Supercritical antisolvent micronization of PVP and ibuprofen sodium towards tailored solid dispersions

The supercritical antisolvent technology is used to precipitate polyvinylpyrrolidone (PVP) particles and crystallise ibuprofen sodium (IS) crystals separately and in the form of solid dispersion together. Supercritical carbon dioxide (scCO₂) is used as antisolvent. For PVP particle generation, ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5 wt% and 1.5 wt%, the operation pressure between 10 MPa and 30 MPa and the composition of ethanol/acetone solvent mixtures between 100 wt% and 0 wt% of ethanol at a constant temperature of 313 K. Furthermore, the mean molecular weight of the polymer was varied between 40 kg mol⁻¹, 360 kg mol⁻¹ and 1300 kg mol⁻¹. An increase of the content of the poor solvent acetone in the initial solvent mixture as well as the usage of PVP with a higher molecular weight, leads to a significant decrease in mean particle size. At all the investigated parameters always fully amorphous PVP powder precipitates. For IS, only ethanol was used as the solvent, the initial IS concentration in the solution was varied between 1 wt% and 3 wt% and the operation pressure between 10 MPa and 16 MPa. A variation of these parameters leads to a manipulation of the size and the morphology of the crystallised IS crystals. Irrespective of the parameters used, always the same polymorphic form of ibuprofen sodium is produced. The solid dispersions were generated at different compositions of PVP to IS and with two different molecular weights of PVP at otherwise constant conditions. Fully amorphous solid dispersions consisting of IS and PVP together were generated at different ratios of PVP to IS.The mechanisms that control the final particle properties are discussed taking into account two different models for “ideal” and “non-ideal” solutes. Furthermore, the study of the “unconventional” SAS parameters, molecular weight and solvation power of the solvent shows that these parameters qualify to tailor polymer particle properties via SAS processing. Next to the investigation into the behaviour of both solutes separately, fully amorphous solid dispersions consisting of IS and PVP together were generated. While X-ray diffraction was used to analyze the crystalline structure of the particles, respectively, solid dispersions, their morphology was analysed using scanning electron microscopy (SEM).     

Laser analyses of mixture formation and the influence of solute on particle precipitation in the SAS process

Laser based Raman and elastic light scattering measurements were performed to study the process of mixture formation and the influence of the solute paracetamol onto the phase behaviour of the pseudo-binary system ethanol/CO₂ in the supercritical antisolvent process. From the Raman based technique, mole fraction and partial density distributions of CO₂ were obtained. The mole fraction distributions indicate a rapid mixture formation with fast supersaturation of the solute. At the same time, the increase of the CO₂ partial density at conditions considerably above the mixture critical point (MCP) indicate a change from a homogeneous supercritical to a multi-phase subcritical flow. This phase change goes along with particle precipitation. Thus, the results of our investigations proof, why past approaches failed to generate amorphous paracetamol nanoparticles with the system paracetamol/ethanol/CO₂ above the MCP. Process parameters like injection pressure (20.0–35.0 MPa), chamber pressure of CO₂ (7.5–17.5 MPa), temperature (313–333 K) and solute concentration (0–5 wt%) were varied.     

A new approach to select solvents and operating conditions for supercritical antisolvent precipitation processes by using solubility parameter and group contribution methods

A new approach is proposed to select operating temperature and pressure for supercritical antisolvent particle precipitation based on solubility parameter calculated by group contribution methods and using only the critical properties of the solvent. Solubility parameters are also used to choose the most suitable organic solvent for a given application. Supercritical antisolvent precipitation operating conditions of 36 systems are investigated including 8 organic solvents (methanol, ethanol, acetone, DMSO, DCM, chloroform, NMP and acetic acid) and 6 solid solutes (atenolol, tartaric acid, flunisolide, paracetamol, amoxicillin and cholesterol) in the temperature and pressure ranges of 25⿿85 °C and 50⿿250 bar. The results show a good agreement between the experimental and calculated data for these systems. Although particle precipitation depends on several parameters such as mass-transfer rates and hydrodynamics, the focus of this work is on the role of thermodynamics to indicate the preliminary conditions for a successful antisolvent precipitation process. Validation and results of this new approach suggest that it can be a useful tool for a qualitative and completely predictive evaluation of supercritical antisolvent particle precipitation in a cheaper way than carrying out experimental runs.     

Crystallization of silibinin from organic solutions using supercritical and aqueous antisolvents

Silibinin, an anticancer drug, was crystallized from organic solutions using supercritical and aqueous antisolvents. Silibinin was dissolved in acetone and ethanol at concentration range of 0.01–0.04 g/mL, and the drug solutions were placed in contact with two different antisolvents, carbon dioxide and water. The mixing of the drug solutions and antisolvents led to the prompt precipitation of silibinin in a solid crystal form. The experimental variables, such as temperature, solution concentration, mixing rate and solution/antisolvent volume ratio were manipulated. When the experiments were conducted with a supercritical antisolvent, the effects of external additives on the crystal habit were examined. α-d-Glucose penta acetate, triton X-100 and urea were added to the solution at concentration range of 0.001–0.003 g/mL as external additives. The temperature increase of 20 °C induced 25% increase in particle size. As the solution concentration was increased from 0.01 to 0.04 g/mL, the average particle size decreased from 35.5 to 22.0 μm in supercritical antisolvent experiments, while the particle size increased from 8.9 to 30.4 μm in aqueous antisolvent experiments. The use of different kinds of external additives resulted in different modifications of the particle shape and structures.     

Influence of Pd-loading on gas sensing characteristics of SnO2 thick films

Nanocrystalline pristine and 0.5, 1.5 and 3.0 wt% Pd loaded SnO₂ were synthesized by a facile co-precipitation route. These powders were screen-printed on alumina substrates to form thick films to investigate their gas sensing properties. The crystal structure and morphology of different samples were characterized by using X-ray diffraction, scanning electron microscopy and transmission electron microscopy techniques. The 3.0 wt% Pd:SnO₂ showed response of 85% toward 100 ppm of LPG at operating temperature of 250 °C with fast response (8 s) and quick recovery time (24 s). The high response toward LPG on Pd loading can be attributed to lowering of crystallite size (9 nm) as well as the role of Pd particles in exhibiting spill-over mechanism on the SnO₂ surface. Also selectivity of 3.0 wt% Pd:SnO₂ toward LPG was confirmed by measuring its response to other reducing gases like acetone (CH₃COCH₃), ethanol (C₂H₅OH) and ammonia (NH₃) at optimum operating temperature.     

Synthesis,characterization and enhanced acetone sensing performance of Pd loaded Sm doped SnO2 nanoparticles

In the present communication, we have presented a high performance acetone sensor based on Pd loaded Sm doped SnO₂ nanomaterial. The (0.5, 1, 2 and 3) wt% Pd loaded 6 mol% Sm doped SnO₂ nanoparticles were prepared using a co-precipitation method. The characterization of samples was done by using X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FEG-SEM), Energy Dispersive Analysis by X-rays (EDAX), High Resolution-Transmission Electron Microscopy (HR-TEM) and Selective Area Electron Diffraction (SAED) techniques. The gas response studies such as sensitivity, selectivity and stability towards liquid petroleum gas, ammonia, ethanol and acetone were measured at 100 ppm concentrations. The results show that optimum Pd loading (2 wt%) results in smaller crystallite size (~3.1 nm), lower operating temperature (200 °C), higher gas response (94%),better selectivity, faster response (~3 s) and quicker recovery (~12 s) towards acetone.     

Antisolvent micronization of BSA using supercritical mixtures carbon dioxide + organic solvent

In this work, expanded liquid antisolvent (ELAS) process has been used to micronize bovine serum albumin (BSA) solubilized in water. Carbon dioxide mixtures with ethanol, acetone or isopropyl alcohol, at expanded liquid conditions, have been used as the antisolvent. The effect of process parameters, such as the kind of co-antisolvent and the organic co-antisolvent/water/carbon dioxide mole fraction on the morphology and dimensions of the precipitates, was studied. Changing co-antisolvent and operating conditions, we obtained nanoparticles (with a mean diameter of about 60 nm ± 10 nm), sub-microparticles (with a mean diameter of 470 nm ± 130 nm), microparticles (with a mean diameter of 0.93 μm ± 0.37 μm) and expanded microparticles with an empty core (with a mean diameter of about 9 μm ± 5 μm). Fourier transform infrared analysis on BSA powders revealed that, using acetone as co-antisolvent, no modifications of the protein secondary structure were induced by ELAS processing.     

Dense CO2 antisolvent precipitation of levothyroxine sodium: A comparative study of GAS and ARISE techniques based on morphology and particle size distributions

Morphology and particle size distribution of levothyroxine sodium are experimentally investigated by comparing gas antisolvent (GAS) and atomized rapid injection for solvent extraction (ARISE) techniques using dense CO₂. Precipitation of levothyroxine sodium from ethanol was carried out at 25, 40 and 50 °C, with pressure in the 90–120 bar range and different concentrations of the organic solution. Particles produced by the GAS process are nanospheres whereas ARISE processed particles are either spherical or rod-like micro and nanoparticles. Particle size and size distributions of GAS processed levothyroxine sodium are in the 370–500 nm range, while the ARISE process produced particles in the 360–1200 nm range. In most cases, both techniques produced bimodal size distributions, due to particle agglomeration. The different morphological characteristics and particle size distributions of levothyroxine sodium obtained using GAS and ARISE at different operating conditions can be useful depending on the type of drug formulation chosen, as well as the route of drug administration and delivery system.     

Effect of pressure and non-isothermal injection on re-crystallization by CO2 antisolvent: Solubility measurements,simulation of mixing and experiments

This work investigated for the first time a CO₂ antisolvent crystallization (SAS) operating in non-isothermal conditions, i.e. injection of a solution warmer than that of the CO₂ – in order to impose an additional driving for crystallization when CO₂ was not a strong antisolvent. The approach focused on phase equilibria (with a distinctive feature of being modeled by artificial neural network) and 3D-simulation of the mixing (considering both heat and mass transfers) in order to detail the supersaturation profiles in the mixing zone and confronted them to the crystallization results. The effect of pressure was investigated as well. The solubility of a model compound, mefenamic acid (MEFE) was measured in CO₂–acetone at 35 °C/8.5, 10 and 15 MPa, and 10 MPa/25, 35 and 45 °C and further correlated by a neural network to provide an easy-to-handle equation of MEFE concentration. Simulations results showed that supersaturation levels were low (around 2) and that the expanding jet spread similarly whatever the pressure. The effect of differential temperature on the mixing behavior and supersaturation was investigated. Compared to isothermal cases, higher superaturations were obtained but only if a more concentrated solution allowed by the higher temperature was processed as well. The benefit for the crystal size was difficult to evidence because of the long sizes of the needles and the difficulties of processing almost saturated solutions. Investigation of a less CO₂–acetone compound would be more promising.     

Electromagnetic properties of SiO2 reinforced with both multi-wall carbon nanotubes and ZnO particles

SiO₂ reinforced with both multi-wall carbon nanotubes (MWCNTs) and ZnO particles was prepared. Owing to the consumption of an amorphous carbon layer on the outer surface of MWCNTs and the generation of oxygen vacancies in ZnO during sintering, the contact resistance between MWCNTs is lowered and a higher concentration of charge carriers is produced in ZnO. The permittivity of the composite is improved by both changes. The composite containing 15 wt% ZnO particles and 3 wt% MWCNTs exhibits a wider effective absorption bandwidth and lower minimum reflection coefficient than both SiO₂ reinforced with 15 wt% ZnO particles and SiO₂ reinforced with 3 wt% MWCNTs.     

Foaming strategies for bioabsorbable polymers in supercritical fluid mixtures. Part II. Foaming of poly(ɛ-caprolactone-co-lactide) in carbon dioxide and carbon dioxide + acetone fluid mixtures and formation of tubular foams via solution extrusion

This paper reports on the foaming of poly(ɛ-caprolactone-co-lactide) in carbon dioxide and carbon dioxide + acetone mixtures. Experiments were carried out in specially designed molds with porous metal surfaces and fluid circulation features to generate foams with uniform dimensions at 60, 70 and 80 °C at pressures in the range 7–28 MPa. Depending upon the conditions, foams with pores in the range from 5 to 200 μm were generated. Adding acetone to carbon dioxide improved the uniformity of the pores compared to foams formed by carbon dioxide alone. In addition, a unique high-pressure solution extrusion system was designed and used to form porous tubular constructs by piston-extrusion of a solution from a high-pressure dissolution chamber through an annular die into a second chamber maintained at controlled pressure/temperature and fluid conditions. Long uniform porous tubular constructs with 6 mm ID and 1 mm wall thickness were generated with glassy polymers like poly(methyl methacrylate) by extruding solutions composed of 50 wt% polymer + 50 wt% acetone, or 25 wt% polymer + 10% acetone + 65% carbon dioxide at 70 °C and 28 MPa. Pores were in the 50 μm range. The feasibility of forming similar tubular constructs were demonstrated with poly(ɛ-caprolactone-co-lactide) as well. Tubular foams of the copolymer with interconnected pores with pore sizes in the 50 μm range were generated by extrusion of the copolymer solution composed of 25 wt% polymer + 10 wt% acetone + 65 wt% carbon dioxide at 70 °C and 28 MPa. Reducing the acetone content in the solution led to a reduction of pore sizes. Comparisons with the foaming behavior of the homopolymer poly(ɛ-caprolactone) that were carried out in the molds with porous metal plates show that the foaming behavior of the copolymer is more akin to the foaming behavior of the caprolactone homopolymer component.     

Dispersion and co-dispersion of ZrB2 and SiC nanopowders in ethanol

The dispersion and co-dispersion behavior of ZrB₂ and SiC nanopowders in ethanol solution was studied by sedimentation test, particle size measurement and transmission electron microscope (TEM) analysis. The dispersion behavior of ZrB₂ and SiC nanopowders in ethanol solution was strongly dependent on the pH values, types and amounts of dispersant. PEI was found to be effective for the dispersion of both ZrB₂ and SiC nanopowders in ethanol solution. With the addition of PEI, the isoelectric points of ZrB₂ and SiC nanopowders in ethanol solution were at pH 10 and pH 9.5, and shift to pH 13 and pH 12.3, respectively. The stability of ZrB₂ suspension increased with the dispersant content increasing until reached 0.7 wt% and well-dispersed SiC slurry can be obtained with more than 2.5 wt% PEI. The suitable pH value for the dispersion of ZrB₂ and SiC nanopowders should be lower than 12 and 10, respectively. The well co-dispersed ZrB₂ and SiC nanocomposite powders can be achieved by using 1 wt% or more PEI below pH 10.     

Influence of molecular weight of polydimethylsiloxane precursors and crosslinking content on degree of ethanol swelling of crosslinked networks

Using PDMS (polydimethylsiloxane) as a basic polymeric matrix to the preparation of ethanol-permselective pervaporation membranes is a vibrant field of research. In this paper, a detailed study of the effects of the molecular weight of PDMS precursors and the content of the TEOS (tetraethyl orthosilicate) crosslinker on the degree of swelling in ethanol and ethanol contact angle is reported. Five PDMS precursors with molecular weights of 26.6 K, 35.5 K, 50.2 K, 71.7 K, and 110.4 K, and five crosslinking contents (1 wt%, 2 wt%, 5 wt%, 10 wt%, and 15 wt%) were chosen to prepare twenty-five PDMS networks. Considering only the maximum tensile strength of the networks, the optimum molecular weight of the precursor was found to be 35.5 K and the optimum crosslinker content was 5 wt%. The average Young’s modulus of the PDMS network prepared under these conditions reached 0.63 MPa after using toluene to extract the network. Some uncrosslinked precursors always occur in the networks, and have some influence on the molecular weight of the precursors and the crosslinker content that is used. It was found that the content of the uncrosslinked precursors has direct effect on the contact angle of ethanol sessile drops at the surface of the extracted PDMS networks, and higher extraction corresponded to a smaller ethanol contact angle. A combined parameter (S), defined as the quotient of the extraction amount (A_E) and the tensile elastic modulus (E_Y), gives a good linear relationship with the increase in weight of networks swelled in ethanol. This means that the degree of equilibrium swelling of the networks is simultaneously strongly influenced by the tensile modulus and the content of the uncrosslinked precursors.     

Controlled liquid antisolvent precipitation using a rapid mixing device

Particle formation by the liquid antisolvent (LAS) process involves two steps: mixing of solution–antisolvent streams to generate supersaturation and precipitation (which includes nucleation and growth by coagulation and condensation) of particles. Uniform mixing conditions ensure rapid and uniform supersaturation, making it a precipitation controlled process where the particle size is not further affected by mixing conditions and results in precipitation of ultra-fine particles with narrow particle size distribution (PSD). In this work, we demonstrate that the use of an ultrasonically driven T-shaped mixing device significantly improves mixing of solution and antisolvent streams for precipitation of ultra-fine particles in a continuous operation mode. LAS precipitation of ultra-fine particles of multiple active pharmaceutical ingredients (APIs) such as itraconazole (ITZ), ascorbyl palmitate (ASC), fenofibrate (FNB), griseofulvin (GF), and sulfamethoxazole (SFMZ) in the size range 0.1–30 μm has been carried out from their organic solutions in acetone, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and ethanol (EtOH). Classical theory of homogeneous nucleation has been used to analyze the result, which suggests that higher nucleation rate results in finer particle size. Interestingly, experimental determination of degree of supersaturation indicates that higher supersaturation does not necessarily result in higher nucleation rate and nucleation rates can be correlated to solvent polarity.     

Synthesis of spherical NiO nanoparticles using a solvothermal treatment with acetone solvent

Nanometer-sized nickel oxide (NiO) particles were synthesized by thermal reactions with nickel (II) carbonate as a metal-containing precursor and four solvents: water, ethanol, butanol, and acetone. The optimal reaction conditions to obtain spherical NiO were determined to be the acetone solvent, nickel carbonate precursor, and a reaction temperature and time of 200 °C and 48 h, respectively. TEM images revealed perfectly spherical NiO nanoparticles of size ranging from 2.0 to 10.0 nm in the acetone solvent. The reaction mechanism for the formation of the NiO nanoparticles is proposed based on a pathway of chelated Ni complex during crystal growth. Although metallic Ni was also formed from reactions using the two alcoholic solvents, the Ni(OH)₂ structure remained in the water solvent after thermal treatment.     

Use of solvent mixtures in supercritical antisolvent process to modify precipitates morphology: Cellulose acetate microparticles

In the supercritical antisolvent precipitation (SAS), the jet fluid dynamics is characterized by two-phase mixing at subcritical conditions, and by one-phase mixing at completely developed supercritical conditions. The amplitude of the pressure range, in which binary systems organic solvent/scCO₂ exhibit the transition between two-phase to one-phase mixing, depends on the organic solvent that is in contact with supercritical carbon dioxide (scCO₂) and conditions the morphology of the microparticles produced by SAS. When this pressure range is wide, as in the case of dimethylsulfoxide (DMSO), solutes solubilized in the organic solvent can be precipitated as microparticles by atomization, droplets formation and drying; when this pressure range is narrow, as for acetone, gas mixing prevails and only nanoparticles are generally observed. Therefore, generally speaking, solutes that are soluble only in solvents exhibiting gas mixing in scCO₂, do not exhibit microparticles morphology and this fact is a limitation for several industrial applications.In this work, a model compound, cellulose acetate (CA), that is slightly soluble in DMSO and freely soluble in acetone, was processed by SAS using mixtures of the two solvents that exhibit intermediate behaviors between the two pure solvents, to extend two phase mixing and produce CA microparticles. Using different DMSO/acetone mixture percentages, the effects of the polymer concentration in the liquid solution and of the pressure were studied. A mixture of DMSO/Acetone 50/50 (v/v), at a pressure of 85 bar and a concentration of the liquid solution equal to 40 mg/mL, efficiently produced non-coalescing CA microparticles with a mean diameter of 0.42 μm and a standard deviation of about 0.15 μm, demonstrating that this SAS strategy can be successful.     

Formation of hollow MgO-rich spinel whiskers in low carbon MgO–C refractories with Al additives

MgO–C refractories with different carbon contents have been developed to meet the requirement of steel-making technologies. Actually, the carbon content in the refractories will affect their microstructure. In the present work, the phase compositions and microstructure of low carbon MgO–C refractories (1 wt% graphite) were investigated in comparison with those of 10 wt% and 20 wt% graphite, respectively. The results showed that Al₄C₃ whiskers and MgAl₂O₄ particles formed for all the specimens fired at 1000 °C. With the temperature up to 1400 °C, more MgAl₂O₄ particles were detected in the matrix and AlN whiskers occurred locally for high carbon MgO–C specimens (10 wt% and 20 wt% graphite). However, the hollow MgO-rich spinel whiskers began to form locally at 1200 °C and grew dramatically at 1400 °C in low carbon MgO–C refractories, whose growth mechanism was dominated by the capillary transportation from liquid Al at these temperatures.     

Protective properties of Al2O3 + TiO2 coating produced by the electrostatic spray deposition method

Mechanical resistance of Al₂O₃ + TiO₂ nanocomposite ceramic coating deposited by electrostatic spray deposition method onto X10CrAlSi18 steel to thermal and slurry tests was investigated. The coating was produced from colloidal suspension of TiO₂ nanoparticles dispersed in 3 wt% solution of Al₂(NO₃)₃, as Al₂O₃ precursor, in ethanol. TiO₂ nanoparticles of two sizes, 15 nm and 32 nm, were used in the experiments. After deposition, coatings were annealed at various temperatures, 300, 1000 and 1200 °C, and next exposed to cyclic thermal and slurry tests. Regardless of annealing temperature and the size of TiO₂ nanoparticles, the outer layer of all coatings was porous. The first five thermal cycles caused a rapid increase of aluminum content of the surface layer to 30–37 wt%, but further increase in the number of thermal cycles did not affect the aluminum content. The oxidation rate of coating-substrate system was lower during the thermal tests than during annealing. The oxidation rate was also lower for smaller TiO₂ particles (15 nm) forming the coating than for the larger ones (32 nm). The protective properties of Al₂O₃ + TiO₂ coating against intense oxidation of substrate were lost at 1200 °C. Slurry tests showed that coatings annealed at 1000 °C had the best slurry resistance, but thermal tests had weakened this slurry resistance, mainly due to decreasing adhesion of the coating.     

Fabrication of cylindrical SiCf/Si/SiC-based composite by electrophoretic deposition and liquid silicon infiltration

Cylindrical SiC-based composites composed of inner Si/SiC reticulated foam and outer Si-infiltrated SiC fiber-reinforced SiC (SiC_f/Si/SiC) skin were fabricated by the electrophoretic deposition of matrix particles into SiC fabrics followed by Si-infiltration for high temperature heat exchanger applications. An electrophoretic deposition combined with ultrasonication was used to fabricate a tubular SiC_f/SiC skin layer, which infiltrated SiC and carbon particles effectively into the voids of SiC fabrics by minimizing the surface sealing effect. After liquid silicon infiltration at 1550 °C, the composite revealed a density of 2.75 g/cm³ along with a well-joined interface between the inside Si/SiC foam and outer SiC_f/Si/SiC skin layer. The results also showed that the skin layer, which was composed of 81.4 wt% β-SiC, 17.2 wt% Si and 1.4 wt% SiO₂, exhibited a gastight dense microstructure and the flexural strength of 192.3 MPa.     

The highly active saddle-like Ag3PO4 photocatalyst under visible light irradiation

Saddle-like Ag₃PO₄ particles of tetrahedron structure were successfully synthesized using a co-precipitation method by mixing H₃PO₄ ethanol solution and AgNO₃ ethanol aqueous solution, where the percentage of ethanol in AgNO₃ ethanol aqueous solution was varied at 0, 50, 80, 90 and 100% (v/v). The photocatalytic performance of the synthesized samples was evaluated by photodegradation of Rhodamine B (RhB) under blue light irradiation (λ = 455 nm). The results showed that the morphology of the Ag₃PO₄ particles greatly changed depending on the ethanol content in the reaction solution. Excellent photocatalytic activity was observed at 80% (v/v) of ethanol, where the Ag₃PO₄ showed saddle-like morphology derived from the tetrahedron structure.