Aerosol Solvent Extraction System Research Articles

Preparation of cefpodoxime proxetil fine particles using supercritical fluids

Fine particles of cefpodoxime proxetil (CPD) were prepared using an Aerosol Solvent Extraction System (ASES) with supercritical CO 2. The resulting primary particles were approximately 0.1–0.2 μm in size and were almost spherical in shape. The secondary particles were approximately 0.2–0.6 μm in size and had irregular shapes. The larger particle size and irregular shapes were due to the agglomeration of the primary particles. The effects of solvent type, CO 2-to-CPD solution weight ratio, and CPD solution concentration on the extent of agglomeration were investigated. As a result, the use of ethyl acetate and acetone as solvents also reduced the degree of agglomeration. The degree of agglomeration was reduced with the use of a high CO 2-to-solution weight ratio, and a low solution concentration. In particular, spherical particles, approximately 0.1–0.4 μm in size, were obtained when a 10.0 wt% CPD solution was used. As a result of dissolution study, almost 90% of the processed CPD had dissolved within 10 min. The recovery yield of the CPD powder reached approximately 80% using a membrane filter.

A new correlation to predict the stability of liquid jet in dense carbon dioxide

The stability of liquid jet of dichloromethane in dense carbon dioxide was investigated in an aerosol solvent extraction system (ASES). The stability experiments were carried out at pressures ranging 30–150 bar and a temperature of 308 K, with a nozzle size diameter of 0.254 mm. Interfacial tensions of dichloromethane–carbon dioxide system were measured using a capillary rise method to correlate the stability of liquid jets with a dimensionless number. A new dimensionless number, Z*, was proposed to define an atomization flow regime of the liquid jets in dense carbon dioxide.

Influence of Stabilizers on the Physicochemical Characteristics of Inhaled Insulin Powders Produced by Supercritical Antisolvent Process

To examine the effect of stabilizers on aerosol physicochemical characteristics of inhaled insulin particles produced using a supercritical fluid technology. Insulin with stabilizers such as mannitol and trehalose was micronized by aerosol solvent extraction system (ASES). The supercritically-micronized insulin particles were characterized for size, shape, aerosol behavior, crystallinity and secondary structure. Experimental results indicated that when insulin was incorporated with the most commonly used stabilizer mannitol (insulin/mannitol: 15/85 wt.%, designated IM), the particles formed were irregular and needle-shaped and had a tendency to agglomerate. With the incorporation of a second stabilizer trehalose (insulin/mannitol/trehalose: 15/70/15 wt.%, designated IMT), the particles were relatively uniform, more spherical, less cohesive, and less agglomerated in an air flow, when compared to IM particles. The mass median aerodynamic diameter of the IMT particles was 2.32 mum which is suitable for use in inhalation therapy. In vitro deposition test using micro-orifice uniform deposit impactor showed 69 +/- 7 wt.% of the IMT particles was deposited in stage 3, 4, 5 and 6 while 41 +/- 15 wt.% of the IM particles was deposited in the same stages. In terms of insulin stability, secondary structures of insulin particles were not adversely affected by the ASES processing studied here. When properly formulated (as in IMT particles), ASES process can produce particles with appropriate size and size distribution suitable for pulmonary insulin delivery.

Precipitation Polymerization of 2-Methylene-1,3-dioxepane in Supercritical Carbon Dioxide

Free radical homopolymerization experiments were conducted with 2-methylene-1,3-dioxepane in supercritical carbon dioxide (scCO2) using a heterogeneous precipitation polymerization method and AIBN as the initiator. We also synthesized copolymers of 2-methylene-1,3-dioxepane with N-vinyl-2-pyrrolidone. The influence of comonomer feed ratios on the yield, glass transition temperature (Tg) and copolymer composition was investigated. The copolymers produced were characterized by 1H NMR, FT-IR spectroscopy and DSC. Reactivity ratios of comonomer in the initial step of the precipitation copolymerization process were estimated from copolymer composition analysis. In addition, we investigated the effect of reaction temperature on the reactivity ratios and determined that the reactivity ratios slightly increased and that MDOP had a larger deviation of reactivity ratio than that of NVP with the increased temperature. And the fine sub-micron sized copolymer particles containing with various comonomer ratios were prepared by aerosol solvent extraction system (ASES).

Preparation of Polystyrene submicron particles using ASES process in supercritical carbon dioxide

The ASES (aerosol solvent extraction system) process, which is one of the SAS (supercritical anti-solvent) processes, was used to fabricate the PS (Polystyrene) into nano-size particles. Dichloromethane (DCM, CH 2Cl 2) and carbon dioxide were adopted as a solvent and as an anti-solvent for PS, respectively. SEM (scanning electron microscope) was used to observe the morphology and size of PS particles recrystallized by ASES process. The mean particle size and its distribution of processed particles were measured by using a laser diffraction PSA (particle size analyzer). In the ASES process, there are two key factors. One is atomization for fine droplets, and the other is mass transfer of droplets during precipitation in the vessel, which causes nucleation and growth of particles. They are affected by several elements such as temperature, pressure, concentration of solution, injection rate of solution and so on. The objective of this study was to investigate the effect of the various process parameters such as temperature, pressure, solution concentration and solution injection rate on PS particles. From this work, it was found that Polystyrene could be fabricated into submicron particles by ASES process using DCM as a solvent, and CO 2 as an anti-solvent. And it was also found that the particle size was increased with increasing temperature, pressure and concentration of solution. And, by varying the solution injection rate, we found out that the solution injection rate is an important factor for making fine PS particles.

Preparation of itraconazole/HP-β-CD inclusion complexes using supercritical aerosol solvent extraction system and their dissolution characteristics

The purpose of this study was to investigate the feasibility of a supercritical fluid process, called aerosol solvent extraction system (ASES), for producing solid-state inclusion complexes of itraconazole (ITR) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). ITR was complexed with HP-β-CD at temperatures of 35–55 °C, pressures of 83–140 bar, CO 2 densities of 0.498–0.801 g/cm 3, and solution concentrations of 1–5% (w/v). The ASES-processed inclusion complex powders were observed to consist of agglomerates of very fine (100–500 nm) particles. From the experimental results of X-ray diffraction and differential scanning calorimetry, it was found that ITR intermolecularly interacted with the HP-β-CD cavity, resulting in the formation of inclusion complex. Furthermore, the ASES-processed ITR/HP-β-CD powders showed a significant enhancement in the ITR solubility (up to 753.6 μg/mL) in an aqueous medium of pH 1.2. The aqueous solubility of ITR increased with pressure at a constant temperature, and we could obtain a relatively high solubility of 341 μg/mL at 140 bar and 35 °C. In a solution concentration range of 1–5% (w/v), the solubility increased with decreasing concentration, yielding 289–407 μg/mL. When the molar ratio of ITR to HP-β-CD was varied from 1:1 to 1:3, the ITR solubility increased with HP-β-CD content, giving a value of 753.6 μg/mL for the 1:3 ratio. For the ASES-processed ITR/HP-β-CD powders, the percent dissolution of ITR also increased considerably and about 90% of ITR was dissolved within 5–10 min.

Preparation of poly(L-lactic acid) submicron particles in aerosol solvent extraction system using supercritical carbon dioxide

The aerosol solvent extraction system process (ASES), which is one of the supercritical anti solvent processes (SAS), was used to produce poly(L-lactic acid) (PLLA) into the submicron particles. Dichloromethane (DCM, CH2Cl2) and carbon dioxide were selected as a solvent and as an antisolvent for PLLA, respectively. The objective of this study was to investigate the effect of the various process parameters such as temperature, pressure, and solution concentration on PLLA particles. With increasing temperature and pressure, particle size was increased. Also, higher PLLA concentration led to larger particle size and broader particle size distribution. A scanning electron microscope (SEM) was used to observe the morphology and size of PLLA particles recrystallized by ASES process. The mean particle size and its distribution of processed particles were measured by using a laser diffraction particle size analyzer (PSA).

Effect of albumin on physical characteristics of drug particles produced by supercritical fluid technology

In this study, two drugs, terbutaline sulphate (TS) and ipratropium bromide (IB), were micronized by means of a CO 2-based aerosol solvent extraction system (ASES). TS and IB particles with albumin as additive were also precipitated in order to improve the powder flow behavior in an accelerating air flow. Albumin is considered an inactive ingredient for FDA-approved drugs and is endogenous to the lung. The addition of albumin affected the particle morphology resulting in improved aerosolization properties. In the present study, ASES experiments were conducted using a mixed solvent of ethanol/dimethylformamide (EtOH/DMF) for the micronization of TS and pure DMF was used as solvent for IB. For the respirable TS, optimum processing conditions were at about 100 bar and 50 °C. For the IB particles, the conditions were at 200 bar and 40 °C. The aerosol characteristics of all precipitated drug particles in this work were analyzed by comparing the particle size distribution (PSD) and the associated mass median aerodynamic diameter (MMAD) measured by scanning electron microscopy (SEM) to those obtained from Aerodynamic Particle Sizer (APS) and from the Micro-orifice Uniform Deposit Impactor (MOUDI). The results indicate that the TS and IB particles with albumin are less cohesive and less agglomerated in air flow, thus leading to more effective and consistent lung deposition.

Supercritical fluid-micronized ipratropium bromide for pulmonary drug delivery

Ipratropium bromide (IB) was micronized by means of a CO 2-based aerosol solvent extraction system (ASES) in order to improve the particle shape and size characteristics for use in inhalation therapy. The particle size parameter most relevant to pulmonary delivery is the aerodynamic diameter. In this study, ASES experiments were conducted using various liquid solvents for IB such as dimethylformamide (DMF), ethanol (EtOH), and mixtures of ethanol and acetone (EtOH/Ac). Several operating parameters were varied including temperature, pressure, IB concentration in the liquid solution, and the solution injection rate. The particles were analyzed by scanning electron microscopy (SEM). The true density of the particles was measured using a pycnometer and the mass median aerodynamic diameter (MMAD) determined. The results indicate that the size and morphology of the microparticles are most sensitive to solvent choice. Optimum results were obtained when IB particles were precipitated from DMF. The particles were more regular in shape, slightly elliptical, not agglomerated, and within the aerodynamic diameter range of 0.6–3.0 μm. Fourier transform infrared (FTIR) studies indicate no structural deformation as result of the ASES process. The regional depositions of inhaled IB particles were estimated using a multiple-path model of particle deposition (MPPD). The results indicate that IB particles with MMAD in the range of 2–3 μm deposited mainly in the respiratory airways in the lung.

Physical and Chemical Stability of Miconazole Liposomes Prepared by Supercritical Aerosol Solvent Extraction System (ASES) Process

The aerosol solvent extraction system (ASES) process was applied to prepare miconazole (MCZ) liposomes in a dry and reconstitutable form, the optimized temperature and pressure of which were 35°C and 8.0 MPa, respectively. The influence of compositions of phosphatidylcholine (PC), cholesterol (CHOL), and poloxamer 407 (POLOX) as well as the pH of hydration medium on physical and chemical stability of both dry microparticles and liposomes hydrated from them were examined following storage at 4°C and 25°C for 3 months. MCZ microparticles in dry powder were stable on storage at 4°C but degraded considerably after storage at 25°C. MCZ liposomes hydrated from dry ASES-prepared microparticles at pH 4.0 tended to aggregate, whereas those hydrated at pH 7.2 tended to reduce in size on storage, especially with the addition of CHOL. Liposomes with high MCZ content stored at 4°C degraded faster than when stored at 25°C. Addition of POLOX tended to retard the degradation of MCZ liposomes, whereas CHOL appeared to enhance the degradation on storage under both conditions. The chemical degradation of MCZ liposomes appeared to follow the acid-catalyzed hydrolysis. The MCZ liposomes prepared by the ASES process in this study were substantially internalized after being incubated with human lymphocytes.

Drug Solubility in Phospholipid Carrier as a Predictive Parameter for Drug Recovery in Microparticles Produced by the Aerosol Solvent Extraction System (ASES) Process

The solubility of various drugs in a constant ratio of phosphatidylcholine-cholesterol carrier were studied to investigate their influence on drug recovery in drug-lipid microparticles produced by the aerosol solvent extraction system (ASES) process. Solubility of the drugs in such lipid carrier were determined by using differential scanning calorimetry and confirmed by X-ray powder diffraction study. The results showed that drug possessing relatively high solubility in the lipid carrier used could lead to a higher amount of drug recovered in the drug-lipid microparticles produced. However, too high amount of dissolved drug imposed an adverse effect on the solidification of the lipid carrier during ASES processing, which led to partial film formation in the production column and hence a lower yield of microparticles. Such adverse effect was not the case for the drugs with low solubility in the carrier but there was an incomplete recovery of drug in the produced microparticles due to the partial extraction by the supercritical gas instead. The maximum amount of drug recovered in the ASES-prepared microparticles was found to correlate to the solubility of drug in the lipid carrier so that it might be utilized as a predictive parameter for determining the amount of drug to be incorporated into the microparticles.

Crystallization of acetaminophen micro-particle using supercritical carbon dioxide

Fine particles of acetaminophen were produced by Aerosol Solvent Extraction System (ASES). The experiments were conducted to investigate the effects of various temperatures, pressures, solvents, solution concentrations and solution feed volume rates on particle size and morphology. The choice of solvent appears to be very important for getting specific particle shape and size. The result shows that when ethyl acetate is used as a solvent, the irregular and acicular morphology of raw material is recrystallized to be regular and monoclinic. The average particle size of recrystallized acetaminophen from ethyl acetate solution has been measured to be 3–4 Μm, which was about 1/20th of raw acetaminophen in size. The particle size distribution range also became narrow from 82 Μm to 4.9 Μm.

Application of aerosol solvent extraction system (ASES) process for preparation of liposomes in a dry and reconstitutable form

The aerosol solvent extraction system (ASES) process was applied to prepare liposomes in a dry and reconstitutable form. Dry ASES microparticles containing miconazole (MCZ) as a model drug were prepared by an optimized ASES process with various compositions of spraying solution containing phosphatidylcholine, cholesterol, and Poloxamer 407. The influence of such compositions and the pH of hydration medium on the physico-chemical properties of the produced microparticles were investigated before and after hydration. At optimized conditions, partially crystalline, spherical, and nonporous microparticles associated in aggregates varying from a few microns to 40 μm were produced with the residual content of methylene chloride and methanol lower than 30 and 86 ppm, respectively. The percentage of drug recovered in the produced microparticles was increased with an increase of the drug concentration in the spraying solution. The entrapment efficiency of hydrated MCZ microparticles was improved by increasing the pH of the hydration medium.

Fabrication of fine powders by RESS with a clearance nozzle

Manufacture of fine particles is one of the major supercritical fluids (SCF) applications. Nozzle design plays an important role to obtain micro-particles in the rapid expansion supercritical solution (RESS), particles generation from gas saturated solutions (PGSS) and other supercritical anti-solvent (SAS) techniques like the aerosol solvent extraction system (ASES) and the solution enhanced dispersion by supercritical fluids (SEDS). A clearance nozzle has been developed so that spray from a narrow exit in size of a few microns can be realized. In the RESS demonstration experiments using the clearance nozzle, comparison of the micronization effects between laser-drilled orifice nozzles and the clearance nozzle was made. It was found that the particle size could be remarkably reduced to sub-micrometers by using the clearance nozzle. The morphology and crystal patterns of the particles sampled out of the nozzle or collected in aqueous solutions were observed. A possible micronization mechanism was proposed based on the experimental findings. It was found that the nozzle size as well as particle collecting method both had great impact on the final crystal forms. Surface control seems necessary to prevent formation of huge crystals during the particle collection process.

Preparation of fine particles of poly( N-vinyl-2-pyrrolidone- co-2-methylene-1,3-dioxepane) using supercritical antisolvent

Fine particles of poly( N-vinyl-2-pyrrolidone- co-2-methylene-1,3-dioxepane) (poly(NVP- co-MDOP)) were produced by means of aerosol solvent extraction system (ASES). Dichloromethane (DCM) was used as solvent and supercritical carbon dioxide was used as antisolvent. Mean diameter of obtained polymer particles ranged from 0.18 to 0.26 μm. The effects of temperature, pressure and solution flow rate on the particle size were investigated. And the relation of particle size and initial drop size was also considered. The size and morphology of particles were investigated by scanning electron microscope.

Dense Gas Processing of Micron-Sized Drug Formulations Incorporating Hydroxypropylated and Methylated Beta-Cyclodextrin

Because of their importance in pharmaceutical applications, hydroxypropyl-beta-cyclodextrin and methyl-beta-cyclodextrin have been selected to study the formation of micronized complexes incorporating active pharmaceutical ingredients (APIs) and cyclodextrins (CDs) by dense gas (DG) processing. A single-step DG technique was used as an alternative to conventional methods for the manufacturing of API/CD complexes. The DG technology is highly attractive in the pharmaceutical industry because of its potential to generate micronized particles with controlled particle size distributions at moderate operating conditions. The effect of the aerosol solvent extraction system (ASES) processing on the dissolution performance of naproxen (NPX) was examined. The CDs were produced as microspheres smaller than 3 microm. The coprecipitation of each CD with NPX resulted in the production of microparticles with enhanced dissolution rates. The ASES was operated under mild conditions and generated micron-sized spherical particles that could be of particular interest in formulations for pulmonary delivery. Particular advantages of the technique are that (1) nontoxic solvents are used, and (2) it is suitable for the processing of thermally labile compounds. The proposed process can create opportunities to improve current administration routes and exploit novel delivery systems for drug formulations incorporating CDs.

Recrystallization of Poly(l-lactic acid) into Submicrometer Particles in Supercritical Carbon Dioxide

The ASES (aerosol solvent extraction system) process, which is one of the SAS (supercritical antisolvent) processes, was selected to recrystallize PLLA into submicrometer particles. In the ASES process, there are two key factors. One is atomization for fine droplets, and the other is mass transfer of droplets during precipitation in the vessel, which causes nucleation and growth of particles. They are affected by several elements such as temperature, pressure, density, concentration, injection rate of solution, and feed rate of CO 2 . In this work, we studied the effect of CO 2 density, solution injection rate, and CO 2 feed rate on atomization and mass transfer. In addition, to investigate the influence of the solvent on particle production, DCM (dichloromethane), THF (tetrahydrofuran), and 1,4-dioxane were used as solvents for PLLA. In the variation of CO 2 densities, there was not a consistent tendency. From variation of solution injection rate and feed rate of CO 2 we found out that the relative velocity difference between CO 2 and the PLLA/DCM solution was an important factor for fine PLLA particles. The particles increased in size with relatively high temperature and pressure for fixed CO 2 density. Particles in which DCM was used as the solvent for PLLA were finer than the others.

Preparation and characterization of solid dispersions of itraconazole by using aerosol solvent extraction system for improvement in drug solubility and bioavailability

The objective of this study was to elucidate the feasibility to improve the solubility and bioavailability of poorly water-soluble itraconazole via solid dispersions by using supercritical fluid (SCF). Solid dispersions of itraconazole with hydrophilic polymer, HPMC 2910, were prepared by the aerosol solvent extraction system (ASES) under different process conditions of temperature/pressure. The particle size of solid dispersions ranged from 100 to 500 nm. The equilibrium solubility increased with decrease (15 to 10 MPa) in pressure and increase (40 to 60 degrees C) in temperature. The solid dispersions prepared at 45 degrees C/15 MPa showed a slight increase in equilibrium solubility (approximately 27-fold increase) when compared to pure itraconazole, while those prepared at 60 degrees C/10 MPa showed approximately 610-fold increase and no endothermic peaks corresponding to pure itraconazole were observed, indicating that itraconazole might be molecularly dispersed in HPMC 2910 in the amorphous form. The amorphous state of itraconazole was confirmed by DSC/XRD data. The pharmacokinetic parameters of the ASES-processed solid dispersions, such as Tmax, Cmax, and AUC(o-24 h) were almost similar to Sporanox capsule which shows high bioavailability. Hence, it was concluded that the ASES process could be a promising technique to reduce particle size and/or prepare amorphous solid dispersion of drugs in order to improve the solubility and bioavailability of poorly water-soluble drugs.

Preparation of Poly (L-Lactic Acid) Nano- and Micro-Particles Using Supercritical Antisolvent

The objective of this study was to find the effect of the initial droplet size in the ASES (aerosol solvent extraction system) process. We prepared poly(L-lactic acid) (PLLA) nano- and micro-particles using ASES process. The experiments were carried out on various conditions. We got PLLA particles that had mean particle diameter from 0.54 to 1.28 μm. And we calculated theoretical initial droplet size with the equation derived by Lorenzetto and Lefebvre and investigated the relation between the initial droplet size and particle size. The results show that there is a linear relationship between the initial droplet size and particle diameter.

Influence of process parameters in the ASES process on particle properties of budesonide for pulmonary delivery

Budesonide was micronized by precipitation in supercritical carbon dioxide by using the aerosol solvent extraction system at various process conditions. The process is characterised by spraying an organic solution of budesonide into the supercritical fluid (SCF), precipitation of the drug in the SCF and extraction and recovery of the solvent. The micronized budesonide particles were characterized physico-chemically for their morphology, crystallinity, size distribution and for their aerodynamic behaviour. The particle size distribution of the powder products was similar, regardless of the process conditions used for the crystallization. Also, the morphology of the particles did not differ between the batches. However, the aerodynamic properties of the precipitated batches were significantly different between the batches produced and as compared to a jet-milled budesonide powder. In conclusion, the process conditions in the SCF precipitation may influence the aerodynamic properties, although other physico-chemical parameters appear to be similar.