Supercritical Fluid Extraction Of Emulsions Research Articles

Microspheress Types Preparation Evaluation and Applications: A Review

Abstract: Microspheres, also known as microspheres or “monolithic spheres” are small spherical particles that usually range from 1 to 1000 micrometres (µm). This multi-particulate drug delivery system is used in order to obtain controlled and prolonged drug delivery, thus improving the stability, bioavailability, and site specificity at a desired and predetermined rate. There are various methods in order to prepare/formulate the microspheres, such as emulsion-solvent evaporation, extraction of solvent, spray drying, Coacervation, Electrostatic or Electrodynamic, Template or Moulding methods and various other methods that include Thermally Induced Phase Separation (TIPS) and Supercritical Fluid Extraction of Emulsions (SFEE). Every method has its own benefits and disadvantages therefore, the selection of appropriate method is critical in achieving the desired microsphere characteristic. This review covers the different methods used to prepare the microspheres, the variety of parameters used in order to evaluate their effectiveness and their applications in the field of pharmacy.

Modelling and Scaling-Up of a Supercritical Fluid Extraction of Emulsions Process

Supercritical CO2 (scCO2) is utilized in the supercritical fluid extraction of emulsions (SFEE) to swiftly extract the organic phase (O) from an O/W emulsion. The dissolved substances in the organic phase precipitate into small particles and remain suspended in the water (W) with the aid of a surfactant. The process can be continuously conducted using a packed column in a counter-current flow of the emulsion and scCO2, at moderate pressure (8–10 MPa) and temperature (37–40 °C). To ensure the commercial viability of this technique, the organic solvent must be separated from the CO2 to facilitate the recirculation of both streams within the process while minimizing environmental impact. Thus, the aim of this work was to design a plant to produce submicron materials using SFEE, integrating the recovery of both solvents. First, experimental equilibrium data of the ternary system involved (CO2/ethyl acetate/water) were fitted with a proper thermodynamic model. Then, simulations of the whole integrated process at different scales were carried out using Aspen Plus®, along with economical evaluations. This work proposes the organic solvent separation with a distillation column. Thus, the two solvents can be recovered and recycled to the process in almost their entirety. Furthermore, the particles in the aqueous raffinate are produced free of solvents and sterilized for further safe use. The costs showed an important economy scale-up. This work could ease the transfer of the SFEE technology to the industry.

Injectable sustained-release poly(lactic-co-glycolic acid) (PLGA) microspheres of exenatide prepared by supercritical fluid extraction of emulsion process based on a design of experiment approach.

This study aimed to develop an improved sustained-release (SR) PLGA microsphere of exenatide using supercritical fluid extraction of emulsions (SFEE). As a translational research, we investigated the effect of various process parameters on the fabrication of exenatide-loaded PLGA microspheres by SFEE (ELPM_SFEE) using the Box-Behnken design (BBD), a design of experiment approach. Further, ELPM obtained under optimized conditions and satisfying all the response criteria were compared with PLGA microspheres prepared using the conventional solvent evaporation (ELPM_SE) method through various solid-state characterizations and in vitro and in vivo evaluations. The four process parameters selected as independent variables were pressure (X 1), temperature (X 2), stirring rate (X 3), and flow ratio (X 4). The effects of these independent variables on five responses, namely the particle size, its distribution (SPAN value), encapsulation efficiency (EE), initial drug burst release (IBR), and residual organic solvent, were evaluated using BBD. Based on the experimental results, a desirable range of combinations of various variables in the SFEE process was determined by graphical optimization. Solid-state characterization and in vitro evaluation revealed that ELPM_SFEE improved properties, including a smaller particle size and SPAN value, higher EE, lower IBR, and lower residual solvent. Furthermore, the pharmacokinetic and pharmacodynamic study results indicated better in vivo efficacy with desirable SR properties, including a reduction in blood glucose levels, weight gain, and food intake, for ELPM_SFEE than those generated using SE. Therefore, the potential drawback of conventional technologies such as the SE for the preparation of injectable SR PLGA microspheres could be improved by optimizing the SFEE process.

Pharmaceutical Applications of Supercritical Fluid Extraction of Emulsions for Micro-/Nanoparticle Formation.

Micro-/nanoparticle formulations containing drugs with or without various biocompatible excipients are widely used in the pharmaceutical field to improve the physicochemical and clinical properties of the final drug product. Among the various micro-/nanoparticle production technologies, emulsion-based particle formation is the most widely used because of its unique advantages such as uniform generation of spherical small particles and higher encapsulation efficiency (EE). For this emulsion-based micro-/nanoparticle technology, one of the most important factors is the extraction efficiency associated with the fast removal of the organic solvent. In consideration of this, a technology called supercritical fluid extraction of emulsions (SFEE) that uses the unique mass transfer mechanism and solvent power of a supercritical fluid (SCF) has been proposed to overcome the shortcomings of several conventional technologies such as solvent evaporation, extraction, and spray drying. This review article presents the main aspects of SFEE technology for the preparation of micro-/nanoparticles by focusing on its pharmaceutical applications, which have been organized and classified according to several types of drug delivery systems and active pharmaceutical ingredients. It was definitely confirmed that SFEE can be applied in a variety of drugs from water-soluble to poorly water-soluble. In addition, it has advantages such as low organic solvent residual, high EE, desirable release control, better particle size control, and agglomeration prevention through efficient and fast solvent removal compared to conventional micro-/nanoparticle technologies. Therefore, this review will be a good resource for determining the applicability of SFEE to obtain better pharmaceutical quality when researchers in related fields want to select a suitable manufacturing process for preparing desired micro-/nanoparticle drug delivery systems containing their active material.

Formation, stability and antimicrobial activity of laurel leaves essential oil (Laurus nobilis L.) particles in suspension obtained by SFEE

Laurel leaves essential oil is widely studied and valued due to its bioactive functions as antimicrobial, antifungal, antioxidant, antiviral, insecticide and food applications. Encapsulation may be an alternative for protection of their active components. Therefore, the objective of this work is to evaluate the influence of process variables of the Supercritical Fluid Extraction of Emulsions (SFEE) on encapsulation efficiency and, the innovative, on the stability of the particles in suspension (ZP), as also morphological characteristics (TEM), thermal stability (TGA) and finally, as a differential, antimicrobial activity (agar diffusion method and broth dilution test) of the SFEE particles in suspension. Spherical and massive microparticles were formed by SFEE, with encapsulation efficiency ranging from 80.0 % to 56.6 %, particle size (Dp) ranging from 200 to 1000 nm, and stability enhancement with increasing pH. Encapsulation improved the thermal stability of the particles and maintained the bacteriostatic and fungistatic activities of the laurel essential oil.

The encapsulation of hydroxytyrosol-rich olive oil in Eudraguard® protect via supercritical fluid extraction of emulsions

The SFEE technology was used to micronize the food-approved-biopolymer Eudraguard® protect. After setting the ratio of emulsion phases to 20:80 ethyl acetate:water, higher surfactant (0.1–10.0%) and lower polymer (1–10%) concentrations reduced the size of the particles. By halving the stirring speed to 1250 rpm during the homogenization of the emulsion, larger particles were formed. All these manipulations allowed the creation of particles ranging from 10 nm to 200 nm. A higher viscosity of the organic phase, achieved with 2% vitamin E, increased the particle size to 300 nm. Afterwards, SFEE was used to encapsulate hydroxytyrosol-rich olive oil (HT-oil), obtained from alperujo, in Eudraguard® protect for its preservation. Spherical non-aggregate particles were formed with an average of 230 nm. High degrees of encapsulation were possible (up to 99%) resulting in loadings of HT-oil in the obtained particles of 39% with 0.7 mg HT per g of particle.

Encapsulation of yacon (Smallanthus sonchifolius) leaf extract by supercritical fluid extraction of emulsions

Extracts with biological activities need to be preserved, as they can be degraded if exposed to light or heat. This work reports results of microparticles formation of yacon leaf extract with modified maize starch as encapsulated agent using Supercritical Fluid Extraction of Emulsions (SFEE). The variable investigated were pressure (9–13 MPa) and emulsion flow rate (QE) (0.5–1.5 mL/min) on the encapsulation efficiency (EE) and residual ethyl acetate content. The highest EE was 68.2 %, performed at 9 MPa and QE of 1.5 mL/min. The obtained particles were spherical, with size ranging from 92 to 450 nm. Analyses showed that: (i) the particles presented an amorphous characteristic; (ii) there was no degradation of the extract during the encapsulation; (iii) the SFEE improved the preservation of the antioxidant activity of the samples. This study shows the potential of using a new technology for particle production.

Microencapsulation and Nanoencapsulation Using Supercritical Fluid (SCF) Techniques.

The unique properties of supercritical fluids, in particular supercritical carbon dioxide (CO2), provide numerous opportunities for the development of processes for pharmaceutical applications. One of the potential applications for pharmaceuticals includes microencapsulation and nanoencapsulation for drug delivery purposes. Supercritical CO2 processes allow the design and control of particle size, as well as drug loading by utilizing the tunable properties of supercritical CO2 at different operating conditions (flow ratio, temperature, pressures, etc.). This review aims to provide a comprehensive overview of the processes and techniques using supercritical fluid processing based on the supercritical properties, the role of supercritical carbon dioxide during the process, and the mechanism of formulation production for each process discussed. The considerations for equipment configurations to achieve the various processes described and the mechanisms behind the representative processes such as RESS (rapid expansion of supercritical solutions), SAS (supercritical antisolvent), SFEE (supercritical fluid extraction of emulsions), PGSS (particles from gas-saturated solutions), drying, and polymer foaming will be explained via schematic representation. More recent developments such as fluidized bed coating using supercritical CO2 as the fluidizing and drying medium, the supercritical CO2 spray drying of aqueous solutions, as well as the production of microporous drug releasing devices via foaming, will be highlighted in this review. Development and strategies to control and optimize the particle morphology, drug loading, and yield from the major processes will also be discussed.

Ultrasound-assisted emulsion of laurel leaves essential oil (Laurus nobilis L.) encapsulated by SFEE

Essential oil of laurel leaves presents, as the main component, the bioactive 1,8-cineole. The Supercritical Fluid Extraction of Emulsions (SFEE) is an alternative method for the encapsulation of natural substances, such as laurel essential oil, particularly allied with the ultrasound technique, which has been promising for the formation of emulsion. The objective of this work was to evaluate the influence of essential oil concentration and sonication time to reduce the hydrodynamic size of the emulsion droplets (Dg) in order to enhance the efficiency of encapsulation by SFEE. The essential oil concentrations in the emulsion varied from 6 to 12 mg/mL, for sonication time from 2 to 6 min. Stable miniemulsions were obtained up to 24 h assays, with Dg ranging from 239.5 to 357.0 nm. The encapsulation efficiency in modified starch was up to 75.5%, performed at 100 bar and 40 °C, favored by the increase in essential oil concentration.

Production of copaiba (Copaifera officinalis) oleoresin particles by supercritical fluid extraction of emulsions

Suspended particles of copaiba (Copaifera officinalis) oleoresin were produced by supercritical fluid extraction of emulsions (SFEE), using modified starch Hi-Cap 100® as core material. First, ultrasound was applied to produce oil in water (O/W) emulsions with droplet diameter of 261.7 ± 2.2 nm. In SFEE, CO2 and emulsion flow rates, and solvent extraction time were evaluated in terms of residual ethyl acetate content (REA) and β-caryophyllene recovery in the suspension. SFEE achieved 94.1% reduction of ethyl acetate and β-caryophyllene recovery of 7.3%. This REA is within the exposure limit of ethyl acetate (5000 ppm per day). The suspended nanoparticles’ size showed little variation from the emulsion droplet diameter. Finally, the suspensions were dried to obtain powder particles. Field emission scanning electron microscopy (FESEM) revealed different structures depending on the drying method (freeze-drying or spray-drying). Moreover, confocal laser scanning microscopy (CLSM) confirmed that copaiba oleoresin was encapsulated in the particles.

Preparation of polycaprolactone nanoparticles via supercritical carbon dioxide extraction of emulsions

Polycaprolactone (PCL) nanoparticles were produced via supercritical fluid extraction of emulsions (SFEE) using supercritical carbon dioxide (scCO2). The efficiency of the scCO2 extraction was investigated and compared to that of solvent extraction at atmospheric pressure. The effects of process parameters including polymer concentration (0.6–10% w/w in acetone), surfactant concentration (0.07 and 0.14% w/w) and polymer-to-surfactant weight ratio (1:1–16:1 w/w) on the particle size and surface morphology were also investigated. Spherical PCL nanoparticles with mean particle sizes between 190 and 350 nm were obtained depending on the polymer concentration, which was the most important factor where increase in the particle size was directly related to total polymer content in the formulation. Nanoparticles produced were analysed using dynamic light scattering and scanning electron microscopy. The results indicated that SFEE can be applied for the preparation of PCL nanoparticles without agglomeration and in a comparatively short duration of only 1 h.

The encapsulation of low viscosity omega-3 rich fish oil in polycaprolactone by supercritical fluid extraction of emulsions

Supercritical fluid extraction of emulsions technology (SFEE) was used to encapsulate a liquid lipophilic compound, specifically fish oil rich in ω-3 polyunsaturated fatty acids. Three different emulsion formulations containing stabilizing agents were tested using Tween 80 as a surfactant, polycaprolactone as a coating polymer and acetone as an organic solvent. Spherical and non-aggregated nanoparticles with sizes ranging from 6 to 73nm were obtained, depending on the formulation. The nanoparticle encapsulation efficiency produced by SFEE was around 40%, similar to that generated by conventional solvent evaporation. Operating at 8.0MPa and 313K, less than 25kg CO2·kg acetone−1 were required to reduce the acetone concentration in the nanoparticle suspension to 5000ppm (pharmaceutical requirements). However, to obtain nanoparticles for use in the food industry (maximum acetone concentration of 50ppm), CO2 consumption required being increased to 127kg CO2·kg acetone−1.

Production of encapsulated quercetin particles using supercritical fluid technologies

Quercetin is an antioxidant compound with highly promising pharmacological properties against a wide variety of diseases. A major limitation for the clinical application of quercetin is its low bioavailability, due to its low solubility in water. In this work, quercetin is microencapsulated in a surfactant material with the objective of increasing its bioavailability. For this, quercetin is first treated using Supercritical Fluid Extraction of Emulsions in order to precipitate it in nanometric scale in an aqueous suspension, and then this suspension is further treated by Particles from Gas Saturated Solutions (PGSS)-drying technology, to obtain quercetin loaded dried particles in micrometric scale. Soy-bean lecithin and Pluronic L64® are used as surfactant and encapsulating materials. Mircoencapsulation of quercetin by lyophilisation of SFEE-produced aqueous suspensions is also studied in order to compare it with the results of PGSS-drying. Samples are characterized considering encapsulation efficiency, antioxidant activity and Franz-cell measurements of transdermal diffusion of encapsulated quercetin product as assessment of its bioavailability. It is observed that samples encapsulated by SFEE and PGSS-drying are more homogeneous and less crystalline than samples obtained by lyophilisation, which results in a higher transdermal diffusivity.

Quercetin loaded particles production by means of supercritical fluid extraction of emulsions: Process scale-upstudy and thermo-economic evaluation

Quercetin is an antioxidant compound with promising activity against a wide variety of diseases. However, a major limitation for the clinical application of quercetin is its low bioavailability, due to its low solubility in water. One way to increase the bioavailability of quercetin is to precipitate it in sub-micrometricscale, encapsulated by a surfactant material, using the Supercritical Fluid Extraction of Emulsions (SFEE) method. The objective of this work is to study the scale-up of a semi-continuous SFEE process for the production of microencapsulated quercetin. An experimental study of the encapsulation of quercetin in soy-bean lecithin–Pluronic L64®surfactants was performed in order to evaluate the variation of product characteristics with significant parameters, such as duration of SFEE, density of CO2 medium, used CO2/L of emulsion (kg/L), and thus determine the suitable conditions for scale-up. In addition, a themo-economic evaluation was done in order to identify bottlenecks during scale-up and promote solutions. According to the thermo-economic evaluation, the decrease of CO2 flow demonstrated to be the main parameter to decrease the energy demand and cost of manufacturing of the SFEE process. Thus further experimental studies should be done towards optimization of this parameter.

Measurement and modelling of mass transport properties during the supercritical fluid extraction of emulsions

Supercritical fluid extraction of emulsions (SFEE) is a method used for producing aqueous suspensions, containing encapsulated particles in nanometric scale, through the extraction of an organic phase from an emulsion with supercritical CO2. Optimization of SFEE process conditions is complex as they influence several process steps. In this work, ethyl acetate and dichloromethane o/w emulsions were prepared using soybean lecithin and polaxamers as surfactants and contacted with supercritical CO2. Mass transport properties were measured by magnetic suspension balances, which provide an on-line contactless weight measurement method, and a mass transfer model based on the experimental results was developed. Experimental results indicate that the density of supercritical CO2 has a strong influence in mass transfer parameters, while no influence of other conditions such as type or concentration of surfactant was observed. In the case of dichloromethane/water emulsions, emulsion destabilization took place immediately after pressurization of the system.

Continuous supercritical fluid extraction of emulsions to produce nanocapsules of vitamin E in polycaprolactone

Vitamin E in polycaprolactone nanoparticles was continuously produced by supercritical fluid extraction of emulsions using a high-pressure packing column in countercurrent mode. This operating mode reduces the amount of solvent required, increases production capacity and enables lower residual organic solvent concentrations in the raffinate. At 8.0MPa and 313K, with a packing height of 2m, and a solvent to feed ratio of 5kgL−1, the residual acetone concentration was 1400ppm, far below 5000ppm, and therefore suitable for pharmaceutical applications. The process was also simulated with Aspen Plus. It would be necessary to increase the packing height to 3.5m or the CO2 flow rate to 60gmin−1 in order to get a residual acetone concentration suitable for food applications (50ppm). The nanoparticles produced were non-aggregated spheres, which had an encapsulation efficiency higher than 70% and particle size at the nanoscale.

Supercritical fluid extraction of emulsions to nanoencapsulate vitamin E in polycaprolactone

Supercritical fluid extraction of emulsions (SFEE) was used to encapsulate a liquid lipophilic compound, concretely vitamin E in polycaprolactone. The influence of the initial formulation on the characteristics of the nanoparticles (encapsulation efficiency, particle size distribution, and morphology) was studied. The obtained particles exhibited a high encapsulation efficiency (around 90%), narrow particle size distribution (polydispersity index between 0.24 and 0.54), and nanoscale particle sizes (between 8 and 276nm). The morphological analysis indicated that the particles were spherical, with a core-shell structure, and non-aggregated. Operating at 8MPa and 313K, with a CO2 flow rate of 7.2kgh−1kg emulsion−1, a low residual concentration of organic solvent (50ppm) was obtained in 240min at a CO2 consumption of 101kg CO2kg acetone−1. Stability tests indicated that the capsules remained unchanged over long storage periods (6 and 12 months).

Medroxyprogesterone-encapsulated poly(3-hydroxybutirate-co-3-hydroxyvalerate) nanoparticles using supercritical fluid extraction of emulsions

In this work, was investigate the effect of the molecular weight of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) on the preparation of medroxyprogesterone acetate (MPA)⿿encapsulated polymeric nanoparticles (PNPs) using the supercritical fluid extraction of emulsions (SFEE) technique. Particles with diameters between 850nm⿿183nm were obtained using PHBV of molar mass reduced and variable between 210kDa to 14kDa, thus establishing a direct relation between the size of the PNPs prepared with SFEE and the molar mass of the polymer. These results were contrasted with those obtained with the conventional emulsion solvent evaporation (ESE) technique. PNPs prepared by SFEE were observed to be smaller than those produced by ESE, for all polymer molecular weights (MW) studied. The encapsulation efficiency (EE%) of MPA in the PNPs prepared with the SFEE technique, and with the lowest MW PHBV was determined to be 70%. The in vitro release kinetics for this system indicated that the mean time for 35% release of MPA was 18h. Both a first and a second-order kinetics models provide a good fit to the release profile of MPA from the PHBV PNPs. Cellular viability results indicate low toxicity profiles of the PHBV PNPs prepared with the SFEE technique, even at high PNP concentrations.

Encapsulation of pepper oleoresin by supercritical fluid extraction of emulsions

Capsaicinoids, which are the responsible for the pungency of peppers, have strong pharmacological effects. The encapsulation of capsaicinoids can be an alternative for its industrial application. The aim of this work was to evaluate the effect of various ultrasound emulsification conditions, such as surfactant concentration, oil/water ratio, and ultrasound power on the emulsion droplet size. Emulsions formed by Hi-Cap 100 and oleoresin of Capsicum frutescens pepper were then applied in a SFEE process. Ultrasound emulsification resulted in high emulsification efficiency and stability. The selected time for emulsion injection into the SFEE system was 10min after its preparation, based on the coalescence kinetics. The SFEE process resulted in a considerable loss of oleoresin by dissolution in the supercritical CO2 and promoted a droplet volume expansion, reflected by the increase in the diameter of the droplets in suspension. The formation of emulsions by ultrasound emulsification in the evaluated conditions showed promising results, but more studies are required to improve the SFEE process.

Study of the Preparation of Amorphous Itraconazole Formulations

The formulation of poorly water-soluble active pharmaceutical ingredients (APIs) has been widely studied in the last few decades to overcome the limited bioavailability imposed by these pharmaceutical ingredients. In this work, supercritical fluid extraction of emulsions has been applied using two different types of excipients, i.e., poly(vinyl alcohol) (PVA) and glycyrrhizic acid (GA), to address the precipitation of itraconazole (ITZ) as an amorphous solid. The delivery profiles of the in vitro dissolution tests of the ITZ–GA particles confirmed the advantage of the manufactured amorphous material in terms of apparent solubility in comparison to the raw ITZ. Furthermore, the stability of an amorphous glassy product and its potential to recrystallize in the presence of water have been experimentally determined using both excipients and interpreted applying molecular dynamics (MD) simulations. Results show that recrystallization of the amorphous ITZ particles starts at their surface, corroborating that th...