Antisolvent Addition Rate Research Articles

Application of Anti-Solvent Crystallization for High-Purity Potash Production from K-Feldspar Leaching Solution

Potassium-containing feldspars provide a high potential for producing potash, a product with widespread use in agriculture. The present work assesses applying the anti-solvent crystallization method for the purification and recovery of high-purity muriate of potash (KCl) from feldspar leaching solutions. Initially, screening experiments were carried out on a synthetic leaching solution with the aim of analyzing the crystallization behavior of key components. Screening experiments were performed using five anti-solvents, namely methanol, ethanol, acetone, 2-propanol, and ethylene glycol. Acetone and 2-propanol were viable options for crystallization of potassium chloride. Then, the effects of anti-solvent ratio (O/A), time, and anti-solvent addition rate on potassium-chloride crystallization were further investigated using acetone and 2-propanol. A recovery of 83% of potassium was achieved when using acetone at the O/A of 5 with the addition rate of 10 mL/min, at room temperature with a hold time of 180 min. The optimum conditions for 2-propanol were determined to be similar, except for using a 5 mL/min addition rate for 79% recovery. The final muriate of potash products had a purity of over 99.9% using either of the anti-solvent. However, differences in morphology and crystal size of products were observed. Acetone-formed potash crystals were aggregates of cubic crystals with an average size of 3 microns, while 2-propanol-formed potash crystals were 20 microns in size as cubic particles with a hollow core. Despite having almost the same performance in potassium recovery, acetone was found to be a more feasible anti-solvent for potash recovery due to simpler downstream solvent recovery.

Controlling Crystal Growth of a Rare Earth Element Scandium Salt in Antisolvent Crystallization

Recovering scandium from hydrometallurgical residue bears the potential of a better supply of an industry depending on imports from countries with more mineral resources than Europe. To recover scandium from unused metal production residue, strip liquors from a solvent extraction process are treated with an antisolvent to crystallize the ammonium scandium fluoride salt (NH4)3ScF6 with high product yields. However, high local supersaturation leads to strong nucleation, resulting in small crystals, which are difficult to handle in the subsequent solid-liquid separation. Reducing local supersaturation makes it possible to reduce nucleation and control crystal growth. Key operation parameters are the concentration of ethanol in the feed and its addition rate. The concentration of the antisolvent in the feed causes a shorter mixing time in the proximity of the antisolvent inlet, which leads to a smaller local supersaturation and therefore less nucleation and more crystal growth. Lowering the antisolvent addition rate enhances this effect. The crystal size distribution during and at the end of the fed-batch process is analyzed by SEM imagery of sampled and dried crystals. To produce reproducible crystal size distribution from SEM images the neural network Mask R-CNN has been trained for the automated crystal detection and size analysis.

Nucleation Kinetics of Rare Earth Scandium Salt: An Experimental Investigation of the Metastable Zone Width

Scandium is a rare earth element that has been declared a critical raw material by the EU. Its availability is low but the demand for it is increasing. Bauxite residue presents a possible European source. A novel process to extract scandium from the residue incorporates anti-solvent crystallization, which delivers the scandium salt (NH4)3ScF6 that can be calcined to ScF3 for direct use in an aluminum alloy. However, this crystallization process produces small crystals in the single-digit micrometer scale, hindering solid–liquid separation. In order to facilitate the separation, the crystallization process needs to be better understood and controlled. Therefore, nucleation kinetics are investigated by measuring the metastable zone width (MSZW) with an optical endoscope probe inside a 300 mL stirred fed-batch crystallizer with varying operating parameters. To study the influence of mixing on the MSZW, the stirring rate, the antisolvent addition rate, and the dilution of the antisolvent before injection are varied. The latter is proven to widen the MSZW by a multiple. It could be confirmed that mixing times on different scales greatly influence the MSZW and the growth of the crystals in the process. With these results, the boundaries for operating parameters are studied in order to control the crystallization process and thus crystal growth.

Development of colloidal lignin particles through particle design strategies and screening of their Pickering stabilizing potential

Colloidal lignin particles (CLPs) have increased interest as green and sustainable materials for Pickering stabilizers, with particle design being an important step towards their effective use. In this context, the antisolvent precipitation method was selected to conduct a study aiming at understanding the effect of process variables (initial lignin concentration, antisolvent pH, final ethanol concentration, and antisolvent addition rate) on particle size, zeta potential, color parameters, and contact angle. Moreover, their Pickering stabilizing potential was preliminarily screened. The evaluation using a Fractional Factorial Design revealed that the particle size is significantly influenced by the initial lignin concentration (as it increases, larger particles are obtained) and the final ethanol concentration (as it increases, smaller sizes result). The zeta potential is significantly affected by the antisolvent pH and the initial lignin concentration; the increase in both parameters results in higher negative values. The color is significantly dependent on the used initial lignin concentration (as it increases, particles become lighter and the yellowish accentuates) and the antisolvent pH (as it increases, particles become darker). Both initial lignin concentration and final ethanol concentration increase promote hydrophobicity, whereas increasing the antisolvent pH and its addition rate turns particles more hydrophilic. Through this strategy, it was possible to achieve CLPs with promising Pickering stabilizing potential, putting in evidence the importance of understanding the production process to design effective particles for target applications.

CO2 utilization as gas antisolvent for the pharmaceutical micro and nanoparticle production: A review

A reduction in particle size improves the solubility and bioavailability of pharmaceuticals. The traditional methods utilized in this regard are associated with problems so the use of supercritical fluid has been highlighted in recent decades. To prepare nanoparticles by employing the gas antisolvent (GAS) technique, a specific amount of solution (solute dissolved in organic solvent) was loaded into a cell in the oven. The supercritical carbon dioxide was injected and dissolved into the organic solvent. Therefore, volume expansion occurred and the solute was precipitated with a new particle size distribution on the filter at the end of the cell. This technique exhibits advantages such as particle size control, solvent-free product, and low-temperature process. Many experimental and modeling research has been conducted to synthesize nano- and microparticles based on the GAS process. The present study seeks to review the effective factors and literature on the GAS technique. All parameters affecting the GAS process including pressure, temperature, antisolvent addition rate, initial soluble concentration, and solvent were investigated. Volume expansion, thermodynamic modeling, and kinetic modeling of the GAS process were reviewed. A comparison was conducted between the advantages and disadvantages of this method with other methods of producing nanoparticles with supercritical fluid.

Kinetic study of complicated anti-solvent and cooling crystallization of disodium 5′-ribonucleotide

Disodium 5′-ribonucleotide, which is composed of disodium 5′-inosine (IMP) and disodium 5′-guanosine (GMP), is an important food additive. The lack of kinetic studies of it causes a lack of clarity in understanding the complicated multi-solute crystallization of IMP + GMP in ethanol-water. In this work, process analytical technology tools were used to obtain the thermodynamics and kinetic data from the experiments, the kinetic parameters of anti-solvent and cooling crystallization were investigated. The crystal form of IMP + GMP mixed crystal was determined, which was consistent with the IMP whether crystallized from pure water or ethanol-water. The effects of different anti-solvent addition rates and cooling rates on the metastable zone widths were studied, and the opposite effect on metastable zone width was found. The modified exponential empirical function was developed to correlate nucleation and growth kinetic equations under different conditions. The kinetic data were well fitted with adjusted correlation coefficient (adj-R2 > 0.7), which is sufficient to provide a valid reference for process design and control.

Nucleation Behavior in a Transformation of the Amorphous State to the Crystalline State during Antisolvent Crystallization

The liquid-mediated phase transformation of an amorphous form to a crystalline heptahydrate form of guanosine 5′-monophosphate was studied in antisolvent crystallization using methanol–water mixtures as solvents. Three steps were monitored: the formation of the amorphous form, dissolution of the amorphous form, and growth of the heptahydrate crystals using in situ Raman spectroscopy, focused beam reflectance measurement (FBRM), and particle vision measurement (PVM) and off-line methods like viscosity, thermal gravimetric analysis (TGA), and powder X-ray diffraction (PXRD). Effects of the antisolvent fraction, initial concentration, and addition rate of the antisolvent on the transformation process were discussed. Solid forms, solute concentration, particle size, counts, induction time, metastable zone width, solution viscosity, and amorphous slurry viscosity were all measured for 18 experiment runs. The induction time of the crystalline hydrate increased with the supersaturation but decreased with the increasing viscosity of the amorphous slurry. Both are not as expected. The induction time correlates nicely in the opposite direction with the viscosity of the amorphous slurry concentration. The amorphous slurry viscosity is about 20 times higher than the solution viscosity. Viscosity of the amorphous slurry was discovered to be a crucial factor influencing the transition of the amorphous slurry to the crystalline form in the pre-exponential component of the classical nucleation rate equation. The metastable zone boundaries of the amorphous and heptahydrate crystalline forms were shown in a plot of the solute concentration versus the mass fraction of methanol in the mixed solvent. The amorphous and heptahydrate crystalline forms can be selectively produced under all the conditions of this study. The pre-exponential factor of the nucleation rate equation factor is crucial in comprehending the transformation from an amorphous to a crystalline state.

Gas anti-solvent coprecipitation of pyrazinamide–PVP composite particles from mixed organic solvents using supercritical CO2: Effect of process parameters

This paper focuses on coprecipitation of pyrazinamide (PZA) with polyvinylpyrrolidone (PVP) using gas antisolvent (GAS) process. Solutions of PZA/polymer in solvent mixtures (acetone and ethanol) with an overall concentration of 20 mg/ml were prepared. The process parameters: pressure, temperature, antisolvent addition rate, solvent composition, and polymer-drug ratio were manipulated to simplify the obtainability of controlled morphology and particle size distribution. Solvent-free particles with reduced crystallinity were precipitated having mean sizes between 311 and 1474 nm. Furthermore, the operating pressure and polymer-drug ratio stood as key parameters affecting the PVP/PZA particle size. The knowledge of the particle characteristics was the main objective in order to identify the crystalline phase and physicochemical properties of the final product. The drug release analyses revealed that by tuning the operating parameters, dissolution rate of PVP/PZA particles could reach near 90%, which was 2.5 times faster than the unprocessed PZA and thus facilitated drug assimilation through the organism.

Tuning the morphology of micro- and nano-spheres from bamboo shoot shell acetosolv lignin

The supramolecular assemblies of lignin into micro- and nano-particles (LMNPs) have attracted much attention recently. In preparing LMNPs, the antisolvent regime has been widely adopted. However, the effects of operation parameters and antisolvent coexisted substances on the morphology of LMNPs are still not well understood. Herein solid, single-holed, multi-holed and smooth-faced but inside porous spheres were obtained from bamboo (Dendrocalamus latiforus L.) shoot shell acetosolv lignin by controlling initial lignin concentration (CL0), the antisolvent addition rate (Raa), temperature and incorporating certain chemicals in antisolvent. The average size of LMNPs increased with CL0 and temperature but decreased with Raa. The relative morphology proportions highly depended on the antisolvent addition pattern, Raa, CL0, and the type and concentration of the chemical adulterated in the antisolvent. Normally, solid and single-holed spheres presented in an average size lower than 200 nm and 400 nm, while the size of multi-holed and smooth-faced but inside porous spheres were in the range of hundreds of nanometers to several microns. These results enable a deeper understanding of the morphology-setting mechanism of LMNPs and open a practical way to prepare LMNPs with diverse morphologies and potential applications.

Badanie wpływu szybkości dozowania nierozpuszczalnika na przebieg krystalizacji CL-20

In this paper, the effect of antisolvent addition rate on the yield and polymorphic purity of the obtained product, in order to optimise the 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20) precipitation process using a solvent/antisolvent system, was determined. It was found that increased dispensing rate of the antisolvent results in increased supersaturation in the mother liquor. This, in turn, increases the nucleation rate. The prevalence of the process of creating new seeds reduces the growth rate of the crystal, which affects the size distribution of the final crystallisation product. Reducing the time of the process results in the transformation of the initially formed, kinetically stable polymorph β, into the thermodynamically stable ε form with a lower yield, than the yield obtained after increased time.

Production of the metastable δ-polymorphic form of pyrazinamide by isothermal internal seeding anti-solvent crystallization

Pyrazinamide, an important drug for treatment of tuberculosis, crystallizes in four different polymorphic forms: commercially available needle-like α-polymorph, plate-like metastable δ-polymorph, prism shaped γ-polymorph, and the highly unstable β-polymorph. Since the fine needle shaped crystals of α-form of pyrazinamide easily agglomerate rendering downstream processing inefficient, the manufacture of plate-like δ-form of pyrazinamide is of significant importance in pharmaceutical industries. In this work, an isothermal internal seeding anti-solvent crystallization is proposed to selectively obtain metastable δ-polymorph of pyrazinamide with desired particle size distribution. The polymorphic purity and the final crystal size distribution can be influenced by careful selection of solvents, anti-solvents, anti-solvent addition rate, stirring rate, and seeding. After a series of screening experiments, 1,4-dioxane and cyclohexane were chosen as solvent and anti-solvent, respectively for the isothermal anti-solvent crystallization at 30 °C. The solubility of pyrazinamide in various 1,4-dioxane-cyclohexane mixtures in the range of 0–50 wt% of cyclohexane was determined gravimetrically at a temperature of 30 °C. A central composite design was then employed to investigate the effects of important process variables such as anti-solvent addition rate, stirring rate, and internal seeding on the process yield and the final crystal size distribution. An empirical model was developed that correlated the mean particle size with these variables and such a model can be used to determine the operating parameters for obtaining a target product size.

Modeling, Simulation, and Influence of Operational Parameters on Crystal Size and Morphology in Semibatch Antisolvent Crystallization of α-Lactose Monohydrate

This work summarizes the study of semibatch antisolvent crystallization of α-lactose monohydrate using ethanol as an antisolvent. The main objective of the work is to study the impact of operational parameters such as antisolvent flow rate, initial concentration of the solute, and the application of ultrasound on the crystal size and morphology. Mathematical modeling of semibatch antisolvent crystallization was formulated comprising a population balance equation (PBE) and material balance. The growth and nucleation kinetic parameters were estimated by fitting the model estimates to the experimental data. It was found that with an increase in antisolvent addition rate and initial lactose concentration the crystal morphology changed from polyhedral shape (α-lactose monohydrate) to curved needle/rod shape (β-lactose). The application of ultrasound led to the formation of smaller size crystals; however, no change in the morphology was observed. The work shows that there is a potential to engineer the shape, s...

Polymorphism control of p-aminobenzoic acid by isothermal anti-solvent crystallization

We report, for the first time, the control of polymorphism of p-aminobenzoic acid by isothermal anti-solvent crystallization using ethanol as solvent and water as anti-solvent. p-aminobenzoic (p-ABA) acid crystallizes in two distinct polymorphic forms: the α-polymorph, which is commercially available form and appears as long fibrous needles; and the β-polymorph, which appears in the form of prisms. The solubility of p-ABA was determined gravimetrically for various water/ethanol mixtures at 15°C and isothermal anti-solvent crystallization experiments were conducted at 15°C over a range of supersaturation ratio from 1.01 to 1.30 and at different anti-solvent addition rates of 4, 6, 8, and10ml/h. The needle-type α-polymorph was always obtained at higher supersaturation ratio and higher flow-rates of anti-solvent addition. The prismatic β-polymorph was obtained at lower supersaturation range of 1.01–1.06 when anti-solvent was added at 4 and 6ml/h. The obtained polymorphs were characterized using scanning electron microscopy, powder x-ray diffraction, and differential scanning calorimetry. The region of occurrence of each polymorph with respect to supersaturation ratio and anti-solvent wt% is presented for these addition rates. The careful selection of supersaturation ratio and anti-solvent addition rate can produce desired polymorph of p-ABA by anti-solvent crystallization.

A kinetic modeling of particle formation by gas antisolvent process: Precipitation of aspirin

ABSTRACTPopulation balance equations (PBEs) are often integro-partial differential in nature due to complexities involved in nonconventional crystallization processes, especially gas antisolvent (GAS). The reason is that they include phenomena such as primary nucleation, secondary nucleation, crystal growth, agglomeration, and/or breakage of crystals. Therefore, the solution to such models has become rather difficult. Considering these difficulties, a powerful numerical algorithm was adopted in this paper to treat the population balance model for the precipitation of aspirin by the GAS process. This method was the combination of Lax–Wendroff and Crank–Nicholson numerical methods. It was used to investigate the effect of significant operating parameters, that is, antisolvent addition rate, process temperature, and solute concentration, on the final product properties for two solvents. The antisolvent addition rate was varied between 8 and 40 bar/min, the process temperature was kept constant at levels 37°C and 42°C, the solute concentration was manipulated at two levels, namely, 0.2 and 0.27 g solute/g solution, and methanol and acetone were used as the organic solvents. The results indicated the successful performance of the applied method in treating PBE, since smooth particle size distributions were produced, which were in an acceptable agreement with the experimental data of the investigated system.

Effect of process parameters on the recrystallization and size control of puerarin using the supercritical fluid antisolvent process

The purpose of this study was to investigate the influence of the supercritical CO2 processing on the particle size and morphology of puerarin crystals. The process parameters included solvents, temperature, pressures, antisolvent times, addition volumes, antisolvent addition rates and solute concentrations. After being processed, the dramatic reduction of the dimensions and the change of the crystal shape were noticed. Decreasing the antisolvent addition rate, increasing the temperature and the addition volume below 50 ml led to a decrease in size. The new crystal of puerarin generated at the optimal conditions was 30.34 µm. The solvent of methanol and the concentration of 60 mg/ml were found to determine the type and degree of crystallinity of particles. These results showed that this process has the potential to produce a drug recrystallization product with newly generated crystal forms and the size of drug particles could be controlled through the tuning of various experimental conditions.

Polymorphic Crystallization and Structural Aspects of Agomelatine Metastable Form X Prepared by Combined Antisolvent/Cooling Process

Polymorphism is of great interest to the pharmaceutical industry because polymorphs have different physicochemical properties such as dissolution rate. In the present work, the influence of process conditions on the polymorphic antisolvent crystallization and transformations during cooling crystallization of agomelatine metastable form X from water/methanol solution has been investigated with a view of designing a robust process that includes not only crystallization but also filtration, filter cake washing, and drying. The competitive stability method was used in order to identify regions of the parametric space (water/methanol ratio, process temperature, and initial concentration) in which the crystallization of form X can be feasible. The formation of agomelatine form X was confirmed by subsequent kinetic experiments. The influence of process parameters such as the intensity of agitation, the antisolvent addition rate, and the precipitation temperature on the yield and particle size of the crystalline ...

Effective Method To Determine Supersaturation of Tar Balls Deposited along the Caspian Sea

The south coast of the Caspian Sea is being faced with oil pollution because of intensive petroleum activities in the region. Stranded tar balls on the beaches are considered as one of the evidence for oil pollution. In this study, the supersaturation of tar balls, which are collected from Caspian Sea beaches, is investigated using the anti-solvent precipitation technique. The scope of this research is the metastable zone width limit and its influence on supersaturation. Supersaturation is measured for precipitated tar ball particles within a n-hexane/methanol mixture. In general, supersaturation acts as a driving force for tar ball precipitation when the anti-solvent is added. Response surface methodology is used to evaluate the influences of vital parameters, such as anti-solvent addition rate, mixing regime, initial solute concentration, and metastable zone, on the supersaturation phenomenon, leading toward obtaining a statistical model to forecast supersaturation. In comparison of the response surface model predictions to the experimental data, a very good accuracy is noticed. Moreover, the analysis of variance (ANOVA) technique is employed to evaluate validity of the proposed model, implying that the metastability zone width has the most important effect on the supersaturation.

Gas-Antisolvent (GAS) Crystallization of Aspirin Using Supercritical Carbon Dioxide: Experimental Study and Characterization

Aspirin, which is used as a pain killer and is recommended to cure diseases such as arthritis, was precipitated using the gas-antisolvent (GAS) process. The objective of this study was to investigate the effects of four operating parameters—namely, antisolvent addition, process temperature, solute concentration, and solvent type (methanol and acetone)—on the final product particle size distribution, morphology, and crystallinity. In accordance to particle size analysis and scanning electron microscopy (SEM), it was observed that the increment of antisolvent addition rate reduced the mean size of precipitated particles and the size distributions became narrower. Furthermore, the process temperature and the solute concentration had a reverse effect on the precipitated aspirin particle size. The crystallized particles had a mean size between 48 μm and 124 μm. In contrast, particles precipitated from methanol solution had smaller mean size than from acetone. X-ray diffraction (XRD) and differential scanning c...

Controlling the polymorphism of carbamazepine-saccharin cocrystals formed during antisolvent cocrystallization using kinetic parameters

The cocrystal approach has been extensively investigated over the last decade as one of the most promising methods toward modifying the dissolution behavior of insoluble drug substances. This study demonstrates that the polymorphism of pharmaceutical cocrystalline powders prepared via antisolvent methods can be controlled using kinetic parameters. A carbamazepine-saccharin (CBZ-SAC) cocrystal was selected as a model drug in this study. This crystal was manufactured through a scaled-up antisolvent process with a total solution volume of 4.5 L. CBZ-SAC cocrystal crystalline powders were synthesized by adding 3 L of water as the antisolvent into 1.5 L of CBZ and SAC in methanol, whereby the antisolvent addition rate and the agitation speed were varied as the principal kinetic parameters. To investigate how cocrystallization proceeds under each condition, periodical sampling was combined with off-line characterization and in-line near-infrared (NIR) measurements to monitor the progress of reaction over the 120-minute process. We found that the creation of form-I was preferred when the addition speed or agitation speed was increased, but a highly pure form-II resulted if kinetic conditions were reversed. These differences in polymorphism can be explained by changes in kinetic characteristics when the process is monitored by NIR. This study is directly applicable to the industrial synthesis of these types of materials, precisely when specific CBZ-SAC cocrystalline polymorphs must be manufactured on a large scale.

Ampicillin Nanoparticles Production via Supercritical CO2 Gas Antisolvent Process.

The micronization of ampicillin via supercritical gas antisolvent (GAS) process was studied. The particle size distribution was significantly controlled with effective GAS variables such as initial solute concentration, temperature, pressure, and antisolvent addition rate. The effect of each variable in three levels was investigated. The precipitated particles were analyzed with scanning electron microscopy (SEM) and Zetasizer Nano ZS. The results indicated that decreasing the temperature and initial solute concentration while increasing the antisolvent rate and pressure led to a decrease in ampicillin particle size. The mean particle size of ampicillin was obtained in the range of 220-430 nm by varying the GAS effective variables. The purity of GAS-synthesized ampicillin nanoparticles was analyzed in contrast to unprocessed ampicillin by FTIR and HPLC. The results indicated that the structure of the ampicillin nanoparticles remained unchanged during the GAS process.