Supercritical Assisted Atomization Research Articles

Precipitation kinetics of PMMA sub-micrometric particles with a supercritical assisted-atomization process

Sub-micrometric particles of PMMA were successfully prepared via a supercritical assisted-atomization (SAA) process using acetone as a solvent and supercritical carbon dioxide as a spraying medium. The effects of several key factors on the particle size were investigated. These factors included the concentration of polymer solution, temperature in saturator and volumetric flow rate ratio of carbon dioxide to polymer solution. The shape of the polymer's primary particles is spherical with the arithmetic mean size ranging from 82 nm to 176 nm and the mass-weighted mean size ranging from 127 nm to 300 nm. As evidenced from the experimental results, the lower concentrations of polymer solution, optimized volumetric flow rate ratios, and higher temperatures in saturator can effectively reduce the mean particle size. The precipitation kinetic parameters were determined from the particle size distributions with the aid of the population balance theory. This study found the primary nucleation to be dominant in the precipitation and diffusion may govern particle growth.

A new supercritical assisted atomization configuration, for the micronization of thermolabile compounds

A novel process configuration of supercritical assisted atomization (SAA) was used to produce microparticles of two model thermolabile compounds: poly l-lactide (PLLA) and bovine serum albumin (BSA). This new configuration allowed to operate the precipitation process below the atmospheric pressure, to perform the drying process at lower temperatures without any damage to thermolabile materials. Process parameters, such as gas to liquid ratio and precipitation temperature, were investigated to evaluate their influence on particle size and morphology. Well defined spherical particles were produced. PLLA microparticles coalescence was avoided using a precipitation pressure from 0.65 to 0.5 bar producing particles with a mean diameter between 1 and 1.5 μm, and a standard deviation of about 0.4. BSA spherical particles with a mean diameter of about 1 μm, and a standard deviation of about 0.7, were obtained operating at 0.8 bar in the precipitator. Fourier transform infrared analysis on BSA microparticles revealed that no modification on protein secondary structure took place during SAA process, thus, protein denaturation was avoided.

Controllable preparation and formation mechanism of BSA microparticles using supercritical assisted atomization with an enhanced mixer

Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was used to prepare bovine serum albumin (BSA) microparticles. Water was used as the sole solvent. A hydrodynamic cavitation mixer was applied to improve mass transfer and achieve a continuous near-thermodynamic-equilibrium solubilization of SC-CO 2 in the liquid solution. Under the different conditions, the prepared BSA microparticles had various morphologies, such as corrugated particles, smooth hollow spherical particles and cup particles, with particle diameters ranging from 0.3 to 5 μm. The microparticle formation process was elucidated with the shell formation and central bubble mechanism. Compared to native BSA, BSA microparticles did not show significant change in primary structure, according to the results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The secondary structure of BSA was characterized by Fourier transform infrared spectroscopy (FT-IR). No new peaks were observed after SAA-HCM processing. In addition, the crystalline structure of the BSA microparticles was demonstrated to be amorphous because of the sudden supersaturation in the precipitation process. The SAA-HCM process is expected to be a promising technique for producing microparticles suitable for pulmonary delivery of therapeutic macromolecules.

Beclomethasone Microparticles for Wet Inhalation, Produced by Supercritical Assisted Atomization

Supercritical assisted atomization (SAA) was used to produce micronized particles of beclomethasone dipropionate (BDP) to be used for inhalation therapy. Methanol, acetone, acetone + water 9% v/v, ...

Albumin/Gentamicin Microspheres Produced by Supercritical Assisted Atomization: Optimization of Size, Drug Loading and Release

In this work, the supercritical assisted atomization (SAA) is proposed, for the first time, not only as a micronization technology but also as a thermal coagulation process for the production of bovine serum albumin (BSA) microspheres charged with Gentamicin sulfate (GS). Particularly, different water solutions of BSA/GS were processed by SAA to produce protein microspheres with different size and antibiotic content. SAA precipitation temperature was selected in the range 100-130 °C to generate protein coagulation and to recover micronized BSA in form of hydrophobic aggregates; GS loading was varied between 10% and 50% (w/w) with an encapsulation efficiency which often reached 100%. In all cases, spherical and noncoalescing particles were successfully produced with a mean particle size of 2 µm and with a standard deviation of about ±1 µm. The microspheres also showed a good stability and constant water content after 60 days of storage. The release profiles of the entrapped drug were monitored using Franz cells to evaluate the possible application of the produced microspheres in wound dressing formulations. Particularly, the microspheres with a BSA/GS ratio of 4:1 after the first burst effect (of 40% of GS loaded) were able to release the GS continuously over 10 days.

Ampicillin micronization by supercritical assisted atomization.

The micronization technique called supercritical assisted atomization (SAA) was used to produce ampicillin microparticles with controlled particle size and particle size distribution suitable for aerosol drug delivery. The process is based on the solubilization of supercritical CO2 in a liquid solution. The ternary mixture is then sprayed through a nozzle and, as a consequence of enhanced atomization, solid microparticles are formed. Water and organic solvents were tested with ampicillin to determine the influence of the solvent on the process mechanism. SAA process parameters were studied by testing different supercritical/liquid solvent flow ratios, ampicillin concentrations in the liquid solution and nozzle diameters. The effect of these parameters on morphology, particle size and particle size distribution of microparticles was analysed. Ampicillin particles suitable for aerosol delivery in the size range 1-5 microm were obtained using buffered water. Moreover, by varying the solute concentration, ampicillin particles in a narrower range (1-3 microm) than that usually suggested for aerosol deliverable drugs were obtained. This is an example of particle size tailoring by SAA.

Griseofulvin micronization and dissolution rate improvement by supercritical assisted atomization

Supercritical assisted atomization (SAA) was used to micronize griseofulvin (GF), selected as a model compound, to verify the performance of this innovative process. SAA is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug. The ternary mixture is then sprayed through a nozzle and microparticles are formed as a consequence of the enhanced atomization. Precipitation temperature and drug concentration in the liquid solution were studied to evaluate their influence on morphology and size of precipitated particles. A good particle size control was obtained and GF spherical particles with mean diameters ranging from 0.5 to 2.5 microm were produced with a narrow particle size distribution. Processed GF was characterized by high-performance liquid chromatography-UV/vis, headspace-gas chromatography-flame ionization detection, differential scanning calorimetry, BET and X-ray analyses. No drug degradation was observed and a solvent residue (acetone) less than 800 ppm was measured. GF microparticles showed good stability and surface areas ranging from about 4 to 6 m(2) g(-1); moreover, the micronized drug retained the crystalline habit. GF capsules were formulated with starch and used to compare the dissolution rate of SAA-processed and conventional jet-milled drug. A faster dissolution and a better reproducibility of the dissolution profile were observed for SAA-processed GF.

Micronization of lysozyme by supercritical assisted atomization

Supercritical Assisted Atomization (SAA) has been used to produce lysozyme microparticles. Lysozyme has been micronized using water, buffered water at pH 6.2 and water-ethanol mixtures at different volume percentages. Precipitated lysozyme particles were spherical, with a narrow particle size distribution (PSD) ranging from 0.1 to 4 microm. The concentration of lysozyme in the liquid solvent mixture had a nonlinear effect on the particle distribution, with an increase of the X(0.9) from about 1 to 3 microm varying the enzyme concentration from 5 to 20 mg/mL. Precipitation temperature was set as low as possible to avoid enzyme degradation. High-performance liquid chromatography analysis showed no degradation of lysozyme and the enzyme activity, measured by turbidimetric enzymatic assay, only slightly decreased after SAA processing. Depending on the process conditions lysozyme retained from 95% to 100% of the biological activity compared to the untreated enzyme.

Experimental investigation on the micronization of aqueous cefadroxil by supercritical fluid technology

The supercritical-assisted atomization (SAA) process is a novel technique proposed recently to prepare micro-particles with controlled particles size distribution suitable for aerosolizable delivery. It has shown a great potential in drug micronization especially for water-soluble drugs. Cefadroxil micro-particles were prepared successfully from water–ethanol mix-solvent by SAA process. The influence of the operation parameters, including the pressure and temperature in the mixing vessel, the solution concentration and the solution feed rate, on the particle morphology, size and size distribution was investigated in detail. The results show that the concave cefadroxil micro-particles suitable for pulmonary drug delivery could be prepared by SAA process in certain conditions. The pressure in the mixing vessel and the solution feed rate are two most effective parameters while the solution concentration is the next. The temperature in the mixing vessel has a little effect. The particle characteristics could be controlled by adjusting operation conditions. The optimal operation parameters for preparing cefadroxil micro-particles in the scope of this work are: the pressure of 10 MPa and the temperature of 60 °C in the mixing vessel, the solution feed rate of 3 ml/min, and the solution concentration of 4 mg/ml.

Anti-solvent effect in the production of lysozyme nanoparticles by supercritical fluid-assisted atomization processes

Particles of lysozyme in the range of 0.1–5 μm were generated by high pressure CO 2 or N 2 (at pressures between 8 MPa and 25 MPa) from aqueous ethanol solutions using an atomization process similar to the supercritical assisted atomization technology. Perfect nanosized spheres of lysozyme were produced using both supercritical fluids. However, while N 2 assisted atomization-produced spheres at all experimental conditions reported here, supercritical CO 2 assisted atomization produced particles of two distinct morphologies depending on the pre-mixing conditions. This work shows that CO 2 assisted atomization produces particles by two different mechanisms depending on the mixture pre-expansion phase equilibria conditions: anti-solvent crystallization and spray drying crystallization. Depending on the governing precipitation mechanism (anti-solvent or spray drying), fibers or spherical particles were obtained with CO 2. Lysozyme activity was severely affected by pure anti-solvent processing, while N 2 processed lysozyme conserved mostly its activity.

Supercritical fluid assisted production of HPMC composite microparticles

Supercritical fluid technology has recently been proposed in literature to obtain drug controlled release systems as alternative to conventional techniques. In this work, the Supercritical Assisted Atomization (SAA) is proposed to produce hydroxypropyl methylcellulose (HPMC) based composite microparticles using ampicillin trihydrate as model drug. Successful micronization of HPMC alone and, then, coprecipitation of HPMC and ampicillin were obtained using a buffer solution as solvent. Well-defined micrometric particles with spherical or “doughnut-like” morphology were produced in both cases, with a sharp particle size distribution: diameters ranged between about 0.05 and 5.20 μm. SAA composite microparticles were characterized by differential scanning calorimetry (DSC), Scanning electronic microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) and UV–vis analysis. A solid solution of HPMC and ampicillin was produced; a stabilizing effect of the polymer on the drug was observed, resulting in the protection of ampicillin from thermal degradation. Coprecipitates were produced at different drug/polymer ratios and two kinds of formulations for oral drug delivery were explored to verify ampicillin controlled release from HPMC: tablets and gelatine capsules of coprecipitated microparticles. Tablets released 97% of AMP in more than 72 h, allowing a slower drug release than capsules, that released 100% of AMP in 8 h. Drug release mechanisms characteristic of swelling-controlled systems were observed, with ampicillin release rate dominated by the erosion of HPMC matrix.

Production of cromolyn sodium microparticles for aerosol delivery by supercritical assisted atomization

The purpose of this study was to produce cromolyn sodium (CS) micrometric particles with controlled particle size (PS) and PS distribution (PSD) suitable for aerosol delivery, using a supercritical fluids-based process. CS was micronized using the supercritical assisted atomization (SAA) technique at different solute concentrations in water and different precipitation temperatures. Two techniques were used to measure PS and PSD of produced particles: scanning electron microscopy image analysis and laser scattering analysis. The 2 techniques were compared to provide a complete description of the powder obtained. High-performance liquid chromatography analysis was used to verify the absence of degradation of CS after micronization; differential scanning calorimetry, thermogravimetric analysis (TGA), and X-ray analysis were performed to study the effect of operative conditions on the crystalline structure and on the water content of SAA micronized particles. The CS particles obtained were spherical, with a volumetric percentage of particles with a diameter ranging between 1 and 5 microm of 50% to 66%. The precipitation temperature had no significant effect on PSD, but high drying temperatures led to product degradation. Increasing the concentration of CS in water solution produced an increase in PS of the micronized particles. TGA showed that the micronized CS had a different hydration state than the untreated CS did. The micronized product was stable after 12 months of storage, and no modifications in structure, morphology, or crystallinity were detected. In conclusion, SAA is an efficient technique for micronization of CS, and stable spherical amorphous particles suitable for aerosol delivery can be produced.

Drug–polymer microparticles produced by supercritical assisted atomization

The supercritical assisted atomization (SAA) was proposed as a new technique to produce composite microparticles for drug controlled release. Ampicillin trihydrate and chitosan were selected as model drug and carrier, respectively, and 1% v/v acetic acid aqueous solution was used as solvent. The effect of the polymer/drug ratio on particle morphology and drug release rate was evaluated. SEM analysis indicated that non-coalescing spherical microparticles formed by chitosan/ampicillin were produced by SAA. All coprecipitates produced have a sharp particle distribution, with diameters ranging between about 0.1 and 6 microm. SAA composite microparticles were characterized by X-ray, DSC, EDX and UV-vis analysis. A solid solution of the chitosan and ampicillin was produced and a stabilizing effect of the polymer on the drug has resulted that protects ampicillin from thermal degradation. A prolonged release from SAA coprecipitates with respect to raw drug and physical mixtures of chitosan and ampicillin was obtained; moreover, the polymer/drug ratio has revealed to be a controlling parameter for drug release. Drug release mechanisms characteristic of swelling-controlled systems were observed, with ampicillin release depending on both relaxation and diffusive mechanisms. An empirical binomial equation was used to describe experimental data, showing a fair good agreement with ampicillin release data if both the relaxational and the diffusional parameters are function of the polymer/drug ratio.

Corticosteroid Microparticles Produced by Supercritical-Assisted Atomization: Process Optimization, Product Characterization, and “in Vitro” Performance

In this work, the production of dexametasone and dexametasone acetate microparticles is proposed using supercritical-assisted atomization (SAA). This process is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug; then, the ternary mixture is sprayed through a nozzle and submicroparticles are formed as a consequence of the enhanced atomization. Several process parameters such as different organic solvent (methanol and acetone), solute concentration and flow rate ratio between the liquid solution and carbon dioxide are investigated; their influence is evaluated on the morphology and size of precipitated particles. Spherical corticosteroid particles with mean diameters ranging from 0.5 to 1.2 µm are produced at the optimum operating conditions and narrow particle size distributions (PSDs) have also been obtained. No drug degradation was observed after SAA processing and solvent residues of 300 and 500 ppm for acetone and methanol, respectively, were measured. Drug microparticles produced by SAA can be semi-crystalline or amorphous depending on the process condition; a micronized drug surface area ranging from about 4 to 5 m2/g was also observed. The “in vitro” activity of both untreated and SAA processed glucocorticoids was tested on the release of pro-inflammatory cytokines from stimulated cells. The results shown that SAA-glucocorticoids have retained the activity of the parent untreated compounds and, in the case of dexamethasone, SAA processing improves drug performance.

Chitosan Microparticles Production by Supercritical Fluid Processing

In this work chitosan (CS) in 1% acetic acid aqueous solutions has been successfully micronized using supercritical assisted atomization (SAA), which is a new and very promising supercritical fluid process. Some process parameters such as precipitation temperature and solute concentration in the liquid solution have been explored to evaluate their influence on the morphology and size of precipitated particles. Noncoalescing spherical microparticles have been produced as confirmed by scanning electron microscopy analysis. Laser scattering particle size analysis has shown that these precipitates have a sharp distribution: 99% of particles produced show diameters ranging between 0.1 and 1.5 μm, when precipitated from solutions with chitosan concentrations ranging between 1 and 10 mg/mL. X-ray and differential scanning calorimetry analyses have also been used to investigate CS modifications induced by SAA processing. A decrease in crystallinity has been observed when higher precipitation temperatures have been used. SAA micronized CS microparticles are expected to be promising vehicles for drug delivery.

Polymer microparticles production by supercritical assisted atomization

Supercritical Assisted Atomization (SAA) was used to micronize poly(methyl methacrylate) (PMMA) and poly- l-lactide (PLLA), selected as a model polymers, to verify SAA processability of polymers and the performance of this process. The effect of process parameters such as the mass flow ratio between carbon dioxide and liquid solution, precipitation temperature and solute concentration in the liquid solution were studied to evaluate their influence on morphology and size of precipitated particles. Successful micronization of the polymers was obtained with a narrow particle size distribution. PMMA and PLLA size-controlled microparticles were produced ranging between 0.05 and 1.6 μm and between 0.1 and 3.5 μm, respectively. Both PMMA and PLLA presented a good processability at temperature conditions far from the glass transition temperature, but high enough to allow a fast solvent evaporation.

Supercritical assisted atomization: Performance comparison between laboratory and pilot scale

SAA (supercritical assisted atomization) process until now has been successfully tested on various compounds using a laboratory scale apparatus. In this work scale-up of the process has been performed, based on the geometrical similitude, the same Reynolds and Weber numbers in the nozzle and the same residence time in the saturator. Experiments have been performed on both laboratory and pilot plant to compare the process performance using zyrconil nitrate hydrate in water and rifampicin in methanol as model compounds. Depending on the concentration, amorphous spherical particles of zyrconil nitrate hydrate with modes ranging between 0.3 and 0.7 μm and of rifampicin ranging between 0.3 and 0.4 μm, have been obtained with small differences between the two apparatuses demonstrating that SAA is a stable, flexible and easily scalable process.

Cyclodextrins micrometric powders obtained by supercritical fluid processing

Supercritical fluid technology offers the possibility to produce dry powder formulations of biocompatible materials, overcoming the drawbacks of classical micronization processes. In this work, Supercritical Assisted Atomization (SAA) has been used to micronize alpha-cyclodextrin (alpha-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Some process parameters, such as precipitation temperature and solute concentration in the liquid solution, have been studied to evaluate their influence on morphology and size of precipitated particles. Cyclodextrins (CDs) micronization has been successful: well-defined spherical microparticles of alpha-CD and HP-beta-CD have been produced. Particle size analysis revealed that sharp distributions have been obtained: 95% of particles have diameters ranging between 0.1 and 5 microm for both CDs. X-ray and DSC analyses have been also performed to investigate CDs modifications induced by SAA processing: amorphous particles have been obtained in both cases, whereas raw alpha-CD was crystalline and raw HP-beta-CD was amorphous.

Supercritical assisted atomization: A novel technology for microparticles preparation of an asthma-controlling drug

The objective of this study was to produce microparticles of a new asthma-controlling drug by supercritical assisted atomization (SAA), proposed as an alternative to conventional jet-milling process. SAA is based on the solubilization of supercritical carbon dioxide in a liquid solution containing the drug; the ternary mixture is then sprayed through a nozzle, and microparticles are formed as a consequence of the enhanced atomization. SAA process parameters studied were precipitator temperature, nozzle diameter, and drug concentration in the liquid solution. Their influence was evaluated on morphology and size of precipitated particles. Spherical particles with mean particle size ranging from 1 to 3 microm of the new anti-asthma drug were produced by SAA. The mass median aerodynamic diameter (MMAD) of the SAA micronized particles and of the conventional jet-milled drug was used to compare the results obtainable using the 2 techniques. Particularly, MMADs from 1.6 to 4.0 microm were obtained by SAA at the optimum operating conditions and by varying the concentration of the solution injected. MMAD of 6.0 microm was calculated for the jet-milled drug. SAA samples also exhibited narrower particle size distribution (PSD). A good control of particle size and distribution together with no drug degradation was obtained by SAA process.

Crystalline Microparticles of Controlled Size Produced by Supercritical-Assisted Atomization

Supercritical-assisted atomization (SAA) is a promising technique that can be used to produce micron- and submicron-sized particles of several kinds of compounds using water or organic solutions. It is based on the solubilization of supercritical CO2 in the liquid solution formed by the solvent and the (solid) solute and on the subsequent atomization of this solution using a thin-walled nozzle. In this work, supercritical-assisted atomization operated at pressures below 12 MPa and at temperatures between 65 and 95 °C has been applied to sodium chloride, potassium iodide, and ammonium chloride to test the possibility of producing microcrystals of controlled dimension. The influence of the concentration of the liquid solution was investigated. Cubic crystals were obtained for two of the tested materials; crystalline particles were also produced in the case of ammonium chloride. A mechanism for crystal formation during SAA at different concentrations is proposed.