**1. Introduction**

The pharmaceutical industry has a major problem concerning the production of active pharmaceutical ingredients, which have a low water solubility and bioavailability. Therefore an appropriate technology for producing these active components is needed with certain properties like particle size (smaller than 1000 nm, typically under 500 nm), solubility, efficacy, state transition (polymorphism and crystallization), cost-effectiveness, etc.

In many nanomedical applications used in nanomedicine, processes based on supercritical fluids (SCFs) can be applied because they allow controlled fabrication of biological active nanostructured microparticles, nanoparticles, and nanoporous/nanostructured materials. Supercritical carbon dioxide (scCO2) as a green solvent that possesses many beneficial properties (it is nonflammable, nontoxic, biocompatible, cost-effective, and abundant) has gained huge interest in the food and pharmaceutical industries; it is considered environmentally benign and one of the few solvents not regulated as a volatile organic compound (VOC) by the US Environmental Protection Agency.

There are several methods for the manufacturing of solid particles scaled from micron to nanosize, divided into bottom-up, top-down, and combination approaches of these [1].

Bottom-up techniques produce nanosized particles by precipitation from a supersaturated drug solution. Precipitation by addition of liquid antisolvent is made by simple mixing methods (using a static mixer) or by modified mixing methods (sonoprecipitation or high gravity controlled precipitation). Other bottom-up

techniques involve supercritical fluids, rapid expansion of supercritical solution (RESS), and supercritical antisolvent technique (SAS) or solvent removal by nanospray dryer and spray freezing into liquid techniques. These methods have some disadvantages which include the size of particles that cannot be properly controlled in the non-sized range, but using of some additives (excipients, surfactants, etc.) can produce the stabilization nanocrystals or nanoparticles regarding the morphological properties and the crystallized polymorphic form [2]. Bottom-up techniques showed some advantages because they are low-energy processes and less expensive than the other methods, and obtained particles have narrow size distribution. In order to obtain smaller particles, these methods have been used in combination with top-down techniques [1].

Top-down techniques are used for particle size reduction of drugs to the nanometer size range by application of friction, involving high-energy processes such as media milling (wet bead milling) and high-pressure homogenization techniques (Dissocubes homogenization and NanoPure technology). These methods have some disadvantages which include a limited control of crystal size and surface properties and thermal or mechanical degradation generated by intensive energy of mixing [3]. These techniques are used in the last decade, but few nanocrystals under 100 nm have been obtained. Drug particles with smaller size than 100 nm have novel physical properties and better permeation through different biological barriers [4] and improved bioavailability of poorly aqueous soluble drugs, having different routes of administration such as oral, ocular, dermal, buccal, and pulmonary.

Supercritical fluids and their mixtures have specific properties like very fast mass transfer, near zero surface tension, and effective solvent elimination. The liquid-like and/or gas-like properties of SCFs and the possibility to modify several process parameters (temperature, pressure, and surface tension) can be benefits to produce several medical products at nanoscale. Several SCF-based processes are applied to nanomedicine applications: supercritical antisolvent precipitation (SAS), rapid expansion of supercritical solutions, supercritical emulsion extraction (SEE), supercritical assisted phase separation, supercritical gel drying, supercritical assisted liposome formation (SuperLip), supercritical assisted atomization (SAA), electrospinning in scCO2, supercritical assisted injection in a liquid antisolvent (SAILA), and depressurization of an expanded solution into aqueous media (DESAM) [5].


**161**

*Synthesis and Functionalization of Nanoparticles in Supercritical CO2*

Numerous methods for nanoparticle fabrication and functionalization using supercritical carbon dioxide have been proposed, in various reaction conditions. In **Table 1**, some examples of temperature and pressure range frequently used for the preparation of nanoparticulated materials are summarized, with particular empha-

The selection of the temperature and pressure condition is crucial for the particle size and drug encapsulation efficiency, and the specific values are chosen according to the characteristics of the active substance, such as solubility in scCO2

**2. Applications of scCO2 for preparation of polymeric nanoparticles** 

SCFs can bring their contributions in different fields for certain applications as chromatography, fluid extractions, and micro- and nanoparticle formation. There are several compounds that can be used as supercritical fluids. Among them, hydrocarbons are toxic and inflammable, water has high critical parameters, but carbon dioxide has appropriate critical temperature and pressure, being suitable to

Methods using supercritical fluids (SCFs) can produce particles with narrow size distribution. Because of their special properties, SCFs can be applied to micronization of several types of compounds: drugs, biopolymers, polymers, food, coloring maters, explosives, etc. Pharmaceutical micronizations using supercritical fluids have some advantages due to the absence of organic solvent, and the particle size distribution could be controlled by process parameters. During the micronizations by SCFs methods, the dissolution rate is increased. The use of scCO2 provides several advantages in comparison with the previous conventional techniques. The scCO2 can be used as a solvent, antisolvent, and extracting agent for the organic phase of oil-in-water emulsions or at particle formation from gas saturated solution

The RESS process is based on the saturation of the supercritical medium with a solute (polymer) followed by a rapidly depressurization of the solution through a heated nozzle at high speed. During the pressure drop, the system passes from supercritical to atmospheric conditions, the solvent power decreases, and a fast nucleation of the solute in the form of very small particles with uniform size takes place. The properties of the obtained particles are influenced by its solubility in scCO2; state parameters from precipitation vessel (temperature and pressure); size, length, and shape of the nozzle; distance of the jet stream; and impact angle onto the surface. A schematic representation of this process is presented in **Figure 1**. The RESS technique has several advantages like the simple control of process parameters, the absence of organic solvents, and easy implementation on lab-scale when a single nozzle is used. RESS has also disadvantages as difficulty in scaling-up,

In this chapter, we present several applications of supercritical carbon dioxide (scCO2) for preparation of polymeric nanoparticles as drug delivery systems, active principle encapsulation, water-in-scCO2 microemulsion in the synthesis of metal nanoparticles, and various methods for surface functionalization of nanoparticles

*DOI: http://dx.doi.org/10.5772/intechopen.89353*

sis on drug or drug delivery systems.

in supercritical and subcritical CO2.

**as drug delivery systems**

be used as a green solvent.

**2.1 Supercritical fluids and their properties**

**2.2 Rapid expansion of supercritical solution**

and improve the spraying process in different techniques [13].

phase, thermal stability, etc.

**Table 1.**

*Reaction conditions (temperature and pressure) in scCO2-assisted synthesis of nanoparticles.*

*Synthesis and Functionalization of Nanoparticles in Supercritical CO2 DOI: http://dx.doi.org/10.5772/intechopen.89353*

*Advanced Supercritical Fluids Technologies*

top-down techniques [1].

techniques involve supercritical fluids, rapid expansion of supercritical solution (RESS), and supercritical antisolvent technique (SAS) or solvent removal by nanospray dryer and spray freezing into liquid techniques. These methods have some disadvantages which include the size of particles that cannot be properly controlled in the non-sized range, but using of some additives (excipients, surfactants, etc.) can produce the stabilization nanocrystals or nanoparticles regarding the morphological properties and the crystallized polymorphic form [2]. Bottom-up techniques showed some advantages because they are low-energy processes and less expensive than the other methods, and obtained particles have narrow size distribution. In order to obtain smaller particles, these methods have been used in combination with

Top-down techniques are used for particle size reduction of drugs to the nanometer size range by application of friction, involving high-energy processes such as media milling (wet bead milling) and high-pressure homogenization techniques (Dissocubes homogenization and NanoPure technology). These methods have some disadvantages which include a limited control of crystal size and surface properties and thermal or mechanical degradation generated by intensive energy of mixing [3]. These techniques are used in the last decade, but few nanocrystals under 100 nm have been obtained. Drug particles with smaller size than 100 nm have novel physical properties and better permeation through different biological barriers [4] and improved bioavailability of poorly aqueous soluble drugs, having different routes of administration such as oral, ocular, dermal, buccal, and pulmonary. Supercritical fluids and their mixtures have specific properties like very fast mass transfer, near zero surface tension, and effective solvent elimination. The liquid-like and/or gas-like properties of SCFs and the possibility to modify several process parameters (temperature, pressure, and surface tension) can be benefits to produce several medical products at nanoscale. Several SCF-based processes are applied to nanomedicine applications: supercritical antisolvent precipitation (SAS), rapid expansion of supercritical solutions, supercritical emulsion extraction (SEE), supercritical assisted phase separation, supercritical gel drying, supercritical assisted liposome formation (SuperLip), supercritical assisted atomization (SAA), electrospinning in scCO2, supercritical assisted injection in a liquid antisolvent (SAILA), and depressurization of an expanded solution into aqueous media

**Nanoparticles Temperature (K) Pressure** 

SAA Drug nanoparticles 343–353 7–9 [11] SAILA Drug nanoparticles 343–353 7–10 [5]

**(MPa)**

313–373 8–25 [6, 7]

303–323 9–15 MPa [8]

308–323 8–10 MPa [5, 9, 10]

308–318 10–20 [12]

**References**

**160**

**Table 1.**

(DESAM) [5].

**scCO2 method**

RESS Drug micro−/nanoparticles

SAS Drug micro−/nanoparticles

SEE Drug encapsulated in lipid or

RESOLV Drug nanoparticles

Polymeric micro−/nanoparticles Drug encapsulated in polymeric microparticles

Inorganic nanoparticles

polymeric nanoparticles

Polymer-stabilized drug NPs

*Reaction conditions (temperature and pressure) in scCO2-assisted synthesis of nanoparticles.*

Numerous methods for nanoparticle fabrication and functionalization using supercritical carbon dioxide have been proposed, in various reaction conditions. In **Table 1**, some examples of temperature and pressure range frequently used for the preparation of nanoparticulated materials are summarized, with particular emphasis on drug or drug delivery systems.

The selection of the temperature and pressure condition is crucial for the particle size and drug encapsulation efficiency, and the specific values are chosen according to the characteristics of the active substance, such as solubility in scCO2 phase, thermal stability, etc.

In this chapter, we present several applications of supercritical carbon dioxide (scCO2) for preparation of polymeric nanoparticles as drug delivery systems, active principle encapsulation, water-in-scCO2 microemulsion in the synthesis of metal nanoparticles, and various methods for surface functionalization of nanoparticles in supercritical and subcritical CO2.
