Antisolvent Crystallization Research Articles

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.

Development of Sodium Chloride Crystal Size during Antisolvent Crystallization under Different Sonication Modes

This paper reports for the first time the development in the size and shape of sodium chloride crystals during the anti-solvent crystallization in ethanol under different sonication modes. Sonication using 98 kHz and calorimetric power of 6 W was applied either continuously for a range of crystallisation times (5 – 90 s) or intermittently (5 s pulse). Under silent conditions, crystallization time of 90 s generated crystals with an average size of 73.8 ± 6.9 μm, compared to 8.7 ± 2.8 μm under 90 s of continuous sonication. However, it was observed that within the first 5 s of sonication at the beginning of the crystallization, the average crystal size was already reduced to 7.0 ± 3.3 μm. If the system was left to crystallise further to 90 s without ultrasound, the crystal size grew only slightly to 8.2 ± 1.4 μm. When 5 s burst of ultrasound was applied during the crystallization process, a bimodal distribution of small (from sonication) and large crystals (from the silent period) was obtained. These results imply that the major influence of sonication is crystal nucleation rather than fragmentation, and equilibrium is reached with 5 s sonication by precipitating most of the crystals in solution.

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...

A novel hollow fiber membrane‐assisted antisolvent crystallization for enhanced mass transfer process control

Herein, a novel hollow fiber membrane‐assisted antisolvent crystallization (MAAC) was proposed to enhance the mass transfer control over the antisolvent crystallization. A polyethersulfone membrane module was introduced as the key device for antisolvent transfer and solution mixing. An antisolvent liquid film layer was formed on the membrane surface and mixed with the solution. The liquid film also prevented the membrane from directly contacting with crystallization solution. By controlling both the shell side flow velocity and the antisolvent transfer, the antisolvent permeation rate achieved sensitive, stable, and accurate control during long‐term and repeated utilization. The interfacial mass transfer rate of MAAC was 0.66 mg cm−2 s−1, which was only 1/50 that of conventional droplet antisolvent crystallization. MAAC also provided crystal products with better morphologies and narrower size distributions than the conventional process. The stable performances of MAAC in terms of its accurate antisolvent mass transfer and antifouling capabilities were also highlighted. © 2018 American Institute of Chemical Engineers AIChE J, 65: 734–744, 2019

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.

Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 2. Antisolvent Crystallization

Continuous-Flow Tubular Crystallization To Discriminate between Two Competing Crystal Polymorphs. 2. Antisolvent Crystallization

An efficient micromixer combining oscillatory flow and divergent circular chambers

Oscillatory/pulsatile flow is an important approach for mixing enhancement at micro scales. Here we report a micromixer that consists of a microfluidic oscillator and divergent chambers. The oscillator autonomously produces an oscillatory flow, which further causes efficient stretching and folding of the fluids to improve the mixing. Testing results show that the design works well at relatively high flow rates and high viscosities. At around 40 ml/min, the mixing index can reach 0.97 at 8 mPa s, and 0.89 at 12 mPa s, respectively. Efficient mixing can also be achieved at viscosity ratios of up to 10 (20 mPa s:2 mPa s). Application of the micromixer for preparation of nano sized RDX (cyclotrimethylenetrinitramine) is investigated. Using the anti-solvent crystallization method, nano-RDX particles with the size ranging from 150 to 900 nm are obtained. Its thermal decomposition characteristics are tested and compared with the raw RDX.

A Low‐Sensitivity Nanocomposite of CL‐20 and TATB

AbstractIn order to improve the safety of 2,4,6,8,10,12‐hexanitro‐2,4,6,8,10,12‐hexaazaisowurtzitane (CL‐20) while preserving its high energy yield, a nanocomposite containing CL‐20 and 1,3,5‐triamino‐2,4,6‐trinitrobenzene (TATB) with a particular structure is prepared using an facile and fast antisolvent crystallization method. Using this approach, which takes advantage of strong antisolvent and temperature effects, a lamellar arrangement structure is created consisting of nanosheets containing CL‐20 and TATB, and further coated with dendritic nanometer‐scale TATB. XRD and Raman spectra indicate that CL‐20 in the resulting nanocomposite takes the form of α polymorph owing to the presence of ultrapure water. The HPLC results show that the TATB content of the nanocomposite is 20.2 wt%. When the surface coating of TATB is removed, 8 wt% TATB remains between the internal nanosheets. Due to the multiple desensitization effects of this structure, the nanocomposite has much lower sensitivity, roughly comparable to that of the insensitive explosive LLM‐105. Thermal analysis by thermogravimetry (TG) and differential scanning calorimeter indicates that the thermal decomposition activity of the nanocomposite is higher than those of raw materials, and in addition, its thermal stability is greater.

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.

Scandium Recovery from an Ammonium Fluoride Strip Liquor by Anti-Solvent Crystallization

In this study, the crystallization of scandium from ammonium fluoride strip liquor, obtained by solvent extraction, was investigated using an anti-solvent crystallization technique. Acetone, ethanol, methanol and isopropanol were added individually to the strip liquor as the anti-solvent and scandium was precipitated and obtained in the form of (NH4)3ScF6 crystals. The results show that scandium can be effectively crystallized from the strip liquor to obtain an intermediate, marketable scandium product. Yields greater than 98% were obtained using an anti-solvent to strip liquor volumetric ratio of 0.8. Acetone had the least performance at lower anti-solvent to strip liquor volumetric ratios, possibly due to its limited H bonding capability with water molecules when compared to alcohols.

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.

Determination of metastable zone width and nucleation kinetics for combined cooling and antisolvent crystallization of L-asparagine monohydrate in water-isopropanol mixture

The metastable zone width (MSZW) was measured for combined cooling and antisolvent crystallization of L-asparagine monohydrate (LAM) in water-isopropanol solution by conventional polythermal method. The effects of cooling rate, antisolvent flow rate and saturation temperature on the MSZW were investigated and analysed using both statistical and theoretical models. The relationship of MSZW with these factors are more complex compared to cooling-only or antisolvent-only crystallization. For each of these three factors, a range of values were determined where the MSZW behaves in a more predictable manner and follows the behaviour of cooling-only crystallization. The effect of antisolvent flow rate was more pronounced compared to cooling rate in case of combined cooling and antisolvent crystallization of LAM. The obtained MSZW data were also used for the estimation of nucleation kinetics using the method proposed by Kubota.

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

Continuous crystallization in tubular crystallizers is of particular interest to the pharmaceutical industry to accurately control average particle size, particle size distribution, and (polymorphic) shape. However, these types of crystallizers require fast nucleation, and thus, short induction times at the beginning of the flow process, which is challenging for larger and complex organic molecules. High shear and/or the presence of bubbles were identified to influence the nucleation behavior. This work investigates the effects of both high-shear mixing and ultrasound on the anti-solvent crystallization of paracetamol in acetone–water. Both devices generate intense amounts of shear and gas bubbles. Generally, the results show that increasing input power decreases the induction time significantly for both the rotor–stator mixer and ultrasound probe. However, the induction time is almost independent of the supersaturation for the ultrasound probe, while the induction time significantly increases with decreasing supersaturation for the rotor–stator mixer. In contrast, the particle size distribution for the rotor–stator mixer is independent of the supersaturation, while increasing supersaturation decreases the particle size for the ultrasound probe.

Ultrasensitive Heterojunctions of Graphene and 2D Perovskites Reveal Spontaneous Iodide Loss

Summary Despite the demonstrated high efficiency of perovskite solar cells and light-emitting devices, the understanding of the intrinsic stability of perovskites is far from complete. In this work, using an ultrasensitive, exfoliated 2D perovskite single-crystal sheet/graphene heterostructure device, we reveal spontaneous iodide loss as an important degradation pathway of 2D perovskite single crystals, which n-dopes the perovskite semiconductor by generating positively charged iodide vacancies. Furthermore, we show that covering perovskites with graphene can suppress the iodide loss, significantly improving perovskite stability. A perovskite phototransistor is demonstrated with a graphene/2D perovskite/graphene structure, which shows no degradation after 75 days. Our work not only provides important insights for future stable perovskite optoelectronic device development, but also demonstrates the potential of graphene as a promising sensitive diagnostic tool for device and material degradation studies.

High performance perovskite light-emitting diodes realized by isopropyl alcohol as green anti-solvent

Organic-inorganic hybrid perovskites (OIHPs) have been emerged as promising emitting materials for light-emitting diodes due to their miraculous optoelectronic properties. In pursuit of high perovskite quality, anti-solvent assisted crystallization (ASAC) is currently one of the most widely used low-energy consumption methods. However, traditional large-volume use of ASAC anti-solvent, such as chlorobenzene (CB), chloroform (CF), are hazardous to both the environment and human beings. Therefore, the development of green solvent for the ASAC will be of great important for the fabrication of perovskite light emitting diodes (PeLEDs) in more sustainable and environmental friendly ways. Herein, we employ a green solvent, isopropyl alcohol (IPA), as anti-solvent in ASAC for the first time, resulting in a high efficient PeLEDs with a maximum luminance of 7960 cd m−2, a current efficiency of 2.2 cd A−1, and a low turn-on voltage of 2 V. Compared to traditional toxicity solvents, IPA based ASAC leads to smoother surfaces and smaller grains of perovskites, while keeping the same crystallization features. Our results demonstrate that IPA is an excellent green ASAC anti-solvent alternative for high-quality perovskite film, and thus providing a novel opportunity for the low-cost and eco-friendly fabrication of PeLEDs.

Continuous production of drug nanocrystals by porous hollow fiber-based anti-solvent crystallization

Nanotechnology is being utilized to develop advanced concepts in drug delivery systems including production of nanodrugs such as, nanocrystals and nanosuspensions. Continuous crystallization methods are of increasing interest and porous hollow fiber membrane (HFM) based modules have been recently utilized as an anti-solvent crystallizer. The porous hollow fiber anti-solvent crystallizer (PHFAC) based method has been modified here to produce continuously nanocrystals of Griseofulvin (GF). In the PHFAC device, deionized water introduced from the HFM bore into the shell side is used as the anti-solvent; acetone containing dissolved GF is introduced into the shell side of the HFM module as the drug solution. Water, the anti-solvent, mixed vigorously with the drug solution leading to drug crystallization and the drug crystals were separated by vacuum filtration and freeze-dried. The experimental conditions were varied to control the particle size, size distribution and the appearance of the nanoparticles. The properties of the drug nanocrystals were characterized via Transmission Electron Microscopy (TEM), Scanning Electron Microscope (SEM), Dynamic Light Scattering (DLS), Raman Spectroscopy, Energy Dispersive X-rays Spectroscopy (EDX), Differential Scanning Calorimetry (DSC), FT-IR Spectrometer, X-ray Diffraction (XRD); drug dissolution tests were also implemented. Drug nanocrystals as small as 86.4 nm were produced under modest pressure and temperature conditions in a controllable and continuous manner.

OpenCrys: Open-Source Software for the Multiscale Modeling of Combined Antisolvent and Cooling Crystallization in Turbulent Flow

The open-source software, called openCrys, is provided for the multiscale simulation of antisolvent and combined antisolvent-cooling crystallization. It simulates the macro- and micromixing scales, and the complete energy and population balance equations during crystal nucleation and growth. The model is based on the Reynolds-Averaged-Navier–Stokes equation, coupled with a three-environment presumed probability density function model, and the spatially varying population balance equation semidiscretized using a high resolution finite-volume method. openCrys is implemented in C++ object oriented programming language using the open-source CFD package OpenFOAM. The software is used to compare the performance of dual impinging jet, coaxial, and radial crystallizers. It is shown that improving the micromixing does not necessarily result in a narrower crystal size distribution when temperature effects are taken into account. The complex interplay of crystallizer kinetics and momentum, mass, and heat transfer makes the selection of the best mixer for a particular application to be nonobvious, which motivates the development and application of high-fidelity multiscale simulations for the design of antisolvent crystallizers.

Design and in vivo evaluation of entecavir-3-palmitate microcrystals for subcutaneous sustained delivery

The objectives of this study were to formulate microcrystals of entecavir-3-palmiate (EV-P), a palmitic acid ester of entecavir (EV), and evaluate the influence of particle size on its pharmacokinetic behavior following subcutaneous (SC) injection. Systemic toxicity and local tolerability of the hepatitis B anti-viral suspension were further evaluated in normal rats. EV-P microcrystals possessing median diameters of 2.1, 6.3, and 12.7 µm were fabricated using anti-solvent crystallization technique with polysorbate 20 and polyethylene glycol 4000 as steric stabilizer. Dissolution rate of EV-P microcrystals was controlled by adjusting the particle size, under sink condition. Pharmacokinetic profiles of 2.1 µm-sized and 6.3 µm-sized EV-P microcrystals were quite comparable (1.44 mg/kg as EV), over 46 days in rats. The absorption rate and extent of EV after SC injection of 12.7 µm-sized microcrystals were significantly retarded, due to its slower dissolution rate in aqueous media. No single-dose systemic toxicity was observed after SC injection of high dose of EV-P microcrystal suspension (30–300 mg/kg as EV). The microcrystals were tolerable in the injected site, showing mild inflammatory responses at a dose of 30 mg/kg. Therefore, the novel microcrystal system with median particle size of below 6.3 µm is expected to be a unique long-acting system of the anti-viral agent, improving patient’s compliance with chronic disease.

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...

Controlling interfacial mixing zone for microfluidic flow of liquid streams

Controlling the position and dimension of interfacial mixing width within microchannels helps in variety of applications ranging from anti-solvent crystallization to precisely locating the chemical reaction in microchannels, selective separation by convective transport, synthesis of mono-dispersed nanoparticles, reducing the transport resistance in microfluidic fuel cells, optofluidic lenses, etc. This is a big challenge especially while dealing with the miscible liquid streams. Here, we show the variation of the interfacial mixing width for two miscible liquid streams flowing in microchannels. Dynamics of mixing of the liquid streams has been studied in the near vicinity of the junction in the microchannels of different aspect ratios. We found that the convective mixing inside the microchannel is very much dependent on the relative flow rates of the streams and their Reynolds numbers. Interdiffusion mixing width decreased with increasing Reynolds number at any specific point in the direction downstream to the junction. The relative flow rates and Reynolds number of the streams have been found as influencing factors controlling the position of the interface in the microfluidic flow of liquid streams in co-laminar flow.