Narrow Crystal Size Distribution Research Articles

CFD-population balance modelling for a flat sheet membrane-assisted antisolvent crystallization

A comprehensive model has been developed to couple CFD with the population balance equation (PBE) for a flat sheet membrane-assisted antisolvent crystallization (FS-MAAC) process. The model accurately depicts the fluid dynamics, mass transfer, heat transfer and crystal size distribution (CSD) in the FS-MAAC crystallizer. The crystallization system considered was to produce α-form crystals of glycine. The model investigates the effects of different parameters, such as the velocities of the crystallizing and antisolvent solutions, antisolvent composition, temperature, and gravity. A good agreement was observed between the simulation results and experimental data for the α-form crystals of glycine. The simulation results show a steady-state antisolvent concentration profile in the liquid layer and varied only in the z-direction. Regardless of the variations in the velocity of either the antisolvent solution or the crystallizing solution, the CSD remained narrow, with mean crystal sizes ranging from 27 to 40 μm. Furthermore, increasing mass transfer through the antisolvent transmembrane flux leads to a narrower CSD. Slower antisolvent permeation rates at higher temperatures also promote crystal growth. Also, a narrow CSD is maintained regardless of the initial circulation position of the antisolvent solution. In conclusion, membrane antisolvent crystallization provides a reliable and consistent solution for obtaining crystals with desired CSD under optimal operating conditions.

Tuning membrane properties to control supersaturation of antisolvent crystallization

The crystal morphology influences the properties of organic compounds, especially in pharmaceutics such as the dissolution and absorption of drugs in the human cells. In antisolvent crystallization, the crystal size and shape are tied to the degree of mixing and dosage of antisolvent, which could be controlled using membranes with specific morphology/surface properties. Little is known though on the relationship between membrane characteristics, antisolvent mass transfer and crystal properties. Flat sheet polyvinylidene fluoride (PVDF) membranes were prepared using non-solvent induced phase separation, to illustrate the impact of membrane characteristics on the resulting crystal size distribution (CSD) obtained using membrane-assisted antisolvent crystallization (MAAC). The crystallization of glycine was taken as case study. We showed the antisolvent transmembrane flux increased when the membrane thickness decreased, or when the hydrophobicity or the porosity increased. After MAAC operation, membranes had no significant change in surface functional groups, hydrophobicity nor structure. The best-performing membrane was found to have 119° hydrophobicity, 89.4 % porosity and 140 μm thickness, reaching high reproducibility of CSD corresponding to stable transmembrane fluxes throughout 180 min of operation. The capacity of MAAC to consistently produce a narrow CSD at optimum membrane characteristics makes this technology very competitive with conventional crystallization processes.

Performance of membrane distillation assisted crystallization and crystal characteristics for resource recovery from desalination brine

Membrane distillation crystallization (MDC) has been widely studied in recent year for its potential for resource recovery from desalination brine with high concentrations. In this study, crystal samples produced from a bench-scale MDC system have been analysed for crystal morphology, crystal purity and crystal size distribution (CSD). In addition, orthogonal fractional factorial (OFF) experimental design has been introduced to evaluate the influence of various operating conditions on the crystal size and CSD. Feed temperature (40 to 60 °C), crystallization time (60 to 180 min) and the feed composition have been used as the control factors. The results show that the MD in the MDC system maintains a consistent flux of 1.32 to 4.2 kg/m2·h across various feed compositions; higher feed temperatures led to the formation of larger crystal clusters, while longer crystallization time yielded more cubic-shaped crystals; an overall NaCl purity exceeding 99.08 % has been achieved throughout all the experiments; and the increased feed temperature and prolonged crystallization time results in a narrower CSD. The result of OFF experimental design identifies feed temperature as the dominant factor affecting crystal size and CSD. However, the presence of impurities in the feed water could pose challenge to the thermal stability and longevity of the membrane.

Valorization of acid mine drainage into potable water and valuable minerals through membrane distillation crystallization

Owing to the rise in population growth and demands for the current living standards, mineral and water resources are depleting at the alarming rate. Also, the mineral–water-energy nexus raises a concern of high-quality water and mineral production at low costs. Membrane distillation crystallization (MDC) has emerged as a promising technology capable of simultaneous water and mineral recovery from wastewater or industrially discharged brines. Herein, the MDC was evaluated for recovery of water and precious minerals from acid mine drainage discharged from the mine tailings. High quality fresh water with 99.9 % salt rejection and permeate flux of 2.32 kg·m−2·h−1 was recovered at 52 °C feed inlet temperature. Also, feed temperatures were varied to determine their impact on mineral crystal morphology, size distribution and growth rate. Predominantly recovered minerals were gypsum, manganese fluoride, potassium iron oxide, nickel oxide hydroxide, sodium sulphate and dihydrogen sulphate. Orthorhombic crystal structure of mineral salts was attained at low feed inlet temperature (34 °C). Higher feed inlet temperatures (i.e. 41° C and 52° C) promoted co-crystallization giving rise to orthorhombic polymorph structures. Narrow crystal size distribution was reported at low water recovery factor (initial growth) for all temperatures. However, the particle size distribution broadened as the recovery factor increased. The crystal sizes ranged from 3.91 ± 0.97 µm to 14.04 ± 3.31. Remarkably, crystal growth rate increased with an increase in feed inlet temperature. These findings open a research direction towards economic recovery of mineral and water to supplement the existing shortages. With a myriad of crystals obtained from the MDC process, an additional operational unit is required to selectively recover high economic minerals.

Cooling Crystallization of Paracetamol in a Slug-Flow Crystallizer with Silicone Oil as Continuous Phase

Continuous tubular crystallizers that can provide high yield and better control of crystal size would be of great interest to the industrial crystallization process. However, most continuous crystallizer designs face challenges either due to surface fouling or crystal breakage. In this paper, we explore the ability of slug-flow cooling crystallizers to continuously generate acetaminophen crystals using silicone oil as the continuous phase. Each slug acts as a crystallizer, and the crystals formed inside the dispersed phase avoid encrustation. Three crystallizer configurations were studied at a wide range of supersaturation and flow rates. It was found that a narrow crystal size distribution can be achieved at high flow rates and high supersaturation. Additionally, the average crystal size and the crystallization yield increased with supersaturation and residence time. The configuration of the tubular crystallizer was found to influence the crystallization yield by affecting the internal mixing in the slugs. With further studies, slug-flow cooling crystallizer can be developed for continuous crystallization of crystals with a narrow size distribution, polymorphic purity, and good yield.

Anti-solvent crystallization behavior of triphenylmethanol in a droplet-based microfluidic device

Anti-solvent crystallization behavior of triphenylmethanol, a multifactorial problem, was studied utilizing a droplet-based microfluidic device by integrating the in-situ visualization and off-line analyses. We successfully mitigated the adsorption and aggregation of crystals at the interface by adding the surfactant in microdroplets, obtaining high-quality crystals with the smaller median size (D50) reduced by 29% and narrower crystal size distribution (CSD) compared to samples without surfactant added. This study systematically investigated the effects of surfactant, initial concentration of solute and anti-solvent content on the crystal size, CSD and the crystal number per droplet. The phase diagram consisting of microdroplets array was constructed, clearly dividing the unsaturated zone and nucleation zone. The microfluidic chip with features of mixing and dispersing was designed, expanding the microfluidics application in rapid nucleation systems. The basic data we provided pave the way for further research on the metastable zone width, kinetics and thermodynamics of crystallization in microscale-confinement.

In-drop thermal cycling of microcrystal assembly for senescence control (MASC) with minimal variation in efficacy.

The secretome from mesenchymal stem cells (MSCs) has recently gained attention for new therapeutics. However, clinical application requires in vitro cell manufacturing to attain enough cells. Unfortunately, this process often drives MSCs into a senescent state that drastically changes cellular secretion activities. Antioxidants are used to reverse and prevent the propagation of senescence; however, their activity is short-lived. Polymer-stabilized crystallization of antioxidants has been shown to improve bioactivity, but the broad crystal size distribution (CSD) significantly increases the efficacy variation. Efforts were made to crystalize drugs in microdroplets to narrow the CSD, but the fraction of drops containing at least one crystal can be as low as 20%. To this end, this study demonstrates that in-drop thermal cycling of hyaluronic acid-modified antioxidant crystals, named microcrystal assembly for senescence control (MASC), can drive the fraction of microdrops containing crystals to >86% while achieving significantly narrower CSDs (13±3μm) than in bulk (35±11μm). Therefore, this approach considerably improves the practicality of CSD-control in drops. In addition to exhibiting uniform release, MASC made with antioxidizing N-acetylcysteine extended the release time by 40%. MASC further improves the restoration of reactive oxygen species homeostasis in MSCs, thus minimizing cellular senescence and preserving desired secretion activities. We propose that MASC is broadly useful to controlling senescence of a wide array of therapeutic cells during biomanufacturing.

Key Parameters Impacting the Crystal Formation in Antisolvent Membrane-Assisted Crystallization.

Antisolvent crystallization is commonly used in the formation of heat-sensitive compounds as it is the case for most active pharmaceutical ingredients. Membranes have the ability to control the antisolvent mass transfer to the reaction medium, providing excellent mixing that inhibits the formation of local supersaturations responsible for the undesired properties of the resulting crystals. Still, optimization of the operating conditions is required. This work investigates the impact of solution velocity, the effect of antisolvent composition, the temperature and gravity, using glycine-water-ethanol as a model crystallization system, and polypropylene flat sheet membranes. Results proved that in any condition, membranes were consistent in providing a narrow crystal size distribution (CSD) with coefficient of variation (CV) in the range of 0.5-0.6 as opposed to 0.7 obtained by batch and drop-by-drop crystallization. The prism-like shape of glycine crystals was maintained as well, but slightly altered when operating at a temperature of 35 °C with the appearance of smoother crystal edges. Finally, the mean crystal size was within 23 to 40 µm and did not necessarily follow a clear correlation with the solution velocities or antisolvent composition, but increased with the application of higher temperature or gravity resistance. Besides, the monoclinic form of α-glycine was perfectly maintained in all conditions. The results at each condition correlated directly with the antisolvent transmembrane flux that ranged between 0.0002 and 0.001 kg/m2. s. In conclusion, membrane antisolvent crystallization is a robust solution offering consistent crystal properties under optimal operating conditions.

Minerals recovery from a rare earth extraction wastewater by a combined chemical precipitation and membrane distillation process

Rare earth extraction wastewater (REEW) derived from rare earth (RE) extraction contains high value-added resources, such as magnesium. Therefore, it is highly desirable to recover the minerals from REEW to reuse in the RE extraction process. This study investigated the combined chemical precipitation and direct contact membrane distillation (DCMD) process to treat REEW for minerals recovery. Results showed that 99.7% Mg2+ in REEW was precipitated as Mg(OH)2 by adjusting pH of the solution. The MgO was obtained through the calcination of Mg(OH)2. The specific surface area (SSA) and reactivity of the calcined MgO decreased with the increase of calcination duration. MgO calcined at 500 °C for 2 h exhibited higher reactivity and SSA of 188.2 m2/g. DCMD performance decline was mainly caused by gypsum during treatment of the Mg-separated stream and membrane fouling was effectively mitigated by almost complete removal of Ca2+, resulting in the concentrated Na2SO4 solution. Subsequently, Na2SO4 was successfully recovered via freeze crystallization by controlling its solubility. The recovered Na2SO4 exhibited narrow crystal size distribution with mean size of 43.3 μm. With this combined process, it was possible to successfully recover 20.1 g/L MgO, 49.7 g/L Na2SO4 along with 72.6% of the water from REEW. The recovered MgO and Na2SO4 with purity of 98.5% and 99.2%, respectively, achieving industrial grade. The results suggest that the combined technologies, chemical precipitation and DCMD process, can be used as a viable engineering solution for minerals recovery from REEW.

Continuous crystallization of levamisole hydrochloride in a segmented flow crystallizer

Continuous crystallization is a promising and widely used method for obtaining drug crystals with controlled morphology and crystal size distribution (CSD). Levamisole hydrochloride (LH) is an important broad-spectrum, highly effective, low-toxic nematode repellent which is available as single-drug preparation and also in combinative therapies. However, the production of uniform LH crystals under flexible operation is still a challenge for chemical engineers. In this contribution, a crystallization process for the production of LH crystals with narrow CSD and improved crystal properties in a continuous segmented flow crystallizer has been proposed. Specifically, at the inlet of the reactor tube, the hot LH methanol solution and anti-solvent solution were mixed through a Y-type connector in the plug flow while cooling down in the nucleation zone to generate the supersaturation. After that, the liquid flow was cut by air to form the stable liquid slugs in which the crystals grew under strong recirculation. Effects of feed concentration, aspect ratio, residence time in nucleation zone, and tube material on the growth rate and CSD have been investigated. Using this coupling crystallization method, LH with a crystal size of 80–130 µm has been successfully prepared at a residence time of less than 15 min

On-line monitoring and analysis of membrane-assisted internal seeding for cooling crystallization of ammonium persulfate

Effective seeding is crucial for the accurate control of cooling crystallization. Herein, the supercooled solution near the membrane interface underwent nucleation, and the membrane-assisted seeding (MAS) was performed for the nucleation and growth control of ammonium persulfate cooling crystallization. Process analytical technologies (PAT) were introduced to obtain on-line nucleation and growth information for the evaluation of the developed MAS process. Experimental comparisons between MAS and conventional seeding crystallization indicated that an appropriate MAS condition could provide a moderate seeding condition. By controlling two key operating parameters, the optimized membrane-involved temperature (18 °C) and duration (30 min), the terminal products possessed narrow crystal size distribution (mean size, 1181 μm; coefficient of variation, 0.162), desired morphology, and high purity (>99.0 wt%). Overall, the results have verified the feasibility of MAS to crystalize products with high quality.

Process intensification of atorvastatin calcium crystallization for target polymorph development via continuous combined cooling and antisolvent crystallization using an oscillatory baffled crystallizer

In this paper, continuous crystallization of Atorvastatin calcium (ASC) using a continuous oscillatory baffled crystallizer (COBC) has been investigated. Like most API manufacturing, ASC is manufactured batchwise and the pure API is recovered via batch combined cooling and antisolvent crystallization (CCAC) process, which has the challenges of low productivity, wide crystal size distribution (CSD) and sometimes polymorphic form contamination. To overcome the limitations of the batch crystallization, continuous crystallization of ASC was studied in a NiTech (United Kingdom) DN15 COBC, manufactured by Alconbury Weston Ltd. (AWL, United Kingdom), with the aim to improve productivity and CSD of the desired polymorph. The COBC has the advantage of high heat transfer rates and improved mixing that significantly reduces the crystallization time. It also has the advantage of spatial temperature distribution and multiple addition ports to control supersaturation and hence the crystallization process. This work uses an array of process analytical technology (PAT) tools to assess key process parameters that affect the polymorphic outcome and CSD. Two parameters were found to have significant impact on the polymorph, they are ratio of solvent to antisolvent at the point of mixing of the two streams and presence of seeds. The splitting of antisolvent into two addition ports in the COBC was found to give the desired form. The CCAC of ASC in COBC was found to be -30-fold more productive than the batch CCAC process. The cycle time for generating 100 g of desired polymorphic form of ASC also significantly reduced from 22 h in batch process to 12 min in the COBC. The crystals obtained using a CCAC process in a COBC had a narrower CSD compared to that from a batch crystallization process.

Investigation of Operation Strategy Based on Solution pH for Improving the Crystal Quality Formed during Reactive Crystallization of l-Aspartic Acid.

The production of crystalline particles with a thick and low degree of agglomeration is required because the agglomerated crystals with thin primary particles, which are frequently formed during reactive crystallization, deteriorate the crystal size distribution (CSD) of the final product due to their fragile morphology. This study aimed to develop an operation strategy for improving the degree of agglomeration and thickness of crystalline particles in the reactive crystallization considering the effect of the solution pH using l-aspartic acid as an experimental system. The scanning electron microscopy observations showed that the thickness of primary particles which form agglomerated crystals could be increased by operating the crystallization under low solution pH conditions. In contrast, it was found that operating the crystallization under high solution pH led to a decrease in the nucleation rate of crystalline particles, which resulted in a decrease in the degree of agglomeration. Then, an operation method, that is, changing the addition method of feed solutions to overcome the trade-off between the thickness and degree of agglomeration, was proposed by considering the effect of solution pH. Consequently, crystalline particles with a narrow CSD could be successfully obtained using the proposed method due to the suppression of the agglomeration and increase of the thickness. Therefore, the development of the operation strategy based on the effect of the solution pH on the degree of agglomeration and thickness is important to produce crystalline particles with improved CSD in reactive crystallization.

Integrated membrane emulsification and solution cooling crystallization to obtain a narrow and predictable crystal size distribution

• A novel concept integrating membrane emulsification and solution crystallization. • Membrane emulsification enabled the confinement of solution crystallization. • Different droplet size distributions showed different yield and crystal quality. • A narrow crystal size distribution was achieved through monodisperse droplets. • The crystal number density was affected both by supersaturation and droplet size. Solution crystallization processes are challenged by the need to control crystal quality attributes such as the crystal size distribution (CSD). Emulsion crystallization is an attractive process intensification strategy to control crystal quality attributes through miniaturization. Droplets of an emulsion can act as tiny crystallizers by confining crystals so that crystal nucleation and growth are limited by the droplet size with available supersaturation. This work presents a novel process concept based on the integration of membrane emulsification and solution crystallization. A water-in-oil emulsion is created through membrane emulsification and glycine is crystallized inside droplets by cooling. The process is characterized in terms of the droplet size distribution, crystal number density, and CSD as a function of the emulsification method and supersaturation. Large and monodisperse droplets obtained from membrane emulsification can achieve a narrow and predictable CSD with higher productivity compared to a mechanical emulsification method. The crystal number density is strongly affected by the initial supersaturation when using membrane emulsification but not the final CSD. In contrast, the CSD changes with supersaturation when applying a mechanical emulsification method. The CSD obtained from a conventional bulk crystallization process is broader and lacks the control imposed by the uniform droplets from membrane emulsification.

Tailoring the crystal size distribution of an active pharmaceutical ingredient by continuous antisolvent crystallization in a planar oscillatory flow crystallizer

An active pharmaceutical ingredient is currently produced in a traditional batch antisolvent crystallization process. Although well-established, this process lacks flexibility to control the crystal size distribution (CSD). Therefore, a new process was developed to enable the control of the CSD according to different specifications. This new process was implemented in continuous in a planar oscillatory flow crystallizer (planar-OFC). In this work, the main goal was to enable the production of small crystals to meet very specific formulation requirements and, simultaneously, promote the aggregation of these small particles to optimize the filtration operation. First, the operating conditions were optimized for continuous operation. Then, the planar-OFC was divided into two spatially independent sections, the nucleation zone (where nucleation is dominant) and the crystal growth zone (where crystal growth is dominant), so as to control the CSD as a function of the residence time in each zone. In particular, the formation of aggregates could be promoted by increasing the residence time in the nucleation zone. Ultimately, the planar-OFC was able to produce smaller particles with significantly narrower CSDs than the traditional batch process. This is particularly important when small particle sizes are required, thus reducing manufacturing time and operating costs.

Development of a triple impinging jet mixer for continuous antisolvent crystallization of acetylsalicylic acid reaction mixture

This study aims to develop a continuous antisolvent crystallization technique using a novel non-submerged triple impinging jet mixer for multiple feeding volume ratios to perform the direct procession of a flow acetylsalicylic acid (ASA) reaction mixture. The impinging jet mixer was supplemented by an overflow mixed suspension mixed product removal (MSMPR) crystallizer to provide a longer aging period for the crystals. The effect of temperature, residence time, and antisolvent to ASA solution ratio on product purity, yield, productivity, crystal size, and crystal size distribution was examined applying a 23 two-level full factorial experimental design. It was found that due to the intensive initial mixing achieved with triple impinging jet significantly smaller crystal size (<180 µm) with narrower unimodal crystal size distribution and higher maximum yield (83.1%) could be obtained compared to the conventional MSMPR technique. Furthermore, the developed continuous crystallization was accomplished in smaller equipment with the same productivity. Consequently, the processing of the ASA reaction mixture using a triple impinging jet mixer system enables the morphology modification and the direct connection of flow synthesis with continuous crystallization step.

Continuous enantioselective crystallization of chiral compounds in coupled fluidized beds

• Highly productive continuous enantioselective crystallization. • Exploitation of two coupled fluidized bed crystallizers. • Provision of narrow product crystal size distributions. • Validation of a reduced population balance model. • First results regarding high resolution CFD-DEM simulations. This review summarizes results of an interdisciplinary project devoted to improve the access to enantiopure components by applying an advanced continuous separation process exploiting the principle of kinetically controlled preferential crystallization within two coupled fluidized beds located in conically shaped tubular crystallizers. The process efficiently combines selective crystallization with integrated product classification. Along with summarizing the related literature, new original results are presented with respect to theoretical process description and experimental validation. Although only one chiral system is considered specifically, namely the separation of the enantiomers of a racemic mixture of asparagine monohydrate using water as solvent, general conclusions will be drawn to highlight the large potential of the process principle. The conceptual approaches presented are seen as useful tools for the development of productive continuously operating enantioselective crystallization processes. They are applicable to separate enantiomers of numerous chiral molecules.

Thermal evolution effects on the properties of converting Cs-polluted soil into pollucite-base glass-ceramics for radioactive cesium immobilization

The Fukushima nuclear accident in Japan on March 11, 2011, produced large amounts of Cs-polluted soil which must be controlled to prevent the spread of hazardous Cs into the environment. In this paper, the effects of heat treatment on the structure and properties of Cs-containing glass-ceramics, as a simulated nuclear waste form, were systematically investigated. Cesium atoms are chemically bonded in the pollucite structure, and the amorphous phase further encapsulates the pollucite crystals in the glass-ceramics, thus providing an extra protective layer for the immobilized Cs. XRD analysis, Raman and FT-IR studies on the glass-ceramics synergistically indicated that the optimum crystallization temperature for pollucite is around 1000 °C. The pollucite is predominantly the main crystalline phase with a narrow crystal size distribution between 0.5 and 2 μm. Standard leaching test results show that the leaching rate of Cs was very low (3.0 × 10−3 g/(m2·d)). The study offers a practical method for immobilizing Cs in pollucite-base glass-ceramics. Moreover, the experimentally obtained data may provide some important references for converting Cs-polluted soil into pollucite-base glass-ceramics waste form.

Antisolvent crystallization intensified by a jet crystallizer and a method for investigating crystallization kinetics

In this study, the antisolvent crystallization of NaCl in water-ethanol binary solvent mixtures in a multi-orifice-impinging transverse (MOIT) jet crystallizer is studied both experimentally and numerically. Plug flow model coupled with population balance equation (PFM-PBE) is employed for the estimation of nucleation and crystal growth rate parameters at different supersaturation levels. Computational fluid dynamics coupled with population balance equation (CFD-PBE) is used to evaluate the macromixing and micromixing effect on the crystallization process. It is found that several microns NaCl crystals with narrow crystal size distribution (CSD) are prepared. The mixing process of the antisolvent and the solution is intensified by the MOIT jet crystallizer so that the mixing effect becomes insignificant due to a small Da number. The crystallization kinetics have also been obtained and confirmed by combining PFM-PBE and CFD-PBE approaches with the experiments.

Formation of nanocrystalline BiFeO3 during heat treatment of hydroxides co-precipitated in an impinging-jets microreactor

Nanocrystalline bismuth orthoferrite was synthesized by heat treatment of hydroxides co-precipitated in a free impinging-jets microreactor (FIJMR). The formation of BiFeO3 nanoparticles without other phase impurities, with a narrow crystal size distribution and an average crystal size of about 20 nm, is shown to be possible after heat treatment at 420–440 °C of the hydroxides co-precipitated in a FIJMR. The BiFeO3 nanoparticles obtained under these conditions are single-crystalline. This effect is attributed to the crucial intensification of mixing process compared to the usual types of reactors: the energy dissipation rate for FIJMR estimated as being in the range of 107–108 W/kg, which is several orders of magnitude higher than in almost all types of reactors, and is comparable with the level achieved when using ultrasonic generators. The sizes of the nanocrystals are shown to be consistent with the sizes of the nanoparticles that can be formed in Kolmogorov microvortices that are formed when jets of reagent solutions collide.