Supercritical Antisolvent Technology Research Articles

Preparation of indapamide-HP-β-CD and indapamide-PVP nanoparticles by supercritical antisolvent technology: Experimental and DPD simulations

The poor aqueous solubility of indapamide (INP) limits its applicability in various biomedical applications. To overcome this issue, nanosized INP particles (INP-HP-β-CD NPs and INP-PVP-K30 NPs) were fabricated using the supercritical antisolvent (SAS) approach to improve the bioavailability of INP. The process, formula, and supercritical antisolvent process were optimized using single-factor and orthogonal methods. The tiny INP-HP-β-CD NPs with a particle size of 142.5 nm and INP-PVP-K30 NPs with a particle size of 150.4 nm were obtained under optimum conditions. Further analysis and characterization, such as SEM, FTIR, XRD, DSC, 1H NMR, and dissipative particle dynamics (DPD) simulations, were carried out to verify the formation mechanism of the INP complex nanoparticles. The altered physical state of INP from crystalline to amorphous loaded onto the polymer resulted in a significant improvement in the solubility and dissolution rate and high biocompatibility with cells compared to raw INP. Therefore, we propose that INP nanoparticles processed by a supercritical antisolvent process can be used as an advanced drug delivery system, especially for insoluble drugs.

Fabrication of hesperetin/hydroxypropyl-β-cyclodextrin complex nanoparticles for enhancement of bioactivity using supercritical antisolvent technology

Hesperetin (HST) is a bioflavonoid from citrus fruits and its clinical application is still markedly limited by its poor water solubility (1.27 µg/mL). Herein, a complex nanoparticle containing HST and hydroxypropyl-β-cyclodextrin (HP-β-CD) was prepared through supercritical antisolvent (SAS) technology to improve HST solubility, dissolution rate and bioactivity. The effects of crystallization temperature, crystallization pressure, mass flow rate, and drug concentration were systematically investigated using single-factor experiment and orthogonal experiment. The physicochemical properties and structure of the complex were examined using SEM, FTIR, DSC, BET, XPS and XRD analyses. After processing through SAS technology, the in vitro performance of HST was significantly improved such as solubility, dissolution rate and antineoplastic activity. HST as a potential antiproliferative and antioxidant compound appear to have anti-tumor effect on A549 cells. The above results proved that supercritical antisolvents crystallization was a feasible method to fabricate polymer-pharmaceutical complex nanoparticles for drug delivery system.

Fabrication of betamethasone micro- and nanoparticles using supercritical antisolvent technology: In vitro drug release study and Caco-2 cell cytotoxicity evaluation

Poor solubility limits the pharmacological activities of betamethasone (BM), including its anti-inflammatory and anti-allergic effects. To improve the aqueous solubility and dissolution rate of BM, supercritical antisolvent (SAS) technology was used to prepare BM microparticles and BM–polyvinylpyrrolidone (PVP) solid dispersion nanoparticles. The effects of temperature, pressure, solution feeding rate, and drug concentration on particle formation were investigated using both single-factor and orthogonal experimental methods, and the optimal preparation process was screened. The physicochemical properties of the BM particles were characterized by scanning electron microscopy, differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffraction. After the SAS process, the particle size was reduced significantly and the crystalline shape was altered, which considerably increased the solubility and dissolution rate of BM. Furthermore, the toxicity of BM to live cells was reduced because of the BM–PVP solid dispersions.

Microparticle Production of Active Pharmaceutical Ingredient Using Supercritical Antisolvent Process: A Case Study of Allopurinol

Allopurinol is a relatively water-insoluble drug and, consequently, its efficacy was frequently limited by the dissolution or solubility phenomena. The purpose of this study was to improve the solid-state properties and dissolution behavior of allopurinol via a supercritical antisolvent (SAS) process using CO2 as an antisolvent. The effects of operating parameters: temperature (35–55 °C), pressure (80–100 bar), solution concentration (8–15 mg/mL), CO2 flow rate (2–4 L/min), and solution flow rate (0.25–0.50 mL/min) were studied. Moreover, the physical properties of unprocessed and SAS-processed allopurinol were analyzed by SEM, FTIR, DSC, TGA, and PXRD. The dissolution rate of unprocessed and SAS-processed allopurinol was also investigated and compared. In this case study, allopurinol was effectively micronized from 15.3 μm to 1.35 μm at the optimal operating condition. The results verify that the solid-state properties and dissolution rate of allopurinol can be controlled and improved via the micronization process by using SAS technology.

Synergistic chemo-/photothermal therapy based on supercritical technology-assisted chitosan-indocyanine green/luteolin nanocomposites for wound healing.

Despite the success, it is highly challenging to battle against pathogenic biofilms-based chronic bacterial infections by conventional antibiotic therapy. Herein, we report a near-infrared (NIR)/acid-induced nanoplatform based on chitosan (CS)-coated indocyanine green (ICG, photosensitizer)/luteolin (LUT, a natural quorum sensing inhibitor) nanocomposites (ICG/LUT-CS) as antibacterial and antibiofilm agents for skin wound healing. Initially, the ICG/LUT nanoplatforms are prepared by the supercritical antisolvent technology and coated with the CS layer. The obtained ICG/LUT-CS with ultra-high encapsulation efficiency exhibited more favorable photothermal conversion effects and improved NIR laser/acid dual-induced drug release behavior than individual modalities, achieving exceptional bacteria-killing and biofilm elimination effects. Moreover, the ICG/LUT-CS realized the synergetic effects of chemotherapy and photothermal therapy outcomes for wound healing. Together, our findings provided an appealing strategy for the rapid preparation and future translational application of ICG/LUT-CS as an ideal agent for fighting against biofilm infections.

Dispersion of bioactive substances in oils by supercritical antisolvent technology (BIOSAS process)

This work presents the novel method named BIOSAS to formulate homogenous dispersions of bioactive substances in an oily matrix. The method is based on the carbon dioxide supercritical antisolvent (SAS) technique to produce small drops of a solution containing the bioactive substances, in the presence of a lipid substance. Ethanolic and aqueous solutions were used to solubilize complex mixtures of phytochemicals depending on the polarity of compounds. Ethanol was removed entirely from the droplets by SAS effect, and solid bioactive particles with mean diameters below 1 μm were uniformly dispersed in the lipid matrix; for aqueous solutions, the water droplets produced were high-pressure mixed with the lipid phase containing an emulsifier, and stable emulsions were obtained. BIOSAS permits particle size control and can be used to formulate lipid-based nutraceuticals or food supplements in an inert atmosphere and at low temperatures, contributing to reducing the oxidation and thermal degradation of bioactive substances and lipid matrix.

Preparation, characterization and evaluation of the antioxidant capacity and antitumor activity of myricetin microparticles formated by supercritical antisolvent technology

Myricetin (MYR) shows a lot of pharmacological activity such as antioxidant capacity and antitumor activity. However, the poor aqueous solubility of MYR (2 μg/mL) limits its pharmaceutical applications. To improve the dissolution rate of MYR, microparticles and inclusion complexes of MYR were successfully prepared by supercritical antisolvent (SAS) technology. The effects of the drug concentration, temperature, pressure, CO2 and solution volumetric feeding rate on the formation of MYR microparticles and the MYR/hydroxypropyl-β-cyclodextrin (HP-β-CD) complex microparticles were investigated systematically. The physical and chemical properties of the MYR microparticles were characterized by SEM, DSC, FTIR and XRD. After SAS processed, the particle size of MYR microparticles decreased and the crystal form of MYR changed due to the complexation with HP-β-CD, which lead to enhanced solubility, dissolution rate and further improve the antioxidant activity and antitumor activity.

Particle design of itraconazole by supercritical anti-solvent technology: Processing-microstructure-solubility relationship

Particle design in recent years has attempted to overcome solubility limitations in drug development. In this work, the particle microstructures of itraconazole (ITZ) were designed by a supercritical anti-solvent (SAS) process, with or without hydroxypropyl methylcellulose (HPMC) as the dispersing material, where the processing-microstructure-solubility relationship was investigated. The results showed that ITZ particles with different shapes and crystal forms were obtained, which enhanced the ITZ solubility from 4.4 μg/mL to 108.5 μg/mL. For the optimal sample, ITZ crystal transformed into amorphous state, resulting in high solubility and fast dissolution rate. Moreover, hydrogen bond interaction was formed between HPMC and ITZ, which could hinder the recrystallization of dissolved ITZ, resulting in its complete dissolution. Also, the production efficiency was increased to 38.5 mg ITZ/min, which laid a foundation for the scale-up. These results show the great potential of SAS process on the particle design of poorly soluble drugs for solubility enhancement.

Preparation and characterization of baicalein/hydroxypropyl-β-cyclodextrin inclusion complex for enhancement of solubility, antioxidant activity and antibacterial activity using supercritical antisolvent technology

In this study, the preparation of an inclusion complex of baicalein (BAI) and hydroxypropyl-β-cyclodextrin (HP-β-CD) using the precipitation with compressed antisolvents (PCA) process was studied. The goal was to improve the solubility, antioxidant activity, antibacterial activity and bioavailability of BAI, an active component in traditional herbal medicines. DSC, XRD, and SEM results confirmed the formation of an inclusion complex between BAI and HP-β-CD. The solubility of BAI in the BAI/HP-β-CD inclusion complex improved remarkably. A relatively high BAI solubility of 147.38 μg/mL was reported in the inclusion complex (particle size = 0.295 μm) formed under the following conditions (pressure = 14 MPa, temperature = 318 K, mole ratio of BAI/HP-β-CD = 1:2). Both in vitro and in vivo study, proved the bioavailability enhancement of BAI by a supercritical antisolvent process via coprecipitation with HP-β-CD. After efficient complexation using the PCA process, the limited antioxidant activity and antibacterial activity of BAI was highly enhanced together with the aqueous solubility. Hence, this study provides valuable information for the potential clinical application of inclusion complexes of BAI using the PCA process.

Improved cardioprotective effects of hesperidin solid lipid nanoparticles prepared by supercritical antisolvent technology

Doxorubicin (DOX) is commonly used for the treatment of many types of cancers but its cardiotoxicity, owing to free radical formation, limits its clinical use. Hesperidin (HES), a flavanone glycoside, has been shown to exert multiple pharmacological actions including cardioprotective effects. Herein, we aim to formulate HES loaded solid lipid nanoparticles (SLNs) using supercritical antisolvent (SAS) technology to improve the oral delivery of HES. Process parameters were optimized to produce small size (175.3 ± 3.6 nm) HES-SLNs with high encapsulation efficiency (87.6 ± 3.8 %). DSC and XRD showed that HES is amorphously dispersed in SLNs. Compared to HES, HES-SLNs resulted in a nearly 20-fold increase in aqueous solubility and a nearly 5-fold increase in apparent permeability. Pharmacokinetics in rats revealed nearly 4.5-fold higher bioavailability of HES from SLN formulation compared to HES suspension. Data showed that HES-SLN significantly attenuated DOX-induced cardiotoxicity through lowering creatine kinase-muscle/brain, cardiac troponin I and improving histopathological scores as compared to the DOX group. HES-SLN also decreased malondialdehyde, increased catalase and superoxide dismutase of rats’ heart to levels relatively comparable to control. Marked reductions in caspase-3 were also observed following HES-SLN treatment. Conclusively, these results describe a cardioprotective effect for HES-SLN against DOX-induced cardiotoxicity likely facilitated via suppression of oxidative stress and apoptosis.

Synthesis and properties of copper niobate (I) obtained by supercritical antisolvent technology

Synthesis and properties of copper niobate (I) obtained by supercritical antisolvent technology

Simultaneous micronization and purification of bioactive fraction by supercritical antisolvent technology.

Simultaneous micronization and purification of DLBS3233 bioactive fraction, a combination of two Indonesian herbals Lagerstroemia speciosa and Cinnamomum burmannii has been successfully performed via supercritical anti-solvent (SAS) technology. The objective of the present study was to investigate the effectiveness of SAS technology to micronize and reduce coumarin content of DLBS3233. The effects of four SAS process parameters, i.e. pressure, temperature, concentration and solution flow rate on particle formation were investigated. In SAS process, DLBS3233 was dissolved in dimethylformamide (DMF) as the liquid solvent. The solution was then pumped through a nozzle into a chamber simultaneously with supercritical carbon dioxide (SC-CO2) which acts as the anti-solvent, resulting in DLBS3233 precipitation. Physicochemical properties of unprocessed DLBS3233 and SAS-processed DLBS3233 particles were analyzed using scanning electron microscopy (SEM) and high pressure liquid chromatography (HPLC). Total polyphenol content (TPC) was also analyzed. Particles with mean particle size ranging from 0.107±0.028 μm to 0.298±0.138 μm were obtained by varying the process parameters. SAS-processed DLBS3233 particles showed no coumarin content in all experiments studied in this work. Results of TPC analysis revealed no significant change in SAS-processed DLBS3233 particles compared to unprocessed DLBS3233. Nano-sized DLBS3233 particles with no coumarin content have been successfully produced using SAS process. This study demonstrates the ability of SAS for processing herbal medicine in single step process.

Solid-state property modification and dissolution rate enhancement of tolfenamic acid by supercritical antisolvent process

In this study, the supercritical antisolvent (SAS) process is applied to crystallization of an active pharmaceutical ingredient, tolfenamic acid, using carbon dioxide as the antisolvent. Six operating parameters in the SAS process including solvent system, operating temperature, operating pressure, solution concentration, solution flow rate and nozzle diameter are studied. The effects of operating parameters on solid-state properties of the processed tolfenamic acid including crystal habit, mean particle size and polymorphic form are compared and discussed. The crystal habit of original tolfenamic acid crystals is irregular shape with Form I polymorph. The mean particle size of original powders is about 30μm. After recrystallization using SAS process, two polymorphic forms of tolfenamic acid with different crystal habits and mean particle sizes are obtained. Form I tolfenamic acid shows a needle-like crystal habit with mean particle size of about 20μm; while Form II tolfenamic acid shows a rod-like crystal habit with mean particle size of around 10μm. In addition, the dissolution profiles of original and recrystallized tolfenamic acids are also studied and compared. Experimental results show that the recrystallized Form II tolfenamic acid crystals has an enhanced dissolution rate compared with the original sample, demonstrating that the SAS technology is an efficient process for controlling and modifying the solid-state properties of tolfenamic acid and also produces microparticles with enhanced dissolution behavior.

Supercritical antisolvent micronization of PVP and ibuprofen sodium towards tailored solid dispersions

The supercritical antisolvent technology is used to precipitate polyvinylpyrrolidone (PVP) particles and crystallise ibuprofen sodium (IS) crystals separately and in the form of solid dispersion together. Supercritical carbon dioxide (scCO2) is used as antisolvent. For PVP particle generation, ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of PVP in the solution was varied between 0.5wt% and 1.5wt%, the operation pressure between 10MPa and 30MPa and the composition of ethanol/acetone solvent mixtures between 100wt% and 0wt% of ethanol at a constant temperature of 313K. Furthermore, the mean molecular weight of the polymer was varied between 40kgmol−1, 360kgmol−1 and 1300kgmol−1. An increase of the content of the poor solvent acetone in the initial solvent mixture as well as the usage of PVP with a higher molecular weight, leads to a significant decrease in mean particle size. At all the investigated parameters always fully amorphous PVP powder precipitates. For IS, only ethanol was used as the solvent, the initial IS concentration in the solution was varied between 1wt% and 3wt% and the operation pressure between 10MPa and 16MPa. A variation of these parameters leads to a manipulation of the size and the morphology of the crystallised IS crystals. Irrespective of the parameters used, always the same polymorphic form of ibuprofen sodium is produced. The solid dispersions were generated at different compositions of PVP to IS and with two different molecular weights of PVP at otherwise constant conditions. Fully amorphous solid dispersions consisting of IS and PVP together were generated at different ratios of PVP to IS.The mechanisms that control the final particle properties are discussed taking into account two different models for “ideal” and “non-ideal” solutes. Furthermore, the study of the “unconventional” SAS parameters, molecular weight and solvation power of the solvent shows that these parameters qualify to tailor polymer particle properties via SAS processing. Next to the investigation into the behaviour of both solutes separately, fully amorphous solid dispersions consisting of IS and PVP together were generated. While X-ray diffraction was used to analyze the crystalline structure of the particles, respectively, solid dispersions, their morphology was analysed using scanning electron microscopy (SEM).

Manipulating the size, the morphology and the polymorphism of acetaminophen using supercritical antisolvent (SAS) precipitation

The supercritical antisolvent technology is used to crystallize paracetamol particles. Supercritical carbon dioxide (scCO2) is used as antisolvent. Ethanol, acetone and mixtures of ethanol and acetone are used as solvents. The initial concentration of paracetamol in the solution was varied between 1 and 5wt%, the composition of the ethanol/acetone solvent mixture between 50 and 90wt% of ethanol and the operation pressure between 10 and 16MPa at a temperature of 313K. The most important finding is that the polymorph of paracetamol crystals can be adjusted between monoclinic and orthorhombic by varying the content of ethanol in the solution. The second important finding is that the occurrence of primary and secondary crystal structures can be explained solely by the overall supersaturation during the crystallization process. While X-ray diffraction was used to analyze the polymorph of the particles, their morphology was analyzed using scanning electron microscopy.

Interactions of phase equilibria, jet fluid dynamics and mass transfer during supercritical antisolvent micronization: The influence of solvents

This work reports the mixing behavior of some organic solvents, used for the supercritical antisolvent technology (SAS), when they are injected into supercritical carbon dioxide. Different mixing characteristics can condition the morphology of the particles produced during the precipitation process. The results, obtained using an elastic light scattering technique, show, that for chloroform and acetone, there is sharp transition from two-phase mixing to single phase jet mixing at pressures larger than the mixture critical pressure of the binary system solvent–carbon dioxide. N-methyl-2-pyrrolidone, ethanol and dimethylsulfoxide show a large transition range between the two-phase mixing regime below the mixture critical pressure and the completely developed one-phase mixing regime above the mixture critical pressure. The transition may cover a pressure range of up to 6MPa. Mixtures of acetone and dimethylsulfoxide show a mixing behavior that is intermediate between the one of the two pure solvents. The influence of an increase of temperature on the mixing behavior was analyzed for dimethylsulfoxide only; the transition range moved to higher pressures according to the corresponding shift of the mixture critical pressure of the binary system with temperature. A practical indication is, that it is very difficult or even impossible to produce spherical microparticles by SAS, if solvents with a sharp transition between the two-phase and the one-phase mixing regime are used.

Supercritical Antisolvent-based Technology for Preparation of Vitamin D 3 Proliposome and Its Characteristics

Vitamin D 3 (VD 3) proliposomes (VDP), consisted of hydrogenated phosphatidycholine (HPC) and VD 3, were prepared using supercritical anti-solvent technology (SAS). The effects of operation conditions (temperature, pressure and components) on the VD 3 loading in VDP were studied. At the optimum conditions of pressure of 8.0 MPa, temperature of 45°C, and the mass ratio of 15.0% between VD 3 and HPC, the VD 3 loading reached 12.89%. VD 3 liposomes (VDL) were obtained by hydrating VDP and the entrapment efficiency of VD 3 in VDL reached 98.5%. The morphology and structure of VDP and VDL were characterized by SEM (scanning electron microscope), TEM (transmission electron microscope) and XRD (X-ray diffractometer). The structure of VD 3 nanoparticles in HPC matrix was formed. The size of VDL with an average diameter of about 1μm was determined by dynamic light scattering instrument (DLS). The results indicated that VDP can be made by SAS and VDL with high entrapment efficiency can be formed easily via the hydration of VDP.

Preparation of lutein proliposomes by supercritical anti-solvent technique

Proliposomes (PL) composed of lutein and hydrogenated phosphatidylcholine were prepared using supercritical anti-solvent technology (SAS). The effects of the process parameters on the lutein loading and the particle sizes of the proliposomes were investigated. HPLC was applied to determine the content of lutein in the samples. At the optimum conditions for the experimental conditions investigated—temperature of 35 °C, pressure of 8 MPa and the solution flow rate of 1 ml/min—the lutein loading of the proliposomes reached 55 mg/g. The images characterized by SEM were evaluated for the different PL samples in order to study the influences of operational conditions on the particle sizes and morphology. When PL was hydrated, the lutein liposome suspensions were formed automatically. The crystallinity of PL was analyzed using DSC to analyze the distribution of lutein in PL. The structure of PL and the lutein liposome was detected by TEM. The results indicate that PL with the high lutein loading was made successfully and the lutein liposome was obtained with the encapsulation efficiency of more than 90% after hydrating PL. These results demonstrate that SAS technique is a simple and effective process for the preparation of PL from which liposome can be easily formed.

Recrystallization and micronization of sulfathiazole by applying the supercritical antisolvent technology

Recrystallization and micronization for an antibacterial active pharmaceutical ingredient (API), sulfathiazole, was investigated in this study using the supercritical antisolvent (SAS) technology. The effects for the type of solvent, temperature and pressure on particle formation were investigated using the SEM, DSC and XRD analyses. It was observed that various solvents resulted in different polymorphisms. The original sulfathiazole had the crystal form III. It was recrystallized and micronized into form I when acetone was used as the solvent in the semicontinuous SAS process. The polymorph changed to form IV when ethanol was employed as the solvent. The mean particle size of sulfathiazole was reduced from its original 43.0 ± 15.5 μm to 2.1 ± 0.8 μm at the optimal operating condition. The optimally micronized sulfathiazole exhibited a much narrower particle size distribution. It also presented an enhanced dissolution rate by 3.2 times to the original API in a simulated intestinal fluid.

Comparison of solid dispersions produced by supercritical antisolvent and spray-freezing technologies

Oxeglitazar is a new orally administered poorly water soluble active substance used in the treatment of type II diabetes. The objective of this work was to improve its dissolution kinetics using supercritical antisolvent (SAS) and spray-freezing (SF) techniques. Oxeglitazar was formulated with various excipients, including: Poloxamer 188 and 407, polyethylene glycol (PEG) 8000 and polyvinilpyrrolidone (PVP) K17 in a 1:1 weight ratio. In the SAS technology, pharmaceutical ingredients were dissolved in an appropriate solvent, and the feed solution was dispersed through a capillary nozzle in supercritical CO 2 (SC CO 2). Dichloromethane (DCM), chloroform (CHCl 3), and a binary co-solvent system of chloroform–ethanol (EtOH/CHCl 3 50:50, v/v%) were tested. In the SF process, tert-butanol ( tBuOH) was used as solvent. The feed solution was injected into liquid nitrogen through a capillary nozzle located above the surface of the boiling nitrogen. Frozen particles were collected and freeze-dried for 30 h. Formulations were compared in terms of particle morphology, particle size, flow properties, crystallinity, polymorphic purity, residual solvent content, precipitation yield, drug content, specific surface area and dissolution kinetics. SAS and SF processed formulations exhibited enhanced dissolution rates. Within 5 min, the amount of dissolved drug varied from 31.6 to 64.3% for SAS and from 77.9 to 96.9% for freeze-dried formulations while only 30.5% was dissolved from raw drug. Apart from oxeglitazar/PVP K17, SAS prepared solid dispersions were characterized by high crystallinity and acicular shape. Freeze-dried formulations consisted of porous spherical particles with high amorphous content (94.2–100%).