acid crystallized from methanol and Of beta L-glutamic acid crystals in water. The shape of these particles determined by the algorithm was found to compare well with observations from electron microscopy images. (C) 2009 Elsevier Ltd. All rights reserved.