Supercritical Fluid Precipitation Research Articles

A review of microencapsulation methods for food antioxidants: Principles, advantages, drawbacks and applications

Bioactivities and numerous health benefits against a number of oxidative stress related diseases have been attributed to the role of dietary antioxidants. The development of physical (spray drying, lyophilization, supercritical fluid precipitation and solvent evaporation), physico-chemical (coacervation, liposomes and ionic gelation) and chemical encapsulation techniques (interfacial polymerization and molecular inclusion complexation) enable to obtain healthier and acceptable bioactive compounds. This review focuses on the impacts of microencapsulation techniques on the encapsulation characteristics of food antioxidants. Additionally, this study also provides detailed information on the principles, effective parameters, advantages, disadvantages and applications of microencapsulation techniques.

Structural and regulating characteristics of adjustable annulus-clearance nozzle used in supercritical fluid precipitation

A new type of adjustable nozzle with an annulus clearance between the surfaces of a revolved solid and the matched hole was analyzed, which contained matching parts, regulating parts, guiding elements, and sealing part. The general regulating function of the adjustable nozzle was derived and the regulating and matching characteristics were also analyzed. Through the analysis, it was concluded that the matching-profile curve of either the revolved body or matched hole should be chosen as a straight line in order to keep the linear regulating feature. Moreover, the multi-annulus-clearance nozzle was designed, and some experiments were carried out on preparing budesonide particles with the nozzle. According to the experimental results, it was proved that the annulus nozzles is practical in preparing micro-particles by supercritical fluid precipitation method.

A Review of Methods for Evaluating Particle Stability in Suspension Based Pressurized Metered Dose Inhalers.

Advances in particle engineering techniques, such as spray drying, freeze drying and supercritical fluid precipitation, have greatly enhanced the ability to control the structure, morphology, and solid state phase of inhalable sized particles (1 - 5 µm) for formulation in pressurized metered dose inhalers (pMDI). To optimize the properties of these engineered particles for formulation in hydrofluoroalkane propellants (HFA 134a / 227) it is necessary to measure both bulk and individual particle properties before, after, and during formulation. This review examines established and recently developed methods for evaluating a variety of particle properties including but not limited to size, surface and internal morphology, chemical composition, and solid state phase. Novel methods for evaluating particle physical and chemical stability directly in propellant or similar environments are also discussed.

Supercritical fluid precipitation of ketoprofen in novel structured lipid carriers for enhanced mucosal delivery – a comparison with solid lipid particles

Structured lipid carriers based on mixture of solid lipids with liquid lipids are the second generation of solid lipid particles, offering the advantage of improved drug loading capacity and higher storage stability. In this study, structured lipid carriers were successfully prepared for the first time by precipitation from gas saturated solutions. Glyceryl monooleate (GMO), a liquid glycerolipid, was selected in this work to be incorporated into three solid glycerolipids with hydrophilic-lipophilic balance (HLB) ranging from 1 to 13, namely Gelucire 43/01™, Geleol™ and Gelucire 50/13™. In general, microparticles with a irregular porous morphology and a wide particle size distribution were obtained. The HLB of the individual glycerolipids might be a relevant parameter to take into account during the processing of solid:liquid lipid blends. As expected, the addition of a liquid lipid into a solid lipid matrix led to increased stability of the lipid carriers, with no significant modifications in their melting enthalpy after 6 months of storage. Additionally, Gelucire 43/01™:GMO particles were produced with different mass ratios and loaded with ketoprofen. The drug loading capacity of the structured lipid carriers increased as the GMO content in the particles increased, achieving a maximum encapsulation efficiency of 97% for the 3:1 mass ratio. Moreover, structured lipid carriers presented an immediate release of ketoprofen from its matrix with higher permeation through a mucous-membrane model, while solid lipid particles present a controlled release of the drug with less permeation capacity.

Application of nano-particle coatings to carrier particles using an integrated fluidized bed supercritical fluid precipitation process

Production of active ingredients such as pharmaceuticals in nano-particulate form is highly desirable but the resulting product is difficult to handle and to use in applications. A novel process is described for coating nanoparticles onto excipient particles of c. 300μm by rapid expansion of a supercritical solution (RESS) into two types of modified proprietary equipment: a Wurster coater and a fluidized bed. This novel approach has been demonstrated through the successful deposition of six mimics for active ingredients (benzoic acid, adamantane, ferrocene, phenanthrene, stearic acid and vitamin K3) on carrier excipient particles of microcrystalline cellulose (MCC). Evidence from SEM, EDX and Confocal Raman microscopy suggests that the coating particles are below 30nm in size. Unlike most conventional coating processes, this approach avoids the use of liquids and high temperatures. As a wide range of actives and excipients can potentially be employed, the approach is applicable across the process and product industries, in particular pharmaceutical, household goods, personal care and catalyst industries.

ChemInform Abstract: Improved Dissolution Behavior of Lipophilic Drugs by Solid Dispersions: The Production Process as Starting Point for Formulation Considerations

AbstractReview: 143 refs.

Advances in Pharmaceutical Formulation and Processing

Copyright: © 2012 Walker GM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A significant number of new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient and low bioavailability [1,2]. Currently, >40% of the new drug candidates are speculated to be highly lipophilic and thus poorly bioavailable [3]. Typical methods to produce solid dispersions include the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation [4]. The most common difficulty encountered in producing such dispersions is stabilisation of amorphous drugs, which prevents them from recrystallization during storage [5,6]. Therefore, research in this area is now focussed on the physical stabilization of the amorphous form of drugs in solid dispersions as a function of several factors: (i) investigations on mixing at the molecular level, miscibility of the drug with the polymer is directly related to the stabilization of an amorphous drug against crystallization; (ii) investigations on configurational thermodynamics, the polymeric carrier generally increases the glass transition temperature (Tg) of the glass solution compared to the pure amorphous drug, lowers the mobility of drug molecules and kinetically acts as a crystallization inhibitor; (iii) investigations on the intermolecular drug-polymer interactions for the stabilization of the drug in solid dispersions [7]. The aim of much of this research is to create a predictive design space for solid dispersions rather than relying on empirical approaches, which is still prevalent in industry.

Preparation of Stable Aqueous Nanodispersions of β-Carotene by Supercritical Assisted Injection in a Liquid Antisolvent

Abstract In food industry, nanodispersions of water-insoluble active compounds are attractive food ingredients as they improve food formulations and the bioavailability of the active compounds. β-carotene, is a natural colorant used in food industry and, besides its excellent colorant properties, it has been employed as precursor of retinol and retinoic acid which have an important role in human health as vitamin A precursor and as cellular regulatory signal, respectively. Carotenoids are practically insoluble in water; it is possible to enhance their dissolution rate by lowering the particle size. For these reasons, precipitation processes are needed for the production of stabilized nanodispersion of β-carotene, thaking into account that carotenoids are unstable compounds, very sensitive to oxidation processes. Supercritical fluid precipitation techniques are exceptionally suitable for labile products. The precipitation process can be performed at mild temperature conditions, on an inert atmosphere, particle sizes in the micron and sub-micron range can be obtained. Recently a new supercritical assisted process was developed for the direct production of stabilized nanoparticles suspensions. The process, named Supercritical Assisted Injection in Liquid Antisolvent (SAILA), produces stable nanoparticle suspensions in water. In this work SAILA process was successfully applied for the production of β-carotene nanoparticle water suspensions. Nanoparticles in the range 50-150 nm were produced varying the process conditions. The produced nanodispersions produced were characterized by high Zeta-potential values and maintain their stabily over months.

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

Introduction:Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered.Areas covered:The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed.Expert opinion:Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.

Direct Drug Loading into Preformed Porous Solid Dosage Units by the Controlled Particle Deposition (CPD), a New Concept for Improved Dissolution Using SCF-Technology

The controlled particle deposition (CPD), a supercritical fluid precipitation process, is used to load porous tablets with ibuprofen to improve drug dissolution. Porous tablets (porosity 44.3 +/- 5.5%), consisting of microcrystalline cellulose pellets and hydroxyethylcellulose, or sugar cubes (porosity 37.2 +/- 0.5%), are used as carrier material. Loading experiments are conducted at 313 K and 25 MPa, drug concentrations between 6.25 and 33.3 mg ibuprofen/mL supercritical carbon dioxide and contact times of 15.5 h or 5 min. The resulting products have drug contents of 3-5 g ibuprofen/mL void volume in the carrier. Comparison of a predicted value, calculated from pore volume and loading concentration to the actual drug concentrations yielded by the loading process demonstrates the efficiency and controllability of the process. The mean particle size d(50) of deposited ibuprofen is around 25 microm, half the size of the starting material. Drug dissolution from loaded carriers is significantly increased by a rise in the dissolution coefficient from 0.07 min(-1) for the starting material to 0.13 or 0.14 min(-1) for the CPD products. The CPD method therefore is presented as a feasible and controllable process to load porous solid dosage forms with drug particles in order to improve dissolution.

Formation of Carotene/Proanthocyanidin Composite Microparticles via the Solution-Enhanced Dispersion by Supercritical Fluids (SEDS) Process through Prefilming Atomization

The Solution-Enhanced Dispersion by Supercritical Fluids (SEDS) process is a promising technology for the production of ultrafine powders, composite microparticles, and other powders. Carotene/proanthocyanidin composite microparticles were obtained using supercritical CO2 (SC-CO2) as an antisolvent in a mixed solution of dichloromethane and ethanol. For the purpose of evaluating the efficiency of the supercritical fluid precipitation technologies in processing the composite microparticles and studying the effects of operating variables on the composite microparticle, the SEDS process through Prefilming Atomization (SEDS-PA) was used in this paper. Morphologies and particle sizes of the composite microparticles were analyzed by scanning electron microscopy and optical microscopy. The carotene concentrations in the composite microparticles were determined by spectrophotometry. The results show that the precipitates obtained under the experimental conditions are platelet-shaped carotene and proanthocyanidin ...

Micronization of the officinal component baicalin by SEDS‐PA process

AbstractApplication of micronizing technologies in processing Chinese herbal medicines is very important to improve the forms of prepared Chinese herbal medicines and promote their therapeutic efficacy. Baicalin, a major active component of the typical Chinese herb medicine Scullateria baicallensis Georgi, was micronized using the Solution Enhanced Dispersion by Supercritical fluids though Prefilming Atomization (SEDS‐PA) process with the aim of evaluating the efficiency of applying supercritical fluid precipitation technologies in Chinese herb medicine. This study has shown that acicula or rod‐like baicalin crystals with Particle Size (PS) of about 20×100 μm were successfully micronized by the SEDS‐PA process to long rod‐like, twisted fiber‐like or fibrous net‐like microparticles with PS of 0.1‐2.2 μm in width within the range of experiments performed. It was found that a substantial reduction of baicalin microparticles' sizes could lead to a marked increase of adhesions among them and subsequent microparticles agglomeration. With the increase of supercritical CO2 flow rate and the decrease of solution concentration and solution flow rate, smaller and much more agglomerated microparticles were obtained. Increasing pressure led to formation of smaller microparticles. A larger tendency of particles agglomeration was produced at a higher temperature. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Size prediction of recombinant human growth hormone nanoparticles produced by supercritical fluid precipitation

Solution-enhanced dispersion by supercritical fluids (SEDS) was applied to produce nano-sized recombinant human growth hormone (hGH) particles. Ethanol was used to help the supercritical carbon dioxide to extract water from the aqueous protein solution. Various sizes of hGH nanoparticles were successfully prepared with a narrow particle size distribution from aqueous ethanol solution without using any additive. The theoretical particle sizes were deduced from the calculated droplet sizes based on a modified Jasuja's equation. The calculated mean particle sizes and the experimentally obtained ones were compared and the results showed an excellent correlation coefficient (R (2)) of 0.995.

Micronization of the natural pigment-bixin by the SEDS process through prefilming atomization

Bixin was micronized from dichloromethane solution using Supercritical CO 2 (SC-CO 2) as antisolvent by the SEDS process through Prefilming Atomization (SEDS–PA) with the aim of evaluating the efficiency of the supercritical fluid precipitation technologies in processing natural pigments and studying the effects of operating variables in the SEDS–PA process. Morphologies and sizes of microparticles were analyzed using scanning electron microscopy. This study has shown that the sizes of the bixin microparticles could be substantially reduced by the SEDS–PA process. The precipitates obtained at all experimental conditions were needle-like or coalesced net-like particles. With the increase of SC-CO 2 flow rate the impingement of SC-CO 2 on the liquid film and the consequent mixing of SC-CO 2 and droplets are reinforced, producing smaller particles. For constant SC-CO 2 flow rate, with the increase of solution flow rate the impingement of SC-CO 2 on the liquid film becomes weak leading to formation of bigger particles. Higher solution concentration results in formation of bigger particles and increase of agglomeration. Sizes of bixin microparticles decrease with pressure. Serious agglomeration and coalescence phenomena at the high operating temperature result in precipitation of net-like products.

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.

Microencapsulation methods for delivery of protein drugs

Recent advances in recombinant DNA technology have resulted in development of many new protein drugs. Due to the unique properties of protein drugs, they have to be delivered by parenteral injection. Although delivery of protein drugs by other routes, such as pulmonary and nasal routes, has shown some promises, to date most protein drugs are administered by parenteral routs. For long-term delivery of protein drugs by parenteral administration, they have been developed, and the currently used microencapsulation methods are reviewed here. The microencapsulation methods have been divided based on the method used. They are: solvent evaporation/extraction; phase separation (coacervation); spray drying; ionotropic gelation/polyelectrolyte complexation; interfacial polymerization; and supercritical fluid precipitation. Each method is described for its applications, advantages, and limitations.

Biopharmaceutical powders: particle formation and formulation considerations.

It is well known that protein/peptide-based drug formulations are more stable in the solid state than in the liquid state, thereby offering stability advantages in ambient temperature storage, product shipping/distribution, and long-term shelf life. Novel powder-based drug delivery systems recently emerging for applications in sustained release, inhalation, intradermal delivery, etc, add more value to protein solid dosage forms. Despite great research interests in understanding the drying effects on protein stability and a large collection of publications focusing on this area, systematic accounts of powder formation techniques are lacking. This review is to summarize a number of methods currently available for protein powder preparation. Some are common methods such as lyophilization, spray drying, pulverization, and precipitation, and some methods are more recently developed such as supercritical fluid precipitation, spray-freeze drying, fluidized-bed spray coating and emulsion precipitation. In addition to examining the individual process effect on protein stability that is always the focus of formulation scientists, this review also likes to evaluate each method from a more practical sense in terms of process versatility and scalability. The conclusion is that each method has its own advantages and the use of a method is formulation and application specific. With the understanding of the principles and advantages of these methods, it can benefit our choice on selecting appropriate techniques for preparing a desired protein powder formulation for specific applications.

Supercritical fluid precipitation of recombinant human immunoglobulin from aqueous solutions

Supercritical carbon dioxide was used as an antisolvent for producing recombinant human immunoglobulin G (rIgG) particulate powders. Liquid carbon dioxide (CO(2)) was premixed with ethanol to create a single-phase, modified supercritical fluid (SCF). The modified SCF was then vigorously mixed with a pharmaceutically acceptable, aqueous formulation of rIgG, and the mixture was immediately atomized into a pressurized vessel where rapid expansion of the modified SCF extracted the aqueous phase, resulting in precipitation of the protein powder. The process was reproducible, and resulting powder products were characterized by their aqueous solubilities, and the spectroscopic profile, molecular integrity, and antigen binding activity of the individual soluble fractions. Molecular integrity was assessed via size-exclusion high-performance liquid chromatography (SEC), whereas antigen binding activity was determined using an enzyme-linked immunosorbent assay (ELISA). Attempts to characterize particle size and morphology were confounded due to the extremely deliquescent nature of the powders, causing them to absorb moisture rapidly and become gummy. Operational conditions were optimized to a point which yielded powders that were completely soluble, and had ultraviolet (UV) spectroscopic and SEC profiles indistinguishable from those of the reference standard starting solution from which the powders were derived. Antigen binding activities of the powders, however, were </=50% of expected levels, revealing the need for improvement of this SCF processing approach for rIgGs. From this study, two important conclusions were drawn: (1) Biopharmaceutical product quality assessments must include definitive activity analyses, because profound activity losses, such as those suffered here by the rIgGs, may not be revealed when using standard physicochemical analyses alone; and, (2) A more comprehensive understanding and control of the range of SCF processing effects, particularly on aqueous-based macromolecular protein therapeutics, is necessary for SCF precipitation to gain full acceptance as a viable option for secondary manufacturing of biopharmaceutical powders.

Supercritical fluid precipitation of recombinant human immunoglobulin from aqueous solutions

Supercritical carbon dioxide was used as an antisolvent for producing recombinant human immunoglobulin G (rIgG) particulate powders. Liquid carbon dioxide (CO2) was premixed with ethanol to create a single-phase, modified supercritical fluid (SCF). The modified SCF was then vigorously mixed with a pharmaceutically acceptable, aqueous formulation of rIgG, and the mixture was immediately atomized into a pressurized vessel where rapid expansion of the modified SCF extracted the aqueous phase, resulting in precipitation of the protein powder. The process was reproducible, and resulting powder products were characterized by their aqueous solubilities, and the spectroscopic profile, molecular integrity, and antigen binding activity of the individual soluble fractions. Molecular integrity was assessed via size-exclusion high-performance liquid chromatography (SEC), whereas antigen binding activity was determined using an enzyme-linked immunosorbent assay (ELISA). Attempts to characterize particle size and morphology were confounded due to the extremely deliquescent nature of the powders, causing them to absorb moisture rapidly and become gummy. Operational conditions were optimized to a point which yielded powders that were completely soluble, and had ultraviolet (UV) spectroscopic and SEC profiles indistinguishable from those of the reference standard starting solution from which the powders were derived. Antigen binding activities of the powders, however, were ≤50% of expected levels, revealing the need for improvement of this SCF processing approach for rIgGs. From this study, two important conclusions were drawn: (1) Biopharmaceutical product quality assessments must include definitive activity analyses, because profound activity losses, such as those suffered here by the rIgGs, may not be revealed when using standard physicochemical analyses alone; and, (2) A more comprehensive understanding and control of the range of SCF processing effects, particularly on aqueous-based macromolecular protein therapeutics, is necessary for SCF precipitation to gain full acceptance as a viable option for secondary manufacturing of biopharmaceutical powders. © 2000 John Wiley & Sons, Inc. Biotechnol Bioeng 67: 457–464, 2000.