Antisolvent Crystallization Process Research Articles

Curcumin nanoparticles containing poloxamer or soluplus tailored by high pressure homogenization using antisolvent crystallization

Curcumin is a natural active constituent of Curcuma longa from Zingiberaceae family that shows many different pharmacological effects such as anticancer, antioxidant, anti-inflammatory, antimicrobial and antiviral effect. However, its bioavailability is profoundly limited by its poor water solubility. In this study antisolvent crystallization followed by freeze drying was used for the preparation of curcumin nanoparticles. The presence of different ratios of hydrophilic polymers (poloxamer 188 & soluplus) on physicochemical properties of curcumin nanoparticles was also investigated. In addition, the effect of high pressure homogenization (HPH) on solubility and dissolution properties of curcumin was investigated. All nanoparticle formulations were examined to determine their particle size distribution, saturation solubility, morphology (SEM), solid state (DSC, XRPD and FT-IR) and dissolution behavior. It was observed that curcumin crystallized in the presence of polymers exhibited better solubility and dissolution rate in comparison with original curcumin. The results showed that the concentration of the stabilizer and the method used to prepare nanoparticles can control the dissolution of curcumin. The crystallized nanoparticles showed polymorph 2 curcumin with lower crystallinity and higher dissolution rate. Curcumin nanoparticles containing 50% soluplus prepared via HPH method presented 16-fold higher solubility than its original form. In conclusion, samples crystalized and proceed with HPH technique showed smaller particle size, better re-dispersibility, higher solubility and dissolution rate in water compared with a sample prepared using a simple antisolvent crystallization process.

Solution-phase, template-free synthesis of PbI2 and MAPbI3 nano/microtubes for high-sensitivity photodetectors.

Organic-inorganic hybrid perovskite materials with exotic semiconducting properties have become inevitable candidates for next-generation electronic devices. Very recently, a low dimensional nanostructure of the perovskite materials has attracted the scientific community due to its enhanced performance in optoelectronics as compared to its bulk counterparts. Herein, a facile method was developed for the scalable, room-temperature synthesis of CH3NH3PbI3 (MAPbI3) nano/microtubes by direct conversion of lead iodide (PbI2) microtubes through a solution-phase method. At first, the PbI2 microtubes were synthesized by the anti-solvent crystallization process and subsequently converted to CH3NH3PbI3 nano/microtubes by the addition of CH3NH3I (MAI) precursor directly in the solution phase. The corresponding photodetectors (PDs) in the lateral metal-semiconductor-metal (MSM) configuration of the PbI2 microtubes and MAPbI3 nano/microtubes on glass substrates were investigated systematically. Compared to the PbI2 based PDs (557 mA W-1, 3.65 × 1012 Jones, 0.251 s/0.252 s), the MAPbI3 based PDs exhibit higher photoresponsivity, specific detectivity, and faster response time (25 A W-1, 9.9 × 1013 Jones, 49 ms/20 ms) under irradiation with 4.6 μW cm-2 intensity light of the 532 nm laser at a bias of 5 V. The proposed method is a low-temperature process, easy to apply in large scale synthesis, and finds potential applications in optoelectronic devices.

Statistical methodology for scale-up of an anti-solvent crystallization process in the pharmaceutical industry

The scale-up of crystallization processes is a challenging step in production of active pharmaceutical ingredients (APIs). When moving from lab to industrial scale, the mixing conditions tend to modify due to the different geometry and agitation performance, which is particularly important in anti-solvent crystallizations where the size of the crystals depends on the mixing and incorporation of the anti-solvent in the solution. In this work, the results obtained in anti-solvent lab-scale crystallization experiments were used to develop multivariate statistical models predicting Particle Size Distribution (PSD) parameters (Dv10, Dv50 and Dv90) in function of predictors such as percentage of volume, power per volume and tip speed. Firstly, the collinearity among the predictors was assessed by Variance Inflation Factor (VIF) diagnosis. Subsequently, least squares method was employed to find correlations among the predictors and output variables. The optimization of the models was executed by testing quadratic, logarithmic and square root terms of the predictors and removing the least statistically significant regression coefficient. The quality of the fitting was evaluated in terms of adjusted R2 (R2adj). The modelled Dv10, Dv50 and Dv90 values presented a good fitting to the experimental data, with R2adj higher than 0.79, either when using power per volume or tip speed along the percentage of volume as predictors. Afterwards, the particle size distribution parameters of industrial scale production were predicted using the previously developed models. The deviations between predicted and experimental values were lower than 17%. This demonstrates that multivariate statistical models developed in lab-scale conditions can be successfully used to predict particle size distribution in industrial-size vessels.

Self-Induced Nucleation During the Antisolvent Crystallization Process of Candesartan Cilexetil

We report that the induction time goes through a maximum with increasing the agitation rate, while the majority of studies in the literature have noted a monotonic decrease in the nucleation rate w...

Additive-Free Morphology Control of Organic Polyhedral Molecular Crystals by the Antisolvent Molecular Geometry: From Rod, Disk, to Cube

The role of antisolvent molecular geometry on the determination of the final molecular crystals morphology formed by the reverse antisolvent crystallization (r-ASC) process has been unveiled. Herein, we newly report that the rod-, disk-, and cube-shaped tetra(4-aminophenyl)porphyrin molecular crystals were selectively obtained by employing o-, m-, and p-xylene as an antisolvent during r-ASC process with ethanol employed as a good solvent. The X-ray diffraction results of the crystals provide a clear indication about the correlation between the solute–solvent interactions and the resulting crystal morphologies. The results show that the geometry of xylene has a pivotal effect on the crystal growth direction and morphologies, especially for polyhedrons. This finding would provide opportunities not only for realization of quite rare organic polyhedral crystals but also for in-depth studies about the fundamental crystallization process.

Study the operating conditions on agglomeration of RDX particles in anti-solvent crystallization by using statistical optimization

Abstract The unfavorable growth and agglomeration of micro-particles of RDX explosive was almost observed in manufacture process. For preventing of growth of micro-particles and agglomeration in anti-solvent crystallization process, the effect of additives glucose, sucrose and poly ethylene glycol-2000 and wetting solvent of isopropyl alcohol were studied. Taguchi experimental design was used for optimization of the operating conditions. The type of additive, the amount of additive (%wt.), solvent of wetting and wetting time were selected for optimization of the conditions. By using 4 factor and 3 levels, 27 experiments were conducted (L27). Results showed that in the presence of 2 %wt. of sucrose additive and isopropyl alcohol solvent, the agglomerations of particles were decreased so that a decrease 30–50% in the average of particles size was seen. Addition additives were effective in storage container and for reduce the agglomeration of particles during storage. Also, the agglomeration rate of particles was reduced over time at optimized conditions. Imaging optical microscopy, scanning electron microscopy (SEM), and particle size analyzer (PSA) methods were used for particles size analyzing as a response in statistical optimization and quality control of the final product. The sensitivity to some mechanical and shock stimuli on the RDX in presence of sucrose additive was tested and the obtained results showed the insignificant effect of additive on the safety properties of pure RDX.

Determination and Correlation of the Solubility of l-Fucose in Four Binary Solvent Systems at the Temperature Range from 288.15 to 308.15 K

Experimental solubility data of l-fucose in methanol + water, ethanol + water, 2-propanol + water, and acetone + water systems were measured at temperatures ranging from 288.15 to 308.15 K under atmosphere pressure (P = 0.1 MPa), using the gravimetric method. The experimental results indicate that the solubility of l-fucose increases with increasing temperature and water content, as well as decreasing with the composition of organic solvents used in this work. According to the data measured in this experiment, methanol is less effective than ethanol, 2-propanol, and acetone in the antisolvent crystallization process of l-fucose. By means of our research, the solubility of l-fucose in the pure solvents was affected by polarity and hydrogen bond. The modified Apelblat model, CNIBS/R-K model, and Apelblat–Jouyban–Acree model were used to correlate the solubility data, and all three of the thermodynamic models were found to agree well with the measured experimental solubility data.

CFD Simulation of a Drowning‐out Crystallizer for Hexanitrohexaazaisowurtzitane

AbstractHexanitrohexaazaisowurtzitane (HNIW) is widely used for explosives, filling warheads, and solid propellants due to its high energy density and no halogen content. A pilot‐scale drowning‐out crystallizer is suggested to produce ε‐form HNIW and computational fluid dynamics simulation (CFD) was carried out. Acetone and isopropyl alcohols served as solvent and antisolvent, respectively. Population balance with quadratic method of moment was employed for the prediction of crystal size distribution and the results were compared with experimental data. The driving force of antisolvent crystallization includes impeller speed, ratio of antisolvent to solvent, and feed flow rate. A case study with various operating conditions was performed to identify the influence of such driving forces on crystal mean diameter. The aim was a scale‐up of the antisolvent crystallization process based on experimental results and CFD simulation.

Quantitative Monitoring the Anti-Solvent Crystallization and Storage Process for Nandrolone by Near-Infrared Spectroscopy

A novel hydrate (SH2O) of nandrolone was prepared by anti-solvent methods. The crystallization processes with 2 schemes (A and B) were monitored by in-line near-infrared (NIR) spectroscopy. The amounts of SH2O in powder samples obtained by the anti-solvent crystallization and storage process were quantified by NIR combined with chemometrics methods. In-line NIR spectra from 4500 to 8000 cm−1 were chosen to capture physicochemical changes during the whole crystallization process. The combination of the principal component results with offline characterization (scanning electron microscopy, powder X-ray diffraction, NIR) data showed that both schemes yielded high purity SH2O products, but the crystallization speed of scheme B was significantly accelerated. It was demonstrated that in-line NIR spectroscopy combined with principal component analysis can be very useful to monitor in real time and control the anti-solvent crystallization process. Moreover, the solubility and the solid-state transformation of nandrolone under different storage conditions were investigated. The apparent solubility of SH2O was 2.19-2.44 times of Form I, and SH2O was relatively stable when stored at a high relative humidity and temperature below 25°C.

Determination, Correlation, and Application of Sodium l-Ascorbate Solubility in Nine Pure Solvents and Two Binary Solvents at Temperatures from 278.15 to 323.15 K

The solubility data of sodium l-ascorbate in water, methanol, ethanol, acetone, chloroform, ethyl acetate, isopropyl alcohol, isobutyl alcohol, n-hexane, water–methanol mixture and water–ethanol mixture have been determined in the temperatures range of 278.15–323.15 K by a static analytic method at atmospheric pressure. The experimental data were correlated with the modified Apelblat equation, CNIBS/R-K model, and Jouyban–Acree model. On the basis of the solubility data, a novel model-free design approach (semisupersaturation control, SSSC) for combined cooling and antisolvent crystallization (CCAC) processes has been proposed and evaluated for sodium l-ascorbate in a methanol–water mixture. This approach can be easily implemented without complicated online monitors. Sodium l-ascorbate crystals with large and uniform morphology were obtained using the CCAC process, which was designed by the SSSC approach.

Size and Shape Control of Micron-Sized Salicylic Acid Crystals during Antisolvent Crystallization

During an antisolvent crystallization process, micron-sized crystals of salicylic acid in the particle size range 20 to 150 μm were prepared under specific sets of crystallization conditions, with a focus on drug concentration, temperature, and solvent composition. For each experiment, the size outcome was determined by a number of knock on (often competing) influencing factors, including supersaturation, mass available for deposition during crystallization, and influence of temperature and solvent composition on crystallization kinetics. A certain fraction of the crystals, especially at higher solute concentration, developed a spectacular hollow shape with an almost perfect rectangular outer cross-section. A mechanistic explanation for the formation of hollow crystals is proposed. The use of additives during crystallization introduced further control over the size and, perhaps more noticeably, over the shape of the salicylic acid crystals. The lengths of salicylic acid crystals decreased to as low as 6 μ...

Insight into the Role of Additives in Controlling Polymorphic Outcome: A CO2-Antisolvent Crystallization Process of Carbamazepine

Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge in pharmaceutical science and engineering. For instance, CO2-antisolvent crystallization typically favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with impurities of other forms. This work demonstrates for the first time that a supercritical CO2-antisolvent crystallization process in combination with certain molecular additives allows control of the polymorphic outcome of CBZ. We show herein that in the presence of sodium stearate and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate, ethyl cellulose, and maltitol. This selectivity for pure forms in this supercritical set up contrasts to the results when the same set of additives where used in a solvent evaporation method that yielded mixtures of form I, II, and III. The type of additi...

Solubility of taurine and its application for the crystallization process improvement

The solubility of taurine in the binary water+acetone solvent mixture at temperatures from 278.15K to 323.15K was measured using the laser monitoring technique, and the experimental data were well correlated by the Jouyban–Acree model. The solubility decreased quickly when the mole fraction of acetone increased in the binary solvent mixture and also the metastable zone width got narrowed at the same time. Then the nucleation mechanism was investigated based on the induction time. The results showed that the homogeneous dominated at higher supersaturation while the heterogeneous nucleation dominated at lower supersaturation. Finally, a combined cooling and anti-solvent crystallization process was put forward. The product yield was raised to 96% from 73%, compared with the original cooling crystallization process in aqueous solution. What's more, the caking of taurine crystals was reduced and the fluidity of the product obtained was improved.

SOLUBILITY OF A NEW ANTIRETROVIRAL DRUG (CRS 74) IN AQUEOUS ETHANOL MIXTURES

This study concerns a new antiretroviral drug named CRS 74, which has a limited bioavailability because of its low aqueous solubility and dissolution rate. To improve these properties, CRS 74 can be recrystallized by using Liquid Anti-Solvent (LAS) crystallization. Ethanol is chosen as the solvent under study for the molecule and water as the anti-solvent. Since solubility data is limited, it is necessary to collect experimental data for the molecule in relation to ethanol and water-ethanol mixtures at different temperatures in order to select suitable mixture compositions and temperature for LAS process design. In this work, the CRS 74 solubility measured in the temperature range 288.15-303.15 K in pure ethanol and in 95% water 5% w/w ethanol mixtures, and the CRS 74 solubility measured at 303.15 K in water-ethanol mixtures containing from 30 to 70% w/w ethanol are presented. Measurements were performed using the shake-flask method for generating the saturated solutions followed by compositional analysis by HPLC of the solution. The experimental data showed that the solubility of CRS 74 in binary hydroalcoholic mixtures increases upon increasing the temperature and mass fraction of ethanol. In order to better understand the behavior of the system and to estimate supersaturation conditions for a larger range of CRS 74 crystallization conditions, two models have been chosen to describe the experimental data: UNIQUAC and Jouyban-Acree models. The modeling of experimental solid-liquid equilibrium data proved that both models could correlate satisfactorily the solubility of the studied drug. This study provided valuable data for the recrystallization of CRS 74 by using the Liquid Anti-Solvent (LAS) crystallization process.

Understanding the enhanced solubility of 1,3-benzenedicarboxylic acid in polar binary solvents of (acetone + water) at various temperatures

Understanding solid dissolution in polar binary solvents showing maximum or minimum solubility phenomenon is essential for the design and operation of anti-solvent crystallization process. Solubilities of 1,3-benzenedicarboxylic acid in binary solvents of acetone with water are measured from 278.15 to 323.15K using the static equilibrium method, covering the entire range of solvent composition. The solubility always increases with increasing temperature, while, at fixed temperature, a maximum solubility is observed in mixed solvents of certain composition. The experimental temperature-dependent solubility data of 1,3-benzenedicarboxylic acid in cosolvents of different compositions are correlated using the Apelblat model with an average relative deviation (ARD) of 0.18%. Calculations of the derived thermodynamic functions show that the dissolution of 1,3-benzenedicarboxylic acid in the solvent mixtures is endothermic and mainly driven by the enthalpy change. The Simplified Modified Wilson (SMW) model is adopted to reproduce the isothermal solubility data over the entire acetone composition with an overall ARD of 1.41%, with which the maximum mole fraction solubility and the corresponding solvent composition at different temperatures are determined, and are subsequently used to estimate the solubility parameter of 1,3-benzenedicarboxylic acid.

A generalized stochastic modelling approach for crystal size distribution in antisolvent crystallization operations

A generalized formulation for the development of stochastic models to predict the crystal size distribution (CSD) in antisolvent crystallization processes is proposed. Exploiting the result of the noise induced dynamic in stochastic processes, new results are provided to represent the CSD as function of the operational parameters. The generalized formulation enables the full description of the CSD using nonlinear drift term in conjunction with multiplicative noise, i.e., state dependent diffusion. For the first time a deterministic nonlinear differential equation to represent the mean and most probable size (mode) time evolution as function of the model parameters is provided. Furthermore, the analytical solution of the asymptotic probability distribution of the CSD can also be obtained. Finally, a global model formulation is finally presented by defining relationships between the model parameters and the operating conditions. Experimental results and validations are provided using the ternary system of NaCl, water, and ethanol. © 2016 American Institute of Chemical Engineers AIChE J, 63: 551–559, 2017

An advantageous technique to load drugs into aerogels: Gas antisolvent crystallization inside the pores

Over the past few years, both organic and inorganic nanoporous aerogels have shown a great promise as drug delivery vehicles. Different methods are utilized to load drugs into aerogels such as the addition of the drug to the reaction mixture in one of the steps before the gel formation or by supercritical deposition to the aerogels. These techniques have disadvantages such as possible reactions of pharmaceutical compounds with reactants used to form gels and low solubility of pharmaceutical compounds in supercritical carbon dioxide (scCO2). An alternative technique is to load the drug after gel formation by contacting the gel with a solution of the drug. The drug diffuses into the liquid inside the pores. When this drug-loaded gel is subjected to supercritical drying, scCO2 not only removes the solvent from the pores but also acts as an antisolvent, which causes the precipitation of the drug in the pores of the aerogel. This is similar to the gas antisolvent crystallization (GAS) process but in this case the process takes place inside the pores. In this study, this technique was used to load paracetamol into silica aerogels. The factors affecting the amount and distribution of the drug inside the aerogel matrix were investigated and a mathematical model to account for the movement of paracetamol inside the pores during supercritical drying leading to a varying drug concentration in the matrix with position was developed. It was concluded that high initial concentrations resulted in more homogeneous drug distributions. Moreover, XRD analysis demonstrated that paracetamol was in crystalline form. The process enables higher amount of loadings than conventional systems and also offers an advantage as it combines two processes such as drying and loading in a single one reducing the time and the operating expenses.

Mathematical Modeling, Design, and Optimization of a Multisegment Multiaddition Plug-Flow Crystallizer for Antisolvent Crystallizations

In the pharmaceutical industries, the requirements of rapid process development and scalable design have made the tubular crystallizer a promising platform for continuous manufacturing and crystallization processes, capable of replacing conventional capital- and labor-intensive batch operations. This paper takes a process systems engineering (PSE) approach to the optimal design of a continuous antisolvent addition crystallizer to deliver the most promising product qualities, such as the crystal size distribution. A multisegment multiaddition plug-flow crystallizer (MSMA-PFC) is considered as an example of a continuous antisolvent crystallization process, in which the total number, location, and distribution of antisolvent additions are to be optimized. First-principles dynamic and steady-state mathematical models for the MSMA-PFC are presented, based on example kinetic models for nucleation and growth of paracetamol crystallizing in acetone, with water as the antisolvent. The performances of different cry...

A deterministic formulation and on-line monitoring technique for the measurement of salt concentration in non-isothermal antisolvent crystallization processes

A deterministic formulation and on-line monitoring technique for the measurement of salt concentration in non-isothermal antisolvent crystallization processes

Naproxen–Nicotinamide Cocrystals: Racemic and Conglomerate Structures Generated by CO2 Antisolvent Crystallization

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to the CO2 antisolvent batch crystallization process. The structure of the molecular complex and its intermolecular interactions were investigated by single-crystal X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopy. The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO2 feed rate, while very fast introduction of CO2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis, and temperature-resolved X-ray powder diffraction were used to probe the relationship between the different phases. In addition, all powders produced with CO2 technology were obtained as cocryst...