The authors have declared that no competing interests exist.
The challenges ever faced by pharmaceutical industry is mainly due to discovery of new drugs and development of new technologies. Supercritical fluid (SCF) technology is one such technique, which has become an important tool in the production of different particulate systems along with extraction and drying of protein and peptides during last couple of decade because of its specific properties such as flexibility in use, reduced environmental concern and its simplicity. In this review, we briefly describe the operating principles and parameters influencing each one of SCF processes along with their merits and perspectives. The application of SCF technology in pharmaceutical industry, including particle and crystal engineering, composite particles’ preparation, coating of solid dosage form, liposome preparation, extraction and protein and peptide drying are discussed.
Although SCF technology is in use from late 19th century as a tool to understand the natural mineralization, the commercial exploitation of SCF technology has began in the 1970s. This was particularly motivated by environmental concern, capability of some SCFs for replacing toxic industrial solvent and finally, the SCF processes might be economical to liquid extraction and distillation methods
A fluid is said to be supercritical, when its pressure and temperature exceed their respective critical value (Tc- critical temperature and Pc- critical pressure). In the phase diagram
However, the SCF has a unique thermo-physical property. As the pressure is raised, the density of the gas increases without significant increase in viscosity while the ability of the fluid to dissolve compounds also increases. A gas may have little to no ability to dissolve a compound under ambient condition can completely dissolve the compound in supercritical range. Therefore, SCF provide a greater avenue as its solvation power is altered by careful control of changes in temperature and/or pressure
All gases can form SCF above specific sets of Pc and Tc values, but in most of the cases, the transition to the supercritical state occurs at high temperatures not compatible with pharmaceutical compounds (e.g. SC water) (
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H2O | 374 | 22 | 0.315 | 23.4 |
N2 | -147 | 3.39 | 1.16 | -- |
Xe | 16.6 | 5.9 | 1.10 | 6.1 |
SF6 | 45.5 | 3.8 | 0.74 | 5.5 |
N2O | 36.5 | 4.1 | 0.45 | 7.2 |
C2H4 | 9.1 | 5.1 | 0.22 | -- |
CHF3 | 25.9 | 4.7 | 0.526 | 5.4 |
CO2 | 31.3 | 7.4 | 0.468 | 7.5 |
In this review, we present various SCF processes with their advantages and limitations. In particular, different parameters influencing the above processes are discussed. Further, pharmaceutical applications of SCF processes including particle and crystal engineering, composite particles preparation, coating of solid dosage form, liposome preparation, extraction, protein and peptide drying and supercritical fluid chromatography (SFC) are presented through some selected examples.
SCF technology can be classified in to three broad categories depending on the way SCF-CO2 is being used.
SCF-CO2 used as solvent for active substances and its excipients (RESS, PGSS, RESOLV, RESAS, DELOS)
SCF-CO2 used as antisolvent for the precipitation of active substances and their excipients in organic solvent (GAS, ASES, PCA, SAS, ASAIS, SEDS)
SCF-CO2 assisted spray drying or aerosolization based methods (CAN-BD, SAA).
RESS process is consisting of two steps; (a) dissolving the solid substance in a SCF and (b) formation of particles due to supersaturation. In the RESS process, at first SCF-CO2 is pumped at desired pressure and temperature to extraction chamber containing solid substance(s) through heat exchanger as seen in the
The parameters influencing RESS process are classified into pre-expansion and post-expansion condition. Pre-expansion condition includes equipment related parameters (temperature and pressure) and raw material related parameters like SCF, structure of solute (crystalline or amorphous, composite or pure) and cosolvent. The post-expansion condition depends on nozzle temperature, geometry, size, distance and angle of impact against the surface of the jet stream
The advantages of RESS process are that it is simple, effective when single nozzle is used and it minimizes the use of organic solvent and reuses the SCF in continuous process. The main drawback is represented by poor solubility of most of the pharmaceutical material (e.g. polymer) in SCF-CO2, which, in turn require large amount of fluid, and therefore, RESS increases the cost of production. Difficulty of scaling up the process because of particle aggregation and nozzle blockage caused by cooling due to the rapid expansion of the supercritical solution and also poor control over particle size distribution
To overcome the low solubility of polar drug in SCF and the aggregation of particles in the expansion zone, the RESS process is modified to use a solid cosolvent (RESS-SC)
The solid cosolvent should have sufficient high vapour pressure for easy removal by sublimation, sufficient solubility in SCF, solid at nozzle exit point and non-reactive to SCF and the desired solute. One of such solvent is menthol which is used as solid cosolvent to phenytoin in the production of fine particles. The solubility of phenytoin in SCF is only 3 µmol/mol, but when used with menthol as solid cosolvent at 196 bar and 328 K, the solubility improved by 400 times. This improvement in solubility is attributed to the interaction between phenytoin and menthol
This process combines the principles of RESS and SEDS process. In this method, like RESS process, SCF is introduced into a high pressure vessel upon preheating it to desired operating temperature. After maintaining the stable temperature and pressure in the high pressure vessel, polymer solution is delivered into the same chamber through co-axial nozzle. When the spraying of polymer solution is finished, the high pressure vessel is depressurized in ambient vessel and the product is collected. The ability of this technique to prepare microparticles continuously and constantly is the advantage over individual process
Chiou
Many pharmaceutical materials are polar or high molecular weight substance, such as protein and peptide and due to which it is difficult to dissolve them in CO2, which has no polarity even in supercritical state. High amount of CO2 is needed to compromise this low solubility, which in turn increases operational cost. In PGSS process, the polymer(s) are first melted or suspended in solvent at a given temperature in an autoclave and then solubilizing SCF-CO2 in above melted or liquid suspended substance(s), leading to a so called gas saturated solution or suspension that is further depressurized through a nozzle with the formation of droplets or solid particles
Advantages of PGSS process are; (i) substance need not be soluble in SCF-CO2, (ii) simplicity of this process, leading to low processing cost and wide range of application, (iii) can be used with suspensions of active ingredient(s) in polymer(s) or other carrier substance leading to composite particles, (iv) can be applied to process inorganic powders to pharmaceutical compounds, and (v) low solvent gas usage and pressure than RESS process as operational condition
RESOLV method consists of spraying of solution (drug in SCF-CO2) into an aqueous medium from vessel maintain at given temperature and pressure. The rapid expansion of solution and followed by quenching leads to particle formation. Number of water soluble polymer (e.g. PVP) may be added to the aqueous medium to stabilize the particulate suspension. Finally, particles recovered from the suspension
This is a modification of RESS technique and is developed so that the stabilization of submicron particle in the aqueous phase became feasible. In this process, the supercritical solution (SCF with polymer and drug) is expanded through a nozzle in to an aqueous solution containing stabilizers. Usually, non-ionic surfactants such as lecithin, polysorbates and poloxamer are the choice for the stabilization because of their low toxicity. Parameters that are influencing the resultant particle size are stabilizer type, concentration of stabilizer in aqueous phase, solid to surfactant ratio and finally the temperature of the stabilizer solution
Nanosizing of particles, high drug payload and long term stability are making this technique attractive than RESOLV method. But there are some demerits like it is not a suitable method for the drug which are unstable in aqueous solution and broad particle size distribution
In DELOS process, the substances are first dissolved in suitable organic solvent and then it is mixed with SCF-CO2 in a vessel of particular temperature and pressure. This mixture is depressurized through a nozzle into a vessel to form fine particle
The low solubility of pharmaceuticals in SCFs limited the large scale production of micro/nano sized particles by PGSS and RESS method. Using SCFs as antisolvent was thought off by many researchers to solve the above problem. Here, the solute is insoluble in an antisolvent, whereas the antisolvent should be completely miscible with liquid solvent. This is based on the principle that when a solution sufficiently expanded by a gas, the liquid phase is no longer a good solvent for the solute and particle formation by precipitation occurs. The SCFs as antisolvent includes GAS, SAS, ASES, PCA and SEDS processes.
GAS is a batch process where the precipitator is partially filled with the solution of solute of interest and then the supercritical antisolvent is pumped into the vessel, preferably from the bottom until the fixed pressure is reached as shown on
The SCF is first pumped to the top of the high pressure vessel until the system reaches a constant temperature and pressure
Main advantage of this technique over GAS is its suitability for continuous operation, which prerequisite for large scale mass production of particles. Complex mass transfer process is one of the major limitations in SAS scale up. Complex mass transfer process is originated due to two issues. First one is the result of variety of jet dispersion patterns in the supercritical spray leading to formation of droplets of non uniform sizes. It is obvious that mass transfer within the droplets of smaller size is considerable faster than that of larger droplets owing to higher surface area of the former. Furthermore, there is more time for crystal growth in larger particles. Another problem related to mass transfer in SAS is due to residence time of particles under supercritical condition until the cycle ends. Particle may still grow, when present on the filter for separation, under above condition. To solve above problems in SAS, concentric tube antisolvent reactor (CTAR) technique was developed. In this process, particles are formed inside a small concentric tube instead of usual spraying of drug solution into SCF
This is another modification to SAS technique. In ASAIS process, antisolvent induced precipitation occurs in a small tube, where antisolvent mixed with the solution to generate a suspension. This suspension of particles is then sprayed into a precipitator at atmospheric condition for solvent separation, which eliminates the high volume and high pressure precipitator. In addition, very small to moderate antisolvent concentration is required. Contrary to both SAS and CTAR process, the particles recovery is performed by cyclone separator rather than using filter. Here, the first step (suspension formation) occurs in the small tube and next step in the precipitator and finally particle recovery in cyclone separator
This is a modification of SAS process in which the SCF and drug solution are introduced simultaneously in to the precipitation vessel at particular temperature and pressure through the coaxial nozzle. The design of co-axial nozzle is such that to facilitate the dispersion of drug solution by SCF, thereby enhancing mass transfer and formation of fine particles
The particle formation/size by SEDS depends on the mass transfer of SCF into sprayed droplets and by the rate of solvent transfer into the SCF phase. In general, high mass transfer causes faster supersaturation and smaller particle size with less agglomeration
Baldyga
In order to obtained ultrafine particles with narrow size distribution, He
To overcome the limitation of water solubility in SCF, SEDS has been further modified to in order to process water soluble compounds (e.g. protein and peptides). The above modification includes the use of three way coaxial nozzle to introduce aqueous drug solution, SCF and organic solvent (polar) in to particle formation chamber as separate stream. The organic solvent acts both as precipitating agent and a modifier, enabling the non-polar SCF to remove water
This technique is based on counter-current extraction of emulsion by SCF. The process is as follows, first the o/w emulsion is introduced into the extraction chamber (at particular temperature and pressure) through the nozzle present at the top at a constant rate
The emulsion droplet diameter is the key size control parameter, besides fraction of lipid and drug in organic solvent. The advantage of this method over traditional methods like evaporation and liquid extraction are fast and complete removal of the solvent and formation of uniform particle size. In addition, whenever lipid is used as matrix material, the thermodynamic stability is established due to plasticizing effect of lipid as the depression of lipid melting point occur in the extraction column. Furthermore, lipid is purified due to extraction of impurities present along with lipid
These techniques used SF to assist or enhance the nebulization or aerosolization of the solution of the substance to be processed, which is then rapidly dried in a drying atmosphere to form fine particles. There are two methods based on this principle.
This process focused on the nebulization of the liquid solution rather than using dense gas (SCF) to achieve precipitation by solubility reduction for the solute to be micro- or nano-sized. At first, the solute(s), preferably in between 1% to 10%, is dissolved or suspended in aqueous or organic solvent or their mixture and then mixed intimately with near critical or SC by pumping both fluid through a near zero volume tee as shown in
Parameters influencing the particle formation are flow rate of solution (for lab scale 0.3-0.6 ml/min is sufficient), percentage of dissolved or suspended substance, inner diameter flow restrictor (50-175 µm and length ∽ 10 cm), temperature of the drying chamber, residence time of droplets or micro bubbles (as micro bubbles are dried faster than droplets)
Advantages of CAN-BD process are; (i) minimum decomposition of thermolabile drugs, (ii) preferred method for water soluble drug, (iii) organic solvent compatible with SCF can be substituted in part or totally for water, and (iv) very fine size of the produced particle (<3 µm diameter)
SAA process is based on the solubilization of SCF in aqueous solution to be dried and subsequently atomization through a thin wall nozzle at atmospheric pressure. The difference between SAA and CAN-BD is the region where the mixing is achieved
Crystalline solids that are the same compound/composition but have different crystalline forms are called polymorphs or modification
Traditional process such as crushing/milling, micronization, spray drying, freeze drying and crystallization used to produce particles. These processes offer limited control over the physicochemical properties of the produced particles including size, shape and crystalline purity due to numerous unintentional conversion of polymorphs, desolvation of solvates, and solvates formation occur during aforementioned processes
The influence of GAS technique on the polymorphism of a poorly water soluble drug, puerarin, was investigated by Li
Different crystal forms of terbutalin sulphate were produced including stoichiometric monohydrate and amorphous material by SEDS technique
Zhiyi
Nijlen
Hezave
Martin
Charpentier
Kim
Reverchon
Atila
Keshavarz
Varshosaz
Montes
Young
Brion
Jordan
Duarte
Zhang
Uzun
Patomchaiviwat
Both CO2- and N2-assisted atomization processes were used to develop ibuprofen/lipid (myristic acid and tripalmitin) composite microparticles. The average size of obtained particles was slightly larger than that of pure lipid particles in case of N2-assisted process due to the difficulty of solidification using N2. In CO2-assisted process, the mean particle size was slightly smaller than that of pure myristic acid, but slightly larger than that of pure tripalmitin particles. The morphology of composite microparticles was similar to that of pure lipid particles
Chattopadhyaya
Traditional coating process involves the application of coating solution/suspension to the exterior of solid dosage form. This process associated with many disadvantages like solvent residue in the final dosage form, cost and environmental concern due to the use of organic solvent. To avoid above concern, organic solvent replaced with aqueous solvent. However, it increases drying time and a number of polymers are not soluble in aqueous solvent. The SCF technology is used to overcome the above shortcomings.
Santos
Microparticles of red phosphorous (RP) coated with paraffin were developed by RESS technique with a newly designed nozzle. The characteristic feature of this model nozzle was the width of the aperture, which can be adjusted so that the supercritical solution expands rapidly through an exit with a controllable size. In addition, it can not easily be stopped (as seen in case of conventional nozzle) which makes the encapsulation process smooth. The obtained coated particle size of RP was 65 µm, when the raw RP particle of 45 µm size was taken. The surface of the coated microparticle shown to be perfectly smooth, indicating that the RP particles were completely and effectively encapsulated by the paraffin
Mishima
Extraction by SCF involves the dissolution of the desired component from sample of plant and animal origin under the controlled condition of temperature and pressure followed by the separation of desired component from the SCF by a significant drop in solution pressure
Conventional extraction processes require large amount of hazardous solvent (e.g. chloroform, methanol) and are generally cumbersome. Soxhlet extraction technique was developed in the intention to make extraction process continuous and was used for extraction of volatile oil and lipids. This process is associated with disadvantages such as requirement of highly pure solvents, use of hazardous and flammable liquid organic solvent, potential toxic emission during extraction, and finally, it is a time consuming process
The major advantages of SFE over conventional solvent extraction process are: (i) the penetration power of SCF into porous solid materials is higher than liquid solvent due to its low viscosity and high diffusivity, (ii) a complete extraction is possible in SFE as a fresh fluid is continuously forced to flow through the samples, (iii) the solvation power of the SCF can be adjusted according to requirement by varying temperature and pressure, resulting a high selectivity, (iv) suitable for thermolabile material, (v) it can be associated with various compound detecting tool like gas chromatography and mass spectroscopy, which is useful in direct quantification in addition to extraction
Salgin
Liposomes are simple microscopic vesicles in which an aqueous volume is entirely enclosed by a membrane composed of lipid molecules (e.g. phosphotidylcholine, cholesterol)
Frederiksen
More recently the concept of pro-liposomes was developed in the view of the shortcomings such as oxidation, fusion, aggregation, and phospholipid hydrolysis resulting in physico-chemical instability associated with liposomes
Feix
The number of protein such as cyclosporine, insulin, protein hydrolysate are introduced to the market, which is the result of genetic engineering
Bouchard
Impregnation is generally used to incorporate active ingredients in the polymeric matrix. Traditionally, impregnation was carried out by two steps; (1) active ingredients is first dispersed or dissolved in a suitable solvent, and (2) the polymer is soaked in the so formed dispersion or solution
Masmoodi
Supercritical fluid chromatography (SFC) uses CO2 as mobile phase to dissolve compounds. Unfortunately, CO2 is not a good solvent for polar compounds. But, this problem can be corrected by adding moderate amount of organic solvent, called as modifier
such as (a) faster and more efficient separation of compounds due to lower viscosity and higher diffusivity of CO2, (b) most of the pharmaceutical ingredients used for the synthesis purpose are as soluble or more soluble in mixture of CO2 and organic modifier, (c) recovery of purified compounds from the collected fractions is easier and economical as solubility in CO2 decreases rapidly with decrease in pressure, (d) moreover, mobile phase, CO2, is cheaper, greener and safer as compared to organic solvent
The application of SFC includes: (a) chiral (enantiomer) separation e.g., separation of chiral sulfoxide belonging to the family of substituted benzimidazoles by using Chiralpak AD and methanol as stationary phase and modifier, respectively
Sl.no | SCF Technique | Active Ingredient | Material | Application | Ref. |
1 | RESS | ArtemisininDiclofenacBechlomethasone-17,21-diapropionateLidocaineDigitoxinRaloxifenCefuroxime axetilRed phosphorousLipase and lysozyme Dextran and fluoroscein isothiocyanate | ParaffinPolymethylmethacrylate, PEG, polylactic acid (PLA), polylactide-co-glycolide (PLGA) and PEG-PPG (polypropelene glycol)-PEG Phospholipids and cholesterol | MicronizationMicronizationParticle morphology Particle MorphologyMicronizationMicronizationNanonizationCoatingCoating Liposomes | 515254 555758597172 90 |
2 | PGSS | YNS3107 Human growth hormone | PEG 400, PEG 4000 and Poloxamer 407 PLGA and PLA | Micronize solid dispersion Microparticles | 63 64 |
3 | RESAS | Cyclosporine | Phospholipid | Nanoparticles | 61 |
4 | GAS | Puerarin | Polymorphs | 48 | |
5 | PCA | Budesonde | Polylactic acid | Microparticles | 53 |
6 | SAS | AmoxicillinNaproxen Cefuroxime axitelRifampcinVitamin-D3 | Methyl cellulose and ethyl cellulose Polyvinylpyrrolidone-K30Poly (L-lactide)Phosphotidylcholine | MicronizationMicrospheres MicroparticlesMicroparticlesPro-liposome | 6065 676897 |
7 | ASAIS | Theophylline | Polymorphs | 30 | |
8 | SEDS | Terbutalin sulphateMorphineLysozyme | PLA | Polymorphs MicroparticlesDrying of proteins and peptides | 4966101 |
9 | SFEE | Indomethacin and ketoprofen | Tripalmitin, tristearin and Gelucire 50/13 | Solid lipid nanoparticles | 38 |
10 | SFE | Jojoba oil | Extraction | 87 | |
11 | CAN-BD | Ibuprofen | Myristic acid and tripalmitin | Solid lipid microparticles | 69 |
12 | SAA | CefadroxilCromolyn sodium | MicronizationMicronization | 5056 |
A large number of SCF based processes were developed in recent years. There are still possibilities to improve the existing SCF processes by optimizing operational conditions (physical and chemical parameters). Furthermore, many new processes can be developed by understanding the properties of SCFs, nature of solute and their interaction. Of course, SCF based techniques are superior over existing and well established techniques such as milling/crushing for size reduction, soxhlet extraction, spray coating, impregnation by soaking, etc. However, extensive research is required to make it feasible in industrial scale.
For instance, a commercial operation under the trade name of HIPLEX process is used for the processing of soybean at SafeSoy technologies in Ellsworth, Iowa. This CO2-assisted process resulting in between 80-90% vegetable oil recovery for soybeans and over 90% recovery for canola oil