Supercritical Assisted Atomization Research Articles

Enhancement of neuroprotective and anti-edema action in mice ischemic stroke model using T3 loaded nanoparticles

Background: cerebral ischemia still represents one of the most common causes of death and disability worldwide. A prompt treatment using strong neuroprotective medications is one potential method of pharmacological therapy for brain ischemic stroke patients. Thyroid hormone (T3) has been demonstrated to protect against ischemic damage. Despite the fact that thyroid hormone may pass across the blood-brain barrier (BBB). Objective: we hypothesized that the effectiveness of thyroid hormone in ischemic brain stroke can be improved by encapsulation in nanoparticulate delivery vehicles. Methods: We tested our hypothesis by generating thyroid hormone encapsulated in nanoparticles or brain-targeted nanoparticles using biodegradable polymers by utilizing an environment-friendly Supercritical Assisted Atomization (SAA) process as an alternative to a thyroid hormone solution in the setting of the MCAO stroke model. The biggest benefit of our proposed exploit of thyroid hormones in ischemic stroke is the fact that this strategy uses the body’s endogenous hormones at sub-toxic levels to afford significant improvement in a life-endangering situation. According to our preliminary studied considerations, some tests were performed setting the saturator operating conditions in a pressure range between 5 and 15MPa and a temperature range between 70 and 90oC. Results: The best results in terms of stability of the process and morphology of thyroid hormone nanoparticles were observed operating at 10MPa and 80oC. Our preliminary investigations also show that treatment with T3 significantly decreased infarct area (~36%) and analysis of hemispheric areas for edema formation showed that the edema formation induced by transient-MCAO was reduced by ~60% upon T3 treatment. Conclusion: Thus, innovation in our proposal lies in our hypothesis, and our novel approaches directed at tackling edema in stroke.

Production of inclusion complexes containing corticosteroids by SAA process

Slightly water-soluble drugs are frequently coprecipitated with a suitable carrier to speed up active principle ingredient (API) dissolution, improving its bioavailability. In this work, combined systems constituted by a corticosteroid and a cyclodextrin were micronized by Supercritical Assisted Atomization (SAA). When SAA processes corticosteroids alone, it is impossible to obtain micronized powders. The selected corticosteroids were prednisolone and dexamethasone, and a derivative of β-cyclodextrin was chosen as the carrier. The drug:cyclodextrin molar ratio and the initial solution concentration were varied to verify their influence on the powders’ particle size and particle size distribution. At all ratios and concentrations assessed, spherical micrometric particles were obtained. Under the optimized process conditions, compared to the unprocessed material, the dissolution time decreases from 18 h to 4 h in the case of prednisolone and from 22 h to 5 h in the case of dexamethasone.

Instant Formulation of Inhalable Beclomethasone Dipropionate-Gamma-Cyclodextrin Composite Particles Produced Using Supercritical Assisted Atomization.

Medical composites derived from Gamma-cyclodextrin (γ-CD) and beclomethasone dipropionate-gamma-cyclodextrin (BDP-γ-CD) are synthesized over supercritical-assisted atomization (SAA) herein. Carbon dioxide, which serves the dual function of spraying medium and co-solute, is incorporated in this process along with the ethanolic solvent. Results indicate that, for fine spherical particles, optimized aerosol performance could be obtained with 50.0% (w/w) ethanolic solvent, precipitator, and saturator at 373.2 K and 353.2 K, respectively, and carbon dioxide-to-γ-CD flow ratio of 1.8 in the presence of 10 wt% leucine (LEU) as dispersion enhancer. It is also noted that γ-CD solution at low concentration typically renders better aerosol performance of the particles. During drug particle-derivation, the solubility of drug BDP elevated considerably due to the formation of inclusion complexes, further assisted by the ethanolic solvent which increases the lipophilicity of BDP. Meanwhile, the in vitro aerosolization and dissolution performance of drug composites derived from varied γ-CD-to-BDP mass ratio (Z) were also evaluated. It was found that high Z promises higher fine particle fraction in the obtained drug composite while the dissolution rate of active ingredient (BDP) exhibits positive correlation to the content of water-soluble excipient (γ-CD) in the formulation. This study offers a new avenue for instant drug formulation with promising pulmonary delivery over the SAA technique.

Salicylic Acid Co-Precipitation with Alginate via Supercritical Atomization for Cosmetic Applications.

Alginate-based microparticles were produced via supercritical assisted atomization (SAA) with the aim of obtaining a biocompatible and low-cost carrier for the delivery of active compounds in cosmetic applications. Salicylic acid was selected as an active model compound, and it was co-precipitated with alginate via SAA, operating at 82 bar and 80 °C. In particular, the drug-to-polymer weight ratio was fixed at 1/4, whereas polymer concentration was varied from 5 to 20 mg/mL in the starting aqueous solution. Operating in this way, alginate-salicylic acid microparticles were characterized by a mean diameter of 0.72 ± 0.25 µm, and the active compound became amorphous after processing. A salicylic acid encapsulation efficiency close to 100% was reached, and the drug release time from the biopolymeric microparticles was prolonged up to nine times with respect to untreated salicylic acid powder.

Lycopene extract from tomato concentrate and its co-precipitation with PVP using hybrid supercritical processes

In this work, a hybrid supercritical approach was proposed for the production of a dried lycopene extract and its co-precipitation in polyvinylpyrrolidone (PVP) sub-microparticles. In particular, lycopene extract was obtained from a tomato pulp concentrate, using ethyl acetate as the optimal organic solvent. Then, the lycopene extract was dried via supercritical antisolvent extraction, operating at 9.0 MPa and 50 °C. In a single step, a solvent-free powder that preserved up to 80 % of antioxidant activity was obtained. To improve lycopene extract shelf-life, supercritical assisted atomization was performed. The aim was to co-precipitate the active principle with a hydrophilic polymer, like PVP, to protect lycopene from oxidation phenomena. Operating at 8.5 MPa and 80 °C, sub-microparticles of 194 ± 230 nm mean diameter were produced that maintained around 85 % of antioxidant activity at least for 6 months of storage at room temperature.

Immediate Release Formulation of Inhaled Beclomethasone Dipropionate-Hydroxypropyl-Beta-Cyclodextrin Composite Particles Produced Using Supercritical Assisted Atomization.

In this study, the enhanced solubilization performance of a poorly soluble drug, beclomethasone dipropionate (BDP), was investigated using hydroxypropyl-β-cyclodextrin (HP-β-CD) and ethanol. The enhanced solubility of the drug was determined using the phase solubility method and correlated as a function of both HP-β-CD and ethanol concentrations. The effective progress of drug solubility originated from the formation of cyclodextrin and BDP inclusion complexes and increase in the lipophilicity of the medium, by aqueous ethanol, for hydrophobic BDP. BDP and HP-β-CD composite particles were produced using supercritical assisted atomization (SAA) with carbon dioxide as the spraying medium, 54.2% (w/w) aqueous ethanol as the solvent, and an optimal amount of the dispersion enhancer leucine. The effect of the mass ratio of HP-β-CD to BDP (Z) on the in vitro aerosolization and in vitro dissolution performance of BDP–HP-β-CD composite particles was evaluated. The aerosolization performance showed that the fine particles fraction (FPF) of the composite particles increased with increasing mass ratio. The water-soluble excipient (HP-β-CD) effectively enhance the dissolution rate of BDP from composite particles. This study suggests that BDP–HP-β-CD composite particles produced using SAA can be employed in immediate-release drug formulations for pulmonary delivery.

Experimental analysis of temperature effects in supercritical-assisted atomization

Supercritical CO2 is proved as an excellent choice in supercritical-assisted atomization of nanoparticle suspensions for fabrication of micro/nano-powders. As the rheological properties of the supercritical fluids are strongly dependent on the temperature, the breakup mechanism of the CO2-liquid mixture upon injection is significantly affected by crossing the critical temperature of the binary mixture. In this study, we investigate the breakup of CO2-water mixture (CO2-A) at subcritical, critical, and supercritical states and compare it with the cases where N2 is utilized as the assisting fluid (N2-A) at the same injection conditions. High-speed imaging and laser diffraction systems are utilized to analyze the primary and secondary atomization of the injected CO2-water mixture (over 20 to 40 °C injection temperature range). In general, CO2-A showed smaller and more homogenous droplets compared to N2-A. Therefore, the use of CO2 as the atomization gas is superior to N2. The underlying mechanism in primary breakup of CO2-A involves the emergence, expansion, and burst of CO2 bubbles and formation of ligaments that break up into droplets. The core of the jet in CO2-A system expands up to 50% due to emergence of gas bubbles, while the expansion ratio remains unchanged in the N2-A jet. The finest and most homogenous droplet sizes are achieved by operating near the critical point at 31.5 °C and 7.5 MPa. High solubility of CO2 in water and low interfacial tension of the CO2-water mixture are the main contributors.

Effect of the Carrier on the Coprecipitation of Curcumin through Supercritical-Assisted Atomization

In this paper, composite systems containing curcumin (CUR) were prepared through supercritical-assisted atomization (SAA), using different carriers. Curcumin is particularly interesting in the pharmaceutical and nutraceutical fields for its antioxidant, antitumoral, and anti-inflammatory properties. However, its therapeutic effect on human health is restricted by its poor water solubility and low dissolution rate, limiting its absorption after its oral administration. To increase the dissolution rate and then the bioavailability of the active compound, CUR was coprecipitated with polymeric, i.e., polyvinylpyrrolidone (PVP) and dextran (DXT), and not polymeric, i.e., hydroxypropyl-β-cyclodextrin (HP-β-CD), carriers. The effects of some operating parameters, namely the concentration of solutes in solution and the active compound/carrier ratio, on the morphology and the particle size distribution of the powders were investigated. Submicrometric particles were produced with all the carriers. Under the best operating conditions, the mean diameters ± standard deviation were equal to 0.69 ± 0.20 μm, 0.40 ± 0.13 μm, and 0.81 ± 0.25 μm for PVP/CUR, DXT/CUR, and HP-β-CD/CUR, respectively. CUR dissolution rates from coprecipitated particles were significantly increased in the case of all the carriers. Therefore, the results are exciting from a pharmaceutical and nutraceutical point of view, to produce supplements containing curcumin, but assuring a high dissolution rate and bioavailability and, consequently, a more effective therapeutic effect.

Characterization and Aerosolization Performance of HydroxyPropyl-Beta-Cyclodextrin Particles Produced Using Supercritical Assisted Atomization.

In this study, hydroxypropyl-beta-cyclodextrin (HP-β-CD) particles were produced using supercritical assisted atomization (SAA) with carbon dioxide as the spraying medium or co-solute and aqueous ethanol solution as the solvent. The effects of several key factors on the morphology and size of the HP-β-CD particles were investigated. These factors included the solvent effect, temperatures of the precipitator and saturator, concentration of the HP-β-CD solution, and flow rate ratio of carbon dioxide to the HP-β-CD solution. The conducive conditions for producing fine spherical particles were 54.2% (w/w) aqueous ethanol as the solvent; precipitator and saturator temperatures of 373.2 K and 353.2 K, respectively; a flow rate ratio of carbon dioxide to HP-β-CD solution of 1.8; and low concentrations of HP-β-CD solution. The addition of leucine (LEU) enhanced the aerosol performance of the HP-β-CD particles, and the fine particle fraction (FPF) of the HP-β-CD particles with the addition of 13.0 mass% LEU was 1.8 times higher than that of the HP-β-CD particles without LEU. This study shows that LEU can act as a dispersion enhancer and that HP-β-CD particles produced using SAA can be used as pulmonary drug carriers.

Experimental analysis of supercritical-assisted atomization

Supercritical CO2 is used in supercritical-assisted atomization (SAA) systems to promote the atomization of nanoparticle suspensions in powder generation in pharmaceutical, electronics, and coating applications. Due to the sensitivity of the mixture properties to the operational conditions, the SAA process is not fully resolved to date. This study experimentally investigates the underlying mechanisms behind SAA utilizing CO2 or N2 as the assisted-atomization fluid (CO2-A or N2-A) using high-speed imaging and laser diffraction techniques. The effects of injection temperature, pressure, and gas-to-liquid ratio (GLR) are explored, and empirical droplet size models are developed. It is found that the primary breakup of CO2-A is governed by the emergence of the near-nozzle gas bubbles originated from the dissolved CO2, which expand radially and squeeze the liquid due to the inertial forces. As a result, the edges of the liquid core become thinner and deform into relatively long ligaments that further break up into droplets. CO2-A exhibited a shorter liquid length, wider spray angle, and smaller droplet size compared to N2-A. The discrepancies observed in the breakup process are mainly attributed to the higher solubility of CO2 in water and lower surface tension of the CO2–water system. The smallest droplet size distribution and the narrowest droplet size distribution are detected for CO2-A injected at the critical pressure of the CO2–water binary system where the solubility of CO2 in water significantly rises. Linear instability analysis indicates that both shear and acceleration that indirectly incorporate the experimentally observed bubble expansion are the main factors driving the instabilities.

Formulation of inhalable beclomethasone dipropionate-mannitol composite particles through low-temperature supercritical assisted atomization

Mannitol carrier and drug-carrier composite particles were produced via low-temperature supercritical assisted atomization (LTSAA). The enhanced aerosolization of the mannitol carrier particles with added L-leucine could be attributed to the formation of fine corrugated particles, which reduced the interparticle cohesion and led to better flowability of the mannitol carrier particles. A poorly water-soluble drug, beclomethasone dipropionate (BDP), and mannitol co-precipitated during LTSAA with the optimal addition of 9.1 mass % L-leucine. The in vitro aerosolization and dissolution experiments indicated that the fine particles fraction (FPF) of the drug-carrier composite particles was 3.4 times (FPF = 49.9 %) higher than that of the as-received BDP (FPF = 14.7 %) and the 63.2 % drug release time of the drug-carrier composite particles was 15.6 times faster than that of as-received BDP. This study suggests that the drug-carrier composites produced using LTSAA can be employed in the instant formulation of inhalable dry powder.

Formation of Polyethylene Glycol Particles Using a Low-Temperature Supercritical Assisted Atomization Process.

Polyethylene glycol (PEG) particles were prepared using low-temperature supercritical assisted atomization (LTSAA) with carbon dioxide as the spraying medium or the co-solute and acetone as the solvent. The effects of several key factors on the particle size were investigated. These factors included the concentration of the PEG solution, precipitator temperature, saturator temperature, ratio of the volumetric flow rate of carbon dioxide to the PEG solution, and the molecular weight of PEG. Spherical and non-aggregated PEG particles, with a mean size of 1.7–3.2 µm, were obtained in this study. The optimal conditions to produce fine particles were found to be a low concentration of the PEG solution, a low precipitator temperature, and low molecular weight of the PEG. The phase behavior of the solution mixture in the saturator presented a qualitative relationship. At the optimized volumetric flow rate ratios, the composition of CO2 in the feed streams was near the bubble points of the saturator temperatures. X-ray and differential scanning calorimetry analyses indicated that LTSAA-treated PEG had a reduced degree of crystallinity, which could be modulated via the precipitator temperature. PEG microparticles prepared by a LTSAA process would be promising carriers for drug-controlled formulations of PEG-drug composite particles.

CONTROLLED RELEASE OF THEOPHYLLINE-CHITOSAN COMPOSITE PARTICLES PREPARED USING SUPERCRITICAL ASSISTED ATOMIZATION

Abstract This study investigated the formation of composite particles of chitosan (CS) and theophylline (TPH) via supercritical assisted atomization (SAA) using aqueous ethanol (50%, v/v) as the solvent and supercritical CO2 as the spraying medium. According to XRD, DSC, and FTIR analyses, the crystal form of the SAA-treated TPH from the as-received TPH was unchanged. The effect of different mass ratios of CS to TPH on the in vitro release of TPH showed that the dissolution of the highly water-soluble TPH was retarded when included in the composite particles and could be controlled by the mass ratio of the component in the SAA process. The in vitro dissolution data showed a good fit with the Peppas-Sahlin model, which was used to conclude that the drug release from the composite particles resulted from a combination of drug diffusion and relaxation of the polymer. As the mass ratio of CS to TPH increased, the mechanism relating to polymer relaxation became crucial in the TPH-CS composite particles.

β-Carotene/PVP microspheres produced by Supercritical Assisted Atomization

β-carotene (BC) is one of the best known and used bioactive compounds with antioxidant activity. In this work coprecipitation of BC with polyvinylpyrrolidone (PVP) by Supercritical Assisted Atomization (SAA) has been studied, to enhance BC bioavailability and to provide its protection against oxidation. Two solvents have been used: ethanol and a mixture acetone/ethanol 70/30 (v/v). In both cases SAA produced spherical and amorphous microspheres with d50 ranging between 0.42 and 0.84 μm using ethanol, and 0.28 and 0.48 μm using the solvent mixture. UV–vis analyses revealed a BC content up to 94% and high scavenging activities confirm that PVP is able to protect it from degradation. BC dissolution rate in a phosphate buffered saline solution (PBS) was up to 22 times faster than that of physical mixture. The major difference between coprecipitates was in their dissolution rate: it depended also on the kind solvent used, indicating a possible different internal particles organization during droplet drying.

Preparation of pH-responsive DOX-loaded chitosan nanoparticles using supercritical assisted atomization with an enhanced mixer

Chemotherapeutics are used extensively in cancer and encapsulating the drug in nanoparticles is an effective method to enhance therapeutic efficacy and reduce side effect. In this work, DOX-loaded chitosan nanoparticles were prepared using supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) from aqueous solution. The influences of solution concentration, CO2/solution ratio, mixer pressure, chitosan/DOX ratio and chitosan molecular weight on particle morphologies and sizes were investigated in detail. Well defined spherical nanoparticles with average diameter ranging from 120 nm to 250 nm were obtained, and the loading efficiency was up to 90%. FT-IR result showed that the structure of DOX was not changed after the SAA-HCM process. Zeta potential of the nanoparticles was about +50 mV. The in vitro drug release behavior conducted in the media with pH of 4.5, 6.5 and 7.4 respectively showed strongly pH responsive. In vitro cytotoxicity profiles revealed that the activity of DOX was well maintained after loaded into chitosan nanoparticles. The SAA-HCM process was demonstrated to be a promising technique for one-step production of polymer/drug composite nanoparticles suitable for cancer drug delivery from aqueous solution.

Characterization and aerosolization performance of mannitol particles produced using supercritical assisted atomization

Different shapes and sizes of water-soluble mannitol (MAN) particles were prepared using a supercritical assisted atomization (SAA) process. The needle-shaped and spheroidal mannitol particles were prepared using water and aqueous ethanol, respectively, as solvent of the MAN solution. The size of mannitol particles increased with increasing the concentrations of MAN solution and deceased with increasing saturator temperatures and CO2-solution flow ratios. The in vitro aerodynamic behavior of the mannitol particles as dry powder inhaler (DPI) formulations was investigated using an Andersen cascade impactor. The effects of the morphology and the size of mannitol particle on powder deagglomeration and flowability were evaluated. In vitro aerosolization tests showed that the spheroidal particles favor deagglomeration of mannitol powder and the fine particle fraction (FPF) was enhanced by the excellent powder flowability of the larger mannitol microparticles.

Production of PEA composite microparticles with polyvinylpyrrolidone and luteolin using Supercritical Assisted Atomization

Palmitoylethanolamide (PEA) has anti-inflammatory, pain controlling and neuroprotective properties, but its use is limited by its low water solubility and corresponding bioavailability. In this work, Supercritical Assisted Atomization (SAA) coprecipitation is used to reduce PEA tendency to crystallize, using polyvinylpyrrolidone (PVP) and luteolin (LUT) and operating at different process parameters.Spherical microparticles were produced at PEA/PVP ratio 1:8 wt/wt in ethanol, with D50 of 400 nm and with the best result as particle morphology. X-ray analysis reveals that these PEA-PVP particles are amorphous and PEA loading efficiency reaches 100%.In the case of PEA-LUT coprecipitates, very small quantities of LUT stabilized the microparticles, inhibiting PEA crystallization process. Indeed, quasi spherical microparticles were produced at 10:1 wt/wt PEA/LUT ratio, with D50 of 970 nm and PEA loading efficiency over 99%. To explain how very small quantities of LUT can modify PEA crystallization behavior, specific PEA-LUT interactions were evidenced by FT-IR analysis.

Preparation and characterization of Chilean propolis coprecipitates using Supercritical Assisted Atomization

Propolis is a natural resinous material with antimicrobial, anti-inflammatory, antioxidant, antibiotic and anti-carcinogenic properties. Propolis coprecipitation was attempted by Supercritical Assisted Atomization (SAA) using two carriers: hydroxypropyl-β-cyclodextrin (HPβCD) and polyvinylpyrrolidone (PVP), with the aim to protect propolis bioactivity against oxidation and to improve its bioavailability. Propolis/carrier ratio and overall solute concentration were investigated to understand their effect on the success of coprecipitation as solid dispersion of propolis in the carrier matrix and on particle morphology and particle size distribution. The results confirmed the efficiency of SAA process: spherical amorphous particles were obtained in which propolis and carrier were coprecipitated, with a mean diameter ranging between about 0.20 and 0.37μm for HPβCD coprecipitates and between about 0.23 and 0.50μm for PVP coprecipitates. SAA particles showed a polyphenol loading efficiency up to 100% for HPβCD coprecipitates and up to 96% for PVP coprecipitates, with a half inhibition concentration of DPPH radical up to (17.2±2.8) μg/mL and (17.3±1.0) μg/mL, respectively. These particles rich in bioactive compounds can be used as functional component in formulations of new food or pharmaceutical products.

Luteolin/dextran-FITC fluorescent microspheres produced by supercritical assisted atomization

Supercritical Assisted Atomization was used to produce a complex particulate system, consisting of a polysaccharide (Dextran, DEX) loaded with a fluorescent agent (Fluorescein isothiocyanate, FITC) and a poorly water soluble compound (Luteolin, LUT). Different LUT/(DEX+FITC) weight ratios and different concentrations were investigated to develop microparticles that can act as an imaging agent and as a drug delivery carrier. SAA produced spherical, well-separated and amorphous particles. Analytical studies revealed that LUT was uniformly dispersed in DEX matrix and specific interactions appeared between LUT and DEX. LUT loading efficiencies reached 100% and dissolution tests in a phosphate-buffered saline solution were up to 18 times faster compared to the physical mixture, due to an efficient dispersion of LUT in DEX matrix and to the formation of hydrogen bonds between LUT and DEX. All results confirmed that the presence of FITC in SAA coprecipitates did not influence particle size, morphology and LUT dissolution rate.

Production of Luteolin/Biopolymer Microspheres by Supercritical Assisted Atomization

Supercritical assisted atomization (SAA) was used to produce coprecipitated submicroparticles of luteolin (LUT)/poly(vinylpyrrolidone) (PVP) for pharmaceutical applications. LUT has antioxidant, antiinflammatory, and antitumoral properties but is poorly water-soluble, whereas PVP is highly water-soluble. This polymer can be used to protect the active molecule and to improve its bioavailability. Different LUT/PVP weight ratios were selected ranging between 1:4 and 1:8. SAA produced partly collapsed spherical particles with controlled particle size and mean diameters ranging between 0.22 and 0.33 μm. UV–vis analyses revealed very high loading efficiency of LUT in SAA particles (99–100%). The powders are amorphous, whereas the untreated material shows crystalline patterns. Fourier transform infrared revealed that hydrogen bonds were created between the drug and polymer. Drug-release analysis indicated that the supercritical processing was successful: the LUT dissolution rate in a phosphate-buffered saline so...