Rapid Expansion Of Supercritical Solutions Research Articles

Demonstration of NIR inline monitoring for hops extraction and micronization of benzoic acid in supercritical CO2

The use of supercritical CO2 as solvent for separation processes and chemical reactions is widespread. Many industrial extraction processes using CO2 consume a huge amount of energy and hence are very cost-intensive. In the past, the duration of extraction was often longer than required for an optimum result. Therefore, an inline monitoring device for terminating CO2 extraction processes at the right time has been desirable. In collaboration between KIT and SITEC-Sieber Engineering, Switzerland, a mobile near infrared (NIR) inline monitoring device has been developed to close this gap and to offer an opportunity to implement it into industrial extractions processes using CO2 and to use the data for process optimization. NIR spectroscopy with fiber optics adaption has been proven to be a very good choice, because the CO2 bands are well separated from all other bands of interest caused by the extracts (organics and water). The NIR inline monitoring device can easily be implemented into industrial plants to visualize the extraction progress and to terminate the process at the right time in order to save energy and money. Measurements on customer's demand are available for extraction and reaction processes in supercritical CO2.This paper will actually focus on two applications. Firstly, in collaboration with NATECO2, Germany, the NIR inline monitoring device has been implemented into a plant for hops extraction with supercritical CO2. Extractions have been performed and successfully monitored for the varieties Hallertauer Magnum, Hallertauer Herkules, and French Strisselspalter at 60°C and 25MPa, 28MPa, and 50MPa, respectively. The detectability was 0.1wt% of hops in CO2.Secondly, the applicability of this NIR inline monitoring method on processes for the production of submicron particles in supercritical CO2 has been demonstrated in a feasibility study. For this purpose, a RESS (Rapid Expansion of Supercritical Solution) high pressure plant (160ml, max. 35MPa, max. 120°C) was built and the NIR inline monitoring device integrated. Two syringe pumps were coupled for an almost pulsation-free-feeding. Benzoic acid was used as a reference solid. In this feasibility study, the focus has not been to perform an optimized RESS process, but rather to monitor the loading of the CO2 phase with benzoic acid continuously, as this information is crucial for the optimization of a RESS process and has not been available up to the present. The experiments have been carried out at 55°C and 25MPa as reference conditions. The performed calibration resulted in a detection limit of 0.1 mg benzoic acid per g CO2. The loading of the CO2 phase has been successfully and continuously monitored and can now be applied for other systems.A side effect of these investigations has been the finding that this NIR inline monitoring device can also be used for very precise solubility measurements and to visualize the establishment of thermodynamic phase equilibrium as a function of time, especially in cases of low solubility of a substance in CO2. The NIR inline monitoring device can also be used for the inline monitoring of reactions producing data for kinetic modeling and process optimization.

Particle Formation by Supercritical Fluid Extraction and Expansion Process

Supercritical fluid extraction and expansion (SFEE) patented technology combines the advantages of both supercritical fluid extraction (SFE) and rapid expansion of supercritical solution (RESS) with on-line coupling, which makes the nanoparticle formation feasible directly from matrix such as Chinese herbal medicine. Supercritical fluid extraction is a green separation technology, which has been developed for decades and widely applied in traditional Chinese medicines or natural active components. In this paper, a SFEE patented instrument was firstly built up and controlled by LABVIEW work stations. Stearic acid was used to verify the SFEE process at optimized condition; via adjusting the preexpansion pressure and temperature one can get different sizes of particles. Furthermore, stearic acid was purified during the SFEE process with HPLC-ELSD detecting device; purity of stearic acid increased by 19%, and the device can purify stearic acid.

Micronization and Dissolubility of Griseofulvin Using Rapid Expansion of Supercritical Solution with Cosolvent Process

Micronization and Dissolubility of Griseofulvin Using Rapid Expansion of Supercritical Solution with Cosolvent Process

Processing naproxen with supercritical CO2

Naproxen has been processed with supercritical fluids in order to improve the dissolution rate and bioavailability. Microparticles of naproxen have been obtained by a Rapid Expansion of Supercritical Solutions (RESS) process in which carbon dioxide has been used as a solvent and methanol as a cosolvent. The influence of extraction pressure (200–300bar) and extraction temperature (60°C and 100°C) on the naproxen precipitation has also been investigated. In general, the morphology of the precipitated particles improved and particle size (PS) decreased in comparison to the raw material. Lower extraction pressure and higher extraction temperature led to a smaller particle size. On the other hand, a supercritical antisolvent (SAS) process has been applied due to the relative medium solubility values of naproxen in supercritical carbon dioxide, with precipitation obtained successfully in all cases. The initial concentration of the solution and the solvent effect has both been analysed. Morphologies and mean diameter ranges have been analysed by scanning electron microscopy (SEM) and the influence on crystallinity of both supercritical processes has been evaluated by X-ray diffraction (XRD) measurements.

Formation of gemfibrozil with narrow particle size distribution via rapid expansion of supercritical solution process (RESS)

Abstract Micronized gemfibrozil (GEM) particles were produced by the process of rapid expansion of supercritical solutions (RESS). An experimental design was used to investigate the effects of three process parameters including extraction temperature (25 to 55 °C), extraction pressure (100 to 250 bar) and nozzle diameter (150 to 240 μm) on the particle size distribution (PSD) and morphology of the produced particles. The characterization of the particles was carried out using scanning electron microscopy (SEM) and X-ray diffraction (XRD) measurements to evaluate the produced particles. The average particle size of the unprocessed material was 30 μm ± (2.5). The average particle size of GEM after processing via the RESS process was between the minimum of 0.8 μm ± (0.03) and the maximum of 2.2 μm ± (0.057) depending upon the process parameters. The results showed that both increasing the temperature from 25 to 55 °C and increasing the nozzle diameter from 0.15 to 0.24 mm caused an increasing effect on the average particle size, whereas increasing the extraction pressure (100–250 bar) led a decrease in the average particle size.

Fabrication of Micron Level Particles of Amoxicillin by Rapid Expansion of Supercritical Solution

In this study, the rapid expansion of supercritical solution (RESS) process was used to precipitate fine solid particles of amoxiccilin where supercritical carbon dioxide was used as a solvent. The process has been done by changing the RESS parameters, including extraction pressure (150–210 bar), extraction temperature (313–333 K), nozzle length (2–15 mm), effective nozzle diameter (450–1700 µm), and spraying distance (1–10 cm), to investigate the effect of these parameters on the size and morphology of the precipitated amoxicillin particles. The characterization (size and morphology) of the particles was examined using scanning electron microscopy (SEM). Based on the different experimental conditions, the mean particle size of the fabricated particles were between 1.08 and 5.72 µm, while the intact particles of amoxicillin were about 41.46 µm. Also, no regular changes in the morphology of the processed particles were observed.

Micronization of ethosuximide using the rapid expansion of supercritical solution (RESS) process

Ethosuximide is a succinimide anticonvulsant active pharmaceutical ingredient (API). It was used in our rapid expansion of supercritical solution (RESS) experiments with supercritical carbon dioxide as the solvent. Effects of four process parameters on the particle formation of ethosuximide were investigated. These parameters include the extraction pressure (Pext), orifice nozzle diameter (Dn), pre-expansion temperature (Tpre) and post-expansion temperature (Tpost). It is observed that an operation at a higher extraction pressure, lower post-expansion temperature and smaller orifice nozzle diameter is favorable for the production of smaller ethosuximide particles while the effect of pre-expansion temperature is insignificant. This API was micronized from its original mean size of 175.5μm to the smallest average size of 1.5μm at the optimal RESS process conditions. A polymorph conversion of ethosuximide was observed after the RESS process by physical properties characterization using the X-ray diffractometer (XRD) and differential scanning calorimetry (DSC). Measurements of the dissolution profiles for ethosuximide before and after the RESS process were also conducted. The micronized ethosuximide product shows novel dissolution behavior and significantly enhanced dissolution rate after the RESS treatment.

Recrystallization of Microparticles of Fenoprofen Using Rapid Expansion of Supercritical Solution

In this study, rapid expansion of supercritical solution with supercritical carbon dioxide as a solvent is used to micronize fenoprofen particles. Effects of different operating parameters were discussed by the method of changing one factor at a time for the extraction temperature (313–333 K), extraction pressure (140–220 bar), collection distance (1–10 cm), nozzle length (2–15 mm), and effective nozzle diameter (450–1700 µm) on the size and morphology of the fenoprofen particles. The conducted experiments revealed that not only the fenoprofen particles were micronized from 24.3 µm to the range of 10.6 µm and 3.3 µm but also the fenoprofen particles experience a modification on their morphologies.

Determination on Solubility and RESS of Risocaine

To prepare ultra-fine particles and offer correlative applications such as the micronization of drugs with rapid expansion of supercritical solution (RESS), the first work in measuring the solubility of risocaine has been carried out at different operation conditions in this paper. The trend of solubility due to changes in specific operational parameters has been examined. The results of pressure (9-30 MPa) and temperature (308-328K) effecting on solubility show that the solubility increases mainly along with the increasing density. With applying different models to correlate the solubility data, we found Chrastil models had better correlation effects than the Peng Robinson EOS model, Mendez-Santiago and Teja equation model, with providing a nearly perfect average absolute relative deviation (AARD) of 0.0596. In the second part of work, RESS was applied to prepare risocaine particles at five different process conditions, including extraction temperature (308-328K), extraction pressure (9-30MPa), nozzle temperature (100-120°C), nozzle diameter (0.1-0.4nm) and spray distance (2-4cm).The size and morphology were determined by scanning electron microscopy (SEM). On the basis of the different experimental operation conditions, granular, filmily and threadlike particles with diameter (1-100nm) were obtained, it was also demonstrated that a successful size reduction of risocaine particles.

Process variables in the formation of nanoparticles of megestrol acetate through rapid expansion of supercritical CO2

Submicron particles of megestrol acetate (MA) were precipitated by rapid expansion of supercritical solution (RESS) method, using CO2 as supercritical solvent in the presence of menthol as solid co-solvent. The effects of extraction temperature, extraction pressure and weight fraction of menthol on the mean particle size of precipitated particles were investigated using full factorial design. The experiments were carried out at three temperature levels from 40 to 60°C, three pressure levels from 15 to 25MPa, and 2 to 6wt.% of co-solvent. Megestrol acetate nanoparticles were formed with mean particle sizes between 102.8 and 516.3nm and statistical analysis showed that pressure had the most considerable effect on the size of nanoparticles. Increasing the temperature and pressure, and decreasing the amount of solid co-solvent resulted in the formation of finer particles.

Precipitation and stabilization of ultrafine particles of Fenofibrate in aqueous suspensions by RESOLV

A method of rapid expansion of supercritical solutions into a liquid solvent (RESOLV) was used to precipitate and stabilize ultrafine particles of a poorly water soluble drug, Fenofibrate (FNB). In order to control particle size and its distribution (PSD), which are greatly affected by the inevitable growth and agglomeration, supercritical solutions of FNB prepared in SC CO2 at 100–200 bar and 333 K, were expanded in water with stabilizers using fine nozzles with diameters of 127–762 μm and length varying between 3 and 6 cm. Stabilizers such as Tween 80, Sodium Dodecyl Sulfate (SDS), Pluronic F-68, Hydroxypropyl methyl cellulose (HPMC), and Sodium Alginate (SA) were used. Synergistic effect of SDS with polymeric stabilizers such as HPMC and Sodium Alginate was also examined. Co-precipitation of FNB with Poly (lactide-co-glycolide) (PLGA) was attempted to minimize particle growth and prevent agglomeration. Electrostatic stabilization compared to steric stabilization was found to be more effective in controlling PSD. FNB particles with sizes from 500 nm to 5 μm could be precipitated with the use of different stabilizers. Overall, SDS was found to be a better stabilizer resulting in almost 66% particles less than 1 μm, which remained stable after 24 h. Further, minor synergistic effects or PLGA co-precipitation or Sodium Alginate with SDS were observed. Finally, in order to increase practicality of this approach, multiple expansions of supercritical solutions of FNB in to a single collection sample were carried out to achieve higher particle concentrations of FNB in aqueous suspensions, albeit at the expense of increased particle size. However, even at high suspension concentration of 1.8 mg/mL, average particle size was under 3 μm, and stable after 24 h, comparing very favorably with other approaches to produce FNB suspensions with high drug loading.

Investigation of key influence parameters for synthesis of submicron carboxymethylcellulose particles via rapid expansion of supercritical CO2 solution by Taguchi method

The viscosity of suspensions depends strongly on the properties of the applied particles like particle size, particle size distribution, and solid load and especially on the specific surface area. Carboxymethelcellulose is an anionic water soluble polymer. CMC HV is a high viscosity carboxymethylcellulose which is used as a viscosifier and fluid loss reducing agent in different types of water based drilling fluids. The micronization of carboxymethylcellulose using the rapid expansion of supercritical solution (RESS) process was investigated in this study. The effects of the operation parameters for the RESS process were discussed by design of experiment (DOE) for the extraction temperature (35–55°C), extraction pressure (150–200bar), nozzle diameter (500–1200μm), spraying distance (1–5cm) and cosolvent (deionized water, isopropanol). Results from analysis of variance (ANOVA) showed that extraction pressure and cosolvent were the most significant factors, and using deionized water favored the production of smaller particles as cosolvent. The CMC particles were micronized from the original average size of 15μm to the smallest average size of 0.14μm through the RESS process in this study. The optimal operation condition for preparing CMC micro-particles in the range of this work is: the pressure of 200bar, the temperature of 55°C, with 500μm nozzle and 1cm spraying distance in the presence of deionized water as cosolvent. Smaller particles were produced with increasing extraction pressure and temperature. In addition, the smaller the nozzle diameter, the smaller the particles and the narrower the PSD obtained.

Formation of ultrafine deferasirox particles via rapid expansion of supercritical solution (RESS process) using Taguchi approach

The poor water solubility of many drugs is a challenge in pharmaceutical research. Recently, there have been great interests in finding environmentally friendly methods producing fine particles of pharmaceutical products for applications in pharmaceutical engineering. A promising method to improve the bioavailability of pharmaceutical agents is the rapid expansion of supercritical solutions. Deferasirox (DFS), a tridentate chelator, requires two molecules for iron (III) coordination. The bioavailability (the percentage of the drug absorbed compared to its initial dosage) is limited by this insolubility. The effect of four different RESS parameters including, extraction temperature (308–318K), extraction pressure (140–200bar), effective nozzle diameter (500–1200μm), with and without cosolvents were investigated on the size and morphology of the precipitated particles of deferasirox based on Taguchi design. The results show great reduction in the size of the precipitated particles of deferasirox (50nm–5μm) via RESS process compared with the original particles of deferasirox (5–500μm).

Preparation and Characterization of Micronized Artemisinin via a Rapid Expansion of Supercritical Solutions (RESS) Method

The particle sizes of pharmaceutical substances are important for their bioavailability. Bioavailability can be improved by reducing the particle size of the drug. In this study, artemisinin was micronized by the rapid expansion of supercritical solutions (RESS). The particle size of the unprocessed white needle-like artemisinin particles was 30 to 1200 μm. The optimum micronization conditions are determined as follows: extraction temperature of 62 °C, extraction pressure of 25 MPa, precipitation temperature 45 °C and nozzle diameter of 1000 μm. Under the optimum conditions, micronized artemisinin with a (mean particle size) MPS of 550 nm is obtained. By analysis of variance (ANOVA), extraction temperature and pressure have significant effects on the MPS of the micronized artemisinin. The particle size of micronized artemisinin decreased with increasing extraction temperature and pressure. Moreover, the SEM, LC-MS, FTIR, DSC and XRD allowed the comparison between the crystalline initial state and the micronization particles obtained after the RESS process. The results showed that RESS process has not induced degradation of artemisinin and that processed artemisinin particles have lower crystallinity and melting point. The bulk density of artemisinin was determined before and after RESS process and the obtained results showed that it passes from an initial density of 0.554 to 0.128 g·cm−3 after the processing. The decrease in bulk density of the micronized powder can increase the liquidity of drug particles when they are applied for medicinal preparations. These results suggest micronized powder of artemisinin can be of great potential in drug delivery systems.

Nanoparticles in the Pharmaceutical Industry and the Use of Supercritical Fluid Technologies for Nanoparticle Production

Poor aqueous solubility of drug candidates is a major challenge for the pharmaceutical scientists involved in drug development. Particle size reduction appears as an effective and versatile option for solubility improvement. Nanonization is an attractive solution to improve the bioavailability of the poorly soluble drugs, improved therapies, in vivo imaging, in vitro diagnostics and for the production of biomaterials and active implants. In drug delivery, application of nanotechnology is commonly referred to as Nano Drug Delivery Systems (NDDS). In this article, commercially available nanosized drugs, their dosage forms and proprietors, as well as the methods used for preparation like milling, high pressure homogenization, vacuum deposition, and high temperature evaporation were listed. Unlike the traditional methods used for the particle size reduction, supercritical fluid-processing techniques offer advantages ranging from superior particle size control to clean processing. The primary focus of this review article is the use of supercritical CO2 based technologies for small particle generation. Particles that have the smooth surfaces, small particle size and distribution and free flowing can be obtained with particular SCF techniques. In almost all techniques, the dominating process variables may be thermodynamic and aerodynamic in nature, and the design of the particle collection environment. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three groups of processes which lead to the production of fine and monodisperse powders. Few of them may also control crystal polymorphism. Among the aforementioned processes, RESS involves dissolving a drug in a supercritical fluid (SCF) and passing it through an appropriate nozzle. Rapid depressurization of this solution causes an extremely rapid nucleation of the product. This process has been known for a long time but its application is limited. Carbon dioxide, which is the only supercritical fluid that is preferentially used in pharmaceutical processes, is not a good solvent for many Active Pharmaceutical Ingredients (API). Various researchers have modified the RESS process to overcome its solubilizing limitations, by introducing RESOLV, RESAS, and RESS-SC. Overall, all RESS based processes are difficult to scale up. The SAS processes are based on decreasing the solvent power of a polar organic solvent in which the substrate (API & polymer of interest) is dissolved, by saturating it with carbon dioxide (CO2) at supercritical conditions. CO2 causes precipitation and recrystalization of the drug. SAS is scalable and can be applied to a wide variety of APIs and polymers. Minor modifications of basic SAS process include GAS, ASES, SAS-DEM and SAS-EM. Processes where SCF is used as an anti solvent and dispersing agent include SEDS, SAA, and A-SAIS. The mechanisms and applications of these processes were briefly discussed. In PGSS, CO2 is dissolved in organic solutions or melted compounds and it is successfully used for manufacturing drug products as well as for drying purposes. The two widely used methods, PGSSdrying and CAN-BD SCF, were also included in discussions. Among the limitations of the techniques involved, the poor solvent power of CO2, the cost and necessity of voluminous usage of the CO2 can be mentioned. There is still confusion in contribution of each variable on the particle morphology and properties regardless of the number of mechanistic studies available. The advantages of especially SAS and PGSS based techniques are the production of the nano or micro sized spherical particles with smooth surfaces and narrow particle size distribution. Regardless of its advantages, the reasons why 25 years of active research, and more than 10 years of process development could not promote the use of (SCF) technology, and produced only few commercial drug products, necessitate further evaluation of this technique.

Production of ultrafine drug particles through rapid expansion of supercritical solution; a statistical approach

Performance of Rapid Expansion of Supercritical Solution (RESS) process, under different operation conditions, was conditions were evaluated through the analysis of the drug particle characteristics. The original particles of Lynestrenol with average size of 10μm as a drug material were dissolved in supercritical CO2 and then expanded rapidly through a nozzle with 0.6mm diameter. The effect of temperature, pressure and fraction of solid co-solvent (menthol) was investigated by a two-level factorial experimental design. Our results showed that the pre-expansion pressure, temperature and solid co-solvent can significantly affect the morphology and size of the precipitated particles. In addition, the binary interaction effects of temperature–pressure and pressure–cosolvent were observed to apparently influence the size of outlet particles. In the temperature range from 45 to 60°C, pressures from 15 to 30MPa and the menthol fraction of 0 to 5wt.%, the RESS process produced ultrafine Lynestrenol particles (from 58 to 326nm) from its original particles as reflected by SEM and zetasizer analysis.

Investigation of different particle sizes on superhydrophobic surfaces made by rapid expansion of supercritical solution with in situ laser diffraction (RESS-LD)

In situ laser diffraction, scanning electron microscopy (SEM) imaging, and thermography have been used to investigate particle formation and particle size distribution of alkyl ketene dimer (AKD) produced by rapid expansion of supercritical solution (RESS). The investigated RESS process is based on an earlier reported method to prepare superhydrophobic coatings. Spray distance, pre-expansion temperature and pressure have been varied and the results from the methods have been compared. SEM images and light scattering data correlate well, and show that the mean particle size increased and the size distribution became significantly broader with increasing spray distance. Mean particle diameters of above 5μm were only observed for pre-expansion temperatures at 50°C or below. Furthermore, results show that by placing the surface to be coated within the cold expansion zone of carbon dioxide (CO2), i.e. in this study at 55mm or shorter for a pre-expansion temperature (Tpe) and pressure (Ppe) of 57°C and 180bar, respectively, will produce a surface evenly covered by 3-μm crystalline AKD flake-like particles. Obtained results also indicated, but did not prove, that agglomerates of AKD particles were carried to the surface by liquid CO2 droplets in the jet.

Solubility and Micronization of DL-2-Phenoxypropionic Acid in Supercritical CO2

To understand the process of DL-2-phenoxypropionic acid fine particles formation with rapid expansion of supercritical solution (RESS), it is vital to determine the solubility of DL-2-phenoxypropionic acid at different operation conditions and to detect an empirical model to correlate the solubility data. In this investigation, solubility in supercritical carbon dioxide (SC-CO2) was measured by a static method with the pressure ranged from (10 to 30) MPa and temperature from (308 to 323) K. Chrastil and its modified models have better correlation effects than the Mendez-Santiago and Teja model, especially the Adachi and Lu modified Chrastil model, provides a nearly perfect average absolute relative deviation (AARD) of 0.0532. Then, RESS was applied to prepare DL-2-phenoxypropionic acid microstructures. The effects of the extraction temperature ((308 to 328) K), extraction pressure ((10 to 30) MPa), spray distance ((10 to 30) mm), nozzle temperature ((343 to 383) K), and nozzle diameter ((0.1 to 0.4) mm) w...

L-Menthol crystal micronized by rapid expansion of supercritical carbon dioxide

Rapid expansion of supercritical solutions (RESS) is a promising alternative for micronizing various materials including l-menthol of which dissolution would be mainly controlled by its particle size and morphology. The aim of this work is to study the effect of ethanol co-solvent, pre-expansion temperature and pre-expansion pressure on the size and morphology of l-menthol crystals micronized by rapid expansion of supercritical CO2 in prior to their microencapsulation. Calculation of l-menthol dissolution in supercritical CO2 (SC-CO2) was conducted, suggesting that the appropriate pre-expansion temperature would be below 50°C. Verification based on FT-IR analysis suggested that the fine particles of l-menthol crystals with controlled size and morphology could be prepared by rapid expansion of supercritical CO2 without any structural change.

Microencapsulation of Coenzyme Q10 in Poly(ethylene glycol) and Poly(lactic acid) with Supercritical Carbon Dioxide

The rapid expansion of supercritical solutions (RESS) process was applied to produce polymeric microparticles loaded with coenzyme Q10 (coQ10). Mixtures of poly(lactic acid) (PLA)/(coQ10) and poly(ethylene glycol) (PEG)/(coQ10) containing a cosolvent were dissolved in supercritical CO2 and sprayed through a nozzle to atmospheric pressure. The effect of process parameters such as encapsulating material/coQ10 ratio and cosolvent on the properties of the microcapsules were investigated. The characterization of microcapsules was carried out through Scanning Electronic Microscopy (SEM), Infrared Spectrophotometry (IR), Differential Scanning Calorimetry (DSC), and solubility kinetics. More important effect of the ratio encapsulating material/coQ10, compared with the effect of type of cosolvent, on studied properties was found.