Application of Supercritical Fluids in COVID-19

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Helga Karina Ruiz Saldaña	--	6674	2022-11-27 22:20:17	\|
2	format	Jason Zhu	-3 word(s)	6671	2022-11-29 07:25:02	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14112380

Even though years have passed since the emergence of COVID-19, the research for novel or repositioned medicines from a natural source or chemically synthesized is still an unmet clinical need. There are three main applications of the supercritical fluids in this field: (i) drug micronization, (ii) supercritical fluid extraction of bioactives and (iii) sterilization. The supercritical fluids micronization techniques can help to improve the aqueous solubility and oral bioavailability of drugs, and consequently, the need for lower doses to elicit the same pharmacological effects can result in the reduction in the dose administered and adverse effects. In addition, micronization between 1 and 5 µm can aid in the manufacturing of pulmonary formulations to target the drug directly to the lung. Supercritical fluids also have enormous potential in the extraction of natural bioactive compounds, which have shown remarkable efficacy against COVID-19. Finally, the successful application of supercritical fluids in the inactivation of viruses opens up an opportunity for their application in drug sterilization and in the healthcare field.

supercritical fluids COVID-19 micronization sterilization

1. Introduction

More than two years have passed since the COVID-19 pandemic was declared worldwide, and more than 272 million infections have been registered around the world, with the United States, India and Brazil leading this list, and more than 5.3 million deaths being reported. The pandemic has had an enormous impact on economies, education and society in general, the latter especially due to the considerable effect on mental health due to the loss of family and friends, constant fear, social distancing and all the confinement measures implemented by the authorities ^[1].

COVID-19 has paralyzed, in addition to the health system, political and economic relations in all countries. The world economy has suffered a very large impact, which makes it impossible to calculate when it will return to pre-pandemic levels ^[2].

The global COVID-19 pandemic is currently ongoing with the mass vaccination campaign, which represents an important weapon to stop the pandemic. Since the start of the pandemic, the development of the COVID-19 vaccine and pharmacological treatments have exponentially grown ^[3]. However, vaccine administration is not enough to stop the transmission of the virus and its fatal consequences. Hence, the identification and development of better treatment alternatives are key to alleviating possible complications, such as hyperinflammation and collateral infections ^[4].

Novel drugs are under development, but the approval of new chemical entities takes at least several years until being approved by health authority bodies ^[5]^[6]. For this reason, the repurposing of drugs, such as antivirals and antiparasitic agents, used for several years to treat other diseases has become a realistic and effective strategy against COVID-19 ^[7]. Several clinical trials are ongoing to determine the efficacy of this virus ^[8].

The severe acute respiratory syndrome is a viral respiratory disease caused by a SARS-associated coronavirus. It causes generally mild symptoms very similar to those observed in common cold, including fever, cough, and shortness of breath, after about five days of a suspected infection, but in some cases, these mild symptoms can develop into severe clinical signs typical of a severe respiratory syndrome and can lead to pneumonia, multiple organ failure, severe acute respiratory syndrome, and even death. These more severe symptoms are due to the cytokine release syndrome (CRS), or “cytokine storm”, which is an overproduction of immune cells and cytokines that leads to rapid failure of the multi-organ system and tissue damage to the lungs, kidneys, and heart. Therefore, to decrease the mortality rate, one of the objectives is to develop drugs capable of modulating the immune response or suppressing the production of overactive cytokines. Mortality occurs mainly in elderly people and in patients with medical conditions that position them as high-risk patients such as high blood pressure, diabetes, cirrhosis, coronary heart disease, and patients with surgery for tumors and Parkinson’s disease ^[9]^[10]^[11]^[12].

For the diagnosis of the disease, some clinical findings can be linked to COVID-19, including a decrease in albumin, high C-reactive protein, high lactate dehydrogenase, lymphopenia, eosinopenia, high erythrocyte sedimentation rate, leukopenia or leukocytosis, hyperbilirubinemia, elevated liver enzymes and high creatinine. Images of the thorax using X-ray equipment and especially computed tomography have led to important information on the evolution of the disease. The current standard test for confirming the disease in suspected patients continues to be reverse transcription polymerase chain reaction (RT-PCR) of oropharyngeal and nasopharyngeal swabs because of it is specificity and simplicity as a qualitative assay, although false negative rates of up to 30% have been observed. The serum antibody test is another modality for the diagnosis and monitoring of SARS-CoV-2 and allows the detection of IgM and IgG antibodies, 10 and 12 days, respectively, after the onset of symptoms ^[10]^[13].

Although the future of the pandemic cannot be predicted, the fact that mutations in the virus continue to occur makes it mandatory to search for new or repositioned drugs that will help patients especially in severe cases, avoiding serious sequelae or even deaths.

2. Micronization of Drugs Using Supercritical Fluids

The micronization of drugs allows modifying their pharmacokinetic and pharmacodynamic properties by improving their bioavailability, their solubility and consequently reducing their adverse effects. The application of micronization techniques based on the use of supercritical fluids emerges as a viable and user-friendly environment alternative to more traditional techniques. There are excellent reviews and monographs covering the different supercritical micronization techniques and their applications ^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]^[22].

Conventional processes for generating micronized particles have some limitations, including the possibility of polymorphic transitions, inapplicability to thermolabile or waxy materials, low batch-to-batch reproducibility, complex scale-up, a wide range of variation in particle size distribution and the presence of residual solvents ^[23].

In contrast, the precipitation of pharmaceutical products and natural substances using supercritical fluids presents several advantages over conventional methods. These methods lead to particles of small sizes, being possible to control the morphology and particle size distribution ^[15]^[24]. This is because these characteristics are related to the properties of SCF that can be adjusted with small changes in pressure and temperature ^[15], which allows the preparation of microparticles, sub-micro and nanoparticles in a controlled manner. The temperature used in these processes is low to moderate, so the degradation of the product is much prevented. Furthermore, the use of toxic organic solvents is avoided or reduced, being the residue in the resulting product easily eliminated ^[24]. Reduction in the drug particle size improves its dissolution rate and bioavailability and allows lowering the drug dose and, at the same time, reducing its side effects ^[25]. The application of supercritical fluids is not only being applied for pulmonary administration, but it is also being used to improve the dissolution of poorly soluble compounds for oral administration ^[26].

According to its solvating behavior, these processes can be classified into different groups depending on the scCO₂ processing role: acting as a solvent, cosolvent, solute, antisolvent, or as cosolute ^[20]^[22]. The most common micronization techniques are reviewed in the next section.

2.1. Supercritical CO₂ as a Solvent

Rapid Expansion of Supercritical Solutions (RESS)

RESS was patented in 1986 by Smith and Wash ^[27] after the report of Kukronis ^[28]. This technique is based on the ability of CO₂ to dissolve solids. The process is divided into two steps. In the first step, the compound of interest (solute) is dissolved in the supercritical fluid until saturation. The mixture of the solute and the supercritical fluid is then depressurized in the second step in a precipitation chamber through a nozzle. This creates a decrease in the SCF solvation power, leading to supersaturation and causing the precipitation of the solute ^[15]. The temperature of the extractor/saturator chamber, nozzle and expansion chamber must be carefully controlled.

RESS has been applied to the micronization of poorly water-soluble compounds, increasing the drug dissolution rate ^[20]^[24]^[29]^[30]. Particles precipitated by RESS have particle diameters in the sub-micron range ^[30]. The main advantages are that it is a simple technique and it minimizes the use of organic solvents ^[31]. In a continuous process; the SCF is always reused. This process is only applicable to substances with high solubility in the selected supercritical fluid, for CO₂ mainly non-polar or volatile polar compounds, and it requires the use of relatively high pressures ^[15]^[24]. The low solubility of drugs and polymers in supercritical CO₂ makes the particle recovery difficult, leading to scale-up limitations ^[20]. To overcome these problems, modifications to the RESS technique have been proposed, resulting in RESS-SC ^[32]^[33] and RESOLV ^[34]. In RESS-SC, additives are used to improve the solubility of the compound to micronize in CO₂, whilst in RESOLV, the product is expanded into a liquid solvent. Thus, the main advantage of this technique, related to the absence of solvents in the final product is lost, and additional stages to remove the solvents from the product are required ^[24].

RESS with Solid Cosolvent (RESS-SC)

In RESS-SC, a solid cosolvent such as menthol is added to improve the solubilization of the solute in the supercritical fluid and to provide a barrier for the coagulation of the particles leading to much smaller particles than the conventional RESS technique ^[32]. The mixture is expanded through the nozzle into the expansion vessel where it precipitates. Then, the solid cosolvent is removed from the precipitate by sublimation ^[31].

RESS into a Liquid Solvent (RESOLV)

RESOLV involves the rapid expansion of a supercritical solution into a liquid solvent. This allows obtaining particles with a diameter less than 50 nm ^[20]^[35]. The advantage of this method is the possibility of avoiding particle growth in the precipitator ^[31]. This technique may require an additional stage to remove the solvent from the product ^[24].

2.2. Supercritical CO₂ as Solute

Particles from Gas Saturated Solution (PGSS)

This technique was first proposed by Weidner et al. in 1995 ^[36]. Since then, it has been widely used in the pharmaceutical field to micronize different compounds ^[20]. In PGSS, CO₂ dissolves into the substance to micronize but the system does not have to be fully miscible. Thus, PGSS can be applied to a much wider variety of substances ^[24].

In this technique, CO₂ is fed into a saturation chamber and is dissolved in a melted substance at high pressure, generating a gas-saturated solution with reduced viscosity. Then, this solution is rapidly expanded through a nozzle to a precipitation chamber at lower pressure. Upon expansion, droplets are formed and CO₂ evaporates, leading to supersaturation, solidification and particle precipitation. The driving force for particle formation in PGSS is the large temperature decrease during expansion due to the Joule–Thompson effect ^[37].

This technique was first applied to the micronization of different molecular weight polyethylene glycols (PEGs) ^[38]. PGSS is easily scalable, requires no organic solvents, and can take place at low temperatures. Furthermore, it is a simple process, which leads to a low processing cost and a wide range of applications ^[20]^[31].

PGSS has also been adapted to encapsulate bioactive molecules, such as Vitamin B₂, in solid lipid nanoparticles ^[20]. This process can be also operated in a continuous mode, especially suitable for processing polymers and lipids in which CO₂ has a large solubility ^[22]^[37].

As a disadvantage, the technique is limited to pharmaceutical compounds in which CO₂ is highly soluble. Moreover, if the solute must be melted, that represents a potential issue for heat-sensitive materials ^[20]. Thus, the PGSS technique has been implemented successfully at the industrial level mainly in food applications ^[37].

In order to expand its applications and/or overcome the main limitations of the PGSS process, several modifications were applied, including emerging Concentrated Powder Form (CPF) ^[39]^[40] and Continuous Powder Coating Spraying Process (CPCSP) techniques ^[41].

Concentrated Powder Form (CPF)

In CPF, a liquid compound and a supercritical fluid are mixed in a static mixer, and the resulting solution is sprayed through a nozzle into a precipitator chamber at low pressure. A dispersed spray of fine liquid droplets is formed during the expansion step of the gas-saturated liquid instead of solid particles. Then, an inert gas (e.g., N₂) along with a carrier in powder form is blown into the precipitation chamber. The liquid dispersed in the form of very small droplets mixes with the carrier, forming solid agglomerates ^[16]^[22]^[24]^[39]^[40]. CPF allows obtaining liquid-filled powders with concentrations of up to 80–90 wt % of the liquid ^[22]^[24]^[37].

Continuous Powder Coating Spraying Process (CPCSP)

CPCSP is a modification of the PGSS process that was proposed as an alternative technique for the manufacture of powder coatings. It is very effective in low melting point polyester powder coatings, achieving an average particle size of less than 40 µm ^[41].

In this technique, each component of a powder coating mixture, the binder and hardener, are melted in separated high-pressure vessels, and high-pressure pumps fed both streams to a static mixer where the mixture is homogenized with compressed CO₂. The solution is expanded through a nozzle into the precipitation chamber, and solid particles are formed. Finally, these particles can be separated from the gas using a cyclone separator and a filter, achieving a fine powder coating ^[16]^[22].

2.3. Supercritical CO₂ as Cosolvent

Depressurization of an Expanded Liquid Organic Solution (DELOS)

This process has been developed and patented by Ventosa et al. ^[42]^[43]. It allows the preparation of micron and submicron crystalline particles of high polymorphic purity and morphological homogeneity, free of residual solvent in one step ^[16]^[20]^[23]. DELOS can be also used to produce polymorphs that cannot be obtained with other crystallization techniques ^[43].

In DELOS, scCO₂ is used as a cosolvent to saturate an organic solution of the solute of interest, forming a volumetric gas expanded liquid solution, which is then expanded through a nozzle ^[15]^[22]^[31]. Upon expansion, CO₂ evaporates, the solution then becomes supersaturated, and the solid precipitates. Due to CO₂ evaporation, the system cools rapidly and homogenously, leading to crystalline materials. This process can only be applied to substances for which CO₂ does not have an antisolvent effect, as otherwise, the solute precipitates in the saturator and not in the precipitation chamber ^[42]^[44].

The main advantage of this technique in comparison to PGSS is that thermo-sensitive materials can be handled to prepare fine particles without melting ^[31]. A modification to the DELOS process, named DELOS-SUSP, consists of depressurizing the gas-expanded liquid solution into another solvent that interrupts the crystallization ^[45]^[46]. This process is being applied on an industrial scale ^[14]^[22].

2.4. Supercritical CO₂ as Cosolute

Carbon Dioxide-Assisted Nebulization with a Bubble Dryer (CAN-BD)

This technique enables the micronization of water-soluble compounds such as inorganic salts or proteins ^[20]. It was first proposed by Siever et al. ^[47]^[48].

In the CAN-BD process, the drug is dissolved or suspended in water or an organic solvent (or both), preferably in a concentration between 1% and 10% of the total solids dissolved, and then, it is mixed intimately with near-critical or scCO₂ by pumping both fluids through a near zero volume tee (<0.1 μL) to generate an emulsion. The emulsion expands through a flow restrictor (50–70 mm long) into a drying chamber at atmospheric pressure to generate aerosols of microbubbles and microdroplets. The tee and the restrictor are heated to a temperature between 50 and 100 °C to avoid the restrictor clogging during expansion ^[31]. The precipitation chamber contains heated air or nitrogen gas to assist in the drying of aerosol droplets or bubbles. Dry particles are collected on a filter placed at the bottom of the drying chamber ^[22]^[24]^[31]^[49].

This method allows the processing of thermolabile drugs, and it is the preferred method for water-soluble drugs. Organic solvents miscible with the supercritical fluid can be substituted in part or totally for water. Very small particles (<3 µm diameter) can be produced by this method ^[31].

To make the CAN-BD process more versatile, some modifications have been proposed, including Supercritical Enhanced Atomization (SEA) and Supercritical Fluid Assisted Atomization/Supercritical CO₂-Assisted Spray Drying (SAA/SASD) ^[22].

Supercritical-Enhanced Atomization (SEA)

In this process, the supercritical fluid is used as a nebulization agent. SEA takes advantage of the ability of supercritical fluids to enhance liquid jet dispersion into fine droplets when being depressurized along with liquid solutions. The jet disintegration results in the formation of crystalline sub-micron particles or amorphous materials ^[22]^[50]. The SEA process has been extensively used by Padrela et al. in the preparation of cocrystals of different active pharmaceutical ingredients ^[50]^[51].

The main difference between SEA and CAN-BD is the utilization of a coaxial nozzle with a pre-expansion mixing chamber instead of the micrometric volume tee. The pre-expansion mixing chamber allows the mixing of both fluids at selected conditions of pressure and temperature before its depressurization into a precipitation chamber at atmospheric pressure ^[22]^[50]^[51]. The SEA process can be easily adapted from existing spray-drying facilities widely used in the pharmaceutical industry. As a disadvantage, it may require higher processing temperatures than CAN-BD ^[14].

Supercritical Fluid-Assisted Atomization (SAA)/Supercritical CO₂-Assisted Spray-Drying (SASD)

SAA was originally proposed by Reverchon and co-workers in 2002 as a modification of CAN-BD to improve the mixing between CO₂ and the liquid solution to micronize ^[52]. In SAA, a thermostatically controlled saturator, packed with stainless steel perforated saddles to ensure good contact between the liquid solution and scCO₂, is used instead of a low-volume T-join. The liquid solution formed on the contact device is sent to a thin wall injector. Droplets are produced and reach the precipitation chamber where warm N₂ is supplied for particle formation ^[22]^[24]^[49]^[53]. The SAA process enhances the efficiency of conventional spray drying, but it presents a better control on particle size distribution and leads to smaller particles (<100 nm) ^[14].

In SAA, two atomization processes take place: (i) droplets at the nozzle are produced by pneumatic atomization; and (ii) the rapid expansion of scCO₂ from the primary droplets leads to the jet breakup at the exit of the injector ^[18]^[20].

The SAA process is widely used in the micronization of pharmaceuticals, catalysts, polymers, and dyes. Water, ethanol, methanol, and acetone are mainly employed, pure or mixed, to process active compounds using this technique ^[18]^[24]. The major limitation is the high temperature required for evaporating the liquid solvent, which prevents its application to thermolabile substances ^[24]^[54]. Other authors also refer to this process as SASD. SASD facilitates the micronization of hydrophilic and hydrophobic drugs using organic and inorganic solvents, and it is suitable for the production of inhalable composite particles ^[54]^[55].

2.5. Supercritical CO₂ as Antisolvent

Gaseous Antisolvent (GAS)

The use of CO₂ as an antisolvent to crystallize compounds was first proposed in 1989 by Gallagher et al. ^[56]. This method is used when the solute to micronize is not soluble in CO₂ but can be dissolved in an organic solvent that is fully miscible with CO₂. Different organic solvents such as ethanol, methanol, acetone, dimethyl sulfoxide and tetrahydrofuran are currently used ^[14]^[57]. In the GAS technique, compressed CO₂ is added, very often under stirring, to a solute-containing solution in a high-pressure vessel until the desired pressure. The CO₂ dissolves into the liquid solvent, causing the liquid solvent to expand, its solubilizing power to decrease and the solute precipitates out of the solution ^[16]^[31]^[51].

The main advantage of the GAS process over the RESS process Is its versatility, since a wide range of products can be micronized in the range of 1–10 μm, with the only requirement that the solute must be soluble in an organic solvent and insoluble in scCO₂, which is the most common situation for pharmaceutical compounds. Furthermore, operation pressures are much lower than those used in RESS ^[15].

A disadvantage of GAS is that precipitation takes place under different conditions during the CO₂ addition, being difficult to assess the effect that each parameter has on the properties of the final product ^[24]^[31].

To overcome the limitations, there are several modifications of the GAS process that differ mainly in the way that CO₂ is mixed with the organic solution, the operation conditions, and the flow regime. These techniques are: Supercritical Antisolvent (SAS), Solution Enhanced Dispersion of Supercritical Fluid (SEDS), Aerosol Solvent Extraction System (ASES), Precipitation with a Compressed Antisolvent (PCA), Supercritical Antisolvent with Enhanced Mass transfer (SAS-EM) and Supercritical Fluid Extraction of Emulsions (SFEE) ^[16]^[22]^[58].

Supercritical Antisolvent (SAS)

In this technique, a solution of the compound to precipitate dissolved in an organic solvent and CO₂ are continuously pumped into a precipitation chamber filled with scCO₂ at a fixed temperature and pressure. The solution is injected through a nozzle and forms small droplets. CO₂ dissolves into the organic solvent, leading to solvent expansion and solution supersaturation and causing the precipitation of the solid in the form of micro and nanoparticles ^[20]^[22]. The micronized particles are collected in the precipitation chamber, which is extensively flushed with pure CO₂ to remove any solvent residue in the precipitate. The particle size and morphology are controlled by varying the process parameters such as temperature, pressure, solute concentration, flow rates, etc. ^[59]. Drug amorphization can be achieved by the coprecipitation of the drug with excipients such as PVP ^[60].

This method is widely used to micronize different pharmaceutical substances, catalyst particles, high-energy materials, superconductor precursors, polymers, pigments, and other products which are not soluble in CO₂. Co-crystals of active pharmaceutical ingredients can be also prepared by SAS ^[14]^[51]^[61]^[62]^[63]. Although some SAS micronization processes have been successfully scaled up in pilot plants ^[24]^[37], the complex mass transfer processes involved make the implementation at the industrial level difficult ^[31].

Solution-Enhanced Dispersion of Supercritical Fluids (SEDS)

This process is a modification of the SAS method, being the main difference in the way that the solution and the antisolvent are contacted. The process was patented by Hanna and York in 1994 ^[64]. In SEDS, the supercritical fluid and the drug solution are simultaneously introduced into the precipitation chamber at a temperature and particular pressure using a coaxial nozzle, which increases the rate of mass transfer at the interface ^[18]^[24]^[31]^[65]. Because of the high mass transfer, the nucleation is fast and results in smaller particle sizes with less agglomeration ^[14]^[57]. In SEDS, the particle size depends greatly on the flow rates of scCO₂ and the active substance solution in the coaxial nozzle.

This process is also suitable to process water-soluble compounds (e.g., peptides and proteins) using a three-compartment coaxial nozzle by spraying the aqueous solutions along with the organic solvent and CO₂ separately ^[66]. The addition of an organic solvent helps to overcome the problems associated with the limited solubility of water in scCO₂ ^[49]^[67].

The advantages of this method are related with the improved mass transfer between CO₂ and the liquid solution which produces small and uniform particles with minimal agglomeration. Furthermore, particles present very low residual solvent content even when the process is operated at reduced drying time and high yield ^[67]^[68]. As the SAS technique, the method can be adapted to continuous operations ^[14]. The main disadvantage of this technique is the easy nozzle blockage ^[67].

Supercritical Antisolvent with Enhanced Mass Transfer (SAS-EM)

This technique was proposed to reduce the size of the particles formed during precipitation and improve the mixing of the SAS method ^[65]. It was originally developed to create particles for pulmonary delivery ^[69]. In this process, ultrasound is applied to the injection nozzle, improving the dispersion of the solution into fine droplets ^[18]^[24]. The ultrasound field generated by the vibrating surface increases the turbulence and the mixing of the solution and the supercritical antisolvent, altering the particle size and morphology of the particles produced and resulting in a high mass transfer ^[18]^[53]^[69]. The same concept has been applied in SEDS-EM ^[70].

In comparison to the conventional SAS process, droplet agglomeration is avoided due to the improved and faster mixing, leading to the formation of smaller particles ^[18]^[26].

Supercritical Fluid Extraction of Emulsions (SFEE)

In SFEE, supercritical CO₂ is used to rapidly extract the organic phase of an emulsion oil in water (O/W). The compound to be micronized is previously dissolved in this organic phase, which is then emulsified with the aqueous phase. The addition of a small amount of surfactant or emulsifying agents is required. The emulsion is introduced into the precipitation chamber. Then, scCO₂ is introduced continuously at the bottom, typically at very mild conditions (8.0 MPa and 38 °C). When the solvent is removed, the compound precipitates in small particles that remain suspended in the water. They are stabilized and dispersed in the aqueous phase by the surfactant, preventing aggregation. The process was first patented by Ferro Corporation ^[71].

A variation of the method is used to generate composites. Both the active compound and the support or coating are dissolved in the organic phase; so, when this is removed, homogeneous aggregates or even true core–shell capsules are generated. If the active compound is soluble in water, double emulsions (W/O/W) are used. The SFEE process can be performed continuously in packed columns reducing the CO₂ consumption and processing time, permitting high production ^[72]. Both the organic and the supercritical solvent can be recirculated in the process.

Other Supercritical Antisolvent Techniques

In some publications, the precipitation by compress antisolvent (PCA) technique was proposed ^[49]^[65]^[73]. Depending on the publication, PCA is equivalent to the conventional SAS or SEDS processes. PCA has been efficiently used in the production of a great variety of organic and biopolymer-based particles ^[31], leading to small solvent-free particles with a narrow size distribution at mild operating conditions ^[74].

In other publications, the Aerosol Solvent Extraction System (ASES) technique is used. This method was initially developed for the production of polymeric drug delivery systems and has been extended to the encapsulation of various pharmaceutical compounds ^[14]^[21]. The ASES process is equivalent to a conventional SAS process. At a high scCO₂ to solvent ratio, the mass transfer is improved, and fine particles can be obtained ^[53]^[65].

2.6. Micronization of COVID-19 Drugs

All the COVID-19 drugs, except Remdesivir, are administered orally, and most of these drugs have poor water solubility and low bioavailability. The size of the particles, the crystallinity, the shape and the structure determine the absorption and bioavailability of the drugs ^[53]. Thus, the application of supercritical fluids could significantly improve these attributes.

The Supercritical Antisolvent techniques are the most frequently applied, as most drugs and bioactives are not very soluble in CO₂. Then there are a few reports on the use of CO₂ as a solvent, RESS and its modification, for the micronization of natural materials soluble in CO₂ and the preparation of drug polymer composites and liposomes. The remaining publications refer to the use of CAN-BD and SAA/SASD.

The micronization of azithromycin by SAS has been successful performed, leading to an extraordinary increase in the solubility and dissolution rate due to the formation of very fine and spherical nanoparticles ^[68]. A solution of azithromycin in ethanol with PEG 6000 and sodium lauryl sulfate as surfactants were used. The increased dissolution rate was due to the amorphization of the drug during the micronization process ^[75].

Sievers et al. have micronized the antibiotic doxycycline using water as a solvent by the CAN-BD technique to prepare an inhalable drug ^[22]. Similarly, corticosteroid dexamethasone was micronized by the ASES technique, aiming at their pulmonary administration, using dichloromethane and methanol as solvents. The mean particle size obtained was lower than 5 µm ^[57]^[76]. SAA has been also applied to methanol and acetone solutions of the same drug. Spherical particles with a size of 0.5–1.2 μm were obtained. The resulting particles significantly enhanced the inhibition of tumor necrosis factor in vitro ^[22]^[53]^[77]. In another work, SAS precipitation was proposed for the coprecipitation of dexamethasone in ethanol with polyvinylpyrrolidone (PVP). The particles’ mean diameters ranged from 1.8 to 2.5 μm. The dissolution rate of the composite in phosphate-buffered saline solution (PBS) was more than four times faster than that of the unprocessed drugs ^[78]^[79].

Another antibiotic in which micronization techniques have been applied using supercritical fluids is minocycline. Rodrigues et al. demonstrated the conversion of a hydrated form of commercial minocycline hydrochloride to an anhydrate form using the GAS method with ethanol as solvent, removing water molecules from the crystal structure of the drug and generating a new solid-state form ^[14]^[80]. Cardoso et al. applied the SAS technique to this same drug. Minocycline was precipitated in a continuous mode from an ethanol solution, yielding relatively stable amorphous particles with almost twice the density of the starting material, with a size ranging from 0.1 to 1 µm, depending on the operating conditions ^[57]^[81]^[82].

Ivermectin has been encapsulated in nanoparticles of poly (methyl methacrylate) (PMMA) with a mean size of 0.050–0.170 µm. A continuous SAS process using acetone as the organic solvent was used to obtain a formulation for a controlled release. In this case and due to the characteristics of the drug evaluated, the researchers recommend the administration of these nanoparticles through the intravenous route ^[18]^[78]^[83].

The ASES technique has been applied to the micronization of methylprednisolone (group of corticosteroids), using tetrahydrofuran as solvent. Micronization led to particles of size close to 5 μm, which is suitable for pulmonary administration ^[58].

Melatonin, an alternative drug in the treatment of COVID-19, has been encapsulated in liposomes with phosphatidylcholine and cholesterol, using the RESOLV. The mixture was expanded over an ethanol solution. Round or oval particles with an average size of 0.066 μm and uniform particle size distribution were obtained, improving their characteristics for oral administration ^[84]^[85].

Complementary to the indicated drugs, in some natural compounds, micronization techniques with supercritical fluids have also been used, as is the case of quercetin, which is a flavonoid considered one of the most promising candidates in the fight against COVID-19. Several micronization techniques such as SFEE, SAS, SAS-EM and PGSS have been applied to quercetin.

The SFEE of quercetin with soy lecithin as a coating material an ethyl acetate and water as solvents led to particles of mean particle size equal to 0.190 μm and the complete encapsulation of quercetin in an amorphous state without the presence of segregated crystals ^[18]^[57]^[86].

Quercetin has been also micronized by SAS and several of its variants ^[18]^[78]. Ozkan et al. reported the SAS precipitation of quercetin using dimethyl sulfoxide as solvent and PVP as the polymeric carrier. Spherical microparticles with mean diameters between 0.47 and 9.52 μm were obtained ^[87]. The entrapment efficiency in PVP was 99.8% and the dissolution rate from the coprecipitated powder was 10 times faster compared to the dissolution rates of unprocessed quercetin. García et al. have also used SAS to precipitate microparticles of quercetin with cellulose acetate phthalate (CAP) and acetone. Spherical particles with a range between 0.084 and 0.145 μm of diameter were obtained. Release profile studies showed a faster release and higher solubilities of quercetin ^[88]. Fernández et al. studied the coprecipitation of quercetin particles with the polymer ethyl cellulose (EC) with ethyl acetate as solvent. In this case, amorphous particles in the submicron range with sizes between 0.150 and 0.350 µm were formed. The precipitate characteristics and the high encapsulation efficiency would certainly improve its oral administration route ^[89]. Montes et al. carried out comparative studies of the SAS micronization of quercetin using ethanol as solvent to evaluate the factors that determine a better particle size distribution. The precipitates were crystalline with a particle size range of 0.15–1.24 μm and presented needle-shape particles forming aggregates ^[90]. Fraile et al. encapsulated quercetin in Pluronic F127 poloxamer using acetone as a solvent using SAS. Their results indicated a significant reduction in particle size (≈1 μm), the absence of segregated crystalline particles, and an improvement in the dissolution rate ^[91].

The application of the SAS-EM technique on quercetin was studied by Kakran et al. using ethanol as a solvent. Particles between 0.120 and 0.450 μm were obtained. The dissolution rate of the precipitated material increased significantly in comparison with the original powder ^[53]^[92]. Finally, the PGSS technique was applied to quercetin in an inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD) to improve its solubility and dissolution rate and enhance its bioavailability ^[57].

Other bioactive components have been also micronized using supercritical fluids, Huang et al. have prepared an inclusion complex of apigenin with HP-β-CD using SAS with N,N-dimethylformamide as the solvent with a mean particle size of 0.392 ± 0.008 µm. Significant improvements in the solubility, the dissolution rate and the bioavailability of the bioactive compound were obtained in comparison to the original component ^[78]^[93]. Zhang et al. have also prepared nanocrystals of apigenin using the SAS technique with dimethylsulfoxide as a solvent. Spherical nanocrystals with particle sizes between 0.400 and 0.800 µm were obtained. The nanocrystals exhibited faster dissolution profiles than the original powder ^[18]^[53]^[94].

The SEDS technique has been applied to aescin by Jia et al., using ethanol as the solvent, resulting in the production of spherical-shaped nanoparticles with an average diameter of 0.050 μm, and prospective potential for use in oral drug delivery with reduced side effects ^[53]^[95].

The RESS technique has been applied to artemisinin, another bioactive compound, by Yu et al., who obtained lamella microparticles with a size of 0.550–2.100 μm. The precipitate had lower crystallinity than the starting material and great potential in drug delivery systems ^[14]^[53]^[96]. Van Nijlen et al. have applied the same technique but precipitated this compound over dichloromethane containing PVP K25 (RESSOLV). The polymer acted as a carrier, improving the dissolution rate of the compound in comparison with the starting material. The median particle diameter obtained was 10.6 ± 0.5 µm for oral delivery, and the dissolution rate of the micronized forms was improved in comparison to the untreated form ^[31]^[57]^[68]^[97].

The SAS process has been used by Miguel et al. to re-crystallize lutein from ethyl acetate solutions ^[78]^[98]. As a result of the precipitation, the purity of the lutein increased from 75% to over 90%. They also coprecipitated lutein and poly-lactic acid (PLA). It was possible to reduce the particle size, obtaining spherical particles with a diameter between 1 and 5 μm. Martin et al. have also applied the SAS technique to the precipitation of lutein with polyethylene glycol (PEG) and dichloromethane as a solvent. The size obtained varied between 5 and 10 μm ^[78]^[99]. Additionally, Hu et al. have studied the application of the SEDS technique for the production of lutein nanoparticles using acetone and dimethylsulfoxide as solvents. Sub-microparticles with a mean size of 0.20–0.36 µm and controlled release capability were obtained ^[57]^[78]^[100].

The SEDS process with a prefilming twin-fluid atomizer, using PEG and a mixture of dichloromethane–methanol has been applied on emodin by Lang et al. to obtain composite microparticles with a mean size between 3 and 12 μm ^[78]^[101].

Finally, hesperidin has been loaded in solid lipid nanoparticles by Saad et al. using SAS to improve its oral delivery. Hesperidin was mixed with stearic acid and tween 80, as a surfactant, and it was dissolved in dimethylsulfoxide. The micronization of hesperidin improves its solubility, apparent permeability, stability and bioavailability. The particle size obtained was 0.152–0.267 µm ^[18]^[78]^[102]. Salehi et al. have studied the micronization and coating of hesperidin and hesperitin using RESS; in this case, spherical nanoparticles with a mean size of 0.005 to 0.100 μm were coated ^[103]. The solubility rate and antioxidant activity of the nanoparticles formed in an aqueous medium increased significantly compared to the original form, demonstrating an improvement in the oral bioavailability of the flavonoids.

Overall, there is a clear potential use of supercritical fluids on the micronization of drugs to enhance their oral and pulmonary availability.

3. Extraction of Natural Compounds by Supercritical Fluids

The ability of compressed fluids (pressurized liquids) and supercritical fluids to extract targeted compounds highlights them as powerful green techniques with demonstrated capacity to obtain bioactive compounds with antiviral and anti-inflammatory activity ^[104] applied in different respiratory diseases ^[105].

The main technologies available include the extraction with supercritical carbon dioxide (SFE), liquids under pressure (PLE), subcritical water (SWE), and the use of gas expanded liquids (GXL) ^[106]. By changing the solvents, the extraction methods, and the conditions, it is possible to tune the target extracts.

Concerning the anti-inflammatory activity, some of the component extracts obtained with supercritical fluids contain flavonoids that have been successfully tested against respiratory viruses, and so, they could be also tested to fight SARS-CoV-2 ^[105]. For example, Salehi et al. have pursued the extraction with CO₂ of the hesperidin and hesperitin from sweet orange peels ^[103], while Kawamoto et al. did it from Citrus genkou ^[107]^[108]. Similarly, Nuralin et al. have evaluated the extraction of flavonoids from Pinus brutia ^[109].

The SWE technique has been applied in Citrus unshiu peel extracts and their acid hydrolysates to evaluate the antioxidant and in vitro anti-inflammatory activities of flavonoid compounds such as hesperidin. SWE extract showed a higher anti-inflammatory response compared to hot water and ethanol extractions ^[104]^[110].

Nieto et al. used PLE for the production of extracts from Vitis vinifera L. stem and seed with significant anti-inflammatory activity, due to phenolic compounds, including quercetin ^[104]^[111]. This compound has been also found in the ethanol-modified supercritical CO₂ extracts from Leptocarpha rivularis stalks ^[104]^[112].

Furthermore, the high anti-inflammatory and antioxidant activity of the spinach leaves extracts obtained by SFE and PLE containing carotenoids, such as lutein, was confirmed. In vitro studies demonstrated that the SFE extract showed higher activity than the PLE extract ^[104]^[113].

On the other hand, some natural plant extracts obtained with compressed fluids have also proven antiviral activity for respiratory infections. For example, the subcritical water extract of Brassica juncea L. showed antiviral effects against influenza virus A/H1N1 ^[114]. The supercritical CO₂ extracts from Cinnamomum cassia L. ramulus had strong inhibition efficacy against the respiratory syncytial virus ^[115]. In addition, the extract of Centipeda minima L. (a Chineses medicinal herb) possessed good in vitro activity against influenza. The responsible components of this activity were identified as pseudoguaianolides ^[116]. The edible and medical pericarps of Citrus reticulata ’Chachi’ were extracted with supercritical CO₂, and up to five active polymethoxylated flavones in the extracts were effective in fighting the respiratory syncytial virus ^[117].

Finally, other components have also been obtained by supercritical extraction, such as terpenoid artemisinin from Artemisia annua L. exhibiting antifibrotic activity ^[108]^[118].

4. Virus Inactivation and Sterilization of Contaminated Material

The supercritical processes are inherently sterile and can be completed in a single stage, in closed high-pressure stainless-steel systems, with few moving parts, avoiding too much exposure of the products to external environments ^[14]^[31]. With a proper cleaning program, cross-contamination can be avoided.

Moreover, some compressed fluids have proven to have high antimicrobial and antiviral capacity when in contact with food, tissues, polymers, and materials used in the manufacture of medical devices, implants and biotissues. Thus, it has been proposed as an alternative technique to radiation, autoclaving and oxidizing gases, which can cause damage to hydrolytic and thermosensitive materials, avoiding their reuse ^[119].

For example, the efficacy of scCO₂ treatment has been demonstrated in different virus families. The sterilization of HIV1, Sindbis, Polio Sabin I and Pseudorabies on bone grafts has been achieved on a pilot scale ^[120]^[121] and that of Sindbis, Parainfluenza, PHV1, Vaccinia, HIV1 injected into plasma products at temperatures of less than 32 °C in minutes ^[122]. It even led to the destruction of more than six orders of magnitude of coronaviruses at 40 °C and 16 MPa in 30 min has been described ^[122]. The sterilization conditions of porcine encephalomyocarditis virus were 35 °C, 10 MPa for 15 min, when 55 ppm peracetic acid was added to CO₂ ^[123]. Various bacteriophages have been also removed with CO₂ at 8.5 MPa and 38 °C, modified with water (0.25%) + H₂O₂ (0.15%) + acetic anhydride (0.50%) ^[124].

N₂O has been also tested at a pressure of 25 MPa and temperature between 37 and 50 °C for 2 h for the inactivation of Sindbis, BVDV, PRV, Polio 1 and Reo 3. It has shown to be more efficient for enveloped viruses, which is probably due to the extraction of the lipids of this envelope ^[119].

A patent covers the antiviral capacity of several fluorocarbons (R22, RTR134a, R124, R23) applied at 50 °C and 21 MPa ^[125].

Some recent papers prove the suppression of SARS-CoV-2 virus in different types of biological protective masks to explore the possibility of reusing them, given their scarcity in the COVID-19 pandemic.

One research has looked at surgical, cloth masks and N95 respirators, demonstrating the complete inactivation of HCoV-NL63 and SARS-CoV-2 coronavirus at 10.3–13.8 MPa and 33–35 °C from 5 to 90 min. It also identified different mechanisms of viral inactivation in scCO₂ sanitization, such as membrane damage, germination defect and dipicolinic acid leakage. In addition, no changes in the morphology, topographical structure or integrity of the evaluated kits were detected. Most importantly, the post-processing wettability was preserved ^[126].

Similarly, a SANDIA report released in 2020 describes the findings on the CO₂ treatment of 3M 1860 N95 masks. A sample of fifteen of these masks was exposed to ten consecutive cleaning cycles at 37 °C and 8.3 MPa for 1 h. They were then subjected to a series of standardized quality tests comparing the results with five control samples. These tests covered pressure/flow characteristics, particle filtration efficiency and proper fit of the masks. The results suggested (but did not prove) that supercritical carbon dioxide does not damage 3M 1860 N95 masks. Further testing confirmed the compatibility of supercritical CO₂ with the ventilator tubing that has been in such short supply during the COVID-19 pandemic ^[127].

Another study has evaluated the treatment of filtering facepiece respirators FFP2 with scCO₂ with a cleaning solution, containing ethanol and hydrogen peroxide 30%. The tests were performed for 1 h at 7.5 MPa and 70 °C. A biological indicator was used to test the sterilization efficiency. Then, the washing of organic deposits and the maintenance of the filtration performance was evaluated. It was possible to demonstrate compliance with the requirements for their safe reuse ^[128].

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Helga K. Ruiz

Dolores R. Serrano

Lourdes Calvo

Albertina Cabañas

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1. Introduction