Cooling Crystallization Experiments Research Articles

Design and Validation of a Droplet-based Microfluidic System To Study Non-Photochemical Laser-Induced Nucleation of Potassium Chloride Solutions.

Non-photochemical laser-induced nucleation (NPLIN) has emerged as a promising primary nucleation control technique offering spatiotemporal control over crystallization with potential for polymorph control. So far, NPLIN was mostly investigated in milliliter vials, through laborious manual counting of the crystallized vials by visual inspection. Microfluidics represents an alternative to acquiring automated and statistically reliable data. Thus we designed a droplet-based microfluidic platform capable of identifying the droplets with crystals emerging upon Nd:YAG laser irradiation using the deep learning method. In our experiments, we used supersaturated solutions of KCl in water, and the effect of laser intensity, wavelength (1064, 532, and 355 nm), solution supersaturation (S), solution filtration, and intentional doping with nanoparticles on the nucleation probability is quantified and compared to control cooling crystallization experiments. Ability of dielectric polarization and the nanoparticle heating mechanisms proposed for NPLIN to explain the acquired results is tested. Solutions with lower supersaturation (S = 1.05) exhibit significantly higher NPLIN probabilities than those in the control experiments for all laser wavelengths above a threshold intensity (50 MW/cm2). At higher supersaturation studied (S = 1.10), irradiation was already effective at lower laser intensities (10 MW/cm2). No significant wavelength effect was observed besides irradiation with 355 nm light at higher laser intensities (≥50 MW/cm2). Solution filtration and intentional doping experiments showed that nanoimpurities might play a significant role in explaining NPLIN phenomena.

Nonlinear model predictive control of crystal size in batch cooling crystallization processes

The paper proposes a model-based nonlinear model predictive control (NMPC) method for online control of crystal mean size and standard deviation in cooling crystallization process. Image analysis method using deep learning neural network and mathematical statistical method are performed to obtain the mean size and standard deviation of crystal population. The nonlinear prediction model for the NMPC is derived from the input and output data. The effectiveness of the proposed NMPC method is evaluated by the alum cooling crystallization experiments. Experimental results demonstrate the benefits of the proposed combination of image analysis and feedback control of the crystal mean size and standard deviation. The control performance of NMPC is superior to model-free path following control (PFC) method due to the prediction and optimization capabilities of NMPC.

Polymorphism of Praziquantel: Role of Cooling Crystallization in Access to Solid Forms and Discovery of New Polymorphs

Praziquantel (PZQ) is an anthelmintic first-line drug to treat schistosomiasis, a neglected tropical disease strongly related to poverty. PZQ crystalline structures and polymorphs have been studied mainly via mechanochemical approaches. This work applies a systematic study to investigate the polymorphism of PZQ using cooling crystallization experiments under different conditions not yet explored in the literature for this compound. We accessed all forms previously reported so far obtained via mechanochemistry and the hydrate found through supercritical CO2 processing. A novel dimethylacetamide (DMA) solvate was obtained, and a new form was discovered after desolvation of the DMA solvate by aging and exposure to water-vapor atmosphere. Toluene and triethylamine were solvents capable of enabling the formation of different forms depending on the employed experimental condition. A new form was discovered using triethylamine as solvent, which differs from all known polymorphs. The results of this work demonstrate that solvent selection and variation in the rate of supersaturation generation can generate forms obtained from more complicated techniques as well as potentially finding new forms.

Influence of solvent choice and operating conditions on Chlorzoxazone crystal shape and size

Solubility of pharmaceutical drugs in organic solvents is one of the important parameters to understand the equilibrium concentration of solute-solvent, which helps optimize and design crystallization conditions to obtain the desired product crystals. In the present study, Chlorzoxazone (CHZ) is used as a model pharmaceutical compound to investigate the equilibrium solubility, the influence of solvent and the operating conditions on the shape, and the size distribution. The solubility of CHZ is determined in organic solvents like Isopropanol, Ethanol, and 2-Ethoxyethylacetate, Ethylacetate and Ethyllactate using shake flask method from -5ºC to 60ºC. The solubility of CHZ in these solvents shows an increasing trend as the temperature increases in the following order: ethyllactate + water (0.5+0.5) < ethylacetate < isopropanol < ethanol < 2-ethoxyethylacetate < ethyllactate + water (0.75+0.25). The solvents, isopropanol, ethanol, and ethyl lactate, produce needle-shaped crystals, while 2-ethoxyethylacetate and ethyl acetate tend to produce plate shaped crystals. CHZ crystals obtained from 2-ethoxyethylacetate tend to have plate shaped crystals with a lower aspect ratio and are selected for batch cooling crystallization experiments performed at different cooling rates, and agitation. It is found that the agitation at 300 rpm and the cooling rate 0.2ºC/min produce more uniform crystal size distribution.

Neural-Network-Based Nonlinear Model Predictive Control of Multiscale Crystallization Process

The purpose of this study was to develop an integrated control strategy for multiscale crystallization processes. An image analysis method using a deep learning neural network is used to measure the fine-scale information of the crystallization process, and the mathematical statistical method is adopted to obtain the mean size of the crystal population. A feedforward neural network is subsequently trained and employed in a nonlinear model predictive control formulation to obtain the optimal profile of the manipulated variable. The effectiveness of the proposed nonlinear model predictive control method is evaluated using alum cooling crystallization experiments. Experimental results demonstrate benefits of the proposed combination of feedforward neural network and nonlinear model predictive control method for the multiscale crystallization process.

Continuous Miniaturized Draft Tube Baffle Crystallizer with Particle Screw for Supportive Suspension Discharge

Continuous small-scale processes can enable faster process development and reduce time-to-market. However, for continuous crystallization, there are some hurdles, too, regarding suspension handling. Therefore, to overcome clogging issues concerning the product discharge, due to the smaller dimensions of a continuous draft tube baffle (DTB) crystallizer, a particle screw for supportive suspension discharge was developed and has been described throughout this work. First, the design of the particle screw is described. Furthermore, the particle screw is characterized, and cooling crystallization experiments (with l-alanine/water) are performed with a miniaturized (2 L) DTB. The presented particle screw showed negligible abrasion effects to the conveyed crystals. The investigations showed that the residence time of different particle sizes depends on the particle screw speed. Additionally, the continuous cooling crystallization experiments with 15 g min–1 confirm the supporting character of the suspension discharge by the particle screw. Thus, the newly developed particle screw for a supportive suspension discharge is well suited for continuous small-scale crystallization.

Can the Crystal of Conformational Polymorph Nucleate Directly from Its Conformer? The Case of Flufenamic Acid

The combination of solution IR spectroscopy measurement, fast cooling crystallization experiments, conformational search, and molecular computation was investigated in detail in this study to explo...

A spherical FOX-7 crystal: Preparation, characterization, solubility and thermodynamic study

ABSTRACT The solubility of 1,1-diamino-2,2-dinitroethylene (FOX-7) in four binary mixed solvents (Dimethyl sulfoxide + Acetonitrile, Cyclohexanone, 1,2-Dichloroethane, 2-Propanol) was determined by using a laser dynamic method at temperatures from 293.15 to 333.15 K under 0.1 MPa. The measured results showed that the experimental solubility of FOX-7 increased with increasing temperature and Dimethyl sulfoxide content in the studied mixture solvents. Solubility data were well correlated by the modified Apelblat model, Yaws model and van’t Hoff model, and the modified Apelblat model has the lowest root-mean-square deviation and can be used as the optimal model for data fitting. In addition, the thermodynamic parameters of the dissolution process, the surface tension, and surface entropy factor of FOX-7 were calculated based on the experimental data, which provided basic data for the optimization of crystallization process and industrial amplification of FOX-7. The cooling crystallization experiments were carried out in the investigated mixed solvents. The crystal morphology of FOX-7 obtained in the Dimethyl sulfoxide + Cyclohexanone mixed solvent (x DMSO = 0.3266) was regular, spherical, uniform in particle size, and have better thermal stability. Cyclohexanone could be the excellent non-solvent in the sphericalization of FOX-7.

Crystallization of Sodium Bicarbonate in the Presence of Trace Amounts of HPMA

AbstractThe effect of trace amounts of hydrolytic polymaleic anhydride (HPMA) on the crystallization of sodium bicarbonate (NaHCO3) has been investigated by molecular simulation and experimental methods. Cooling crystallization experiments show that the trace HPMA molecule effectively promotes the formation of larger NaHCO3 crystals. Besides, the crystal morphology changes from needle‐like to flake‐like. The determination of the metastable zone width of NaHCO3 and Atomic Force Microscopy (AFM) observation confirmed that the spontaneous nucleation processes are suppressed. Molecule simulation was used to explore the interaction of HPMA molecule and different crystal faces of NaHCO3. It was found that the binding energy between HPMA and NaHCO3 surface is greater than the corresponding attachment energy of NaHCO3 surface. The electrostatic interaction energy between double‐bonded oxygen on the HPMA molecule and the Na+ of the NaHCO3 crystal plane plays a dominant role in the additive molecule‘s adsorption on the NaHCO3 crystal surface. This work suggests that HPMA could serve as an inhibitor of nucleation and impact NaHCO3 crystallization.

Tailoring crystal size distributions for product performance, compaction of paracetamol

Paracetamol crystals often exhibit poor compressibility properties, which results in capping issues. The Particle Size Distribution (PSD) of paracetamol was engineered to improve the compressibility of paracetamol crystals. This was accomplished by growing paracetamol crystals in the presence of additives. The active pharmaceutical ingredient Phenacetin and impurity 4-chloroacetanalide were used to modify the crystal properties of paracetamol. In solution, the phenacetin or 4-chloroacetanalide molecules adsorb onto the paracetamol crystal faces selectively (110 or 011) and inhibit the further growth of the paracetamol crystal and consequently, the paracetamol crystal growth is reduced substantially. For controlling the PSD of crystal to improve the compressibility of paracetamol crystals, a set of cooling crystallization experiments in the presence of additive was designed. According to a statistical experimental design, the cooling rate was the most effective parameter. The PSD was reduced when paracetamol crystallized from the controlled crystallization in the presence of less than 3 mol% of both additives. These smaller particles increased almost four-fold the compressibility of paracetamol in comparison to the commercial material. Moreover, tablets were prepared for each formulation using a direct compaction method. The results illustrated that a higher tablet hardness of paracetamol was achieved by tailoring the paracetamol crystal size distribution. In addition, the tablet disintegration time was higher for the formulation with increased hardness. Overall, this work presents the potential use of structurally similar compounds as additives to alter the mechanical properties of an API.

Solubilities and Crystallization of Olanzapine Using a Multi-Well Setup: The Effect of Solvents and Cooling Rates

The use of a multi-well system allowed us to measure the solubility of two anhydrous forms of olanzapine in pure solvents with different polarities in a temperature range of 20 to 60° Celsius (°C) with a small quantity of material. After that, we carried out cooling crystallization experiments in a stagnant medium with a small volume of 0.8 mL and a small quantity of material. We found that the solubility increased with the solvent polarity in the order: methanol > ethanol > acetonitrile > ethyl acetate > tetrahydrofuran > toluene. We demonstrated the effect of the solvents and the cooling rates on the crystal habit, crystal phase, and crystal size distribution.

Influencia de palmitato de retinilo en las cinéticas de nucleación y crecimiento en la cristalización batch de la caña de azúcar

The influence of retinyl palmitate (RP) on nucleation and growth kinetics, in the sugarcane fortification process, is analyzed. Batch cooling crystallization experiments using natural and linear profiles were carried out adding different amounts of RP. At each experiment, sugar concentration, crystal mass and crystal size distribution were measured as a function of time. Nucleation and growth rates were determined experimentally and kinetic parameters were determined using power-law type relations. At the end of each experiment, crystals were observed in microscope and morphological changes were analyzed. The results showed that the presence of RP in the fortification process of sugar generated a decrease in both nucleation and growth rates. The decrement was bigger when the initial concentration of RP increased. Moreover, it was observed that fortified crystals suffer morphological changes into their habit.

Crystallization thermodynamics of 2,4,6-trinitrophenol and 2,4,6-trinitroresorcinol∙2/3H2O in different pure solvents

The by-products in nitration of benzene were analyzed by HPLC, X-ray single crystal diffraction and so on, and the main components were: 2,4,6-trinitroresorcinol∙2/3H2O (TNR∙2/3H2O, 76.7% by HPLC) and 2,4,6-trinitrophenol (TNP, 14.6% by HPLC). The solubility of TNP and TNR∙2/3H2O in six pure solvents (dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene and anisole) were determined by laser dynamic method under atmospheric pressure at T = 298.15 K to 333.15 K. When the temperature and solvent are the same, the solubility of TNR∙2/3H2O is significantly lower than that of TNP. The solubility of the two substances is the highest in anisole, the smallest in chloroform, similar in toluene, xylene, dichloromethane and 1,2-dichloroethane at the same temperature and increases at different rates with the increase of temperature in the same solvent. The solubility data of the two substances was correlated by the modified Apelblat equation, Van't Hoff equation, polynomial empirical equation and λh equation. All of these models gave a satisfactory result and the polynomial empirical equation and the modified Apelblat equation are better. The apparent thermodynamic parameters such as the standard dissolution enthalpy (ΔH°dis), standard dissolution entropy (ΔS°dis) and the standard Gibbs energy (ΔG°dis) were calculated by the Van't Hoff method, which indicates the dissolution behavior of TNP and TNR∙2/3H2O is considered to be an “endothermic, non-spontaneous and entropy-driven” process in selected solvents. According to the solubility data, toluene and xylene are more suitable for the purification of TNR∙2/3H2O from the by-products of benzene nitration by cooling crystallization. Cooling crystallization experiments were carried out on the by-products of benzene nitration, and the pure TNR∙2/3H2O can be obtained after twice crystallizations by toluene.

Kinetic parameter estimation for cooling crystallization process based on cell average technique and automatic differentiation

Abstract In this paper, a cell average technique (CAT) based parameter estimation method is proposed for cooling crystallization involved with particle growth, aggregation and breakage, by establishing a more efficient and accurate solution in terms of the automatic differentiation (AD) algorithm. To overcome the deficiency of CAT that demands high computation cost for implementation, a set of ordinary differential equations (ODEs) entailed from CAT based discretized population balance equation (PBE) are solved by using the AD based high-order Taylor expansion. Moreover, an AD based trust-region reflective (TRR) algorithm and another interior-point (IP) algorithm are established for estimating the kinetic parameters associated with particle growth, aggregation and breakage. As a result, the estimation accuracy can be further improved while the computation cost can be significantly reduced, compared to the existing algorithms. Benchmark examples from the literature are used to illustrate the accuracy and efficiency of the AD-based CAT, TRR and IP algorithms in comparison with the existing algorithms. Moreover, seeded batch cooling crystallization experiments of β form L-glutamic acid are performed to validate the proposed method.

Multiscale Experimental Study and Modeling of l-Glutamic acid Crystallization: Emphasis on a Kinetic Explanation of the Ostwald Rule of Stages

This work presents an experimental and a numerical study to highlight a kinetic explanation to of the Ostwald rule of stages (ORS). To demonstrate this explanation, L-glutamic acid (LGlu) (a monotropic system with two polymorphs) were crystallized in three different scales: Liter scale in a 2L stirred crystallizer, milliliter scale in a 4ml stagnant cell and microliter scale in microfluidic channels. Cooling crystallization experiments were performed in water at different temperature and supersaturation conditions. The LGlu polymorphic system was found to follow the ORS at low temperature (between 5°C and 30°C). However, in similar operating conditions, the stable polymorph crystallized preferentially or exclusively in the stagnant cell and in microfluidics. To explain the ORS in the stirred crystallizer at low temperature, a model based on the kinetic equation was used. By taking into account the Gibbs Thomson effect (Solubility variation with size), the simulations in the nanoscopic scale showed the dissolution of the slow-growing stable phase nuclei in favor of the fast-growing metastable phase nuclei. Consequently, the numerical results showed that the Gibbs Thomson effect is a key factor in polymorph competition and that considering this effect, in certain kinetic and equilibrium conditions, could allow explaining and simulating the ORS.

Secondary Nucleation from Nuclei Breeding and Its Quantitative Link with Fluid Shear Stress in Mixing: A Potential Approach for Precise Scale-up in Industrial Crystallization

The development of robust process scale-up involves a clear understanding of mixing hydrodynamics in crystallization. In the present work, particle imaging velocimetry (PIV) was used to determine the fluid turbulent shear stress (TSS) as a function of scale-up involving cooling crystallization experiments at different agitation rates. At a given scale, with increased agitation rate from 300 to 370 rpm, the secondary nucleation threshold (SNT) and product mean particle size were observed to decrease due to increased TSS. In nuclei breeding, the nucleated crystals at the seed surface are readily sheared off by the increased fluid shear stress. This catalytic process enhanced the rate of secondary nucleation, and hence a decrease in SNT. The SNT and mean particle size increased with scale size due to a decrease in average turbulent dissipation rate which resulted from a decrease in TSS. Secondary nucleation due to nuclei breeding was found to have a quantitative link with TSS. This resulted in a constant SNT...

Crystallization of fesoterodine fumarate active pharmaceutical ingredient: Modelling of thermodynamic equilibrium, nucleation, growth, agglomeration and dissolution kinetics and temperature cycling

The crystallization of active pharmaceutical ingredients (API) is an important, but complex unit operation in drug manufacturing industry, due to the diverse chemical nature of medicinal formulation compounds, several physicochemical phenomena that take place during particle formation process, and multi-phase governing resistances. This research paper presents a combined experimental–modelling approach to understanding fesoterodine fumarate crystallization and dissolution in 2-butanone. A rigorous in-house mechanistic model algorithm that includes calibration, thermodynamic equilibrium description, energy, mass and population balance equations, heat transfer limitations, and ordering, agglomeration and detachment step kinetics was developed. On the basis of experimentally-determined saturated solubility, a specified initial number of designed dissolution and cooling crystallization experiments was performed, monitored by attenuated total reflection Fourier-transform infrared (ATR–FTIR) spectroscopy, focused beam reflectance measurement (FBRM) technique and microscopy. The estimated kinetic parameters of transport, nucleation, crystal lattice growth, agglomeration and dissolution were evaluated by fitting the measured/simulated concentration curves with crystallite size distributions. Correlation was validated with additional trial results, observing a rather good agreement. The behaviour of the component during validations’ temperature cycling was thoroughly examined by simulations to achieve a solid final insight into mechanisms, which may aid further production development, optimization, as well as scale-up.

Experimental Evaluation of Fluid Shear Stress Impact on Secondary Nucleation in a Solution Crystallization of Paracetamol

Cooling crystallization experiments were performed at 300 and 370 rpm over a range of saturation temperatures for the measurements of the metastable zone width (MSZW) using a large seed of paracetamol crystal in propan-2-ol solution. Particle imaging velocimetry (PIV) was used to quantify the fluid shear stress at each agitation rate employed, which was found to be 0.07 and 0.11 N/m2 respectively. A decrease in MSZW and growth only zone (GNZ) was observed with increasing shear stress, and the secondary nucleation threshold (SNT) was determined with a relative supersaturation ratio (Sr) of 1.17 at 0.07 N/m2 and 1.08 at 0.11 N/m2. Focused beam reflectance measurement (FBRM) displayed an increase in particle counts as nucleation progressed, with total counts increased by 25% at a higher fluid shear as more nuclei were being sheared off from the seed surface. Crystal nuclei breeding is proposed as a mechanism of secondary nucleation, where the surface of a seed crystal served as a nucleation site for the pre-...

Feedback Control for the Size and Shape Evolution of Needle-like Crystals in Suspension. II. Cooling Crystallization Experiments

The experimental validation of a model-free path following control (PFC) scheme to manipulate the size and shape evolution of needle-like crystals in a seeded, growth-dominated batch cooling crystallization process is presented. To this aim, constant supersaturation control (CSC) and PFC experiments were performed on the needle-shaped compound β l-glutamic acid. First, the feedback controllers were coupled with an online size and shape monitoring tool. Second, attainable regions for the average particle dimensions of two different seed populations were determined experimentally using the CSC strategy, which enabled selecting reasonable targets in the size and shape space for the PFC experiments. Then, PFC experiments were performed to guide the populations of seed crystals to certain targets within the attainable region exhibiting different average sizes and shapes. The PFC strategy was able to successfully and repeatedly complete this task, thereby operating in a model-free fashion in the sense of not re...

Effect of shear rate on primary nucleation of para-amino benzoic acid in solution under different fluid dynamic conditions

The influence of shear rate on the primary nucleation of para-amino benzoic acid in water has been investigated via a series of cooling crystallization experiments. For each experiment, we recorded the induction time at various temperatures and supersaturation ratios, employing two flow devices: a capillary tube in which the solution was divided into hundreds of monodisperse droplets and a set of stirred vials. The capillary tube was used to perform experiments in stagnant conditions (motionless droplets) and low shear rate conditions (flowing droplets), while the stirred vials were used to perform experiments at relatively high shear rates. In this way, a wide range of shear rates was investigated. Comparing the results obtained for the motionless and flowing droplets, we saw that the nucleation rate is significantly increased (by several orders of magnitude) by the shear field; however, when the shear rate increases beyond a certain level (stirred vials experiments), we observed a drop in the nucleation rate. Thus, the results demonstrate a non-monotonic dependence of primary nucleation rate on shear rate. Various mechanisms to explain the effect of shear on nucleation are quantitatively and qualitatively discussed; however, at present no definitive conclusion can be drawn to identify the controlling mechanism.