American Journal of Advanced Technology and Engineering Solutions

Volume 01 Issue 01 (2025)

Page No: 544-578
eISSN: 3067-0470
DOI: 10.63125/n6esv923

Article
SUPERCRITICAL CO₂ AS A GREEN SOLVENT: A COMPREHENSIVE
REVIEW OF ITS APPLICATIONS IN INDUSTRIAL PROCESSES

Najmul Hassan Sajal1; Ripa Sutar2;

1Master Of Engineering Science, Chemical Engineering, Lamar University, Beaumont,

USA
Email: [email protected]

2Master Of Engineering Science, Chemical Engineering, Lamar University, Beaumont,

USA
Email: [email protected]

Citation: ABSTRACT
Rana, Sajal, N. H., & Supercritical carbon dioxide (scCO₂) has emerged as a powerful green solvent
Sutar, R. (2025).
Supercritical CO₂ as a
with broad applications across various industrial domains due to its tunable
green solvent: Asolvating power, low toxicity, and environmentally benign characteristics. This study
comprehensive review of presents a systematic literature review of 163 peer-reviewed articles published
its applications inbetween 2000 and 2024, conducted in accordance with the PRISMA 2020
industrial processes.
guidelines to ensure a structured, transparent, and comprehensive evaluation
American Journal of
Advanced Technology process. The objective of this review is to critically examine the role of scCO ₂ in
and Engineering facilitating sustainable and high-performance processing across multiple sectors,
Solutions, 1(1), 544-578. including natural product and bioactive compound extraction, pharmaceutical
https://doi.org/10.63125/ formulation and purification, polymer processing, green chemical synthesis,
n6esv923
environmental remediation, and industrial waste management. The findings
demonstrate that scCO₂ consistently offers superior extraction efficiencies,
Received: enhanced drug solubility and bioavailability, clean and controlled polymer
January 18, 2025 modification, improved catalytic reaction selectivity, and effective removal of
Revised:
persistent organic pollutants and recovery of valuable resources from waste
February 24, 2025 streams. Notably, case studies from global industry leaders such as Nestlé (coffee
decaffeination), Pfizer (pharmaceutical micronization), and BASF (polymer coating
Accepted: and impregnation) provide concrete evidence of scCO₂’s successful industrial
March 17, 2025
adoption and economic feasibility. In addition to performance metrics, the review
Published: identifies key engineering challenges related to high-pressure reactor design,
April 21, 2025 pump and separator integration, process control, and safety management, all of
which are addressed through advanced modeling, material innovation, and
automation strategies. By synthesizing multidisciplinary research and real-world
Copyright: implementation, this review positions scCO₂ not only as a sustainable alternative to
conventional solvents but also as a mature industrial technology with
© 2025 by the author. This transformative potential in advancing green manufacturing and circular economy
article is published under
the license of American
practices.
Scholarly Publishing
Group Inc and is KEYWORDS
available for open Supercritical CO₂; Green Solvent; Sustainable Industrial Processes; scCO₂
access.
Extraction; Environmental-Friendly Technology;

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Page No: : 544-578
eISSN: 3067-0470
DOI: 10.63125/n6esv923
INTRODUCTION
Growing environmental concerns and the pressing need for sustainable development have spurred
the search for cleaner, safer, and more efficient alternatives to conventional chemical solvents used
across various industrial sectors (Zhang et al., 2015). Traditional organic solvents, while effective, often
pose significant environmental and health risks due to their volatility, toxicity, and persistence in
ecosystems (Heckenbach et al., 2016). In response, green chemistry has emerged as a
transformative approach that prioritizes the design of products and processes that minimize
hazardous substances (Perales et al., 2017). One promising development in this domain is the
adoption of supercritical carbon dioxide (scCO₂) as a green solvent, primarily due to its low toxicity,
abundance, inertness, and recyclability (Jan & Wang, 2020). As a supercritical fluid, CO₂ assumes
properties of both gas and liquid when subjected to conditions above its critical temperature
(31.1°C) and pressure (73.8 bar), granting it exceptional diffusivity, viscosity, and solvation
characteristics (Charoenchaitrakool et al., 2002). These features enable scCO₂ to replace organic
solvents in various operations, supporting safer, more energy-efficient, and environmentally friendly
industrial practices (Bezerra et al., 2018). Following Figure 1, the significance of supercritical carbon
dioxide (scCO₂) as a versatile reaction medium becomes more apparent in the context of industrial
applications explored throughout this study. The unique physicochemical properties of scCO₂—
particularly its tunable density, low surface tension, and high diffusivity—enable it to function as both
a solvent and a co-reactant in various catalytic systems. These features facilitate enhanced
interaction between reagents and catalysts, thereby accelerating reaction rates and improving
selectivity. This characteristic has been leveraged in numerous industrial processes, especially in
pharmaceutical synthesis, polymer modification, and fine chemical production, where conventional
solvents often impose limitations due to toxicity, flammability, or regulatory concerns.
Figure 1: Supercritical carbon dioxide as reaction medium

The application of
scCO₂ in extraction
processes has
garnered significant
academic and
commercial interest
due to its ability to
extract high-value
compounds with
precision and
selectivity (Banchero,
2021). Its solvating
power, which can be
modulated through
pressure and
temperature
Source:Kacem et al. (2022).
adjustments, makes it
particularly effective in isolating non-polar and moderately polar bioactives from complex matrices
(Manna & Banchero, 2018; Yan et al., 2024). This adaptability has found utility in multiple sectors,
particularly the food and nutraceutical industries, where scCO₂ is used for decaffeinating coffee
beans, extracting essential oils, flavors, pigments, and fatty acids (Kayathi et al., 2020). Its ability to
perform at moderate temperatures ensures that thermolabile compounds retain their bioactivity and
structural integrity (Lyu et al., 2021). Regulatory acceptance has bolstered its commercial viability;
for instance, the FDA and EFSA have approved scCO₂-extracted ingredients for consumption,
underscoring its safety profile (Yu et al., 2015). Studies have demonstrated its advantages over
traditional hexane or ethanol-based extractions, especially in minimizing residual solvent
contamination and reducing environmental load (Chemat et al., 2012; de Melo et al., 2014).
Supercritical CO₂ has also revolutionized pharmaceutical manufacturing by facilitating solvent-free
purification and processing of active pharmaceutical ingredients (APIs). Through methods such as

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Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti-Solvent (SAS), and Gas Anti-
Solvent (GAS) techniques, scCO₂ enables the production of fine particles, microencapsulation, and
drug formulation without the thermal degradation or solvent residues associated with conventional
approaches (Vandeponseele et al., 2020). For instance, the pharmaceutical industry employs scCO₂
to create uniform microparticles for controlled drug delivery systems, improving bioavailability and
therapeutic performance (Tukhvatova et al., 2010). In addition, its bacteriostatic and fungistatic
properties contribute to sterility in drug processing environments (Franco & De Marco, 2021).
Extensive studies have documented the tunability of scCO₂ in producing drug polymorphs and co-
crystals with enhanced stability and solubility (Ganapathy et al., 2007). The removal of residual
solvents using scCO₂ has also become a key advantage in compliance with increasingly stringent
pharmaceutical regulations (Faggian et al., 2016). In Figure 2, the diverse industrial roles of
supercritical carbon dioxide (scCO₂) are clearly mapped across pharmaceutical, environmental,
chemical, and polymer sectors. This flowchart succinctly captures how scCO₂ functions not as a
niche solvent, but as a transformative process agent capable of enabling solvent-free purification,
enhancing chemical reactions, reducing pollution, and modifying advanced materials. In the
pharmaceutical domain, scCO₂ has been instrumental in facilitating solvent-free crystallization and
particle engineering—key requirements for developing stable drug formulations that comply with
regulatory guidelines. Environmental applications of scCO₂, as depicted, include its utility in pollution
remediation and material recycling, aligning with findings from this review where extraction
efficiencies above 85% were reported for persistent organic pollutants.
Figure 2: scCO₂ Applications Across Industries

Beyond pharmaceutical and food applications, scCO₂ plays a crucial role in the processing and
modification of polymers. Its use in polymer plasticization, foaming, and impregnation processes has
shown improvements in mechanical properties, surface functionality, and processing efficiency
(Franco & De Marco, 2021; Woodley, 2008). Polymers such as polylactic acid (PLA),
polycaprolactone (PCL), and polyethylene terephthalate (PET) demonstrate enhanced flexibility
and porosity when treated with scCO₂, facilitating their use in biomedical scaffolds, packaging films,
and membrane technologies (Kamali et al., 2018). Additionally, scCO₂ is capable of diffusing into
polymer matrices without altering chemical structures, allowing for the incorporation of drugs, dyes,
or other additives in a clean and residue-free manner (Jia et al., 2018). This solvent-free processing
aligns with environmental regulations while ensuring high-quality output in sectors ranging from
medical devices to textiles and aerospace composites (Lepoittevin et al., 2001). Moreover, in
chemical synthesis, scCO₂ serves not only as a reaction medium but also as a reactant or co-solvent,
facilitating numerous reactions with improved mass transfer and selectivity. It has demonstrated
remarkable effectiveness in facilitating catalytic hydrogenations, oxidations, and carbonylation
reactions (Matsuda, 2012). Its non-polar nature enhances interactions with organic substrates while
supporting solubility of gaseous reagents such as H₂ and O₂, enabling faster and more controlled
reaction rates (Xiang et al., 2019). Research has shown its compatibility with a wide range of
catalysts, including transition-metal complexes, enzymes, and zeolites, making it applicable to both
homogeneous and heterogeneous systems (Li et al., 2017). In polymerization reactions, particularly
free radical and ring-opening polymerizations, scCO₂ allows for precise molecular weight control
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DOI: 10.63125/n6esv923
and product morphology without post-synthesis purification steps (Cooper & DeSimone, 1996). The
benign nature of CO₂ reduces unwanted side reactions and contributes to higher yields and purer
end products (Al-Marzouqi et al., 2007).
Environmental applications of scCO₂ highlight its utility in reducing industrial pollution and supporting
waste management. Numerous studies have examined its use in removing organic contaminants
from soil, sediments, and sludges, demonstrating superior performance compared to water or
organic solvents (García et al., 2015). The low surface tension and high diffusivity of scCO₂ facilitate
penetration into microporous matrices, enabling the efficient extraction of hydrophobic pollutants
such as PCBs, dioxins, and PAHs (Beeck et al., 2015). In textile and electronic waste recycling, scCO₂
has enabled the selective recovery of metals, dyes, and plasticizers, contributing to circular
economy practices (Banchero, 2020). It has also been integrated into supercritical water oxidation
(SCWO) systems to treat hazardous waste with minimal emissions (Sasaki & Ohsawa, 2021). Because
CO₂ is non-flammable and inert, these processes can be safely scaled for industrial application
without posing significant explosion or contamination risks (Toscan et al., 2016). From a technical and
economic standpoint, the industrialization of scCO₂ technologies is progressing, though with certain
operational challenges. Equipment design, particularly high-pressure vessels, pumps, and separators,
requires significant investment and expertise, which has limited adoption in small- and medium-scale
enterprises (Yang et al., 2021). Nevertheless, continuous innovation in heat exchangers, process
integration, and pressure control systems has improved energy efficiency and cost-effectiveness
(Goenawan et al., 2015). Life Cycle Assessment (LCA) models comparing scCO₂ with conventional
solvent-based systems have reported substantial reductions in greenhouse gas emissions, waste
generation, and water usage, particularly in food extraction and pharmaceutical synthesis
(Schievano et al., 2015). Regulatory backing and industrial incentives have further contributed to its
adoption in sectors prioritizing environmental certifications and green labeling (Gao et al., 2020). The
broad range of applications supported by a growing body of empirical evidence positions scCO₂
as a solvent of interest for cleaner and more sustainable industrial chemistry. The main aim of this
review is to systematically examine and synthesize the existing body of scholarly research on the
utilization of supercritical carbon dioxide (scCO₂) as a green solvent across various industrial
domains. This includes a critical evaluation of its physicochemical properties, operational
parameters, and functional advantages in comparison to conventional organic solvents. By
reviewing applications in sectors such as food and nutraceutical extraction, pharmaceutical
manufacturing, polymer processing, chemical synthesis, and environmental remediation, this article
aims to present a coherent understanding of the role scCO₂ plays in advancing sustainable industrial
practices. The review also seeks to identify the technological constraints, safety protocols, and
economic considerations associated with scaling scCO₂ processes, offering a holistic perspective
based on empirical findings. Through this objective, the paper contributes to informed decision-
making and scientific discourse surrounding the integration of green solvents into industrial systems.
LITERATURE REVIEW
The use of supercritical carbon dioxide (scCO₂) as a green solvent has received growing attention
over the past three decades due to its environmentally friendly characteristics and versatile industrial
applications. A wealth of scientific literature has explored its thermodynamic properties, solvent
capabilities, and process engineering advantages in replacing traditional organic solvents. The
literature spans diverse domains, including food processing, pharmaceuticals, polymers, specialty
chemical synthesis, and environmental remediation, where scCO₂ plays an essential role in
advancing sustainability goals. This section critically synthesizes existing studies to present the state of
knowledge on scCO₂-based technologies and identifies the scientific and engineering
underpinnings that contribute to its functionality and adoption in industrial systems. The review is
organized into key thematic categories to reflect the multidisciplinary scope of scCO₂ applications
and address technical, economic, and regulatory dimensions. Each subsection offers a focused
analysis of the current research findings, comparative evaluations, and technical considerations
pertinent to industrial deployment.

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Supercritical CO₂ as a Green Solvent
Supercritical carbon dioxide (scCO₂) has gained recognition as a sustainable and efficient solvent
due to its unique physicochemical properties, including low viscosity, high diffusivity, and tunable
solvating power above its critical point of 31.1°C and 73.8 bar (Arumugham et al., 2021). Its non-toxic,
non-flammable, and chemically inert nature distinguishes it from traditional organic solvents, making
it a safer and more environmentally responsible option (Lima et al., 2021). The solubility behavior of
scCO₂ varies significantly with temperature and pressure, allowing for selective extraction and
reaction facilitation without compromising compound integrity (López-Padilla et al., 2017).
Researchers have emphasized the value of scCO₂ in reducing volatile organic compound (VOC)
emissions and solvent residues
in end products, aligning with Figure 3: Multifunctional Applications of Supercritical CO₂ in Material
green chemistry principles Synthesis and Processing
(Ndayishimiye et al., 2021).
Thermodynamic models and
phase equilibrium data support
the understanding of scCO₂’s
behavior in multi-component
systems, enhancing its
suitability for industrial
applications (Kacem et al.,
2022).
In natural product extraction,
scCO₂ demonstrates superior
selectivity and efficiency,
particularly for thermolabile
compounds in food and
Source: Zhang, X., Heinonen, S., & Levänen, E. (2014).
nutraceutical sectors (Torres-
Valenzuela et al., 2019). Applications include decaffeination of coffee (Yu et al., 2017), extraction of
essential oils (Crampon et al., 2017), carotenoids (de Andrade Lima et al., 2018), omega-3 fatty acids
(Villa et al., 2020), and polyphenols (Melo et al., 2020). The use of co-solvents such as ethanol has
further expanded the polarity range of scCO₂, enabling more diverse compound recovery (Sasaki
& Ohsawa, 2021). The regulatory approval of scCO₂-extracted food ingredients by the FDA and EFSA
has supported its widespread commercial adoption (de Melo et al., 2020). Compared to hexane
and acetone extractions, scCO₂ processes show shorter processing times and leave no solvent
residues (Ndayishimiye et al., 2016). Mass transfer kinetics and equilibrium modeling studies have
contributed to refining extraction efficiency across plant, marine, and microbial matrices (Liu et al.,
2014). In figure 3, the multifaceted applications of supercritical carbon dioxide (scCO₂) in advanced
material synthesis become evident. The figure outlines scCO₂’s utility across a range of processing
techniques, including 3D aerogel fabrication, coating development, template-assisted material
synthesis, layered material exfoliation, and powder processing such as sol-gel reactions and
nanoparticle-supported composites. These applications leverage the unique thermodynamic
properties of scCO₂—namely, its low viscosity, high diffusivity, and tunable solvating power—which
enable it to penetrate complex material structures without the need for high temperatures or toxic
organic solvents. As demonstrated in many of the reviewed studies, scCO₂ facilitates the formation
of homogeneous, finely structured products, which are critical in industries such as energy storage,
biomedical engineering, and nanotechnology.
In the pharmaceutical industry, scCO₂ has been employed in drug formulation, purification, and
particle engineering due to its ability to function as both a solvent and anti-solvent (Wang & Kienzle,
2000). The RESS, SAS, and GAS techniques enable micronization of active pharmaceutical
ingredients (APIs), improving solubility and bioavailability (Pan et al., 2017). Supercritical fluid
chromatography (SFC) has emerged as a reliable method for separating and purifying chiral drugs
and thermally sensitive molecules without residual solvent concerns (Kankala et al., 2017). Studies
highlight that scCO₂ reduces the risk of polymorphic transitions and degradation commonly
observed in conventional crystallization (Serna et al., 2015). The incorporation of scCO₂ in drug

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delivery systems has supported sustained-release mechanisms and encapsulation of volatile actives
in biodegradable polymers (Kamali et al., 2019). Furthermore, its sterilization capabilities and
alignment with good manufacturing practices (GMP) have made it a viable alternative in aseptic
pharmaceutical production (Porto & Natolino, 2017). Polymer processing with scCO₂ has facilitated
applications in plasticization, foaming, blending, and impregnation without chemical degradation
of polymers (Kamali et al., 2019). Its ability to penetrate and swell polymer matrices enhances the
diffusivity of additives, enabling the uniform incorporation of drugs, dyes, or functional agents (Cho
et al., 2005). Studies on polymers such as PLA, PCL, and PET reveal that scCO₂ improves flexibility,
porosity, and thermal stability, supporting their use in biomedical scaffolds and packaging films
(Kamali et al., 2018). Supercritical foaming processes allow the formation of porous structures under
mild thermal conditions, ensuring the retention of sensitive agents (Banchero, 2020). The dyeing of
synthetic fibers and drug impregnation into polymers have benefited from solvent-free scCO₂
systems, mitigating environmental contamination risks (Krakowska-Sieprawska et al., 2021). Several
researchers have shown how scCO₂ influences polymer morphology and crystallinity, enabling
tunable properties in membrane fabrication and microelectronic applications (Kamali et al., 2018).
Physicochemical Properties of Supercritical CO₂
The thermodynamic transition of carbon dioxide into a supercritical state occurs when it surpasses its
critical temperature (31.1°C) and pressure (73.8 bar), resulting in a fluid that possesses both gas-like
and liquid-like characteristics (Choi et al., 2011). In this state, scCO₂ exhibits intermediate properties—
high density akin to liquids and low viscosity like gases—enabling superior mass transfer and
penetration capacity (Greer et al., 2020). Researchers have reported that scCO₂'s density is tunable
through slight changes in temperature and pressure, allowing it to mimic the behavior of various
organic solvents without their associated toxicity (Ostadjoo et al., 2017). This tunability underlies its
effectiveness in dissolving a wide range of solutes, including non-polar and moderately polar
compounds (Zhang et al., 2015). Its ability to rapidly equilibrate in complex systems also makes it
highly efficient for dynamic industrial processes (Pawłowska et al., 2019).
The density of scCO₂, a central factor in determining its solvating power, typically ranges between
200 and 900 kg/m³ under supercritical conditions (Heckenbach et al., 2016). Higher densities
enhance the solvating ability, especially for hydrophobic molecules, allowing effective extraction
and reaction facilitation (Radošević et al., 2014). Studies have consistently demonstrated that
solubility correlates positively with density; for example, caffeine and essential oil extractions become
significantly more efficient at pressures above 200 bar (Costa et al., 2017). Computational modeling
and experimental studies have supported this behavior, revealing the relationship between CO₂
clustering and solute interaction strength (Heckenbach et al., 2016). These characteristics make
scCO₂ adaptable across a range of applications, from pharmaceuticals to polymers (Radošević et
al., 2014). In terms of viscosity and diffusivity, scCO₂ displays superior performance compared to
conventional liquids. Its low viscosity (typically 0.02 to 0.08 mPa·s) and high diffusivity (up to 10⁻⁸ m²/s)
allow rapid transport of solutes through porous matrices, reducing processing time and improving
extraction yields (Pham et al., 2009). These properties facilitate enhanced mass transfer, particularly
in solid-fluid interfaces common in food and environmental remediation applications (Kankala et al.,
2017). Researchers have used mathematical modeling to highlight how the increased diffusivity of
scCO₂ improves penetration in complex sample matrices, outperforming solvents like ethanol,
hexane, and acetone (Serna et al., 2015). The diffusivity also supports fast equilibrium attainment
during supercritical extraction and synthesis, reducing thermal degradation risks (Bezerra et al., 2018).
he solvating power of scCO₂ is considered one of its most adaptable and valuable characteristics,
governed by its polarity and compressibility near the critical point (Wang & Kienzle, 2000). While
scCO₂ is inherently non-polar, the addition of co-solvents such as ethanol or methanol can modify
its polarity, extending its applicability to a wider range of solutes (Manjare & Dhingra, 2019). Solubility
studies indicate that even polar compounds can be solubilized under optimized pressure and
temperature conditions (Melo et al., 2014). For instance, omega-3 fatty acids, carotenoids, and
flavonoids have been successfully extracted using scCO₂ with appropriate process tuning (Pavlić et
al., 2020). The critical point behavior of scCO₂ allows for easy switching between solvent selectivities,
which is particularly advantageous in multi-step or selective extraction procedures (Soldan et al.,
2021).
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Figure 4: Overview of scCO₂ Properties and Applications Comparisons between scCO₂ and
conventional organic solvents highlight
substantial environmental, operational,
and safety advantages. Traditional
solvents such as hexane, acetone, and
methylene chloride present risks related
to flammability, toxicity, and solvent
residue in the final product (Hischier et al.,
2004). scCO₂, on the other hand, is non-
toxic, non-flammable, and does not
leave residual solvent traces, making it
especially suitable for food and
pharmaceutical applications (Perales et
al., 2017). Studies have shown that scCO₂
processes consume less solvent mass per
unit of extracted product while achieving
equal or superior yields (Kumar et al.,
2021). Additionally, scCO₂ is readily
recoverable and recyclable within
closed-loop systems, reducing solvent
waste and eliminating the need for costly
post-processing purification (Haseloh et
al., 2010)(See figure 4).
Thermodynamic models and solubility
parameter theories have been central to
understanding scCO₂’s behavior across
different industrial matrices. The
Hildebrand and Hansen solubility
parameters have been applied to
predict solute-scCO₂ interactions with
increasing accuracy (Reverchon &
Antonacci, 2006). Phase equilibrium data
and empirical correlations such as the
Chrastil equation have provided insight
into how pressure, temperature, and
molecular structure affect solubility
(Manjare & Dhingra, 2019; O’Harra et al.,
2021). In reaction engineering and
crystallization, these models help in the
design of pressure-temperature profiles
for optimal yield and selectivity (Kwan et
al., 2016). Such modeling has
strengthened the foundation for using
scCO₂ not only as a green solvent but also as a reaction medium and functional processing agent
in industrial applications ranging from drug delivery to electronics and energy systems (Izydorczyk et
al., 2020).
scCO₂ in Natural Product and Bioactive Compound Extraction
Supercritical carbon dioxide (scCO₂) has been extensively applied in the extraction of natural
products and bioactive compounds due to its favorable physicochemical characteristics and
environmental benefits. Its ability to selectively solubilize non-polar and moderately polar substances
has been a key factor in its adoption for extracting essential oils, fatty acids, and functional
compounds from plant and animal sources (Pimentel-Moral et al., 2019). The tunability of scCO₂
through pressure and temperature control enhances its solvating power, enabling it to isolate

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specific constituents with minimal thermal degradation (Khaw et al., 2017). Compared to
conventional solvents like hexane or ethanol, scCO₂ provides shorter processing times and yields
cleaner extracts free from residual solvent contamination (Kühn & Temelli, 2017; Pimentel-Moral et
al., 2019). Its application has been documented in various industries including food, cosmetics,
pharmaceuticals, and nutraceuticals (Zeng et al., 2019).Moreover, figure 5 illustrates a schematic of
the Supercritical Fluid Extraction (SFE) process utilizing supercritical CO₂ (scCO₂) with a co-solvent
(ethanol) for the efficient extraction of bioactive compounds. The diagram shows key components
of the process, including the CO₂ pump, co-solvent pump, and SFE extraction chamber, where
optimized pressure, temperature, and solvent ratios facilitate compound separation from natural
matrices such as Hibiscus sabdariffa. The resulting extracts are directed for analytical
characterization using advanced tools like HPLC-ESI-TOF-MS. This setup highlights the process's ability
to produce high-purity extracts under mild conditions, minimizing thermal degradation and avoiding
toxic solvent residues. It also emphasizes the scalability and precision of scCO₂-based extraction in
natural product and nutraceutical industries.
Figure 5: SFE Process for Natural Product Extraction Using scCO₂ and Co-Solvent

Source: Pimentel-Moral et al. (2019)

In food and beverage industries, scCO₂ has been widely utilized for caffeine removal from coffee
and tea, flavor recovery, and essential oil extraction (Da Porto & Natolino, 2017). Decaffeination
using scCO₂ preserves the aroma and taste better than solvent-based methods and has been
adopted commercially (Yousefi et al., 2019). The extraction of essential oils from herbs such as
rosemary, oregano, basil, and ginger has shown higher purity and better retention of bioactive
components when scCO₂ is used (Chai et al., 2020). Compared to steam distillation or organic
solvent extraction, scCO₂ retains more thermolabile and volatile compounds (Jitrangsri et al., 2020).
These advantages have contributed to its regulatory acceptance, including recognition as a
Generally Recognized as Safe (GRAS) solvent by the U.S. FDA (FDA, 2002) and approval by the
European Food Safety Authority.
scCO₂ has shown significant advantages in extracting bioactive compounds such as carotenoids,
polyphenols, flavonoids, alkaloids, and phytosterols, which are sensitive to heat and oxidation (Pavlić
et al., 2020). The extraction of lycopene from tomato peel, β-carotene from carrots, and astaxanthin
from microalgae has been successfully performed using scCO₂ with higher yields and reduced
degradation compared to solvent extraction (Varaee et al., 2019). Polyphenol-rich extracts from
grape seed, green tea, and olive leaves have been isolated with high antioxidant activity using
scCO₂ (Viganó et al., 2017). Studies have demonstrated that the selectivity of scCO₂ can be
enhanced by the introduction of co-solvents such as ethanol, improving the extraction of more polar
compounds (Attard et al., 2015). Extraction parameters such as pressure, temperature, flow rate, and

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particle size have been optimized in various studies to enhance efficiency and selectivity (Priyanka
& Khanam, 2019).
Marine sources have also been extensively explored for scCO₂ extraction of bioactives. Fish oil,
particularly rich in omega-3 fatty acids such as EPA and DHA, has been effectively extracted from
fish by-products using scCO₂ without oxidation or hydrolysis (Jitrangsri et al., 2020). Microalgae such
as Chlorella and Haematococcus pluvialis have been investigated for scCO₂-based extraction of
proteins, lipids, and pigments like astaxanthin (Wang et al., 2019). In addition, the use of scCO₂ has
been reported for isolating bioactive peptides and antioxidants from marine crustaceans and
mollusks (Viganó et al., 2017). The high diffusivity of scCO₂ contributes to better penetration in dense
or cellular matrices, leading to improved yields and quality of marine bioactive products (Rai et al.,
2015). This application also supports sustainability by enabling value addition to fish-processing waste
(Attard et al., 2015).
Nutraceutical and Functional Ingredient Recovery
The use of supercritical carbon dioxide (scCO₂) in nutraceutical applications has gained
considerable traction due to its efficiency in recovering bioactive compounds like omega-3 fatty
acids, carotenoids, and polyphenols without degrading their functional properties (Chemat et al.,
2019). These compounds, known for their antioxidant, anti-inflammatory, and cardioprotective
effects, are often sensitive to heat, light, and chemical solvents (Campone et al., 2018). scCO₂,
operating under relatively mild temperatures and with adjustable pressure, preserves the integrity of
these molecules while ensuring solvent-free and residue-free end products (Faggian et al., 2016). The
non-polar nature of CO₂ makes it ideal for extracting lipophilic nutraceuticals, and its selectivity can
be enhanced using small amounts of polar co-solvents like ethanol (Bukhanko et al., 2020; Macário
et al., 2019). These features make scCO₂ a preferred technology for the production of high-quality
nutraceutical ingredients from both plant and marine matrices (Schievano et al., 2015). Moreover,
Omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are
commonly extracted from fish oil, krill, and microalgae using scCO₂ due to its oxygen-free and
thermally stable environment (Villa et al., 2020). Compared to conventional solvent-based
extraction, scCO₂ provides higher selectivity for EPA and DHA while minimizing oxidation and the
formation of secondary degradation products (de Melo et al., 2020). Studies on anchovy oil (Yousefi
et al., 2019), sardine waste (Wang et al., 2019), and salmon by-products (Hurtado-Benavides et al.,
2016) have demonstrated enhanced extraction yields and better product purity using scCO₂.
Moreover, the ability to fractionate fatty acids by adjusting pressure and temperature allows for
tailored nutritional profiles (Pavlova et al., 2022). In addition, scCO₂ has shown effectiveness in
extracting omega-3 lipids from microalgae species like Nannochloropsis and Schizochytrium, which
are sustainable sources for vegetarian formulations (Feng & Meier, 2017).
Carotenoids, including lycopene, β-carotene, lutein, and astaxanthin, are widely recognized for their
antioxidant and immune-enhancing properties. These lipophilic pigments are particularly susceptible
to oxidation and isomerization during conventional solvent or thermal extraction (Rai et al., 2015).
scCO₂ has been used to extract lycopene from tomato skins (Lenucci et al., 2013), β-carotene from
carrots (Silva et al., 2018), and astaxanthin from Haematococcus pluvialis microalgae (Scaglia et al.,
2020). The extraction of carotenoids using scCO₂ often involves the use of ethanol as a co-solvent to
increase solubility and selectivity for more polar derivatives (Obaidat et al., 2015). Studies employing
response surface methodology (RSM) have optimized pressure and temperature to maximize
pigment yields while maintaining bioactivity (Asafu-Adjaye et al., 2020; Obaidat et al., 2015). These
findings reinforce the efficiency of scCO₂ in recovering stable and potent carotenoid-rich extracts
with applications in functional foods and dietary supplements.Figure 6 effectively summarizes
scCO₂’s strategic role in functional food and dietary supplement development, aligning with the
study’s emphasis on green technologies for nutraceutical formulation and bioactivity preservation.

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Polyphenols, a diverse class of
Figure 6: scCO₂ in Nutraceutical Recovery plant secondary metabolites, are
abundant in fruits, vegetables,
seeds, and by-products of food
processing industries. These
include flavonoids, tannins,
lignans, and phenolic acids, many
of which display strong
antioxidant and anti-
inflammatory properties (Porto &
Natolino, 2017). scCO₂, though
primarily effective for non-polar
compounds, has been used
successfully for polyphenol
extraction when combined with
ethanol or methanol modifiers
(Escobedo-Flores et al., 2018).
Grape seeds, olive leaves, and
green tea leaves are among the
most studied sources, with results
showing high extraction efficiency
and strong radical scavenging
activity (Pal & Jadeja, 2018).
Studies comparing scCO₂ with
maceration and Soxhlet
extraction reported significantly
lower energy usage and solvent
waste, along with comparable or
improved antioxidant capacity in the resulting extracts (Krakowska et al., 2018). Additionally,
encapsulation of polyphenols using scCO₂ has been explored to improve stability and bioavailability
(Ünlü, 2021).
Beyond single-component recovery, scCO₂ facilitates the selective extraction of multi-component
nutraceutical formulations. Extraction processes from pomegranate seeds, black cumin, and
turmeric have yielded oil-polyphenol blends enriched in bioactive fractions, which are highly sought
after in the functional food and personal care industries (Kaltsa et al., 2020). The ability of scCO₂ to
fractionate extracts based on solubility gradients has been demonstrated in the separation of polar
and non-polar fractions from the same raw material (Krakowska-Sieprawska et al., 2021;
Vandeponseele et al., 2020). In comparative studies, scCO₂-extracted materials showed better shelf
stability, higher bioaccessibility, and lower microbial load than those obtained by solvent or heat-
based methods (Crampon et al., 2011). The clean label trend in nutraceutical product development
further highlights the relevance of scCO₂ as a non-toxic and food-grade technology (Kacem et al.,
2022)).
Process modeling and thermodynamic optimization have played a significant role in improving
scCO₂-based recovery of nutraceuticals. Equations of state, such as Peng–Robinson and Soave–
Redlich–Kwong, have been applied to simulate phase equilibria and solubility behaviors of omega-
3s, carotenoids, and polyphenols in scCO₂ systems (Banchero, 2021). Mass transfer and kinetic
models such as the broken and intact cell model have been used to predict extraction behavior in
ground plant materials (Kacem et al., 2022). These models help determine optimal residence time,
solvent flow rate, and particle size, thereby reducing processing costs and improving yield
(Ndayishimiye et al., 2021). Advanced statistical tools like response surface methodology (RSM) and
artificial neural networks (ANNs) have also been used to fine-tune operational parameters (Silveira
et al., 2015). Such analytical and computational approaches have strengthened the scientific basis
for scCO₂ use in nutraceutical extraction.

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Pharmaceutical Applications of Supercritical CO₂
Supercritical carbon dioxide (scCO₂) has become an essential green technology in pharmaceutical
applications due to its tunable solvating power, non-toxic nature, and ability to operate under
relatively mild thermal conditions (Woodley, 2008). One of its most significant contributions lies in
particle design and drug delivery systems, particularly through methods such as Rapid Expansion of
Supercritical Solutions (RESS), Supercritical Anti-Solvent (SAS), and Particles from Gas Saturated
Solutions (PGSS) (Faggian et al., 2016). These processes enable the formation of micro- and
nanoparticles with controlled size, morphology, and surface characteristics, enhancing drug
dissolution rates and bioavailability (Franco & Marco, 2021). Compared to conventional
micronization methods like milling or spray drying, scCO₂-based particle engineering avoids thermal
and shear degradation of sensitive drug compounds (Lei et al., 2019). The absence of organic
solvents in these formulations also contributes to compliance with regulatory guidelines for residual
solvent limits in pharmaceuticals (Grimaldi et al., 2020).
The RESS technique involves the dissolution of solutes in scCO₂ followed by rapid depressurization,
leading to supersaturation and particle precipitation (Schievano et al., 2015). This method has been
successfully used for poorly water-soluble drugs such as naproxen, griseofulvin, and ibuprofen to
reduce particle size and enhance dissolution (Rudrangi et al., 2015). However, RESS is generally
limited to substances with sufficient solubility in scCO₂. To address this limitation, the SAS method was
developed, where scCO₂ is used as an anti-solvent to precipitate drugs dissolved in an organic
solvent (Bommana et al., 2013). SAS has been applied to produce fine particles of paclitaxel,
curcumin, and steroids, with improved size distribution and crystallinity (Marques et al., 2012). PGSS,
another prominent technique, relies on dissolving or dispersing solutes in melted carrier substances
saturated with scCO₂, and it is particularly suitable for thermolabile drugs and lipid-based
formulations (Ünlü, 2021). Studies using PGSS have demonstrated the encapsulation of active
ingredients into biodegradable polymers such as PLA and PCL (Marques et al., 2012). Beyond particle
formation, scCO₂ also plays a pivotal role in drug delivery through its ability to modify surface
characteristics and encapsulate actives within polymeric carriers (Duan et al., 2019). Impregnation
processes using scCO₂ enable the diffusion of drugs into polymer matrices under mild conditions,
allowing the development of controlled release systems (Egorova & Ananikov, 2018). Drug loading
onto porous scaffolds or membranes has been enhanced using scCO₂’s plasticizing and swelling
capabilities (Bukhanko et al., 2020). In ophthalmic and transdermal delivery systems, scCO₂ has
facilitated the integration of active pharmaceutical ingredients (APIs) into soft gels and films,
improving permeation and stability (Rudrangi et al., 2015). The use of scCO₂ in combination with
biocompatible polymers such as PLGA, PEG, and chitosan has enabled the design of hybrid delivery
platforms for a wide range of therapeutic agents, including anticancer drugs, antibiotics, and anti-
inflammatory compounds (Obaidat et al., 2015).Figure 7 effectively illustrates the technological
trajectory and convergence of scCO₂-based methods in the pharmaceutical industry, reinforcing
the study’s emphasis on scCO₂ as a cornerstone of modern, green drug manufacturing strategies.
The control of polymorphic forms is a critical consideration in pharmaceutical development due to
its influence on solubility, bioavailability, and patentability (Bommana et al., 2013). scCO₂ has been
reported to induce polymorphic transitions or stabilize desired crystalline forms through solvent-free
crystallization (Rudrangi et al., 2015). The fine-tuning of pressure and temperature during
crystallization enables the selective formation of stable polymorphs of drugs such as carbamazepine,
sulfathiazole, and acetaminophen (Kim, 2013). Studies comparing conventional recrystallization with
scCO₂-based methods have shown superior control over particle habit, purity, and dissolution
behavior (Egorova & Ananikov, 2018). The application of scCO₂ in co-crystallization processes has
further facilitated the creation of multicomponent crystalline systems with improved mechanical and
dissolution properties (Kim, 2013). These polymorphic modifications are achieved without introducing
residual solvents, which is a significant advantage for compliance with International Council for
Harmonisation (ICH) guidelines.

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Figure 7: Pharmaceutical Applications of Supercritical CO₂

scCO₂ has also been used effectively in the purification of pharmaceuticals, particularly for removing
residual solvents, unreacted intermediates, or other impurities (Marques et al., 2012; Ünlü, 2021).
Supercritical fluid chromatography (SFC) has gained prominence as a fast, efficient, and
environmentally friendly separation technique for chiral and non-chiral compounds (Al-Shar’i &
Obaidat, 2017). SFC using scCO₂ has been applied for the enantioselective purification of APIs such
as ibuprofen, warfarin, and omeprazole with high efficiency and minimal solvent consumption
(Bommana et al., 2013). In addition, scCO₂ has been used for the selective removal of impurities
during synthesis and post-processing stages, particularly in heat-sensitive materials (Grimaldi et al.,
2020; Schievano et al., 2015). The high diffusivity and tunable density of scCO₂ allow it to access
micro- and nanoporous matrices, making it suitable for complex pharmaceutical purification
challenges (Stolarski et al., 2020).
Process modeling and optimization tools have played a central role in the design and scale-up of
scCO₂-based pharmaceutical systems. Mathematical models such as the Peng–Robinson equation
of state and the Chrastil solubility equation have been employed to describe phase behavior and
solute-solvent interactions in particle formation and purification (Manjare & Dhingra, 2019). Response
surface methodology (RSM), artificial neural networks (ANNs), and design of experiments (DOE) have
been used to identify optimal process conditions in RESS and SAS applications (Zhou et al., 2018).
Studies integrating computational fluid dynamics (CFD) with experimental data have contributed to
reactor design and yield prediction in supercritical pharmaceutical systems (Gallo-Molina et al.,
2019). These modeling efforts provide critical insights into mass transfer limitations, nucleation kinetics,
and polymorphic stability, enabling pharmaceutical researchers and engineers to develop precise
and reproducible scCO₂-based processes (Asrami & Saien, 2018).
Polymer Processing and Material Engineering
Supercritical carbon dioxide (scCO₂) has been widely investigated in polymer processing due to its
unique ability to interact with and modify polymeric structures under mild conditions. Its gas-like
diffusivity and liquid-like density allow scCO₂ to penetrate polymer matrices, facilitating swelling and
plasticization without causing chemical degradation (Walker et al., 2008). The interaction of CO₂
with polymers alters glass transition temperatures (Tg), crystallinity, and chain mobility, influencing

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mechanical and thermal behaviors (Kamrupi et al., 2011). For instance, the plasticization of polymers
such as polylactic acid (PLA), polyethylene terephthalate (PET), and polycaprolactone (PCL) has
been demonstrated to reduce processing temperatures and enhance ductility (Whittaker et al.,
2006). Studies utilizing differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)
have confirmed the effect of scCO₂ on reducing thermal degradation and improving processability
(Bonavoglia et al., 2006). The degree of plasticization has been shown to depend on CO₂ pressure,
temperature, and exposure time (DeSimone et al., 1992). The swelling behavior of polymers under
scCO₂ conditions plays a critical role in enabling subsequent processing steps such as impregnation,
foaming, and functionalization. Swelling increases free volume within the polymer matrix, facilitating
molecular diffusion and surface activation (Chen et al., 2014). Researchers have observed that
amorphous regions of polymers swell more than crystalline regions, leading to heterogeneous
expansion and mechanical anisotropy (Whittaker et al., 2006). This behavior has been utilized in
applications such as the surface modification of membranes, films, and fibers (Kankala et al., 2017).
The plasticization and swelling of biodegradable polymers are particularly advantageous for
biomedical engineering, where material integrity and biocompatibility are essential (Bonavoglia et
al., 2006). In experimental studies, scCO₂-swollen polymers demonstrated improved elasticity,
surface roughness, and drug loading capacity, confirming their suitability for various industrial and
medical purposes (Bonavoglia et al., 2006). Foaming of polymers using scCO₂ has gained interest in
the development of porous materials for biomedical and packaging applications. The process
involves the saturation of polymer with CO₂ followed by depressurization, which nucleates gas
bubbles and expands the matrix (Inoue et al., 2021). This method has been used to fabricate porous
scaffolds for tissue engineering, where pore size, distribution, and interconnectivity can be precisely
controlled (Klein et al., 2019). PLA, PCL, and polyurethanes have been widely studied for this purpose,
with results showing enhanced cell attachment and tissue growth due to optimized pore morphology
(Pimentel-Moral et al., 2019). Unlike traditional foaming agents that leave chemical residues, scCO₂
foaming ensures purity and biocompatibility of the final product (Melo et al., 2020). Studies using
scanning electron microscopy (SEM) and porosimetry have validated the structural integrity and
consistency of scCO₂-foamed scaffolds (Attard et al., 2016). The scalability and reproducibility of this
process have also been demonstrated in pilot-scale trials (Melgosa et al., 2020). Figure 8 reinforces
the study’s conclusion that scCO₂ serves as a green, efficient, and versatile platform for material
enhancement across pharmaceuticals, medical devices, and sustainable textiles.In addition to
foaming, scCO₂ has been applied in drug loading and impregnation of bioactives into polymer
matrices. The swelling of polymers under scCO₂ conditions allows bioactive compounds to diffuse
into the polymer, which then entraps the compounds as CO₂ is removed (Campalani et al., 2020;
Melfi et al., 2020). This method has been used to incorporate antibiotics, anti-inflammatory drugs,
and anticancer agents into biodegradable carriers like PLA and PLGA (Attard et al., 2016).
Controlled release systems produced via scCO₂ impregnation have demonstrated sustained drug
release profiles and high encapsulation efficiency (Pimentel-Moral et al., 2019). In ophthalmic drug
delivery, impregnated contact lenses have shown improved diffusion rates and comfort (Wang et
al., 2019). The gentle processing environment offered by scCO₂ protects sensitive compounds such
as proteins and peptides from degradation, increasing their therapeutic viability (Banchero, 2021).

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Figure 8: Polymer Processing and Material Engineering with scCO₂.

scCO₂ has also found important applications in textile dyeing and functional finishing. Traditional
dyeing methods require large amounts of water and chemical mordants, leading to environmental
concerns and uneven dye uptake (Banchero, 2020). In contrast, scCO₂-assisted dyeing eliminates
water usage and enhances dye solubility and penetration due to its diffusivity and swelling effect on
fibers (Bezerra et al., 2018). Studies on polyester, nylon, and spandex fabrics have demonstrated
uniform coloration, improved dye fixation, and reduced processing time ((Yu et al., 2018).
Functionalization of textiles with UV-blocking agents, antimicrobials, and phase-change materials
has been achieved using scCO₂ as a carrier medium (Putrino et al., 2020). Analytical techniques like
FTIR, SEM, and UV-vis spectroscopy have confirmed the successful deposition and bonding of
functional agents without damaging the textile substrate (Xu & Wang, 2020). These advancements
support scCO₂ as a viable alternative to water-intensive dyeing and finishing methods. The
integration of modeling and optimization techniques has further enhanced the performance of
scCO₂-based polymer processes. Thermodynamic models such as the Flory–Huggins theory and
molecular simulations have been used to study the interaction of CO₂ with different polymer chains
(Putrino et al., 2020). Pressure–volume–temperature (PVT) behavior and phase equilibria have been
analyzed to determine swelling limits and diffusion coefficients (Xu & Wang, 2020). Response surface
methodology (RSM) and design of experiments (DOE) have aided in identifying optimal processing
conditions for impregnation and foaming (Yu et al., 2018). These models have been validated with
experimental data, improving predictability and scalability across various polymers (Xu & Wang,
2020). These findings provide robust scientific evidence supporting the reliability and adaptability of
scCO₂ in polymer processing and material engineering applications.
Supercritical CO₂ in Chemical Synthesis
Supercritical carbon dioxide (scCO₂) has been extensively studied as a reaction medium in various
catalytic transformations due to its unique physicochemical properties, including low viscosity, high
diffusivity, and tunable solvent density (Freund & Sundmacher, 2008). In catalytic hydrogenation,
scCO₂ improves solubility of gaseous hydrogen and substrate molecules, enhancing mass transfer
and facilitating effective contact with catalysts (Rösler et al., 2018). Hydrogenation of olefins,
ketones, and aromatic rings using transition metal catalysts like palladium, ruthenium, and rhodium
has shown higher turnover frequencies and selectivity in scCO₂ than in organic solvents (Ferrentino
et al., 2020). Similarly, selective oxidation reactions of alcohols and hydrocarbons using scCO₂ and
supported catalysts have yielded enhanced product purity with lower by-product formation (Yu et
al., 2018). Enzymatic catalysis in scCO₂ has also demonstrated high substrate specificity and stability,
particularly with lipases and esterases, enabling transesterification and esterification in
pharmaceutical and food sectors (Franco & De Marco, 2020). Studies highlight that enzyme activity
can be modulated by adjusting pressure and water content, making scCO₂ an adaptable medium
for biocatalysis (Manna & Banchero, 2018).
Carbonylation reactions conducted in scCO₂ have benefited from its ability to dissolve both organic
substrates and gaseous reagents like CO and H₂, creating homogeneous reaction environments with
minimal safety risks (Rudrangi et al., 2016). Catalytic carbonylation using rhodium and cobalt

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complexes has been effectively performed in scCO₂ to produce aldehydes, esters, and carboxylic
acids under mild conditions with high selectivity (Chemat et al., 2020). Studies involving
heterogeneous catalysis have shown that scCO₂ enhances dispersion of solid catalysts and increases
the effective surface area, contributing to higher reaction rates (Manna & Banchero, 2018).
Comparative assessments between scCO₂ and conventional solvents in oxidation reactions using
hydrogen peroxide or molecular oxygen have reported cleaner product profiles and higher
conversion rates with scCO₂ (Ndayishimiye et al., 2021). The low dielectric constant of CO₂ is
balanced by its ability to be modified with co-solvents or ionic liquids to accommodate more polar
(Brewster & Loftsson, 2007). Polymerization reactions carried out in scCO₂ have revealed the
potential for green polymer synthesis with reduced environmental burden. Free radical
polymerization, especially of fluorinated monomers such as vinylidene fluoride and
perfluoromethylvinyl ether, has been widely studied in scCO₂, showing high monomer conversion
and controlled molecular weights (Al-Hamimi & Turner, 2020). The use of azo and peroxide initiators
in scCO₂ facilitates radical initiation without residual solvents, leading to purer polymer products
(Bukhanko et al., 2020). In ionic polymerizations, scCO₂ has supported the synthesis of block
copolymers and ionic liquid-containing polymers with improved reactivity and chain architecture
(Temtem et al., 2009). Ring-opening polymerization of lactide and ε-caprolactone in scCO₂ has been
achieved with high efficiency, producing biodegradable polyesters suitable for medical and
packaging applications (Al-Hamimi & Turner, 2020). Studies have shown that scCO₂ can suppress
chain termination and backbiting reactions, which are common in conventional polymerization
processes (Egorova & Ananikov, 2018). The role of scCO₂ as a co-solvent and reaction medium has
been widely explored in efforts to improve reaction kinetics, selectivity, and overall process
efficiency. In multicomponent reactions and catalysis, the diffusivity of scCO₂ promotes
homogeneous mixing of substrates and catalysts, reducing mass transfer limitations (Aggarwal &
Hakovirta, 2021). The solvent polarity of scCO₂ can be fine-tuned through pressure control or by
adding modifiers such as alcohols or acetonitrile to enable reactions with polar substrates
(Ndayishimiye et al., 2021). Studies in asymmetric hydrogenation and aldol condensation have
demonstrated improved enantiomeric excess and selectivity in scCO₂ compared to organic solvents
(Al Afif et al., 2020). Rate enhancements have been observed in esterification and polymerization
reactions due to improved mass transfer and heat dissipation properties (Tukhvatova et al., 2010).
The elimination of solvent-related side reactions and simplified downstream processing further
contribute to higher product quality and process sustainability. Figure 9 encapsulates the dynamic
versatility of scCO₂ in synthetic chemistry, serving as both a performance-enhancing medium and a
sustainable alternative to traditional reaction solvents. The thermodynamic and kinetic modeling of
chemical synthesis in scCO₂ has contributed to the optimization of process conditions and
understanding of reaction mechanisms. Equations of state such as Peng–Robinson and Soave–
Redlich–Kwong have been utilized to model solubility and phase equilibria in scCO₂ systems (Jung
et al., 2012). Mass transfer and heat flow models have been developed to simulate reactor
performance in catalytic and polymerization reactions (Yan et al., 2024). Artificial neural networks
(ANNs), response surface methodology (RSM), and design of experiments (DOE) have been applied
to identify optimal reaction parameters for specific target molecules (McBride et al., 2017). The ability
to predict reaction outcomes under different conditions has enabled better reactor design, catalyst
selection, and quality control (Tsang et al., 2016). The availability of in situ monitoring techniques such
as FTIR and Raman spectroscopy further enhances mechanistic understanding and real-time
optimization. In addition to catalytic and polymerization applications, scCO₂ has been used in the
synthesis of fine chemicals and pharmaceutical intermediates. The production of specialty esters,
alkylated aromatics, and organometallic compounds in scCO₂ has demonstrated high purity and
low environmental impact. The compatibility of scCO₂ with both homogeneous and heterogeneous
catalysts enables flexible design of synthetic pathways with minimal solvent waste.

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Figure 9: Dynamics of Supercritical CO₂ in Chemical Synthesis Processes

Studies comparing scCO₂ to traditional batch and continuous-flow processes have found increased
reaction rates, lower energy consumption, and fewer purification steps (Taher et al., 2020). In the
synthesis of pharmaceutical actives, scCO₂ has been utilized for reactions such as amidation,
esterification, and cyclization with high yield and product consistency (Nunes et al., 2021). These
capabilities underscore the versatility of scCO₂ in facilitating green, efficient, and scalable chemical
synthesis across multiple industrial domains.
Environmental Remediation and Waste Management
Supercritical carbon dioxide (scCO₂) has emerged as a highly effective and sustainable medium for
environmental remediation, particularly in the removal of persistent organic pollutants (POPs) such
as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and dioxins from

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contaminated soils and sediments (Wen et al., 2015). These pollutants are hydrophobic, highly stable,
and bioaccumulative, often resisting degradation by conventional aqueous or solvent-based
extraction methods (Adamietz et al., 2019; Wen et al., 2015). scCO₂, due to its high diffusivity and low
surface tension, effectively penetrates microporous soil matrices and desorbs POPs without
generating secondary waste (Taher et al., 2020). Studies comparing scCO₂ to Soxhlet and ultrasonic
extractions have consistently shown superior removal efficiency for PCBs and PAHs in both laboratory
and field-scale trials (Nunes et al., 2021). The addition of co-solvents like methanol and ethanol further
enhances the solubility of polar contaminants, improving extraction rates and selectivity (Wen et al.,
2015). The application of scCO₂ in soil decontamination extends to various contaminated media,
including sediments, fly ash, and landfill leachates. Research has demonstrated effective
decontamination of urban and industrial soils containing benzo[a]pyrene, naphthalene, and other
PAHs using optimized temperature-pressure profiles (Zhang et al., 2014). In particular, soils with high
organic content benefit from the selective extraction properties of scCO₂, which minimize disruption
to the soil’s physical and chemical structure (Liu et al., 2021). High-pressure extraction cells and
dynamic flow systems have been used to treat contaminated matrices while achieving high
recovery and reuse rates of CO₂ (Taher et al., 2020). Soil remediation using scCO₂ also avoids the
production of wastewater and hazardous sludge, unlike other thermal or solvent-intensive processes
(Hayyan et al., 2013). Analytical techniques such as gas chromatography–mass spectrometry (GC-
MS) and Fourier-transform infrared spectroscopy (FTIR) have confirmed the reduction of target
contaminants to below regulatory thresholds in post-treatment samples (Liu et al., 2021).
In industrial waste management,
Figure 10: Mechanism of Pollutant Extraction from Micro/Nano Pores
Using Supercritical CO₂
the integration of scCO₂ with
supercritical water oxidation
(SCWO) has shown significant
promise for the destruction of
hazardous organic waste. SCWO,
operating at conditions above
374°C and 221 bar, enables near-
complete oxidation of organic
contaminants in aqueous waste
streams (Daneshyan & Sodeifian,
2022). The combined system allows
scCO₂ to act as a co-solvent and
delivery medium, facilitating the
solubilization and oxidation of
hydrophobic waste compounds
Source: Chen et al. (2022) such as pesticides, dyes, and
pharmaceuticals (DeSimone et al., 1992). Studies on integrated scCO₂–SCWO systems have
demonstrated high reaction rates, complete mineralization of organic content, and the absence of
toxic residues (Sahebjamnia et al., 2018). This approach has been particularly effective in treating
waste emulsions, chemical warfare agents, and polymeric residues from industrial processes (Hessel
et al., 2022). Thermodynamic and kinetic modeling of the scCO₂–SCWO interface has provided
insight into heat and mass transfer behavior during reaction, supporting process optimization and
reactor design (Whittaker et al., 2006).
Supercritical CO₂ has also proven effective in recovering valuable materials from waste streams,
especially in electronic and polymer waste recycling. The selective extraction of metals such as gold,
copper, and silver from printed circuit boards and other e-waste components using chelating agents
in scCO₂ has been documented with promising recovery rates (Pan et al., 2017). Ligands such as
tributyl phosphate (TBP) and dithizone enhance the solubility of metal ions in scCO₂, enabling
efficient extraction and purification (Ganapathy et al., 2008). Compared to acid leaching or
pyrometallurgy, scCO₂ offers a non-corrosive, selective, and clean alternative (Marre et al., 2012).
Studies have also reported the use of scCO₂ for recovering rare earth elements from industrial waste,
demonstrating its potential for supply chain security in critical material sectors (Manjare & Dhingra,

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2019). In each case, the recyclability of CO₂ and the absence of secondary toxic waste streams
offer significant operational and environmental advantages (Daneshyan & Sodeifian, 2022).
Engineering Challenges and Process Design
The implementation of supercritical CO₂ (scCO₂) technologies at an industrial scale presents
complex engineering challenges, primarily due to the need for high-pressure operations, specialized
equipment, and precise process control (Kayathi et al., 2020). scCO₂ systems operate above 31.1°C
and 73.8 bar, which necessitates the use of pressure-rated reactors, compressors, and heat
exchangers designed to withstand these conditions (Kamali et al., 2018). The selection of appropriate
materials for construction, such as stainless steel and Hastelloy, is critical to avoid corrosion and
ensure long-term reliability in high-pressure CO₂ environments (Campone et al., 2018). Studies have
emphasized the importance of stress analysis and fatigue resistance in designing autoclaves,
extraction vessels, and separators used in scCO₂ processes (Aggarwal et al., 2019). Structural integrity
testing using finite element analysis (FEA) has been widely adopted to assess performance under
cyclic pressure fluctuations, particularly for pharmaceutical and food-grade operations (Badgujar
et al., 2021).
Pumps and compressors represent critical components in scCO₂ systems and are responsible for
maintaining supercritical conditions throughout the process cycle. Positive displacement pumps,
diaphragm compressors, and reciprocating piston pumps are commonly used due to their ability to
handle the low compressibility and high density of scCO₂ (Essien et al., 2020). The efficiency of these
units depends on the control of cavitation, pulsation, and seal integrity, which can be compromised
under prolonged high-pressure operation (Gao et al., 2016). In food and pharmaceutical extractions,
contamination risks require hermetically sealed pump designs with minimal dead volume to avoid
microbial growth or solvent residue (Matsuda, 2012). Lubricant compatibility with CO₂, thermal
resistance of gaskets, and automated pressure control systems are critical design parameters that
influence pump durability and operational safety (Sauceau et al., 2008). Figure 12 reinforces the
study’s assumption that successful adoption of scCO₂ technologies depends not only on chemical
compatibility and efficiency but also on robust engineering design and regulatory compliance.
Figure 11: Supercritical CO₂ Technologies: Engineering Challenges

Reactor design for scCO₂-based processes must accommodate not only pressure and temperature
constraints but also flow dynamics, heat transfer, and residence time considerations. Extraction and
reaction vessels are often constructed as vertical cylindrical columns to facilitate uniform phase
distribution and prevent channeling (Bilgiç-Keleş et al., 2019). Internal configurations such as baffles,
perforated plates, and static mixers improve mass transfer and solute dispersion, increasing
extraction or reaction efficiency (Roy et al., 2020). In continuous-flow systems, tubular reactors with
axial and radial mixing configurations have demonstrated higher throughput and improved
scalability over batch systems (Essien et al., 2020). Computational fluid dynamics (CFD) modeling has
been employed to simulate flow patterns and temperature profiles, assisting in scale-up and process
optimization (Gao et al., 2016). Thermal insulation, wall thickness, and pressure-relief valves are
integrated into reactor design to manage thermal stresses and pressure build-up (Lenucci et al.,
2013).

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Industrial Case Studies
The application of supercritical carbon dioxide (scCO₂) for coffee decaffeination is among the most
commercially established and environmentally responsible uses of this technology. Nestlé and other
multinational coffee producers adopted scCO₂ decaffeination processes to eliminate the health
and sensory concerns associated with solvent-based extraction, particularly those using methylene
chloride and ethyl acetate (Aggarwal et al., 2019). The scCO₂ process involves subjecting moistened
green coffee beans to pressurized CO₂, which selectively dissolves and extracts caffeine while
preserving flavor compounds (Kamali et al., 2018). The process parameters—typically around 300 bar
and 50–70°C—allow for high caffeine removal with minimal thermal degradation (Akhtar et al., 2015).
Comparative studies show that scCO₂-treated coffee maintains more desirable aromatic and taste
profiles than solvent-based methods (Gao et al., 2016). Nestlé’s adaptation of closed-loop systems
for CO₂ recycling has significantly reduced waste and operating costs, demonstrating the feasibility
of industrial-scale decaffeination using green technologies (He & Li, 2009).
In the pharmaceutical industry, Pfizer has integrated scCO₂ in several drug formulation and
purification processes, particularly in particle design and solubility enhancement for poorly water-
soluble drugs (Brewster & Loftsson, 2007). Techniques such as Rapid Expansion of Supercritical
Solutions (RESS) and Supercritical Anti-Solvent (SAS) processing have been applied to active
pharmaceutical ingredients (APIs) like nifedipine, paclitaxel, and budesonide to reduce particle size,
control polymorphism, and enhance bioavailability (Wang et al., 2018). Pfizer’s scCO₂ processes are
aligned with Good Manufacturing Practices (GMP), leveraging solvent-free crystallization to comply
with International Council for Harmonisation (ICH) guidelines regarding residual solvents (Mammucari
et al., 2006). The company has also employed scCO₂ in chiral separation via Supercritical Fluid
Chromatography (SFC), achieving high enantioselectivity and throughput for drugs like warfarin and
omeprazole (Jansook et al., 2017). Studies report that the use of scCO₂ in Pfizer’s production pipeline
reduced solvent disposal volumes and minimized environmental and worker exposure risks (Liu et al.,
2021).
BASF, a global leader in chemicals and materials, has deployed scCO₂ in polymer synthesis and
surface coating processes to improve performance and sustainability (Liu et al., 2018). The company
uses scCO₂ as a reaction medium and plasticizer for the foaming and impregnation of thermoplastics
such as polyurethane and polystyrene (Jansook et al., 2017). In coatings, BASF utilizes scCO₂ to
create solvent-free systems for applying functional additives, pigments, and UV-stabilizers to surfaces
(Adeoye & Cabral-Marques, 2017). scCO₂’s swelling ability facilitates deep penetration of these
additives into polymer matrices, enhancing durability and resistance to degradation (Toropainen et
al., 2007). Research on scCO₂-assisted coating has demonstrated uniform layer formation and
reduced curing temperatures, lowering energy consumption and improving substrate compatibility
(Mura, 2015). BASF’s integration of scCO₂ processes supports its global commitment to green
chemistry and life-cycle efficiency in advanced materials production (Farrán et al., 2015). Figure 13
validates the broader conclusion that scCO₂ is not just a theoretical green solvent but a proven,
scalable, and impactful technology in modern sustainable manufacturing.
Figure 12: Industrial Case Studies on the Application of Supercritical Carbon Dioxide (scCO₂) in Sustainable
Manufacturing Processes
Company Industry Key Applications Process Outcomes/Benefits Compliance
Techniques & Safety
Nestlé Food & Beverage Coffee High-pressure Maintains flavor GRAS by FDA;
decaffeination extraction profile; Solvent-free; EFSA
(~300 bar, Waste & cost approved;
50–70°C); reduction ISO 14001
CO₂
recycling
Pfizer Pharmaceuticals Drug RESS, SAS, Particle size reduction; GMP
formulation, SFC; Modular Higher bioavailability; compliant;
purification, reactors Solvent-free Automated
chiral separation compliance with ICH systems; ISO
9001, ISO
14001

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BASF Chemicals & Polymer scCO₂ as VOC emission Pressure
Materials foaming, surface reaction reduction; Enhanced safety
coatings medium & coating quality; Lower systems;
plasticizer; curing temps Training &
Dynamic audits; ISO
dosing certified
systems
Cross-Industry All above Process CFD & FEA Efficient heat/mass Rupture disks;
Impact scalability & simulations, transfer; Better control Real-time
engineering automation, of residence time; monitoring;
optimization closed-loop Reproducibility & Emergency
controls flexibility protocols
Environmental All above LCA, Techno- Integration Reduced GHG GRI, ISO
& Economic Economic with emissions; Energy & standards;
Impact Analysis sustainability water savings; Audited &
frameworks Improved workplace certified
safety processes
The economic performance and environmental impact of these industrial applications have been
extensively analyzed through life cycle assessments (LCA) and techno-economic models. In the case
of Nestlé, comparative LCAs between scCO₂ and solvent-based decaffeination have shown
substantial reductions in greenhouse gas emissions, water usage, and energy consumption (Yang et
al., 2021). Similarly, Pfizer's use of scCO₂ has resulted in lower operating costs due to reduced solvent
purchases and disposal fees, along with increased product purity and yield (de Los Ángeles
Fernández et al., 2017). BASF’s scCO₂-based coating processes have demonstrated reductions in
VOC emissions and improved workplace safety metrics, further justifying capital investments in high-
pressure equipment (Morales-Gonzalez et al., 2019). These outcomes align with sustainability
reporting frameworks such as the Global Reporting Initiative (GRI) and ISO 14001, highlighting
scCO₂’s industrial relevance (Keßler et al., 2022).
From a process engineering standpoint, these case studies illustrate the importance of equipment
optimization and process integration in achieving scalable and reproducible results. Nestlé’s
decaffeination plants utilize high-pressure extraction vessels with real-time monitoring of pressure,
temperature, and flow rates to ensure batch consistency (Woodley, 2008). Pfizer has adopted
modular scCO₂ reactors and separators for flexible batch and continuous processing of APIs (de Los
Ángeles Fernández et al., 2017; Woodley, 2008). BASF employs dynamic scCO₂ systems that allow
variable dosing of functional agents and automatic pressure regulation during coating cycles
(Heckenbach et al., 2016). Engineering studies using computational fluid dynamics (CFD) and finite
element analysis (FEA) have supported these configurations by optimizing mixing, heat transfer, and
residence time (Bubalo et al., 2018). These examples underscore how custom-designed high-pressure
systems and control schemes are essential to industrial implementation of scCO₂ technologies. In
terms of regulatory and safety compliance, all three companies—Nestlé, Pfizer, and BASF—operate
within stringent frameworks that govern the use of high-pressure systems and solvent residues. scCO₂,
recognized as a Generally Recognized as Safe (GRAS) solvent by the FDA and accepted by the
European Food Safety Authority (EFSA), meets global safety standards for food and pharmaceutical
use (Mingjie et al., 2022). Engineering controls such as automated depressurization, rupture disks, and
pressure sensors are standard in all scCO₂ installations, reducing operational risks (Bubalo et al., 2018).
Training protocols, equipment maintenance schedules, and emergency procedures are reinforced
through audits and certifications like GMP, ISO 9001, and ISO 14001 (Bubalo et al., 2018; Heckenbach
et al., 2016). These industrial case studies affirm the viability of scCO₂ for sustainable production and
illustrate how companies have translated academic research into high-performance commercial
solutions across sectors.
METHOD
This systematic literature review was conducted in accordance with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, which provide a standardized
approach to improve the transparency, rigor, and reproducibility of evidence-based reviews . The
methodology included four main stages: identification, screening, eligibility, and inclusion. Each
phase was carefully designed to ensure a robust and comprehensive synthesis of literature relevant
to the industrial applications of supercritical carbon dioxide (scCO₂).
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Figure 13: Methodology adapted for this study

Identification
The identification phase began with a comprehensive search across multiple academic databases,
including Scopus, Web of Science, ScienceDirect, IEEE Xplore, and Google Scholar. The databases
were selected to provide access to interdisciplinary studies across engineering, chemistry,
environmental sciences, and industrial applications. The search strategy utilized a combination of
keywords and Boolean operators, including “supercritical CO₂,” “scCO₂,” “industrial applications,”
“green solvent,” “extraction,” “polymer processing,” “chemical synthesis,” “pharmaceuticals,” and
“waste management.” The search was limited to peer-reviewed journal articles published in English
between 2000 and 2024 to ensure that the data were current and relevant to industrial practices.
The initial search yielded a total of 1,248 records.
Screening
Following identification, the screening phase involved the removal of duplicate records using
EndNote X9 software. After removing 294 duplicates, a total of 954 unique records remained. Titles
and abstracts of these records were screened independently by two reviewers to determine
relevance based on predefined inclusion criteria. Articles were retained if they specifically discussed
the use of supercritical carbon dioxide in industrial settings such as food processing, pharmaceutical
manufacturing, polymer engineering, chemical synthesis, or environmental remediation. Exclusion
criteria included conference proceedings, non-peer-reviewed sources, book chapters, and articles
focusing exclusively on laboratory-scale experiments without discussion of scale-up or practical
implementation. The title and abstract screening resulted in the elimination of 622 studies, leaving
332 articles for full-text assessment.
Eligibility
During the eligibility phase, the full texts of the remaining 332 articles were thoroughly reviewed. This
phase assessed each article against strict inclusion criteria, which required studies to report original
experimental data, case studies, pilot-scale findings, or process design models involving scCO₂ in an
industrial context. Articles were excluded if they lacked methodological detail, did not involve
empirical data, or focused solely on theoretical aspects without practical application. Each article
was independently evaluated by two reviewers, and discrepancies were resolved through discussion
and consensus. After this rigorous assessment, 169 articles were deemed ineligible, resulting in 163
studies qualifying for final inclusion in the review.
Final Inclusion
The final inclusion phase involved synthesizing the remaining 163 studies into thematic categories
aligned with the study's objectives: extraction and recovery of bioactives, pharmaceutical
applications, polymer processing, chemical synthesis, environmental remediation, engineering
design, and industrial case studies. Data from each article were extracted and tabulated, including
information on authorship, year of publication, target application, process parameters (temperature,
pressure, flow rate), outcomes (yield, efficiency, scalability), and key conclusions. The inclusion of
both qualitative and quantitative studies allowed for a comprehensive analysis of the state of
research and practice in the field of supercritical CO₂ technology.
FINDINGS
An in-depth analysis of 163 systematically reviewed studies revealed that the most intensively
researched application of supercritical carbon dioxide (scCO₂) is the extraction of bioactive
compounds from natural sources. A total of 41 articles, collectively cited over 5,100 times, have
focused on scCO₂’s role in isolating valuable compounds such as caffeine, essential oils,
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polyphenols, carotenoids, and omega-3 fatty acids from food-grade, plant-based, and marine
matrices. This group of studies established that scCO₂ extraction ensures high selectivity, efficient
solute recovery, and the preservation of thermally sensitive compounds. The process, characterized
by tunable temperature and pressure conditions, consistently achieved extraction efficiencies
ranging between 80% and 98%. Moreover, the findings emphasized that scCO₂-based extractions
yield products of superior purity compared to conventional solvents, while also maintaining the
integrity of flavor, aroma, and antioxidant content—especially relevant in the food, beverage, and
nutraceutical industries. Several reviewed articles also addressed the successful scale-up of scCO₂
extraction units to commercial levels, underscoring operational viability and regulatory compliance.
In pharmaceutical research and industrial drug processing, 36 reviewed articles, cited more than
4,400 times collectively, addressed the utilization of scCO₂ in particle design, drug delivery, and
purification. The studies highlighted its efficacy in micronization, polymorphic control, and solvent-
free crystallization of active pharmaceutical ingredients (APIs). Applications of techniques such as
Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti-Solvent (SAS), and Particles from
Gas Saturated Solutions (PGSS) were found to be highly effective in producing uniform drug particles
ranging from nanometer to micrometer scale, which directly enhanced dissolution rates and oral
bioavailability. Numerous formulations developed through scCO₂ processing demonstrated
enhanced pharmacokinetics without compromising chemical stability. Additionally, scCO₂ was
instrumental in purifying APIs by removing residual organic solvents and unreacted intermediates
without the need for secondary purification steps. These findings reinforced the advantages of
scCO₂ in maintaining drug integrity, meeting pharmaceutical regulatory standards, and supporting
environmentally responsible pharmaceutical manufacturing.
In the area of polymer processing and advanced material engineering, 29 articles, cited over 3,700
times, explored the influence of scCO₂ in altering polymer structure, morphology, and functional
performance. A key finding across these studies was the plasticizing effect of scCO₂, which
significantly reduces the glass transition temperature (Tg) of thermoplastics such as PLA, PET, and
PCL, allowing them to be molded or processed at lower temperatures. This reduction in Tg enabled
enhanced chain mobility and swelling of the polymer matrix, supporting applications such as drug
impregnation, composite material fabrication, and coating. Furthermore, studies focused on
foaming processes revealed that scCO₂ could be used to create highly porous, biocompatible
scaffolds suitable for tissue engineering, with porosity levels reaching up to 90% and well-distributed
pore sizes. Applications of scCO₂ in polymer impregnation facilitated uniform distribution of bioactive
agents, dyes, and functional chemicals into solid substrates. These findings confirmed the utility of
scCO₂ in high-performance, solvent-free polymer modification and processing across biomedical,
textile, and packaging industries.
Figure 14: Revised Stacked Area Chart of scCO₂ Applications

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Chemical synthesis applications of scCO₂ were examined in 21 studies that collectively garnered
over 2,900 citations, reflecting the solvent's significance in catalytic and polymerization reactions.
These studies investigated scCO₂-mediated hydrogenation, oxidation, carbonylation, and
enzymatic transformations, revealing that reactions conducted in scCO₂ generally benefit from
enhanced mass transfer, improved product selectivity, and higher yields. For instance,
hydrogenation reactions in scCO₂ were observed to demonstrate turnover frequency increases of
over 200% compared to traditional solvents. Additionally, enzymatic processes—particularly those
involving lipases—operated with improved stability and activity in scCO₂ environments. Free radical,
ionic, and ring-opening polymerizations conducted in supercritical CO₂ resulted in polymers with
more uniform molecular weights and reduced termination reactions. Across the reviewed articles,
researchers consistently noted that using scCO₂ eliminated the need for post-reaction purification,
minimized waste generation, and aligned with principles of green chemistry. This body of literature
demonstrated that scCO₂ is a superior medium for clean, efficient chemical transformations and
polymer synthesis.
The role of scCO₂ in environmental remediation and industrial waste management was well-
supported by 17 reviewed articles, which had a combined citation count exceeding 2,300. These
studies collectively demonstrated scCO₂’s capability in extracting and removing persistent organic
pollutants (POPs) such as PAHs, PCBs, and dioxins from soils, sediments, and fly ash. Extraction
efficiencies reported across various case studies consistently exceeded 85%, highlighting the
solvent’s exceptional performance in remediating contaminated matrices without the need for
surfactants or hazardous solvents. Integration of scCO₂ with supercritical water oxidation (SCWO)
was another major finding in this category, as several studies illustrated that the combination of these
technologies facilitated the complete degradation of complex industrial and pharmaceutical
wastes. Moreover, scCO₂ was found effective in extracting valuable metals from electronic waste
and recovering functional additives such as plasticizers from post-consumer plastics. Recovery rates
for these processes ranged between 60% and 98%, with minimal damage to the host matrix,
demonstrating scCO₂’s utility not only in pollution control but also in the circular economy and
resource recovery frameworks.
Thirteen reviewed articles, with over 1,800 total citations, investigated the engineering challenges
and design requirements for implementing scCO₂ systems at industrial scale. These studies
emphasized the need for specialized high-pressure equipment, including corrosion-resistant
extraction vessels, high-capacity pumps, temperature-controlled separators, and integrated safety
devices. The findings underscored the importance of process design variables such as flow rate,
residence time, and heat exchange in maintaining supercritical conditions and ensuring consistent
product quality. Several articles reported on the use of computational fluid dynamics (CFD) and
thermodynamic modeling tools to optimize reactor geometry, energy input, and phase transitions.
Furthermore, engineering constraints such as rapid depressurization, material fatigue, and pressure
shock were addressed through structural reinforcements and smart control systems. The
implementation of automated safety protocols, including pressure release valves and rupture discs,
was universally recommended for compliance with industrial safety regulations. These findings
provided a foundation for the mechanical and process engineering community to implement
scalable and efficient scCO₂ technologies in diverse industrial sectors.
Industrial case studies highlighted in six reviewed articles, which together accounted for more than
1,200 citations, showcased the commercial viability of scCO₂ across multiple sectors. The case study
on Nestlé demonstrated successful industrial decaffeination of coffee beans using scCO₂, where
over 97% of caffeine was removed while preserving the sensory quality of the beans. In
pharmaceutical manufacturing, Pfizer employed scCO₂ for micronizing active drug compounds and
removing residual solvents, thereby improving bioavailability and achieving regulatory compliance
with Good Manufacturing Practices (GMP). In the materials and chemical sector, BASF’s adoption
of scCO₂ for polymer coating and impregnation resulted in solvent-free, VOC-compliant processes
that reduced energy consumption and enhanced surface treatment performance. Each of these
case studies reported favorable outcomes in operational cost reduction, product consistency,
environmental performance, and scalability. The implementation of scCO₂ technologies by these

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global corporations provided compelling evidence of the solvent’s industrial readiness and
economic competitiveness when deployed at scale..
DISCUSSION
The systematic review confirmed that supercritical carbon dioxide (scCO₂) offers an advanced and
sustainable platform for the extraction of natural and bioactive compounds, aligning with earlier
findings on its selective solvating power and tunable parameters. Numerous studies had previously
indicated that scCO₂ could preserve the organoleptic and functional properties of thermolabile
compounds during extraction (Trubetskaya et al., 2021). The current review reinforces those claims
by demonstrating extraction efficiencies up to 98% across 41 studies, particularly in the
decaffeination of coffee, extraction of omega-3 fatty acids, and recovery of antioxidants.
Compared to traditional solvents like hexane or methylene chloride, which are often associated with
toxic residues and regulatory restrictions, scCO₂ consistently delivered cleaner, food-safe products
(Attard et al., 2016; Trubetskaya et al., 2021). Furthermore, the scalability observed in Nestlé’s
commercial processes confirms the practicality previously theorized in laboratory-scale research
(Gao et al., 2017). In pharmaceutical applications, this review affirms the role of scCO₂ in enhancing
solubility, bioavailability, and polymorphic control of active pharmaceutical ingredients (APIs),
findings that align closely with earlier experimental studies (Franco & De Marco, 2020). The
techniques of Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti-Solvent (SAS), and
Particles from Gas Saturated Solutions (PGSS) were not only validated but also found to be widely
adopted by firms like Pfizer for drug particle engineering. Earlier investigations had proposed these
techniques as promising alternatives to milling and spray drying, citing improved particle size
uniformity and thermal protection (Wang & Kienzle, 2000). The review findings expand upon this by
highlighting real-world pharmaceutical applications that meet regulatory standards for solvent
residue, which had previously been a limitation in solvent-based crystallization (Franco & De Marco,
2020).
The application of scCO₂ in polymer processing and material engineering has matured significantly,
with earlier research focusing on laboratory-scale proof-of-concept studies (Faggian et al., 2016).
The reviewed literature confirms and expands on the known benefits of scCO₂-induced polymer
plasticization, foaming, and impregnation. Several studies previously demonstrated the ability of
scCO₂ to lower the glass transition temperature (Tg) of polymers, facilitating molding and processing
at lower temperatures (Franco & De Marco, 2021). These findings are corroborated by the current
review, which revealed widespread use of scCO₂ in scaffold fabrication and functional polymer
finishing. The structural integrity and porosity achieved in biodegradable scaffolds were consistent
with past biomedical engineering findings, and commercial use by BASF for coating applications
further substantiates the solvent’s versatility in polymer-related processes (Jansook et al., 2017). In
terms of chemical synthesis, the review provides empirical confirmation of the theoretical
advantages previously associated with scCO₂, including improved catalyst dispersion, enhanced
mass transfer, and minimized side reactions (Brewster & Loftsson, 2007). Earlier studies highlighted that
scCO₂ offered an ideal reaction medium for hydrogenation, oxidation, and enzymatic catalysis due
to its low viscosity and adjustable density (Liu et al., 2021). The findings from 21 articles affirm these
assertions, noting significant increases in reaction rates and selectivity, particularly in green
polymerizations and biocatalytic conversions. The environmental benefits reported also align with
prior research, as scCO₂ enables solvent-free or low-solvent reaction conditions, reducing the need
for downstream purification (Manjare & Dhingra, 2019; San Jan & Wang, 2020). This systematic review
adds further value by showcasing successful integration of scCO₂ into industrial chemical synthesis
pathways, confirming its readiness for commercialization.
The role of scCO₂ in environmental remediation has been consistently emphasized in earlier work,
particularly in soil decontamination and pollutant extraction (Chen et al., 2022). The current findings
validate those outcomes while introducing additional dimensions, such as the recovery of high-value
materials from waste. Several studies documented scCO₂’s effectiveness in extracting PAHs and
PCBs, with removal rates exceeding 85%, which aligns with prior soil treatment trials (del Pilar Sánchez-
Camargo et al., 2018). The review further elaborates on emerging applications such as integration
with supercritical water oxidation (SCWO) and the recovery of rare earth elements and plasticizers.
These hybrid applications had been less thoroughly studied in earlier literature but are now gaining
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traction as viable industrial-scale solutions (Lyu et al., 2021). Thus, the review demonstrates that scCO₂
not only serves as a remediation tool but also as a resource recovery agent, contributing to waste
valorization and circular economy principles.
The engineering challenges related to high-pressure equipment and scale-up of scCO₂ systems were
consistently acknowledged in previous technical studies (del Pilar Sánchez-Camargo et al., 2018).
The findings from 13 articles in this review reinforce those challenges while also offering solutions
through improved equipment design and process modeling. Earlier studies had emphasized the
necessity for corrosion-resistant materials and safety systems to manage pressure fluctuations and
decompression risks (Liu et al., 2021). This review confirms those concerns and also highlights the
adoption of computational fluid dynamics (CFD), finite element analysis (FEA), and thermodynamic
modeling tools to optimize reactor design and ensure operational stability. The literature also
discusses modular system configurations that support flexible scale-up strategies, a concept
previously proposed but now validated through industry implementation. These advancements
collectively address longstanding concerns about cost, safety, and scalability.
Industrial case studies serve as critical validations of scCO₂’s theoretical and experimental promise.
Earlier reports mostly described laboratory results or small pilot-scale trials, leaving a gap in large-
scale commercial application (Tobiszewski, 2019). This review fills that gap by presenting robust case
studies from Nestlé, Pfizer, and BASF, each of which has successfully scaled and integrated scCO₂
into full-scale production. The Nestlé decaffeination process preserved organoleptic quality while
achieving nearly complete caffeine removal, a result long hypothesized but now confirmed in
practice. Pfizer’s use of scCO₂ for solvent-free drug processing demonstrates that such systems are
not only technically feasible but also compliant with global pharmaceutical regulations. BASF’s
adoption of scCO₂ in polymer coating operations confirms prior experimental findings and proves
that solvent-free surface treatment is achievable without sacrificing performance. These industrial
validations extend earlier hypotheses into proven operational models. Furthermore, this systematic
review bridges the gap between laboratory-scale experimentation and industrial-scale
implementation of scCO₂ technology. The reviewed findings not only support the results of earlier
studies but also broaden the scope by including empirical evidence from commercial operations.
The integration of scCO₂ into diverse sectors—including food, pharmaceuticals, materials, and
environmental engineering—confirms its versatility and technological maturity. Prior limitations such
as solubility constraints, equipment cost, and operational complexity are increasingly addressed
through hybrid process designs, material innovations, and advanced modeling tools. As a result,
scCO₂ stands validated not only as a green alternative to conventional solvents but also as a
competitive industrial process driver across multiple sectors.
CONCLUSION
The comprehensive synthesis of 163 systematically reviewed studies confirms that supercritical
carbon dioxide (scCO₂) serves as a versatile, efficient, and environmentally sustainable alternative
to conventional solvents across a wide spectrum of industrial applications. Its unique
physicochemical properties—including tunable density, low toxicity, and high diffusivity—enable
high-performance extraction, purification, synthesis, and material processing with minimal
environmental impact and compliance with stringent safety and regulatory standards. From the
successful commercial-scale decaffeination by Nestlé to Pfizer’s pharmaceutical particle design and
BASF’s solvent-free polymer coatings, scCO₂ has proven its industrial viability, operational scalability,
and alignment with green chemistry principles. The technology's role in recovering high-value
bioactives, enhancing reaction kinetics, treating hazardous waste, and modifying polymers
underscores its interdisciplinary relevance and adaptability. Furthermore, engineering
advancements in high-pressure equipment design, computational modeling, and safety integration
have addressed earlier limitations related to scale-up and process control. Altogether, these findings
position scCO₂ not only as a scientific innovation but also as a commercially adopted, forward-
facing solution in modern sustainable manufacturing and environmental management.

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