Particle formation and micronization using non-conventional techniques- review

Due to growing concerns regarding health, safety and the environment, non-conventional methods for particle formation and micronization that are either solvent-less or use environmentally acceptable solvents such as carbon dioxide have come into favor. Supercritical CO₂ (sc CO₂) (T > 31.1 °C, P > 7.3 MPa) has been used in food and pharmaceutical industries to minimize the use of organic solvents, produce new food products, produce environmentally superior food products and to process and micronize (0.1–5 μm) pharmaceuticals. Control of particle size increases the dissolution rate of drugs into the body. Techniques that use sc CO₂ eliminate inherent drawbacks of conventional methods such as thermal or mechanical degradation of the product, poor control of the particle size and morphology, lack of brittleness of some polymers and low encapsulation efficiency. Several techniques have been reported for the particle formation and micronization using supercritical fluids that have been successfully scaled up for commercial use. Supercritical CO₂ has also been used to develop applications for medicines, essential oils, vitamins, food grade polymers, catalysts and pigments. This review highlights the process mechanism of supercritical fluid based techniques as well as some applications on particle formation and micronization.     

Production of microparticles from milk fat products using the Supercritical Melt Micronization (ScMM) process

The ScMM (Supercritical Melt Micronization) process was applied for the production of microparticles from anhydrous milk fat (AMF) and a diacylglycerol-based modified milk fat (D-AMF). Both fats were able to dissolve ca. 30 wt% CO₂ in the studied pressure and temperature ranges, being the CO₂ amount slightly higher for AMF. A melting point depression was observed in both systems in the presence of CO₂. Two powder morphologies were obtained (spherical hollow particles and a mass sponge-like broken particles) depending on the ScMM process conditions. The concentration of CO₂ in the fat melt was the main process variable affecting the particle morphology, followed by the temperature of the melt. The small broken particles originated from the breakage of spherical fat particles that solidified before all CO₂ could escape from the atomized droplets. While the hollow spheres had a tendency to agglomerate, the broken microparticles constituted a free-flowing powder as long as they were stored at low temperatures (up to −18 °C). Both types of particles have a potential for being incorporated in refrigerated or frozen food products as a structuring agent.     

Antisolvent micronization of BSA using supercritical mixtures carbon dioxide + organic solvent

In this work, expanded liquid antisolvent (ELAS) process has been used to micronize bovine serum albumin (BSA) solubilized in water. Carbon dioxide mixtures with ethanol, acetone or isopropyl alcohol, at expanded liquid conditions, have been used as the antisolvent. The effect of process parameters, such as the kind of co-antisolvent and the organic co-antisolvent/water/carbon dioxide mole fraction on the morphology and dimensions of the precipitates, was studied. Changing co-antisolvent and operating conditions, we obtained nanoparticles (with a mean diameter of about 60 nm ± 10 nm), sub-microparticles (with a mean diameter of 470 nm ± 130 nm), microparticles (with a mean diameter of 0.93 μm ± 0.37 μm) and expanded microparticles with an empty core (with a mean diameter of about 9 μm ± 5 μm). Fourier transform infrared analysis on BSA powders revealed that, using acetone as co-antisolvent, no modifications of the protein secondary structure were induced by ELAS processing.     

Generation of chitosan nanoporous structures for tissue engineering applications using a supercritical fluid assisted process

In recent years, considerable attention has been given to chitosan-based materials and their applications in the field of tissue engineering. However, the techniques proposed until now for the formation of chitosan scaffolds present some limitations such as: they are very time-consuming, use organic solvents, have difficulties in the obtainment and preservation of various levels of porosity and the 3-D structure. In this work, a new SC-CO₂ assisted process for the production of chitosan scaffolds is proposed; it consists of three steps: formation of a chitosan hydrogel by thermally induced phase separation; substitution of water with a suitable solvent; drying of the gel using SC-CO₂. Using this process, we produced chitosan nanostructured networks with filaments diameters around 50 nm, without any collapse of the gel nanostructure, characterized by a high porosity (>91%) and high compressive modulus (150 kPa).     

Influence of pressure, temperature and concentration on the mechanisms of particle precipitation in supercritical antisolvent micronization

In this work, supercritical antisolvent micronization (SAS) is used to produce nanoparticles, microparticles and expanded microparticles of a model compound, gadolinium acetate (GdAc), using dimethylsulfoxide (DMSO) as the liquid solvent with the aim of studying the dependence of particles’ diameter and morphology on some process parameters like pressure, temperature and concentration of the starting solution. Experiments are performed varying the precipitation pressure between 90 and 200 bar, the precipitation temperature between 35 and 60 °C and the concentration of GdAc in the liquid solution in the range from 20 to 300 mg/mL. The experimental evidences show that the formation of particles with specific sizes in the micrometric and nanometric range depends on specific values of each one of these parameters. An explanation of the results is proposed in terms of the competition between two characteristic times of the SAS process that can control the precipitation process. The time of jet break-up of the liquid solution that produces liquid droplet formation, and the dynamic surface tension vanishing time, that induces gas mixing with the precipitation of nanoparticles from the gaseous phase. Indeed, GdAc sub-microparticle, or microparticle (diameter in the range 0.23-1.6 μm with mean diameters in the range 0.28-0.52 μm) formation can be attributed to micro-droplet drying, whereas nanoparticles (mean diameter in the range 90-210 nm) are consistently produced when gas mixing is the possible governing process. In conclusion, the precipitation mechanisms can be modulated varying one SAS parameter a time, thus selecting the range of particle diameters required for the specific application.     

Micronization of cilostazol using supercritical antisolvent (SAS) process: Effect of process parameters

The aim of this study was to improve dissolution rate of poorly water-soluble drug, cilostazol, using supercritical antisolvent (SAS) process. The effect of process variables, such as pressure, temperature, drug concentration, type of solvents, feed rate ratio of CO₂/drug solution, on drug particle formation during SAS process was investigated. Particles with mean particle size ranging between 0.90 and 4.52 μm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration, solvent type, feed rate ratio of CO₂/drug solution. In particular, mean particle size and distribution were markedly influenced by drug solution concentration during SAS process. Moreover, the drug did not change its crystal form and the operating parameters might control the ‘crystal texture’ due to the change in crystallinity and preferred orientation during SAS process, as confirmed by differential scanning calorimetry and powder X-ray diffraction study. In addition, the dissolution rate of drug precipitated using SAS process was highly increased in comparison with unprocessed drug. Therefore, it is concluded that the dissolution rate of drug is significantly increased by micronization of cilostazol, leading to the reduction in particle size and increased specific surface area after SAS process.     

Preparation of liposomes using the supercritical anti-solvent (SAS) process and comparison with a conventional method

Two methods to produce liposomes encapsulating a fluorescent marker were compared: the supercritical anti-solvent (SAS) method and a conventional one (Bangham). Liposome size and encapsulation efficiency were measured to assess the methods. Micronized lecithin produced by the SAS process was characterized in terms of particle size, morphology and residual solvent content in order to investigate the influence of experimental parameters (pressure, CO₂/solvent molar ratio and solute concentration). It appears that when the lecithin concentration increases from 15 to 25 wt.%, at 9 MPa and 308 K, larger (20-60 μm) and less aggregated lecithin particles are formed. As concerns liposomes formed from SAS processed lecithin, size distribution curves are mainly bimodal, spreading in the range of 0.1-100 μm. Liposome encapsulation efficiencies are including between 10 and 20%. As concerns the Bangham method, more dispersed liposomes were formed; encapsulation efficiencies were about 20%, and problems of reproducibility have been raised.     

Numerical simulation of particle formation in the rapid expansion of supercritical solution process

In this paper, we numerically study particle formation in the rapid expansion of supercritical solution (RESS) process in a two dimensional, axisymmetric geometry, for a benzoic acid + CO₂ system. The fluid is described by the classical Navier–Stokes equation, with the thermodynamic pressure being replaced by a generalized pressure tensor. Homogenous particle nucleation, transport, condensation and coagulation are described by a general dynamic equation, which is solved using the method of moments. The results show that the maximal nucleation rate and number density occurs near the nozzle exit, and particle precipitation inside the nozzle might not be ignored. Particles grow mainly across the shocks. Fluid in the shear layer of the jet shows a relatively low temperature, high nucleation rate, and carries particles with small sizes. On the plate, particles within the jet have smaller average size and higher geometric mean, while particles outside the jet shows a larger average size and a lower geometric mean. Increasing the preexpansion temperature will increase both the average particle size and standard deviation. The preexpansion pressure does not show a monotonic dependency with the average particle size. Increasing the distance between the plate and the nozzle exit might decrease the particle size. For all the cases in this paper, the average particle size on the plate is on the order of tens of nanometers.     

Controllable preparation and formation mechanism of BSA microparticles using supercritical assisted atomization with an enhanced mixer

Supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) was used to prepare bovine serum albumin (BSA) microparticles. Water was used as the sole solvent. A hydrodynamic cavitation mixer was applied to improve mass transfer and achieve a continuous near-thermodynamic-equilibrium solubilization of SC-CO₂ in the liquid solution. Under the different conditions, the prepared BSA microparticles had various morphologies, such as corrugated particles, smooth hollow spherical particles and cup particles, with particle diameters ranging from 0.3 to 5 μm. The microparticle formation process was elucidated with the shell formation and central bubble mechanism. Compared to native BSA, BSA microparticles did not show significant change in primary structure, according to the results of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The secondary structure of BSA was characterized by Fourier transform infrared spectroscopy (FT-IR). No new peaks were observed after SAA-HCM processing. In addition, the crystalline structure of the BSA microparticles was demonstrated to be amorphous because of the sudden supersaturation in the precipitation process. The SAA-HCM process is expected to be a promising technique for producing microparticles suitable for pulmonary delivery of therapeutic macromolecules.     

Batch production of micron size particles from poly(ethylene glycol) using supercritical CO2 as a processing solvent

The major advantage of using supercritical carbon dioxide (CO₂) as a solvent in polymer processing is an enhancement in the free volume of a polymer due to dissolved CO₂, which causes a considerable reduction in the viscosity. This allows spraying the polymer melt at low temperatures to produce micron size particles. We have used supercritical CO₂ as a solvent for the generation of particles from poly(ethylene glycol) (PEG) of different molecular weights. Since PEG is a hydrophilic compound, it is a most commonly used polymer for encapsulating a drug. PEG particles with different properties may allow keeping a good control over the release of the drug. It has been possible to produce particles with different size, size distribution, porosity and shape by varying various process parameters such as molecular weight, temperature, pressure and nozzle diameter. A flow and a solidification model have been applied in order to have a theoretical insight into the role of different parameters.     

Tuning physicochemical properties of theophylline by cocrystallization using the supercritical fluid enhanced atomization technique

Formation of different micro- to nanosized cocrystals of theophylline is addressed by using the supercritical enhanced atomization (SEA) process. The experimental results presented here help to highlight how to prepare cocrystals of theophylline (TPL) using a supercritical fluid-based technique to accomplish the required physicochemical properties of that active pharmaceutical ingredient (API). The SEA process shows a strong versatility and feasibility towards the formation of highly pure theophylline cocrystals, using tetrahydrofuran as a solvent. The formation of TPL cocrystals with different types of morphology and dissolution behaviour/properties is induced by using different coformers, such as urea, saccharin, gentisic acid, salicylic acid, glutaric acid, sorbic acid, 1-hydroxy-2-naphthoic acid, oxalic acid, maleic acid and nicotinamide. The solubility of each coformer in the dissolution medium of phosphate-buffered saline (pH 7.4 at 25 °C) could determine the dissolving rate behaviour of the produced cocrystals. Consequently, the low-soluble coformers generate TPL cocrystals with a slow-dissolving rate, while the use of highly soluble coformers produces faster-dissolving TPL cocrystals. Albeit the SEA process operating temperature influences the mean cocrystal particle size, this technique shows a high potential as an effective cocrystal screening tool.     

Molecular weight fractionation of poly(methyl methacrylate) using Gas Anti-Solvent techniques

The solubility of poly(methyl methacrylate) in acetone, expanded by carbon dioxide, was studied at 20 °C for a variety of molecular weights and architectures. The suitability of the Gas Anti-Solvent method for fractionation of poly(methyl methacrylate) was investigated with positive results. The threshold pressure for precipitation of various monodisperse molecular weights was investigated, and the effectiveness of this technique to fractionate a polymer with a broad molecular weight distribution was evaluated. The pressure required to precipitate polymers was found to be low, generally below 60 bar.     

Formation of ultrafine aspirin particles through rapid expansion of supercritical solutions (RESS)

The performance of pharmaceuticals in biological systems can be enhanced by reducing the particle size of pharmaceuticals. Rapid expansion from supercritical solution (RESS) has provided a promising alternative to comminute contaminant-free particles of heat-sensitive materials such as drugs. In this work, aspirin has been successfully precipitated by the RESS technology. The performances of the RESS process under different operating conditions are evaluated through the analysis of the particle characteristics. Our results show that extraction pressure and extraction temperature can significantly affect the morphology and size of the precipitated particles whereas the nozzle diameter and pre-expansion temperature are not observed to apparently influence the RESS particles. The RESS process could produce ultrafine spherical particles (0.1-0.3 μm) of aspirin as reflected by SEM observations.     

A new system for particle formation using the principle of the SAS process: The Concentric Tube Antisolvent Reactor (CTAR)

This paper presents a new system to produce micrometric narrow size distribution particles. The principle is the same as for a conventional supercritical antisolvent process (SAS), with the contact of the organic solution containing the solute to be precipitated and the supercritical CO₂ playing the role of an antisolvent. This paper exposes the functioning of the system used for the contact of the two phases. It is constituted by two concentric tubes; an external one partially for the CO₂ and an internal one for the organic solution. Its name is the Concentric Tube Antisolvent Reactor (CTAR). This system is a compacted and simple one. It has been tested with a usual polymer (l-poly lactic acid) often processed by the use of the SAS methods. Different experiments have shown that this system is convenient for the production of particles, leading to almost equivalent results as in other processes with identical operating conditions. There are still remaining problems for the recovery of the powder formed, which is usual for this kind of process. This system could be very useful for the scaling up of the process, by multiplying the number of tubes with an easy permanent control on the operating conditions. Some improvements have been made for operating parameters, as the concentration of LPLA in the organic solution and the molar ratio solvent/supercritical CO₂ that can be processed.     

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

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

Preparation and characterization of camptothecin powder micronized by a supercritical antisolvent (SAS) process

Micronized camptothecin (CPT) is prepared with a supercritical antisolvent (SAS) apparatus using dimethyl sulfoxide (DMSO) as solvent and carbon dioxide as antisolvent. Four factors, namely CPT solution concentration and flow rate, precipitation temperature and pressure are optimized by a four-level orthogonal array design (OAD). By analysis of variance (ANOVA), only precipitation pressure has a significant effect on the MPS of micronized CPT. The optimum micronization conditions are determined as follows: CPT solution concentration 1.25 mg/ml, CPT solution flow rate 6.6 ml/min, precipitation temperature 35 °C and precipitation pressure 20 MPa. Under the optimum conditions, micronized CPT with a MPS of 0.25 ± 0.020 μm is obtained. The micronized CPT obtained was characterized by Scanning Electron Microscopy (SEM), Atomic Force Microscope (AFM), High performance liquid chromatography-mass spectrometry (LC-MS), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Differential scanning calorimeters (DSC) and Gas chromatography (GC) analyses. The results showed that the obtained CPT particles have lower crystallinity and SAS micronization process does not induce degradation of CPT. In addition, the residual DMSO is less than the ICH limit for class 3 solvents.     

Foam processing of poly(ethylene-co-vinyl acetate) rubber using supercritical carbon dioxide

Soft rubber foams like poly(ethylene-co-vinyl acetate) (EVA) are industrially applied in a broad range of products, including sports gear, insulation materials and drug delivery systems. In contrast to glassy polymers, few studies in literature concern the foaming of soft rubbers using supercritical carbon dioxide. In this study, open microporous matrices of EVA have been formed with CO₂. Prior to the foam expansion, sorption and swelling isotherms of CO₂ in EVA have been measured and the obtained isotherms have been correlated using the Sanchez-Lacombe equation of state. Additionally, a pressure-independent diffusion coefficient of CO₂ in EVA has been obtained from these experiments. The microporous foams have been formed by a pressure quench of the CO₂-swollen polymer matrix. Sorption pressure as well as temperature and decompression times appear to determine the pore size and bulk density of the foam. These parameters allow for a control of the foam structure of EVA rubbers.     

Study of the microstructure formation mechanisms of poly(ether-ether-ketone) monofilaments via melt spinning

The microstructure formation mechanism of melt-spun Poly(ether-ether-ketone) monofilaments during poststretching was investigated using in-situ wide-angle X-ray diffraction in combination with polarizing microscopy, differential scanning calorimetry and universal testing machine. As PEEK monofilaments were stretched at 210°C, the crystallinity and microcrystal size first increased during the insulation state (Is-S), then decreased during the poststretching state (Ps-S), and further increased during the postcooling state (Pc-S), at last were observed to selective orientation. At 210°C, the anisotropically aligned molecular chains reach a meritocratic orientation in the stress direction under 4.0 times drawing conditions, resulting in the highest tensile strength and modulus. As the stretching ratio increases, the crystallinity and microcrystal size first increase during Pc-S and then decrease due to the effect of the stretched molecular chains on crystal growth and the degree of tearing in the crystalline region. The molecular chains of PEEK monofilaments stretched by uniaxial stress are aligned more flatly and uniformly along the fiber axis. We hope that this work will provide advice and guidance for the industrial production of high-performance fibers.     

Extraction of bioactive compounds from peach palm pulp (Bactris gasipaes) using supercritical CO2

Natural compounds with biological activity have recently attracted special interest in the agro-industry as sources of additives in nutraceutical food production and pharmaceutical industries. Herein, we evaluated extracts obtained from peach palm fruit (Bactris gasipaes) using supercritical carbon dioxide, in terms of yield, total phenolic content, total flavonoids, total carotenoids, and antioxidant activity by β-carotene bleaching method. Extractions were performed at 40, 50, and 60 °C and 100, 200, and 300 bar; additionally, Soxhlet (with petroleum ether) and methanol extraction were conducted. The results showed that supercritical CO₂ allows obtaining extracts rich in carotenoids and, although it presents lower yield than conventional extraction (SOX), supercritical CO₂ represents a technique with greater advantages. The best operation condition for supercritical extraction was 300 bar–40 °C, given that the highest concentration of carotenoids was obtained, without the yield being significantly different from that obtained with 300 bar–60 °C, this extract had antioxidant activity comparable to that of commercial caffeic acid.