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Exopolysaccharides, obtained from microorganisms as fermentation products, are interesting candidates for biomedical applications as scaffolds: they are biocompatible, nontoxic, antimicrobial, antitumor materials. To produce exopolysaccharide-based scaffolds, sol–gel technology could be used, which ends with the removal of the liquid phase from the polymeric network (i.e., the drying step). The aim of this review is to point out the most relevant strengths and weaknesses of the different drying techniques, focusing attention on the production of exopolysaccharide-based porous structures. Among these drying processes, supercritical carbon dioxide-assisted drying is the most promising strategy to obtain dried gels to use in the biomedical field: it produces highly porous and lightweight devices with outstanding surface areas and regular microstructure and nanostructure (i.e., aerogels). As a result of the analysis carried out in the present work, it emerged that supercritical technologies should be further explored and applied to the production of exopolysaccharide-based nanostructured scaffolds. Moving research towards this direction, exopolysaccharide utilization could be intensified and extended to the production of high added-value devices. [ABSTRACT FROM AUTHOR]

Clary Sage extracts are of industrial interest: in particular, sclareol shows a strong pharmaceutical potential. Supercritical fluid extraction was used to recover compounds of interest from a Salvia sclarea L. waxy n-hexane extract ("concrete"), using semi-continuous fractionation and a multi-step extraction strategy. Multi-step extraction experiments were carried out in two phases: the first one operated at 90 bar and 50 °C; the second one at 100 bar and 40 °C. GC-MS traces showed that during the first extraction step, only lighter compounds (e.g., monoterpenes, sesquiterpenes, and derivatives) were collected, whereas, in the second step, only sclareol and related compounds were recovered. By adjusting operating conditions (temperature and pressure), selective extraction of different families of compounds was accomplished, with no further need for post-processing of the products. Moreover, using two separators in series, the compounds of interest were fractionated from paraffins and, by changing the operating conditions, the extraction yield increased from about 6.0% to 9.3% w/w as CO2 density increased. [ABSTRACT FROM AUTHOR]

Marigold oil is a product of great industrial interest thanks to its wide range of medicinal and wound-healing properties. In this work, supercritical carbon dioxide was used to recover marigold essential oil from the hexane solvent extract of marigold flowers, the floral "concrete". This starting material was mixed with synthetic paraffinic waxes to heighten its melting point and viscosity, thus, improving material processability. Supercritical fluid extraction and fractionation of the modified marigold "concrete" was carried out, and the effect of pressure and CO2 mass flow rate was studied. The pressure was varied from 80 to 180 bar, keeping the temperature constant at 40 °C: the higher the pressure, the larger the CO2 solvent power and extraction yield (up to 9.40% w/w). Nevertheless, the optimum between productivity and process selectivity was found at 100 bar. By changing the CO2 mass flow rate (from 1.20 to 1.50 kg/h), we noted that mass transfer resistance was located externally. GC-MS analysis showed that the most abundant compounds in the oil were δ-cadinene (25%), γ-cadinene (16%), τ-muurolol (6.5%), and α-muurolene (6%). Moreover, the traces of oil and waxes showed no mutual contamination between lighter species and waxes, meaning that the fractionation step was successful. [ABSTRACT FROM AUTHOR]

This work proposes an improvement of the traditional electrospraying process, in which supercritical carbon dioxide (SC-CO2) is used to produce poly(lactic-co-glycolic acid) (PLGA) nanoparticles. The experiments were performed at different PLGA concentrations (1, 3 and 5% w/w), applied voltages (10 and 30 kV) and operating pressures (80, 120 and 140 bar). It was found that working at 140 bar and 30 kV, spherical nanoparticles, with mean diameters of 101 ± 13 nm and 151 ± 45 nm, were obtained, when solutions at 1% w/w and 3% w/w PLGA were electrosprayed, respectively. Increasing PLGA concentration up to 5% w/w, a mixture of fibers and particles was observed, indicating the transition to the electrospinning regime. [ABSTRACT FROM AUTHOR]

Supercritical-CO2 assisted electrospray is a new process used to produce polymeric micro- and nanoparticles characterized by tunable and regular morphologies. The major innovation consists of the addition of supercritical CO2 to the polymeric solution, obtaining a gas expanded liquid having reduced values of viscosity and surface tension. Due to its biodegradability and biocompatibility, cellulose acetate (CA) was selected as polymeric carrier for microparticles production, that can be used for drug delivery applications. Indeed, CA solutions were loaded with a poorly-water soluble compound, rutin (RUT), to improve its bioavailability. The experiments were performed at different CA concentrations (0.5 and 1 wt%) and different RUT concentration, that was varied from 2.5 to 7.5 wt% with respect to CA; the applied voltage was set at 30 kV. CA/RUT microparticles were successfully produced; working at 140 bar and 30 kV, particles characterized by an average diameter of 980±120 nm and networked fibers were obtained, processing 1 wt% CA solution and using a RUT concentration of 7.5 wt% with respect to CA. IR spectroscopy revealed the physical dispersion of RUT into CA particles. [ABSTRACT FROM AUTHOR]

[Display omitted] • Critical analysis of the major steps involved in the cellulose acetate industrial process. • Possible improvements using supercritical CO 2 based sub-processes. • Supercritical antisolvent extraction of the acetic dope is the most attractive alternative. • Micro- and nanoparticles, or filaments, of cellulose acetate can be directly produced. • Acetic acid residue of 23 ppm in the supercritical CO 2 treated cellulose acetate. A critical analysis of the major steps involved in the cellulose acetate industrial process is performed, with the aim of proposing possible improvements using supercritical CO 2 based sub-processes. Once highlighted the main weakness of the traditional process, related to the (i) fine modulation of the acetylation reaction to obtain 2.5 acetate, (ii) acetic acid removal from the acetic dope, and (iii) treatment of the diluted acetic acid–water solution, the most attractive alternative resulted the adoption of a supercritical antisolvent extraction (SAE) performed on the acetic dope. Operating in this way, the problems related to the use of large quantities of water to remove acetic acid from the acetic dope are resolved, since it will be directly extracted by supercritical CO 2. Micro- and nanoparticles, or filaments, of cellulose acetate can be produced. Finally, an acetic acid residue of 23 ppm, in the supercritical CO 2 treated cellulose acetate, confirmed the success of this alternative process configuration. [ABSTRACT FROM AUTHOR]

Supercritical CO2 (SC‐CO2) extraction is commonly used to eliminate caffeine from coffee beans. In this work, the feasibility of tryptamine elimination is considered as a further objective of the process. SC‐CO2 extraction process parameters (eg, pressure, CO2 flow rate, water content) were studied to obtain tryptamine reduction, starting from those used in supercritical decaffeination. A good compromise, in terms of tryptamine residue in coffee beans, and process feasibility and selectivity, was found operating at 280 bar and 0.8 kg/h CO2, at a starting H2O content in coffee beans of 20% w/w. Using these process conditions, a tryptamine residue of 218 ppm (ppm) was measured in coffee beans after 18 hours of processing. A negligible effect on process selectivity and tryptamine yield was obtained by changing the CO2 flow rate and the initial water content. However, working at an initial water content of 30% w/w and using wet CO2 (CO2 plus 3% w/w water), a tryptamine residue of 107 ppm in coffee beans was obtained, but industrial complexity and costs increased. [ABSTRACT FROM AUTHOR]

• Supercritical phase inversion was used to create new composite membranes. • An amphiphilic polymer (levan) was included into CA and PVDF-HFP membranes. • Levan increased cellular adhesion and reduced mechanical properties for PVDF-HFP. • Levan caused a type of "foaming effect" on PVDF-HFP membranes. • Levan increased mechanical resistance and cellular adhesion for CA membranes. With the aim of increasing the mechanical and biological properties of different materials, a supercritical CO 2 (SC-CO 2) assisted technique was used to include a polymer with a natural origin (levan) in membranes of cellulose acetate (CA) and polyvinylidenefluoride-co-hexafluoropropylene (PVDF-HFP). CA-levan membranes were characterized by interconnected pores ranging from 9 to 13 μm; due to levan addition, composite membranes increased their mechanical resistance and cells adhesion (from 8% to 30%). In the second system, the processing of a PVDF-HFP-DMSO-levan colloidal suspension system caused a morphological modification and the generation of a foam-like structure; a decrease of the mechanical resistance and an increase of cells adhesion (from 8% to 35%) were observed. Stress-strain responses for both systems were fitted using two different hyperelastic equations, Yeoh and Ogden; deviations from experimental data lower than 15% were obtained. In conclusion, SC-CO 2 assisted process was able to generate composite structures with levan, accessible to the cells; i.e., transforming polymers like CA and PVDF-HFP in potentially useful materials for biological applications. [ABSTRACT FROM AUTHOR]

• CO 2 dissolved in the starting polymeric solution reduces its surface tension and viscosity. • Changing ΔV and P against PVP concentration, the transition from electrospray to electrospinning was observed. • At lower molecular weight PVP, particles smaller than 0.35 μm were produced. • Microfibers with diameters down to about 1.4 μm were produced. An evolution of traditional electrospray and electrospinning is proposed in this work, adding SC−CO 2 in the liquid polymeric solution. This new process arrangement allows to overcome some intrinsic limitations of the traditional processes, namely surface tension and viscosity control. The influence of various process parameters was studied. The increase of electric potential difference did not significantly modify the particle size distributions and the fiber size distributions; but, the distributions became sharper as the electric potential difference increased. At low PVP percentages in the solution, electrospray was favored, forming small particles, due to low solution viscosity. The viscosity of the solution increased with PVP concentration: therefore, first large and very large particles were formed; then, the process was no more able to produce jet break-up, microfibers were obtained and the process was converted to electrospinning, producing microfibers with diameters down to about 1.4 μm. Using lower molecular weight PVP, smaller particles (down to 0.35 μm) were produced and the particles/fibers transition occurred at larger polymer percentages. Pressure and PVP percentage played opposite roles in generating the different morphologies; therefore, electrospray and electrospinning assisted by SC−CO 2 are like two faces of the same medal: they could be performed using the same apparatus, properly setting the process conditions and polymer concentration. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Spherical microparticles of zein and antibiotic were obtained using SAS process; • for zein + amoxicillin, the mean particles diameter was equal to 0.65 ± 0.51 μm; • for zein + ampicillin, the mean particles diameter was equal to 9.0 ± 5.7 μm; • the antibiotics' release was significantly delayed in the coprecipitated particles. Abstract In this work, the supercritical antisolvent (SAS) coprecipitation of zein with amoxicillin trihydrate (AMOXI) and ampicillin sodium salt (AMPI), two commonly used broad-spectrum antibiotics is proposed. In order to precipitate composite microspheres with controlled dimensions, the proper conditions, in terms of operating temperature and zein/antibiotic ratio, were identified. In the case of amoxicillin trihydrate, at 90 bar, 40 °C, 50 mg/mL and zein/AMOXI ratio equal to 20/1, spherical microparticles with mean diameter equal to 0.65 ± 0.51 μm were successfully produced. In the case of ampicillin sodium salt, at 90 bar, 50 °C, 50 mg/mL and zein/AMPI ratio equal to 5/1, spherical microparticles with mean diameter equal to 9.0 ± 5.7 μm were precipitated. Drug release analyses revealed that the release of the antibiotics was significantly delayed, confirming that zein/antibiotic coprecipitates obtained by SAS can be used for controlled-release formulations. [ABSTRACT FROM AUTHOR]

In this work, poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) membranes for water purification were produced by supercritical phase inversion using a mixture of supercritical CO2 (SC-CO2) and ethanol as non-solvent. Different polymer concentrations (from 10 to 20% w/w) and ethanol amount by volume (from 1 to 50% v/v) with respect to SC-CO2 flow rate, were tested in order to study their influence on membranes morphology, surface area and porosity; supercritical processing was performed at a pressure of 200 bar and a temperature of 45 °C. Membranes characterized by a cellular morphology with a nanoporous substructure and/or by an homogeneous nanoporous morphology were obtained, changing the starting polymer concentration and the ethanol amount during the process. In particular, increasing the amount of ethanol from 1 to 50% v/v, an increase of membranes porosity and surface areas was obtained, and the membranes morphology changed from microporous with nanoporous cell walls to completely nanoporous, due to an increase of the non-solvent power that improved the in-situ gelification mechanism during the supercritical phase separation. [ABSTRACT FROM AUTHOR]

Abstract In this work, Supercritical Antisolvent (SAS) technique is proposed to incorporate ketoprofen (KET), a poorly water-soluble anti-inflammatory drug with analgesic and antipyretic properties, within polyvinylpyrrolidone (PVP), a biocompatible and biodegradable polymer. In order to obtain micrometric particles with controlled dimensions, operating pressures in the range 90–150 bar, concentration of PVP/KET mixture in DMSO from 10 to 100 mg/mL, and PVP/KET ratio from 3:1 to 20:1 were used. Composite spherical microparticles with mean diameters ranging from 2.41 (±1.29) and 3.81 (±2.01) μm were successfully produced, at different operating conditions. Some analytical techniques, such as differential scanning calorimetry, Fourier transform infrared spectroscopy and UV–vis spectroscopy, were used for the powders' characterization. An increase in the drug dissolution rate in the coprecipitated particles of about 4 times with respect to the unprocessed KET was measured. Graphical abstract Unlabelled Image Highlights • Coprecipitation of spherical microparticles of PVP and ketoprofen was obtained using SAS process. • Particles mean diameter ranged between about 2.4 and 3.8 μm. • Ketoprofen dissolution rate was enhanced in the coprecipitated particles. [ABSTRACT FROM AUTHOR]

BACKGROUND: Supercritical (SC)‐CO2 extraction of rotenoids from Derris elliptica roots was proposed using fractional separation of the extracts and operating at increasing pressure. RESULTS: The best processing conditions were found at 200 bar, 40 °C and 1.2 kg h−1 SC‐CO2 flow rate, obtaining a final product with a concentration of 93% w/w of rotenone and rotenoids, and a yield of active principles of 6.70% w/w with respect to the vegetable matrix. Very small quantities of waxes were found, up to 0.05% w/w; this result can be explained considering the reduced surface‐to‐volume ratio of this vegetable material. CONCLUSION: Extraction kinetics data confirmed that, in this case, the extraction process was controlled by solubility limitation of the active compounds in the supercritical solvent. © 2018 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

BACKGROUND Artemisia annua L. extraction is traditionally performed using hexane; the process is simple, but not selective. In this work, a strategy to concentrate artemisinin and the other similar active principles in the final extract is proposed, combining cheapness of maceration and selectivity of SC‐CO2 processing. RESULTS: Hexane extraction produced a solid, waxy extract with a yield of 3.3% w/w with respect to the starting vegetable material. Then, SC‐CO2 processing of this solid extract was performed operating at 0.8 kg h−1 SC‐CO2 flow rate and at different operative parameters. Very selective conditions were found operating at 90 bar and 50°C, obtaining a final product containing more than 71% w/w of active compounds (artemisinin, artemisin and dehydroartemisinin). CONCLUSION: Using this approach, a product more than 2.6 times richer in artemisinin than the one obtained by conventional techniques and about 2 times richer than direct CO2 extraction, was obtained. Another relevant result is that the overall process scheme is cheaper than direct CO2 extraction, since a high pressure extractor about 20 times smaller can be used, to process the waxy product obtained by hexane extraction. © 2018 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Supercritical fractional extraction and separation scheme, was used to process Artemisia annua L., producing extracts enriched in active antimalarial principles. The best results were obtained when extraction was performed at 100 bar, 40 °C and the first separator was operated at the same pressure and at −7 °C. Paraffinic co-extracted compounds were selectively recovered in the first separator, confirming the efficiency of the fractional cooling separation and a concentration of 35% w/w of active compounds was obtained in the second separator. Artemisinin was the major active compound in the extract; but, other two active compounds, artemisin and dehydroartemisinin, were also largely found. Other co-extracted compounds belonged to Artemisia essential oil. Different SC-CO 2 flow rates were tested: an increase from 0.8 to 1.2 kg/h did not determine appreciable variations of the extraction rate of the various compounds, indicating that internal mass transfer resistance mainly controlled the extraction process. [ABSTRACT FROM AUTHOR]

The extraction of pyrethrins from chrysanthemum flowers has been performed using supercritical CO 2 (SC-CO 2 ) extraction coupled to fractional separation, with the aim of producing complete and selective extraction of these insecticidal principles. 90 bar, 40 °C were selected as the operative conditions for a first step of extraction, to work at moderate SC-CO 2 density; two separators in series operating at −10 °C and at a pressure equal to that of extraction, and 25 °C, 15 bar, were used for fractional separation, respectively. A second SC-extraction step, performed at 200 bar 40 °C, demonstrated that many undesired compounds were co-extracted at these process conditions. The comparison with liquid extraction, using petroleum ether, showed that using SC-CO 2 and an exhaustive processing, 30% more pyrethrins were extracted. Using the fractional separation, the produced extracts contained about 99% w/w pyrethrins if the process was stopped after about 80 min. Another suggested duration of the extraction process can be set at about 250 min, at which about 63% w/w pyrethrins were contained in the extracted material. The adopted process strategy could be readily extended to the supercritical processing of several other materials and to the industrial scale. [ABSTRACT FROM AUTHOR]

Maize starch aerogel (MSA), a biocompatible and biodegradable support, was loaded with α-tocopherol (vitamin E) and menadione (vitamin K 3 ), two poorly water-soluble vitamins using supercritical carbon dioxide adsorption. Adsorption experiments were carried out at 15 MPa and 40 and 60 °C. Adsorption equilibrium data were measured and represented as isotherms. Kinetic data, related to adsorption rates, showed that the adsorption process, for both vitamins, was best described by a pseudo second-order model. Vitamin/MSA composites were characterized using FT-IR spectroscopy, X-ray diffractometry and specific surface area determination. In order to study the properties of the adsorbed MSA, as a vitamin delivery system, in vitro dissolution tests were performed. These analyses showed that vitamin loading was about 95–98% with respect to the expected concentration, for both the cases. The dissolution rate in phosphate buffered saline solution (PBS) was largely improved: it was 3.5 times faster than the one of unprocessed vitamin in the case of menadione and about 16 times faster in the case of α-tocopherol. [ABSTRACT FROM AUTHOR]

• SFE was performed on a lavender "concrete", working at 8 MPa and 40 °C. • GC-MS analysis was carried out to assess the composition of fragrance and waxes. • Fractionation was feasible using multiple separation steps. • A maximum yield value of 5.2% was reached using a CO 2 mass flow rate of 1.50 kg/h. • Mathematical modelling was attempted using a modified Chapman–Richards equation. Supercritical Fluid Extraction (SFE) was performed using an unconventional material, the solid extract of lavender flowers obtained by liquid solvent extraction and subsequent solvent elimination. Systematic extraction experiments were carried out at 8 MPa and 40 °C, and the extract was fractionated in semi-continuous mode in the SFE plant. To understand mass transfer phenomena driving the process, CO 2 mass flow rates ranging between 0.60 and 1.50 kg/h were used, and yield vs. time curves were obtained. Fractionation produced a cuticular waxes selective precipitation in the first separator and the floral fragrance in the second separator. The most abundant species in the extract were τ-cadinol (13%), lavandulol (10.5%), β-caryophyllene (10%), viridiflorene (8.5%), isocaryophyllene (6%), cedrenalol (4.5%), linalool (4%) and 1,8-cineol (4%). The fragrance contained no waxes, indicating that the fractionation was successful. At higher mass flow rates (from 0.90 to 1.50 kg/h), an asymptotic extraction yield of 5.2% w/w was obtained; whereas, at lower mass flow rates, the extraction yield was lower (2.3% w/w) since the vegetable bed was not completely wetted by the extraction fluid. The overall results indicated that an external mass transfer resistance controlled the process. [Display omitted] [ABSTRACT FROM AUTHOR]

The applicability of supercritical antisolvent precipitation (SAS) is restricted to hydrophobic substances because of the very limited solubility of water in CO 2 at ordinary SAS operating conditions (40–60 °C, 10–25 MPa). To overcome this limitation, a technique has been developed, named expanded liquid antisolvent (ELAS), in which mixtures of supercritical carbon dioxide (scCO 2 ) and organic solvents, at expanded liquid conditions, are used as the antisolvent: water solubility is widely enhanced. In this work, sodium alginate and polyvinyl alcohol (PVA), two water-soluble polymers, used as carrier for drug delivery systems, were successfully micronized by ELAS. Different antisolvent mixtures were used: scCO 2 + ethanol, scCO 2 + acetone and scCO 2 + isopropyl alcohol. Operating at 15 MPa and 40 °C, varying the organic co-antisolvent, the co-antisolvent mole fraction and the concentration of the polymer in the aqueous solution, nanoparticles (with a mean diameter of about 200 nm), microparticles with smooth surface (with a mean diameter in the range of 0.9–12.5 μm for sodium alginate and 2–9 μm for PVA) and nanostructured microparticles (with a mean diameter of about 11 μm) were produced. XRD analyses on the processed powders revealed that no modifications in the polymer structure were induced by ELAS processing. Solvent residue analyses revealed that the co-antisolvent residue ranged between 50 and 300 ppm depending on the organic solvent used. [ABSTRACT FROM AUTHOR]

Expanded liquid antisolvent (ELAS) precipitation is a modification of the well-known supercritical antisolvent (SAS) process. Different from SAS, ELAS allows the micronization of water-soluble compounds using an antisolvent formed by supercritical carbon dioxide (scCO 2 ) and an organic solvent, used to improve water solubility in carbon dioxide. In this work, ELAS was proposed for the micronization of lysozyme, an enzyme characterized by an intense antibacterial activity, using as antisolvents mixtures formed by scCO 2 + acetone and scCO 2 + isopropyl alcohol. Microparticles of lysozyme, with a mean diameter ranging between 2.8 and 13.8 μm, varying the kind of co-antisolvent, the concentration of the enzyme in the liquid solution and the position of the operating point in the ternary diagram formed by water, carbon dioxide and the process co-antisolvent were obtained. The obtained powders were characterized using XRD and FT-IR. These analyses showed that ELAS process did not influence solute integrity. UV–vis analysis revealed that lysozyme enzymatic activity was not significantly altered. The best results were obtained using acetone, measuring a biological activity of 95% with respect to the native protein. [ABSTRACT FROM AUTHOR]

Nano-niosomes were produced by a continuous supercritical CO 2 assisted process. Operating at 100 bar and 40 °C, different Span® 80 to Tween® 80 wt ratios and two surfactant to cholesterol molar ratios were tested. The 90/10 Span® 80 to Tween® 80 ratio produced the right formulation to obtain spherical and stable niosomes, with a mean diameter of 145 ± 52 nm. Adding cholesterol to niosome formulations, a general slight increase in vesicles mean size was observed and also a larger tendency to their aggregation. Ofloxacin was selected as a model drug to be loaded into nano-niosomes; the largest encapsulation efficiency of 78% and a prolonged drug release up to 5 h were measured when the 90/10 Span® 80 to Tween® 80 ratio was used in the starting formulation, in which also cholesterol, at a surfactant to cholesterol molar ratio equal to 4, was added. [Display omitted] • Nano-niosomes were produced using SuperSomes. • A 90/10 Span® 80 to Tween® 80 ratio produced non-coalescing and stable niosomes. • The optimal surfactant to cholesterol molar ratio was equal to 4. • Ofloxacin encapsulation efficiency of 78% and prolonged drug release up to 5 h. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Tissue engineering is aimed at repairing damaged tissues; several techniques and materials, prevalently polymers, have been proposed to produce synthetic scaffolds that can mimic the extracellular matrix of the organ to be repaired. The scope is to induce adhesion, growth, migration and differentiation of autologous cells and all these steps are promoted by structural, micrometric and nanometric characteristics of the scaffold environment. The limits of traditional techniques used to produce scaffolds are organic solvent residues and limited process flexibility; therefore, supercritical CO2 assisted processes are emerging in this field to try to overcome these limitations. In this work these techniques are critically reviewed with a particular attention to those devoted to the production of 3-D scaffolds; we propose a comparison with the traditional techniques, the analysis of their potential and the obtained results. [Copyright &y& Elsevier]

Abstract: In this work, a new modification of the supercritical carbon dioxide antisolvent precipitation (SAS) process has been used to allow the processing of hydrosoluble compounds; carbon dioxide mixtures with ethanol, used at expanded liquid conditions, allowed to produce micro and nanoparticles of two model water-soluble materials: yttrium acetate (YAc) and bovine serum albumin (BSA). The effect of the process parameters, such as composition of the antisolvent, concentration of the aqueous solution, washing time and injector diameter on the morphology and on the dimensions of the precipitates was investigated. Selecting the appropriate operating conditions, spherical non-coalescing particles were produced. In particular, BSA microparticles with narrow particle size distributions and the mean diameter in the range 0.5–2μm and BSA nanoparticles with a mean diameter down to 0.19μm were produced. [Copyright &y& Elsevier]

Abstract: The supercritical antisolvent precipitation technique was used to precipitate cellulose acetate in form of nanostructured filaments. Two different solvents were used: acetone, chosen because it is a typical laboratory solvent, and a mixture acetic acid+water, that is industrially used in the cellulose acetylation process. The influence of the operating parameters, such as concentration of the liquid solution, pressure and temperature, on the structure of cellulose acetate filaments was studied. Several centimeter long structures, formed by nanoelements ranging from about 50 to 250nm, were obtained. Some experiments were replicated on a pilot plant to demonstrate the scalability of the process. [Copyright &y& Elsevier]

• Ampicillin loaded liposomes were entrapped in alginate aerogels to create a meta-carrier. • SuperLip favored the production of liposomes at nanometric level. • Alginate gel nanoporous structure was preserved by supercritical drying. • Ampicillin release time from meta-carriers was twice than its release from liposomes alone. Ampicillin loaded liposomes were entrapped in alginate aerogels to create a meta-carrier (a carrier within another carrier), to obtain a prolonged drug release. Liposomes with a diameter of 200 ± 77 nm and with an encapsulation efficiency of 69.5 ± 1.2% were produced using a supercritical assisted formation process (SuperLip). Then, they were entrapped into alginate gels, and the final loaded aerogels were obtained by supercritical CO 2 drying. The successful entrapment of liposomes into aerogels was confirmed by EDX analysis. Drug release tests demonstrated that ampicillin release time from these meta-carriers was about 4 days; i.e., about twice than its release time from liposomes alone. Two mass transfer resistances in series operated in the overall drug release: one related to liposomes lipidic layers and one due to the presence of the alginate aerogel matrix. [ABSTRACT FROM AUTHOR]

Conventional liposomes are highly biocompatible thanks to the membrane structure that resembles the cellular one; but they are visible to the immune system. The addition of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to the surface of liposomes (forming PEGylated or stealth liposomes) can prevent their uptake by the reticuloendothelial system (RES) and improve and prolong the action of the lipid-based carrier. In this work, liposomes were produced by a continuous process assisted by supercritical CO 2 (SuperSomes) at 100 bar and 40 °C; then, PEGylation of liposomes by post-modification method was performed. The best formulation to produce stealth liposomes was obtained pre-heating the liposomal suspension to 45 °C, then, adding 1.5 % w/w of DSPE-mPEG2000 and stirring the system at 100 rpm for two hours. The resulting liposomes were stable, exhibiting a −24.1 ± 4.2 Zeta-potential, and were characterized by a mean diameter of 175 ± 27 nm. PEGylated liposomes were loaded with vancomycin, used as a model drug; the encapsulation efficiency was 89 % and, in the case of PEGylated liposomes, the drug release was prolonged up to 20 h, with an increase of 10 h with respect to the non-PEGylated ones. [Display omitted] • Vancomycin loaded liposomes were produced by SuperSomes. • Post-PEGylation was performed using 1.5 % w/w DSPE-mPEG2000, and at 45 °C for 2 h. • Vancomycin encapsulation efficiency was 89 % before and after PEGylation. • Drug release from PEGylated liposomes was prolonged up to 20 h. [ABSTRACT FROM AUTHOR]

A supercritical CO 2 assisted process was used to perform a comparative study between liposomes and niosomes. Process operating conditions were fixed at 100 bar and 40 °C, and the produced vesicles were characterized in terms of mean diameter, size distribution, ζ-potential, and stability over time. Mean diameters of liposomes and niosomes were similar (130 ± 37 nm for liposomes and 141 ± 36 nm for niosomes) and both systems were stable after 1 month from production. Ascorbic acid (AA) was loaded in both kinds of formulation. AA encapsulation efficiency was equal to 92 % and 99 % for liposomes and niosomes, respectively, and DPPH-activity was larger than 90 % in both vesicular systems. Drug release tests revealed that AA was released in 120 min and 240 min from liposomes and niosomes, respectively, due to a different compactness of the vesicle bilayer. [Display omitted] • Successful production of nanoliposomes and nanoniosomes using a supercritical CO 2 assisted process. • Mean diameters of liposomes and niosomes were similar. • Ascorbic Acid (AA) encapsulation efficiency of 92 % and 99 % for liposomes and niosomes, respectively. • Longer AA release time in the case of niosomes due to the compactness of the vesicle bilayer. [ABSTRACT FROM AUTHOR]

This work proposes a modeling of the mechanical properties of porous polymers processed by scCO2, using a phenomenological approach. Tensile and compression tests of alginate/gelatin and cellulose acetate/graphene oxide were modeled using three hyperelastic equations, derived from strain energy functions. The proposed hyperelastic equations provide a fair good fit for mechanical behavior of the nanofibrous system alginate/gelatin (deviations lower than 10%); whereas, due to the presence of the solid in the polymer network, a four-parameter model must be used to fit the composite cellulose acetate/graphene oxide behavior. Larger deviations from the experimental data were observed for the system cellulose acetate/graphene oxide because of its microporous structure. A finite element method was, then, proposed to model both systems; it allowed a realistic description of observable displacements and effective stresses. The results indicate that materials processed using scCO2, when submitted to large stresses, do not obey Hooke´s law and must be considered as hyperelastic. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Supercritical foaming and drug impregnation were obtained in one-step. • Nimesulide/PCL patches can be used for transdermal drug delivery. • The drug release was significantly delayed in the porous structure. Abstract Supercritical carbon dioxide was used to obtain porous polycaprolactone (PCL) patches impregnated with nimesulide. PCL is a semicrystalline biodegradable polyester that can be used in drug delivery, and nimesulide is a non-steroidal anti-inflammatory drug, which has good solubility in supercritical CO 2. The foaming of PCL and its impregnation with nimesulide were carried out in a one-step procedure. The effect of operating conditions, such as pressure, temperature, polymer molecular weight and contact times on the foaming of PCL were studied; then, the simultaneous foaming of PCL and impregnation of nimesulide was attempted. The morphologies of the foamed polymer and of the impregnated structure were investigated using Field emission scanning electron microscopy; moreover, PCL/nimesulide patches were characterized through solid state analysis (differential scanning calorimetry and Fourier transform infrared spectroscopy). The release analyses through UV–vis spectroscopy revealed that the nimesulide release was significantly delayed; therefore, the PCL/nimesulide patches can be used for controlled release formulations. [ABSTRACT FROM AUTHOR]

Supercritical CO 2 (SC-CO 2 ) extraction coupled with fractional separation of the extracts, has been used to concentrate the active principles of Ruta graveolens . Using 250 bar, 40 °C for the extraction process and cooling the first separator to −10 °C, an efficient extraction and fractionation was obtained. Different particle sizes of the vegetable matter were tested (from 0.20 to 0.80 mm); they indicated that the extraction process was faster when particle size was smaller; i.e., internal mass transfer controlled the process. Fractional separation allowed the selective elimination of cuticular waxes, that represented about 78% w/w of the total extract produced by SC-CO 2 processing. The extract collected in the second separator was concentrated in active compounds up to 87% w/w. For comparison purposes, extraction was also performed using an organic solvent: the extract obtained using ethyl-acetate, contained low percentages of active compounds, mainly due to the co-extraction of large quantities of waxes. [ABSTRACT FROM AUTHOR]

Bacterial infections often affect the wound, delaying healing and causing areas of necrosis. In this work, an aerogel in form of core-shell particles, able to prolong drug activity on wounds and to be easily removed was developed. Aerogel microcapsules consisted of a core made by amidated pectin hosting doxycycline, an antibiotic drug with a broad spectrum of action, and a shell consisting of high mannuronic content alginate. Particles were obtained by prilling using a coaxial nozzle for drop production and an ethanolic solution of CaCl 2 as gelling promoter. The alcogels where dried using supercritical CO 2 . The influence of polysaccharides and drug concentrations on aerogel properties was evaluated. Spherical particles with high drug encapsulation efficiency (87%) correlated to alginate concentration in the processed liquid feeds were obtained. The release of the drug, mainly concentrated into the pectin core, was prolonged till 48 h, and dependent on both drug/pectin ratio and alginate concentration. [ABSTRACT FROM AUTHOR]

Supercritical CO 2 phase inversion offers an alternative to obtain solvent free structures with short processing times and preservation of the morphology. We prepared cellulose acetate structures loaded with drug (ibuprofen) to perform experiments at pressures and temperatures ranging between 150 and 250 bars and 35 and 55 °C. The structures were properly characterized by SEM, EDX and DSC; drug controlled release experiments were also performed. Analyses showed that the operating conditions strongly influenced the structure morphology, porosity and drug release profiles. Indeed, connected microparticles, nanofibrous networks and cellular membranes were produced, which have generated different drug release profiles. [ABSTRACT FROM AUTHOR]

Abstract: In this work jet break-up time and of dynamic surface tension vanishing are considered as mechanisms in competition during supercritical antisolvent precipitation and a mathematical model, based on these two characteristic phenomena, is presented. Jet break-up time has been evaluated solving continuity and conservation of momentum equations; on the other hand, dynamic surface tension vanishing time has been evaluated according to the time-evolution model proposed by Cahn and Hilliard. Phase equilibria have also been taken into account, considering the Peng and Robinson equation of state and the related mixing rules. Calculations have been applied to yttrium acetate (YAc) as model solute, dimethylsulphoxide (DMSO) as liquid solvent and carbon dioxide (CO2) as antisolvent. The cross-over times, between jet break-up dominated and dynamic surface tension vanishing dominated regions, have been calculated at different pressures for pure DMSO and at different YAc concentrations in the liquid solution; a good agreement with previous experimental results has been obtained. The numerical results also correctly describe the influence of solute concentration on the pressure at which cross-over between the two regions is obtained. The characteristic times for acetone (AC) have also been evaluated, to perform a comparison with DMSO; in this case, cross-over has been observed in proximity of the mixture critical point pressure of the binary system. [Copyright &y& Elsevier]

• Beclometasone dipropionate and Budesonide were purified by supercritical CO 2. • The optimal conditions for solvent residue extraction were 200 bar, 40 °C, and 0.7 kg/h CO 2 flow rate. • Total organic solvent residues of 11,100 ppm and 41,000 ppm were reduced to 5 ppm and 52 ppm, respectively. • Final solvent residues largely lower than those obtainable using multi-step traditional processes. [Display omitted] The scope of this work was to reduce/eliminate Class 2 and Class 3 solvents, contained in two active pharmaceutical ingredients (APIs), Beclometasone dipropionate (Beclo) and Budesonide (Bude), using supercritical CO 2. The process was carried out at pressures from 80 to 370 bar, CO 2 flow rates between 0.1 and 1.0 kg/h, and at a temperature of 40 °C. When CO 2 density was too low (e.g., at 80 bar and 40 °C), an incomplete extraction of the solvents was obtained. When the extraction pressure was too large (e.g., 370 bar), also a non-negligible co-extraction of solid material was observed. Particles bed caking emerged at CO 2 flow rates larger than 0.7 kg/h. The optimal process conditions were found operating at 200 bar and 40 °C, using a 0.7 kg/h CO 2 flow rate: total final solvent residues of 5 ppm and 52 ppm for Beclo and Bude, respectively, were reached. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • This work focuses on the modelling of the elastic behavior of CA-GO nanocomposites. • Controlled porosity nanocomposites were produced by SC-CO 2 processing. • Development of a reliable FEM procedure that involves nanostructure and microstructure. Abstract This work focuses on the modelling of the mechanical performance of cellulose acetate-graphene oxide nanocomposite membranes, produced by supercritical CO 2 assisted phase inversion, using a set of algorithms able to build and integrate two different parametric variational 3D finite element (FE) models. These models simulate micro- and nano-level morphology of the nanocomposite using a multiscale approach. Microlevel is characterized by interconnected spherical pores; whereas, nanolevel is a composites whose filler is formed by graphene oxide sheets. Information about nanocomposite morphology, derived from electron scanning microscopy analyses, was used to build periodic representative volume elements. A numerical-experimental correlation was performed comparing FE model results with the experimental ones obtained by compression tests, at different weight percentages of graphene oxide with respect to the polymer loaded in the membrane. A good approximation of the experimental trend of Young modulus was obtained by FE simulations. [ABSTRACT FROM AUTHOR]

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 0.37 µm for HPβCD coprecipitates and between about 0.23 and 0.50 µm 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. [ABSTRACT FROM AUTHOR]

In this work, a simple approach at oleuropein (OLE) extraction/concentration from olive leaves was proposed. OLE extraction yield was 5.4% w/w of dry leaves and a concentration of OLE of 20% w/w in the ethanol extract was obtained. Then, supercritical antisolvent extraction (SAE) was performed on the ethanol OLE solution, operating at different pressures between 100 and 200 bar and temperatures between 35 and 60 °C. SAE produced a powder rich in OLE up to 36% w/w at 35 °C, 150 bar. Precipitated powder showed different mean diameters dependent on SAE operating conditions: at 60 °C, 130 bar it consisted of micrometric and coalescing particles; at 35 °C, 150 bar it consisted of nanometric non coalescing particles. Therefore, OLE concentration was successful and its bioavailability should be improved by nanometric size of precipitates. [ABSTRACT FROM AUTHOR]

Porous graphene oxide (GO) structures at different oxidation levels have been obtained by a SC-CO 2 assisted process performed at 200 bar, 35 °C and different durations up to 24 h. Supercritical CO 2 processing was aimed at exfoliating and reducing graphene oxide. Different techniques were used to characterize the materials obtained: transmission electron microscopy (TEM), Raman and FT-IR Spectroscopy, X-ray diffraction analysis and N 2 adsorption-desorption at 77 K. The materials with high surface area up to 930 m 2 /g, obtained after SC-CO 2 treatment, exhibited unique mesoporous structure based on curve graphene sheets and a high capacitive performance with values of 253 F/g at 1 A/g and of 210 F/g at 16 A/g; moreover, a good long cycle stability in aqueous electrolytes (higher than 90% after 2 × 10 3 cycles) has been also obtained. SC-CO 2 processing proved to be successful and simple to be realized, producing high performance materials, characterized by high specific surface areas and supercapacitive performances. [ABSTRACT FROM AUTHOR]

Celluloseacetate (CA)/graphene oxide (GO) nanocomposite membraneswere generated by an assisted phase inversion process, based on theuse of SC–CO2as nonsolvent, operating at 200 barand 40 °C; loadings of GO up to 9% w/w were tested. The structuresmaintained the cellular morphology, characteristics of CA membranes,also at the highest GO loadings used, with a porosity of about 80%,but the presence of GO influenced the pore sizes, that ranged betweenabout 9 and 16 μm. The starting GO and the nanocomposite structureswere characterized by the combination of various techniques that evidenceas sulfur and chlorinated impurities, that were present in the startingGO material, were completely eliminated by the interaction with SC–CO2during structures formation; moreover, a partial reductionof GO to graphene was also observed. [ABSTRACT FROM AUTHOR]

In this work, supercritical CO 2 assisted electrospray is used to produce micro- and nanoparticles of polyvinylpyrrolidone (PVP) loaded with rutin (RUT), testing a new kind of collection system. The adoption of a liquid collector allowed a more accurate capture of the electrosprayed PVP/RUT particles that were generally smaller than the ones collected using an aluminum foil, maintaining constant all of the other operating parameters. In particular, PVP/RUT particles mean diameter ranged from 290 ± 115 nm for 3 % w/w PVP loaded with 3.5 % w/w RUT/PVP to 943 ± 216 nm for 3 % w/w PVP loaded with 10 % w/w RUT/PVP. RUT dissolution rate increased up to 6 times and periodic dynamic light scattering analysis allowed the measurement of RUT nanoparticles formed inside the PVP microparticles, whose mean diameter was 140 ± 14 nm. [Display omitted] • Rutin loaded polyvinylpyrrolidone micro-/nanoparticles produced by supercritical electrospray. • Liquid collector allowed a more accurate capture of nanometric PVP/RUT particles. • RUT dissolution rate was increased up to 6 times. • Mean diameter of RUT nanoparticles embedded into PVP microparticles was measured by periodic DLS. [ABSTRACT FROM AUTHOR]

The effect of the rheological properties of alginate crosslinked hydrogels on their respective aerogels (dried with supercritical carbon dioxide) was investigated in this work. It was observed that aerogels with larger specific surface area (from 115 to 320 m2·g−1) were obtained from precursor hydrogels with higher storage modulus (from 1200 to 22,000 Pa). Likewise, according to the thermogravimetric results, more stable aerogels were obtained from hydrogels with a stronger solid-like behavior. These phenomena were explained considering simultaneously the higher number of formed junctions due to the crosslinking reaction and the higher zero-rate viscosity of the initial solutions. However, the rheological properties did not play an important effect concerning the type of aerogel morphology (nanofibrous) or the isotherm adsorption (type IV). Moreover, this work also showed that hydrogels with a predominant elastic nature provides a lag time in the drug release, that was numerically studied considering for the first time the imbibition phenomenon in a compartmental model. [Display omitted] • Different alginate aerogels were obtained in this work. • A higher elastic modulus of the precursor hydrogels increases aerogel surface area. • The elastic modulus of the precursor hydrogels can modify the compound release. • No differences were found in aerogels structure. • The release data was modeled considering a compartmental model. [ABSTRACT FROM AUTHOR]

In this study, SuperLip, an innovative technology assisted by supercritical carbon dioxide (SC–CO 2), was used to produce unloaded and vitamin D 3 (VD3)-loaded nanoliposomes. Vesicles were produced using hydrogenated and nonhydrogenated phosphatidylcholine from food-grade lecithins at ratios of 30:70, 20:80 and 0:100. SuperLip was operated at 100 bar and 40 °C using water flow rates ranging from 2.5 to 10 mL/min. The results showed that unloaded liposomes produced by SuperLip presented a unimodal size distribution at a water flow rate of 10 mL/min, regardless of the phospholipid ratio, and mean diameters ranging from 125 to 141 nm. VD3-loaded liposomes also presented a unimodal size distribution at this water flow rate, but slightly higher diameters that ranged from 144 to 252 nm. Furthermore, the addition of 20% purified phospholipids to liposomes led to an increase in the mean size of VD3-loaded vesicles from 144 to 218 nm and an increase in the encapsulation efficiency from 66.7 to 88.9%. [Display omitted] • Mixed phospholipid liposomes were produced using a supercritical assisted process. • Nanosized vesicles with unimodal size distribution were obtained. • Higher water flow rates contributed to the formation of more stable nanoliposomes. • The amount of saturated phospholipids influenced vesicle size and PDI. • Vitamin D 3 was efficiently entrapped into nanoliposomes up to 88.9%. [ABSTRACT FROM AUTHOR]

Abstract: Long-chain fatty acid esters are useful functional molecules responding to the requirements of numerous fields of application in cosmetic, pharmaceutical and lubricant industry. In the present work, lipase-catalysed production of n-octyl oleate by esterification of oleic acid with 1-octanol in dense CO2, as reaction medium, was performed in bench-scale packed-bed bioreactor, in order to obtain suitable reaction performance data for up-scaling. Lipase from Rhizomucor miehei (Lipozyme RM IM) was used as the biocatalyst. The experiments were planned to elucidate the effect of several process parameters, such as pressure, temperature, CO2 and substrates flow rates. Pressure of 10MPa, temperature of 323.15K, CO2 flow rate of 210dm3/h and substrates flow rate of 18cm3/h were predicted to be the optimum conditions: a maximum yield of about 93% was attained. Performing the enzymatic reaction in the continuously operating bioreactor, a long-term enzyme lifetime was observed and a decrease of the Lipozyme activity was not registered over 50 days. A comparison with experimental results obtained in batch-wise was also proposed. Operating at the optimum reaction conditions, higher ester yield than those obtained in batch-mode was detected. Supercritical carbon dioxide (SC-CO2) showed to be a potential medium for the n-octyl oleate biosynthesis for a large-scale production in continuous-mode. [Copyright &y& Elsevier]