Recent developments in particle design using supercritical fluids

Current Opinion in Solid State and Materials Science 7 (2003) 371–383

Recent developments in particle design using supercritical fluids Alireza Shariati, Cor J. Peters

*

Delft Chem Tech, Faculty of Applied Sciences, Laboratory of Physical Chemistry and Molecular Thermodynamics, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands Received 22 September 2003; received in revised form 29 October 2003; accepted 4 December 2003

Abstract Supercritical fluid (SCF) techniques for materials precipitation have been the subject of many studies, mostly with the intention of making highly uniform particles. The SCF process is able to microencapsulate many materials that are difficult to treat with existing techniques. It has also been able to control the morphology of materials by adjusting nucleation and growth during the production of particles. It is expected that these techniques will receive much attention in the future. This work aims to review the most recent published literature (from 2001 until the present), about particle design using gas anti-solvent and other SCF processes.
2004 Elsevier Ltd. All rights reserved. Keywords: Supercritical; Gas anti-solvent; Particle design; Crystallization

1. Introduction Since the size and size distribution and sometimes even the morphology of particles produced in different industries are usually not appropriate for the subsequent use of those materials, particle design has been gaining increasing importance in manufacturing advanced ceramic materials, dyes, explosives, catalysts, coating materials, microsensors, polymers, pharmaceuticals, and many other chemicals. For example, when dealing with aerosol delivery of pharmaceuticals in the lungs by inhalers, a narrow size distribution of fine particles is necessary in order to maximize the efficiency of the drug, and hence to minimize the required dosage. This results in the decrease of side effects of the drug while maintaining the same therapeutic result. Another important reason for applying particle design is the increasing number of newly developed drugs that are poorly soluble in both aqueous and organic media. An alternative and promising approach is the production of micro- or nanoparticle pharmaceuticals with improved solubilities. This was explained extensively by M€ uller et al. [*1]. Several conventional methods are currently in use for producing fine powders, including jet and ball milling, * Corresponding author. Tel.: +31-15-278-2660; fax: +31-15-2788668. E-mail addresses: [email protected], [email protected] (C.J. Peters).

1359-0286/$ - see front matter
2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cossms.2003.12.001

spray drying, and recrystallization using solvent evaporation or liquid anti-solvent. But all these techniques have in common the disadvantage of poor control of the size distribution of the particles, i.e., a wide range of particle sizes is usually produced. In addition, each method has its own specific disadvantages. For example, spray drying usually requires high operating temperatures, which may cause thermal degradation of sensitive materials such as the majority of food ingredients and pharmaceuticals. Solvent evaporation and liquid antisolvent recrystallization face solvent and anti-solvent residual problems. In the past two decades, many researchers have tried to solve these shortcomings of conventional techniques of particle design by investigating the potential of SCF. In 2001, Jung and Perrut [**2] performed an extensive review on the different techniques available for particle design using SCF. This study aims to continue that work, highlighting the most recent developments in the gas anti-solvent and other SCF techniques for particle design. Krukonis [3] was the first scientist who ever tried to apply SCF, which had previously been used for extraction operations, for recrystallizing solid materials with the intention of producing fine particles with narrow size distributions. The most attractive features of SCF in this respect include enhanced solubility power compared to regular gases, sensitivity to small changes in either temperatures or pressures and fairly mild operating

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conditions. The technique proposed by Krukonis was named Ôrapid expansion of supercritical solutions (RESS)’. In the RESS process, the supercritical fluid acts as the solvent. The solid material to be micronized is first solubilized in the supercritical fluid using an extractor. Therefore, a supercritical solution is discharged from the extractor. If this solution is expanded via a nozzle and sprayed into an expansion vessel, precipitation of particles will occur, as the conditions are no longer supercritical. Fine particles with narrow size distribution can be produced at relatively low temperatures using the RESS process. However, a major limitation of this process is that the solubilities of many materials, especially pharmaceuticals, are usually very low in SCF. This makes RESS not attractive for industrial-scale productions of such low-soluble materials. But as a general rule, if the solute has a significant solubility in the SCF, the RESS process will be the first choice for particle design because of its simplicity. The next section (Section 2) briefly explains the principles of the gas antisolvent (GAS) and related processes, while Section 3 focuses on other SCF processes used for particle design. Section 4 explains the most recently proposed technique, which couples the GAS process and reactions. Section 5 reviews the recent experimental and theoretical studies for several systems using the processes explained in Sections 2–4. Section 6 deals with scaling-up of these processes, and in Section 7 conclusions are summarized.

2. Principles of the GAS and related processes (SAS/ ASES/PCA/SEDS) In order to overcome the problem of the low solubility of materials in SCF, Gallagher et al. [*4] proposed another technique, called the Ôgas anti-solvent (GAS)’ process. In the GAS process, a high-pressure gas or SCF acts as an anti-solvent. The solid material to be micronized is first dissolved in a conventional organic solvent. Then a high-pressure gas or SCF is injected into the solution, causing expansion of the solution. The resulting decrease in density diminishes the solvency power of the organic solvent, causing the supersaturation of the liquid solution and, consequently, the precipitation of the solute in the precipitator as fine particles with narrow size distribution. An important criterion for a feasible GAS process is that the antisolvent should be highly soluble in the solvent, while the solute is insoluble or insignificantly soluble in the antisolvent in order to promote precipitation [5]. Until now, carbon dioxide (CO2 ) has been the most common antisolvent for GAS and the related processes, due to its unique characteristics such as having low critical temperature and pressure, good solubility in organic solvents, good transport properties, and being inflammable, non-toxic, and inexpensive. The reported particle

sizes produced using the GAS process vary from submicron to a few microns within a narrow size range. In the GAS process, the parameters which affect the size and the size distribution of the precipitated particles include temperature, the rate of addition of anti-solvent corresponding to the rate of pressure increase, the initial concentration of the solvent–solute solution, and the method of introducing the anti-solvent into the system. The GAS process is a batch process. However, a number of semi-continuous processes such as Ôsupercritical antisolvent (SAS)’, Ôaerosol solvent extraction system (ASES)’, Ôprecipitation with compressed anti-solvent (PCA)’, and Ôsolution enhanced dispersion by supercritical fluids (SEDS)’ have also been devised based on the concept of the GAS process. In the SAS, ASES, PCA processes, the liquid solution and the anti-solvent are simultaneously but separately injected to the precipitation chamber. The solution passes through a nozzle and is sprayed into a chamber, which is pressurized with the SCF, resulting in the supersaturation of liquid droplets and the instantaneous precipitation of the solute as fine particles in the chamber. The particles are collected on a filter at the bottom of the chamber. The solvent and anti-solvent are continuously discharged from the chamber. A second vessel, following the precipitator, is operated at low pressures and is used to recover the liquid solvent. When enough particles are collected on the filter, the solution stream is disconnected while the flow of the anti-solvent continues through the precipitation chamber at constant pressure to dry the particles. In the SAS and other related semi-continuous processes, the particle shape and size distribution is strongly dependent on the liquid solution injection device that influences the droplet size and mass transfer between the two fluid phases. It is also dependent on temperature, pressure, and the flow rates at which the solution and the anti-solvent are added to the precipitation chamber. In recent years, some changes have been introduced to the SAS process to improve its performance for producing nanoparticles or to adopt the process to water-soluble materials. In this respect in 2001, Chattopadhyay and Gupta [6] modified the atomization procedure of the SAS process by adding a vibrating surface working at ultrasonic frequencies to atomize the injected jet of solution to microdroplets in order to produce nanoparticles. They named the modified process Ôsupercritical anti-solvent precipitation with enhanced mass transfer (SAS-EM)’. The ultrasound field increases turbulence and mixing within the solution droplets and the anti-solvent which results in high mass transfer between the liquid and gas phases. Subramaniam et al. [7] are the pioneers in using high-energy sonic-waves technique for precipitating particles using SCF. The difference of SEDS compared to SAS is that the mixing of the binary solute–solvent solution and the

A. Shariati, C.J. Peters / Current Opinion in Solid State and Materials Science 7 (2003) 371–383

anti-solvent is done in a different way. In the SEDS process, the mixing takes place in a coaxial nozzle, which causes fast mass transfer and provides uniform crystallization conditions.

3. Principles of the PGSS and related processes (CANBD/SAA/DELOS/CPCSP) The process of Ôparticles from gas-saturated solutions (PGSS)’ is another SCF process for particle design. In the PGSS process, a SCF or compressed gas is dissolved into a solution of a solute in a solvent or into a melted material. Then, a rapid depressurization of the mixture occurs through a nozzle, causing the formation of solid particles, or liquid droplets depending on the mixture and the conditions. Based on the principles of the PGSS process, a few other processes have been developed as well (CAN-BD/SAA/DELOS/CPCSP). The Ôcarbon dioxide assisted nebulization with bubble drying (CAN-BD)’ was proposed by Sievers and coworkers [8] for producing some hydrophilic materials. The CAN-BD process couples an aerosolization process of aqueous solutions using supercritical CO2 as proposed by Xu et al. [9] and Sievers et al. [10] with a bubble drying system. In the CAN-BD process a biphasic mixture of supercritical CO2 and water solution is formed in a micrometric volume tee. The biphasic mixture is then sent to a capillary tube and rapidly depressurized to form a spray of fine aerosols. Then the produced aerosol is dried in contact with hot dry nitrogen and the micronized particles are collected on a filter. The CAN-BD process generates particles less than 3 lm in diameter with 75% efficiency. This process is interesting for water-soluble compounds, which are not soluble in organic solvents. Also ethanol has been used as a solvent by Sievers and coworkers [11,12]. In 2002, Reverchon [13] proposed the Ôsupercriticalassisted atomization (or aerosolization) (SAA)’ process for producing micro- and/or nanoparticles. The SAA process was proposed based on the CAN-BD process. Reverchon [13] reported that it was not possible to work with CAN-BD in a reproducible mode, probably due to the non-negligible pressure drop inside the capillary injector and the consequent precipitation of part of the solute. He also reported that the low-volume tee allowed only an approximate mixing of the two streams. Therefore, Reverchon [13] changed the process setup by using a thermostated packed tower instead of the volume tee to obtain not only mixing, but also the equilibrium solubilization of CO2 in the solution. Recently, Ventosa et al. [14,15] proposed as a process the Ôdepressurization of an expanded liquid organic solution (DELOS)’. In the DELOS process, a compressed gas in an autoclave expands the liquid solution consisting of the solute to be micronized and a con-

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ventional solvent. At this stage, the compressed gas acts as a cosolvent, not as an anti-solvent. Therefore, no crystallization should occur at this stage, although the appearance of an undesired gas anti-solvent process is possible. The cosolvency effect of an anti-solvent has experimentally been shown in detail by Shariati and Peters [16] for the system CO2 + 1-propanol + salicylic acid. If this expanded solution of the ternary mixture of solute–solvent–compressed gas is depressurized by rapid reduction of the system pressure to atmospheric pressure in an expansion chamber, evaporation of the solution takes place resulting in a sharp decrease in solution temperature. As a consequence, a pronounced and homogeneous increase of supersaturation over all the solution takes place, which causes the precipitation of the solute as fine particles with narrow size distribution. The Ôcontinuous powder coating spraying process (CPCSP)’ was proposed by Weidner et al. [17] as an alternative technique for the manufacture of powder coatings based on the PGSS process. This process is applicable to new coating materials which are lowmelting and fast-reacting components. In the CPCSP process, the main components (binder and hardner) are melted in separate vessels in order to avoid a premature reaction of the polymers. The polymer melts are fed to a static mixer. In the static mixer, the melts are homogenized with compressed CO2 under a pressure up to 220 bar. The residence time is very short in the static mixer and also, due to the dissolved carbon dioxide, the melting point of the mixture decreases. Therefore, the temperature in the static mixer is set very low and reaction can be avoided. The solution formed in the mixer is expanded afterwards via a nozzle into a spray tower. Due to the enormous increase of the volume of the expanding CO2 , the melt is atomized into fine droplets. Simultaneously, the droplets freeze and a fine powder coating is formed because of the temperature decrease in the spray tower caused by the expanding gas. With a blower, the gas is removed from the spray tower and by means of a cyclone and a filter the fine particles are separated from the gas. Weidner et al. [17] showed that it is possible to produce powder coatings with an average particle size of less than 40 lm, while manufacturing the coating powders using a conventional process results in particles larger than 40 lm.

4. Coupling of the GAS process to reactions Very recently, Owens et al. [18,19] proposed the Ôcompressed anti-solvent precipitation and photopolymerization (CAPP)’ process. This process uses simultaneously compressed anti-solvent precipitation and photopolymerization reactions for producing polymer microparticles from monomers. In this technique, a solution of an organic solvent, monomer and

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photoinitiator is sprayed into a high-pressure chamber containing compressed gas while simultaneously illuminating the chamber with high-intensity ultraviolet light. As Owens et al. [18,19] pointed out, the spraying step in the CAPP process provides an intimate mixing of the ternary solution of the monomer, initiator and organic solvent with the compressed anti-solvent. The mixing conditions coupled with the anti-solvent effects of the compressed gas facilitate the extraction of the organic solvent from the sprayed solution, presumably leaving microdroplets containing mostly monomer and initiator. Illumination of the droplets of highly concentrated monomers and initiators with a high-powered light source results in rapid polymerization, subsequently followed by precipitation of fine polymer particles.

5. Recent experimental and theoretical attempts in production of fine particles All the subsections to follow aim to update the extensive review on experimental and theoretical results of particle design using SCF collected by Jung and Perrut [**2] in 2001. However, this work excludes particle design using the RESS process, which by itself, deserves a separate review study. 5.1. The GAS process In recent years, some researchers have tried to apply the GAS process for micronizing drug-loaded biopolymers. In 2001, Moneghini et al. [20] showed the effect of the GAS-micronization of carbamazepine (CBZ), an anti-convulsant drug, on its bioavailability by measuring the rates of dissolution in water of treated and untreated CBZ. Also, they showed that the coprecipitation of CBZ with polyethylene glycol (PEG), a hydrophilic polymer, as fine particles using the GAS process could significantly increase the rate of dissolution of the drug. They used acetone as the solvent and CO2 as the anti-solvent. Using the GAS process, the particle size of the pure drug was reduced from 284 to 31 lm. Corrigan and Crean [21] applied the GAS process for producing hydrocortisone-polyvinylpyrrolidone (PVP) particles. They compared the particles produced using the GAS process with the particles produced by coprecipitation and spray drying. Their study showed that the particles produced by the GAS process had a dissolution rate lower than those prepared by the spray drying, but equivalent dissolution with those prepared by coprecipitation. The pure hydrocortisone particles produced from the GAS process and the coprecipitation had the same crystallinity of the original materials, while the particles produced using spray drying were amorphous. Muhrer and Mazzotti [22] studied the effect of some operating parameters (rate of anti-solvent addition,

initial concentration of the solution, and temperature) on tuning the properties of lysozyme prepared by GASprecipitation of lysozyme from dimethyl sulfoxide (DMSO) expanded by supercritical CO2 . They noticed that the rate of anti-solvent addition and the initial solute concentration exhibit no major effects on the average size of the formed particles, while temperature shows a clear effect on the mean particle size of the produced lysozyme. By increasing temperature from 19 to 35 C, a decrease of 50% was observed in the size of the particles. But, the degree of agglomeration of particles was also increased. Warwick et al. [23] applied the GAS process for producing micronized copper indomethacin. They studied the effect of the rate of expansion of the solution on the size of particles. They noticed that the size of particles produced by micronization with GAS was dominated by the rate of expansion of the solution. The size of particles may then be reduced at high expansion rates, because the high levels of supersaturation generated, result in rapid rates of nucleation and consequently little particle growth. The morphology of particles formed by the GAS process, have also been affected by the rate of expansion of the solution. Cocero and Ferrero [24] studied the crystallization of b-carotene using the GAS process. They investigated the influence of operating variables (concentration, temperature, stirring rate, and type of solvent) and the efficiency of the GAS process on the final size of the crystals. Bertucco et al. [25] discussed the gas anti-solvent fractional crystallization extensively. They explained that when a solute has better solubility in an antisolvent, it precipitates at higher pressures. The GAS process was successfully applied in recent years by Bothun et al. [26] for fractionation of the semi-crystalline PLA from amorphous PLA, by Coen et al. [27] for poly(methyl methacrylate) (PMM) with different molecular weights, and by Catchpole et al. [28] for the fractionation of propolis tincture. In order to evaluate the feasibility of the GAS and related processes and to optimise the choice of operational variables, a number of researchers have tried to study the phase behavior, volume expansion and precipitation kinetics of different systems, both experimentally and theoretically. De la Fuente et al. [*29] investigated the molar volume of the solution in the GAS process. They defined a new volume expansion equation based on the molar volume of the solution, which effectively relates the volume expansion of the solution to the precipitation temperature and pressure. They also simulated the thermodynamic equilibrium of two systems in the GAS process. Elvassore et al. [30] measured the total volume expansions of the systems CO2 –DMSO, CO2 –dioxane and CO2 –water–DMSO by a new technique. Recently, Mukhopadhyay [*31] proposed another definition based on the partial molar

A. Shariati, C.J. Peters / Current Opinion in Solid State and Materials Science 7 (2003) 371–383

volume reduction of solvent in the GAS process, and related that definition to the solute solubility in the GAS process. Later, Mukhopadhyay and Dalvi [*32] modified that definition in order to improve its predictions for systems of which the solute has a high solubility in the solvent. Shariati and Peters [16] experimentally investigated the phase behavior of the system CO2 + 1-propanol + salicylic acid. They also modelled the thermodynamic equilibrium of this system. The phase behavior of the system CO2 + acetone + cholesterol was studied by Liu et al. [33]. They also studied the recrystallization of cholesterol using the GAS process. Elvassore et al. [34] studied theoretically the kinetics involved in the GAS process. They proposed a model for kinetics of the GAS process, which needed some experimental values for determining its parameters. In order to evaluate their findings, they developed a UV–vis technique and studied experimentally the kinetics of the precipitation of PLA from dichloromethane using supercritical CO2 . They showed that their model gave a correct phenomenological representation of their experimental data. Muhrer et al. [35] mathematically modelled the effect of mass transfer on the nucleation in the GAS process. Their theoretical findings, together with their qualitative agreement with the experimental results, demonstrated the importance of the anti-solvent addition rate in controlling the final average particle size and particle size distribution and the possibility of tuning it in accordance with the product requirements. The two assumptions of their model were that the vapor and liquid phases attain instantaneous phase equilibrium upon anti-solvent addition and that each phase is homogeneous. Lin et al. [36] studied the effect of mass transfer resistance on the volume expansion that occurs during the GAS process and improved the model of Muhrer et al. [35] by dispensing of their first assumption. They developed a non-equilibrium model for the GAS process and tested this model for the volume expansion of the system CO2 –toluene. Their results indicated that the Muhrer et al. assumption [35] of instantaneous equilibrium between the liquid and vapor phases upon anti-solvent addition is reasonable for the system CO2 –toluene. Table 1 summarizes the recent research on the GAS process.

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nm in size distribution. In order to achieve particulate products with narrow size distribution and homogeneous drug dispersion into the polymeric carrier and to avoid the jet break-up during liquid injection into the precipitation chamber, the insulin/PEG/PLA mixture was dissolved in a 50:50 dichloromethane (DCM)/dimethyl sulfoxide (DMSO) mixture. Rantakyl€a et al. [39] investigated the effects of different parameters on the micronization of a model biopolymer (L -PLA) from dichloromethane by supercritical CO2 . In recent years, Reverchon and coworkers applied the SAS process for micronizing some drugs namely, salbutamol [40], rifampicine [41], and amoxicillin [*42] and two superconductor precursors, europium acetate (EuAc) and gadolinium acetate (GdAc) [43]. They investigated the influences of the SAS operating parameters on morphology, particle size and particle size distribution. The SAS process and its effective process variables were studied for micronizing soy lecithin by Badens et al. [44], a class of hyaluronic acid-derived biopolymers (HYAFF11, HYAFF11p80, HYAFF11p75, HYAFF302) by Elvassore et al. [45], vanadium phosphate catalysts by Hutchings et al. [46], a herbicide (diuron)-loaded PLA by Taki et al. [47], and sulfathiazole and chlorpropamide by Yeo et al. [48]. Chavez et al. [49] studied theoretically, the roles of both nucleation and diffusion in the SAS process. They distinguished between two possible regimes in this process:

5.2. The SAS/PCA/ASES processes

• Diffusion-controlled precipitation (fast nucleation, slow diffusion) in which small values of desolvation energy, low interfacial tension and high values of supersaturation all favor the occurrence of this regime. In addition, factors that decrease diffusivity, such as proximity to the critical point, favor the diffusion-controlled regime. • The other regime, called nucleation-controlled (slow nucleation, fast diffusion) precipitation, occurs homogeneously throughout the interior of the well-mixed droplet. A nucleation-controlled regime would be favored by the appearance of convective currents in the interior of the droplet. Other factors that tend to favor a nucleation-limited regime are large desolvation energy, large interfacial tension, low solute concentration, and low supersaturation.

Elvassore et al. [37,38] produced insulin-loaded biodegradable polymer-based nanoparticles using the SAS process (they called this the semi-continuous GAS process). Since the poly(lactic acid) (PLA) used in their research had low biodegradability and high hydrophobicity, Elvassore et al. [37] showed that by adding PEG to the drug/PLA mixture, the bioavailability and biodegradability of the nanoparticles are improved. The resulting nanoparticles had an average range of 400–600

Carretier et al. [50] studied the hydrodynamics of the SAS process (vessel geometry, type of fluid feed devices and scale of mixing). They concluded that, among all of the different experimental conditions studied, the most significant modifications in morphology and size of the particles were induced by varying the liquid flow rate. Chattopadhyay and Gupta [6] used the SAS-EM to produce tetracycline nanoparticles as small as 125 nm in size with a narrow size distribution. Chattopadhyay and

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Table 1 Compounds micronized with the GAS Process Component

Solvent

Anti-solvent

Process

Results and observations

Ref.

Carbamazepine (CBZ)

Acetone

CO2

GAS

Moneghini et al. [20]

CBZ + PEG 4000

Acetone

CO2

GAS

Hydrocortisone-PVP

Ethanol

CO2

GAS

Lysozyme

DMSO

CO2

GAS

Copper indomethacin

DMF

CO2

GAS

Copper indomethacin

NMP

CO2

GAS

Copper indomethacin

DMSO

CO2

GAS

b-Carotene

DCM

CO2

GAS

b-Carotene L -PLA + D , L -PLA PMM

Ethyl acetate Chloroform Acetone

CO2 CO2 CO2

GAS GAS GAS

Propolis tincture

Ethanol

CO2

GAS

Cholesterol 1,4-Bis-(n-butylamino)9,10-anthraquinone

Acetone Acetone

CO2 CO2

GAS GAS

Size reduction of CBZ from 284 to 31 lm. Needle-like particles were observed Micronized drug-loaded biodegradable polymer was produced Micronized drug-loaded biodegradable polymer was produced Particles with average size between 50 nm and 1 lm were obtained Particle size: 2–100 lm. Morphology: rhombic or bipyramidal depends on the rate of expansion Clusters of needle-like crystals ranging in size from 50 to 100 lm Clusters of needle-like crystals ranging in size from 50 to 100 lm Particles smaller than 1 lm were obtained Small particles were obtained L -PLA and D , L -PLA were separated PMM with different molecular weights were separated High molecular mass components were precipitated by the GAS process Needle-like crystals were obtained The size of 90% of particles was less than 163 lm

Gupta [51] showed that the factor in the SAS-EM, which could highly control the particle size of the produced powders, is the vibrational intensity of the vibrating surface. Chattopadhyay and Gupta [52] also used the SAS-EM technique to micronize griseofulvin. Park et al. [53] used the PCA process for producing nylon particles. The effects of various operating parameters on the size and the size distribution of particles were examined. However, they did not observe any significant effect of the parameters on the size and size distribution of the produced particles. The PCA process and the influence of its operating variables on the produced materials have also been investigated for the precipitation of cycloolefine copolymers (COC) from a toluene solution by Hsu et al. [54], tartaric acid from different solvents (methanol/ethanol, and acetone) by Kr€ ober and Teipel [55], and insulin from 1,1,1,3,3,3hexafluoro-2-propanol (HFIP) by Snavely et al. [56]. Foster and coworkers have worked on the micronization of different materials applying a process named ASES. However, since they designed a special coaxial nozzle for this process, which sprays both the solution and the anti-solvent simultaneously into the precipitation chamber, it makes this process much more similar to the SEDS process. Therefore, in the following paragraphs, whenever we talk about the ASES micronization by Foster and coworkers, it refers to an ASES process with a coaxial nozzle. Warwick et al. [23] used the ASES process to recrystallize copper indomethacin. They

Moneghini et al. [20] Corrigan and Crean [21] Muhrer and Mazzotti [22] Warwick et al. [23]

Warwick et al. [23] Warwick et al. [23] Cocero and Ferrero [24] Cocero and Ferrero [24] Bothun et al. [26] Coen et al. [27] Catchpole et al. [28] Liu et al. [33] Ventosa et al. [15]

realized that the particles produced from the ASES process have an average size of one fifth of the GASproduced particles. Warwick et al. [23] measured the rate of dissolution of the copper indomethacin in water. They noticed that the rate of dissolution of the ASESproduced particles is eight times higher than the untreated drug, meaning that the processed drug has an eight times higher bioavailability than the untreated drug. They also discussed the parameters that affect the size of the ASES-micronized material. Recently, Sze Tu et al. [57] used the ASES process to micronize and microencapsulate para-hydroxy benzoic acid (p-HBA) and lysozyme with PLA from various organic solutions. The effect of various parameters, such as pressure, temperature solution concentration and spraying velocity on the nature of the particles were determined. They used a multiple nozzle for encapsulating the model drugs by the biodegradable polymer, PLA. They suggested that for reaching higher encapsulation efficiency, the contact between the drug and polymer phases should be maximized during the rapid precipitation process by changing the nozzle geometry. Table 2 summarizes the recent researches about the SAS/PCA/ASES processes. 5.3. The SEDS process In 2001, Kordikowski et al. [58] examined the applicability of the SEDS process for micronizing the poly-

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Table 2 Compounds micronized with the SAS/SAS-EM/PCA/ASES processes Component

Solvent

Antisolvent

Process

Results and observations

Ref.

Insulin/PLA

CO2

SAS

CO2

SAS

CO2

SAS

CO2 CO2

SAS SAS

Rifampicin

DMSO

CO2

SAS

Amoxicillin

NMP

CO2

SAS

EuAc

DMSO

CO2

SAS

GdAc

DMSO

CO2

SAS

Lecithin HYAFF11

Ethanol DMSO

CO2 CO2

SAS SAS

HYAFF11p80

DMSO

CO2

SAS

HYAFF11p75

DMSO

CO2

SAS

HYAFF302

DMSO

CO2

SAS

Vanadium phosphate L -PLA

Isopropanol

CO2

SAS

DCM

CO2

SAS

Diuron

DCM

CO2

SAS

Diuron + L -PLA Sulfathiazole

DCM Acetone

CO2 CO2

SAS SAS

Sulfathiazole

Methanol

CO2

SAS

Chlorpropamide

Acetone

CO2

SAS

Chlorpropamide L -PLA

Ethyl acetate DCM

CO2 CO2

SAS SAS

Tetracycline

THF

CO2

SAS-EM

Lysozyme

DMSO

CO2

SAS-EM

Griseofulvin

DCM

CO2

SAS-EM

Griseofulvin

THF

CO2

SAS-EM

Nylon COC

Formic acid Toluene

CO2 HFC-134a

PCA PCA

Tartaric acid

Acetone

CO2

PCA

Tartaric acid

Methanol/ Ethanol HFIP DMF

CO2

PCA

CO2 CO2

PCA ASES

Insulin-loaded biopolymer. The size of 90% of particles was less than 400–600 nm Insulin-loaded biopolymer. The size of 90% of particles was less than 400–600 nm Insulin-loaded biopolymer. Submicron particles were obtained Particle size: 3–10 lm Rod-like particles. Particle length: 1–3 lm Particle diameter: 0.2–0.35 lm T ¼ 40 C. Particle size: 0.4–1 lm for P P 120 bar Particle size: 2.5–5 lm for 90 < P < 110 bar Non-coalescing spherical microparticles with mode diameters ranging from 0.3 to 1.2 lm depending the concentration of amoxicillin in the liquid solution Spherical particles with mean diameters ranging from 0.2 to 10 lm were obtained Spherical particles with mean diameters ranging from 0.2 to 10 lm were obtained Particle size: 10–50 lm with large PSD Submicronic particles suitable for pharmaceutical applications were obtained The obtained morphology can be suitable for encapsulation applications The obtained morphology can be suitable for encapsulation applications The obtained morphology can be suitable for encapsulation applications Discrete spherical particles ranging between 75 nm and 5 lm in size were produced Spherical particles or polymeric fibers were produced depend on the solution concentration Formation of long needle-like crystals with a mean length of 500 lm Herbicide-loaded biopolymer particles were obtained 90% of the particles are smaller than 15 lm with rapid injection The particle size doubled by changing the solvent from acetone to methanol The shapes of crystals were changed by the type of solvent Platy crystals for the rapid injection mode Microparticles with the mean particle diameter of 1–3 lm were produced Very fine particles with narrow size distribution. Particle size: 125 lm The obtained particles were up to 10-fold smaller than the produced particles by the SAS process Volume-average size of particles: 310 nm. Ultrasound power: 180 W Volume-average size of particles: 210 nm. Ultrasound power: 180 W Mean particle size: 2–3.6 lm HFC-134a was found to be an appropriate anti-solvent for this system Produced particles from acetone solution were smaller than the particles from the alcoholic solution The solution concentration had influence on the morphology of the produced particles Formation of nanospheres 50 nm in size The size of 90% of the particles was less than 10 lm

Elvassore et al. [37]

L -PLA Salbutamol

DCM/DMSO (50:50) DCM/DMSO (50:50) DCM/DMSO (50:50) DCM DMSO

Insulin/PEG/ PLA Insulin/PLA

Insulin Copper indomethacin

Elvassore et al. [37] Elvassore et al. [38] Rantakyl€a et al. [39] Reverchon et al. [40] Reverchon et al. [41] Reverchon et al. [*42]

Reverchon et al. [43] Reverchon et al. [43] Badens et al. [44] Elvassore et al. [45] Elvassore et al. [45] Elvassore et al. [45] Elvassore et al. [45] Hutchings et al. [46] Taki et al. [47] Taki et al. [47] Taki et al. [47] Yeo et al. [48] Yeo et al. [48] Yeo et al. [48] Yeo et al. [48] Carretier et al. [50] Chattopadhyay Gupta [6] Chattopadhyay Gupta [51] Chattopadhyay Gupta [52] Chattopadhyay Gupta [52] Park et al. [53] Hsu et al. [54]

and and and and

Kr€ ober and Teipel [55] Kr€ ober and Teipel [55] Snavely et al. [56] Warwick et al. [23] (continued on next page)

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Table 2 (continued) Component

Solvent

Antisolvent

Process

Results and observations

Ref.

Copper indomethacin Copper indomethacin Para-hydroxybenzoic acid (p-HBA) p-HBA p-HBA p-HBA L -PLA p-HBA + L -PLA

NMP

CO2

ASES

Warwick et al. [23]

DMSO

CO2

ASES

Two distinct particles were formed: (1) Sphere: 20 lm. (2) Irregular: 5 lm Irregular platelet particles were generated

Warwick et al. [23]

Methanol

CO2

ASES

Rhomboidal platelets were formed

Sze Tu et al. [57]

DCM Acetone Ethyl acetate DCM Methanol/DCM

CO2 CO2 CO2 CO2 CO2

ASES ASES ASES ASES ASES

Sze Sze Sze Sze Sze

DMSO DMSO/DCM

CO2 CO2

ASES ASES

Microparticles were produced Needle-like crystals were formed Rod-like crystals were formed Formation of particles with 2 lm in size at 25 C The encapsulation efficiency obtained by the ASES process was rather low Nanospheres were produced Clusters of polymeric microspheres and protein nanospheres were produced

Lysozyme Lysozyme + L -PLA

morph sulfathiazole. Polymorph control is very important in pharmaceutical development since the appearance of different polymorphs can affect shelf life, bioavailability, activity and even toxicity of the pharmaceuticals [59]. To obtain a pure polymorph it is necessary to be able to control the supersaturation. Often a polymorph mixture instead of a pure form is obtained. Frequently, several precipitation and dissolution steps are employed to achieve crystallization of the desired form. Kordikowski et al. [58] showed that the SEDS process can be used successfully for producing certain polymorphs. Variation of temperature and flow rate proved that thermodynamic or kinetic control could be applied to generate certain forms. The choice of solvent also influenced the crystallization of the polymorphic forms. It was apparent that methanol as a hydrogen bond donor possessed a much greater ability to stabilize different forms of sulfathiazole than acetone. Tong et al. [60], used the SEDS process for producing two different micronized polymorphs of salmeterol xinafoate (SX-I and SX-II). Shekunov et al. [61] studied the aerodynamic properties and mechanism of particle dispersion of the supercritically processed SX (S-SX) and compared those properties with the same properties of conventionally micronized SX (M-SX). They used the SEDS process for producing S-SX. CO2 was the antisolvent and between methanol, acetone and tetrahydrofurane, methanol was selected as the solvent because of its higher yield. Their measurements indicated that the fine particle fraction (FPF) of S-SX was twofold greater than that of the M-SX powder. FPF was defined as the mass fraction of particles with diameters between 0.5 and 5 lm and is a general quality control criterion for aerosols. This means that the efficiency of S-SX produced by the SEDS process is much higher than that of M-SX. Shekunov et al. [62], investigated the effect of fluid dynamics on the SEDS process. They theoretically studied the effect of flow rate (expressed

Tu Tu Tu Tu Tu

et et et et et

al. al. al. al. al.

[57] [57] [57] [57] [57]

Sze Tu et al. [57] Sze Tu et al. [57]

through the nozzle Reynolds number and nozzle diameter) on the supersaturation profile and particle size in the SEDS process. As a case study, they experimentally studied the system paracetamol (acetaminophen) + ethanol + CO2 . Shekunov and coworkers [63] used the SEDS process to precipitate acetaminophen from its solution in ethanol using supercritical CO2 . They defined the supersaturation in the jet and the residual effluent fluid and related them to the mean particle size. The system nicotinic acid + methanol + CO2 was experimentally studied by Rehman et al. [64]. They determined the optimum condition for nicotinic acid precipitation. Edwards et al. [65] prepared pure anhydrous polymorphs of CBZ by the SEDS process. They studied the effect of crystallization kinetics, solvent effects and temperature on polymorph generation. The applicability of the SEDS process for the formation of hydrocortisone (HC) particles and for controlling their characteristics through determining the influence of process conditions was explored by Velaga et al. [66]. They showed that the choice of solvent could influence the morphology of the produced HC particles. In addition, they also tested the effect of temperature and pressure on the particle formation of HC. Similar experiments for micronizing budesonide and flunisolide were carried out by Velaga et al. [67]. Recently, Okamoto et al. [68] designed a V-shaped nozzle for precipating a drug from an aqueous solution using the SEDS process. They produced pDNA-loaded particles for pulmonary gene delivery. Chitosan was used for increasing the integrity of plasmid DNA (pDNA) during the crystallization process. They used CO2 as the anti-solvent and water as the solvent. In order to increase the solubility of CO2 in water, they used ethanol. Therefore, an admixture of CO2 and ethanol was sprayed into the particle formation vessel through one end of the V-shaped nozzle and the aqueous solution was sprayed through the other end of the

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379

Table 3 Compounds micronized with the SEDS processes Component

Solvent

Anti-solvent

Process

Results and observations

Ref.

Sulfathiazole

Acetone

CO2

SEDS

Kordikowski et al. [58]

Sulfathiazole

Methanol

CO2

SEDS

SX-I

Methanol

CO2

SEDS

SX-II

Methanol

CO2

SEDS

SX

Methanol

CO2

SEDS

Paracetamol Acetaminophen Nicotinic acid

Ethanol Ethanol Methanol

CO2 CO2 CO2

SEDS SEDS SEDS

CBZ

DCM

CO2

SEDS

CBZ

Methanol

CO2

SEDS

HC

Acetone

CO2

SEDS

HC

Methanol

CO2

SEDS

Budesonide

Methanol

CO2

SEDS

Budesonide

Acetone

CO2

SEDS

Flunisolide anhydrous Flunisolide anhydrous Chitosan–pDNA

Methanol Acetone Water

CO2 CO2 CO2 + ethanol

SEDS SEDS SEDS

Form I or a mixture of Form I and amorphous sulfathiazole were obtained Forms I, III, IV, and their mixtures could be crystallized The produced SX-I shoed the same X-ray diffraction pattern as MSX The produced SX-II was less stable than SX-I particles More than 98% of the particles had mean diameter between 0.5 and 10 lm Final particle size: 10–15 lm Micronized particles were obtained Particle size at optimum condition: 1–4 lm Two forms of polymorphic particles were observed at the operating conditions All polymorphic forms of the CBZ were observed A network of needles was produced irrespective of the operational conditions Flake-like particles were observed at 40 C and 180 bar. But at higher temperatures a mixture of flakes and needles were formed Particles with 5–30 lm in size were formed at the operating conditions Particles with 1–3 lm in size were formed at the operating conditions Polymorphic particles were formed Polymorphic particles were formed A V-shaped nozzle was used for producing the particles

nozzle. In this way the fine particles of chitosan–pDNA were precipitated in the precipitating chamber. The mean particle diameter of the micronized drug was 12– 13 lm. Okamoto et al. [68] noticed that the addition of chitosan reduced the degradation of the drug. The addition of sodium acetate also suppressed the degradation of pDNA during the supercritical CO2 process. Table 3 summarizes the recent researches about the SEDS process. 5.4. The PGSS/CAN-BD/SAA/DELOS/CPCSP processes Rodrigues et al. [69] studied the influence of pressure on the morphology and size distribution of particle composites of hydrogenated palm oil (HPO)/theophylline using the PGSS process. They found that pressure had little influence on the particle size but could determine the morphology. It gave preferentially more spherical particles with higher expansion pressures. The microcomposites produced, had a mean particle size within the range of 2.5–3 lm and contained between 0.5 and 3.5 wt% theophylline. Sievers et al. [8] proposed the CAN-BD process and used it for producing micronized a-lactose, albuterol

Kordikowski et al. [58] Tong et al. [60] Tong et al. [60] Shekunov et al. [61] Shekunov et al. [62] Bristow et al. [63] Rehman et al. [64] Edwards et al. [65] Edwards et al. [65] Velaga et al. [66] Velaga et al. [66]

Velaga et al. [67] Velaga et al. [67] Velaga et al. [67] Velaga et al. [67] Okamoto et al. [68]

sulfate and cromolyn sodium from aqueous solutions. Two methods of aerosolization were used: (1) The dynamic method which utilizes a low-dead volume tee for mixing CO2 and the solution and (2) the static method in which CO2 and the aqueous solution are in contact for times from about half an hour up to a few hours before the expanded aqueous solution is decompressed through the flow restrictor. They produced particles with a volume-average size of about 0.95 lm, which indicates that most of the micronized drug has the ideal size for inhalation. Sievers and coworkers have already applied the CAN-BD process for producing a number of micronized drugs as follows [12,70,71]: budesonide, naproxin, palmitic acid, ovalbumin/trehalose, mannitol, trypsinogen, lactose, lactate dehydrogenase (LDH), lysozyme, rhDNase, cromolyn sodium, cyclosporin, tobramycin sulfate, albeterol sulfate, and ciprofloxacin hydrochloride. Huang et al. [72] micronized betamethasone using the CAN-BD process. Besides water, the solvent of some of the above-mentioned drugs was ethanol or water/ethanol mixture. Reverchon [13] tested the SAA process for producing some different kinds of compounds: superconductor and catalyst precursors, ceramics, and pharmaceutical compounds using some different solvents: water,

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A. Shariati, C.J. Peters / Current Opinion in Solid State and Materials Science 7 (2003) 371–383

methanol, and acetone. He micronized yttrium acetate, aluminium sulfate, zirconyl nitrate hydrate, sodium chloride, dexmethasone, carbamazepine, ampicillin, and triclabenzadol. Reverchon [13] analysed the influence of the concentration of the liquid solution, kind of solvent and nozzle diameter on the particle size and particle size distribution of the SAA-produced powders. The process parameter that mainly controlled the particle size in the SAA process was the concentration of the liquid solution. Particle sizes ranged from 0.1 to 3 lm. Reverchon and Della Porta [73,74] used the SAA process for producing nano- and microsized powders of some water-soluble and/or alcohol-soluble pharmaceutics. The same group [73] applied the SAA process to micronize terbutaline from an aqueous solution. Reverchon and Della Porta [74] used methanol as a solvent for producing rifampicin and water for producing tetracycline. Results show that the SAA process is a promising technique for producing controlled-size drug particles. Ventosa et al. [14,15] tested the DELOS process for producing a colorant (1,4-bis-(n-butylamino)-9,10-

anthraquinone) powder from acetone solution using supercritical CO2 . They could produce submicron and micron-sized particles. They also compared this process with the GAS process. The yield of the DELOS process was much higher than the GAS process. Weidner et al. [17] showed the feasibility of the CPCSP process for producing powder coating particles by applying this process to micronizing low-melting polyester (melting temperature range: 80–90 C). They studied the effect of temperature in the static mixer on the morphology and size distribution of the particles. They also showed the effect of pressure in the static mixer on the size distribution of particles. Table 4 summarizes the recent studies on PGSS and related processes.

5.5. The CAPP process Owens et al. [18,19] proposed and tested the CAPP process for producing cross-linked polyethylene glycol diacrylate (PEGDA). 2,2-dimethoxy-2-phenylacetophe-

Table 4 Compounds micronized with the PGSS/CAN-BD/SAA/DELOS/CPCSP processes Component

Solvent

SCF

Process

Results and observations

Ref.

Theophylline/HPO

Methanol

CO2

PGSS

Rodriguez et al. [69]

Albuterol sulfate a-Lactose Cromolyn sodium Lysozyme

Water Water Water Water

CO2 CO2 CO2 CO2

CAN-BD CAN-BD CAN-BD CAN-BD

LDH Ovalbumin/trehalose Budesonide Palmitic acid Naproxen

CO2 CO2 CO2 CO2 CO2

CAN-BD CAN-BD CAN-BD CAN-BD CAN-BD

Amphotericin B Betamethasone Yttrium acetate Sodium chloride Zinc acetate Aluminium sulfate Zirconyl nitrate Carbamazepine Ampicillin Triclabenzadol Dexamethasone Tetracycline

Water Water Ethanol Ethanol 95% ethanol: 5% water Ethanol Ethanol Water Water Methanol Water Water Methanol Water Methanol Acetone Water

Pressure had no significant effect on the mean diameter of the particles Volume-average particle size: 0.95 lm Spherical particles were produced Volume-average particle size: 0.7 lm All produced powders had significant portion of particles well within the range of 1–3 lm The processed LDH lost 85% of its activity Micronized particles were obtained Mean diameter of particles: 1 lm Mean diameter of particles: 0.65 lm Agglomerates ranging in size from 0.5 to 5 lm

CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2 CO2

CAN-BD CAN-BD SAA SAA SAA SAA SAA SAA SAA SAA SAA SAA

Rifampicin

Methanol

CO2

SAA

Terbutaline

Water

CO2

SAA

1,4-Bis-(n-butylamino)9,10-anthraquinone Polyester

Acetone

CO2

–

CO2

Sievers et al. [8] Sievers et al. [8] Sievers et al. [8] Sellers et al. [70] Sellers et al. [70] Sievers et al. [12,71] Sievers et al. [12] Sievers et al. [12] Sievers et al. [12] Sievers et al. [12] Huang et al. [72] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon [13] Reverchon and Della Porta [74]

DELOS

Mean diameter of particles: about 1 lm Particle size: 400 nm to 5 lm Amorphous spherical particles were obtained Cubic crystals were obtained Amorphous spherical particles were obtained Amorphous spherical particles were obtained Amorphous spherical particles were obtained Micronic needle-like particles were observed Amorphous spherical particles were obtained Irregular crystals were formed Amorphous spherical particles were obtained More than 95% of the particles were between 0.5 and 2 lm for 20 mg/ml concentration of the liquid solution Particle size increased with the concentration of the liquid solution In all cases very regular and homogeneous particles were obtained Micronized particles were produced

CPCSP

Micronized particles were produced

Weidner et al. [17]

Reverchon and Della Porta [74] Reverchon and Della Porta [73] Ventosa et al. [14,15]

A. Shariati, C.J. Peters / Current Opinion in Solid State and Materials Science 7 (2003) 371–383

none was used as the photoinitiator. They noticed that small changes in both the incident light intensity and the initiator concentration had great effects on the resulting morphology of the particles formed by the CAPP process. The intensity of light also had a large influence on particle size distribution. Their study showed that small changes in the final composition of CO2 , monomer, and solvent do not greatly influence the resulting size distribution. They also showed that the phase behavior of CO2 –solvent–monomer has strong effects on the particle formation in the CAPP process.

6. Scaling-up Until now, most of the studies done by researchers on the GAS and related processes have been on the laboratory scale. However, a very important issue for these processes is how to scale them up to industrial scales. For this purpose, accurate thermodynamic, nucleation kinetic, mass transfer, heat transfer and hydrodynamic models for precipitation in such processes are necessary. The current models are mostly correlative rather than predictive. In order to have a predictive model, the influences of different variables in the gas anti-solvent micronization techniques should be studied in advance. This is one of the reasons why many researchers have studied the effects of controlling parameters on the GAS and related processes. Thiering et al. [75] discussed the current issues related to the gas anti-solvent micronization techniques and also the scaling-up of such processes. Muhrer et al. [76] used a larger precipitator to study the crystallization of the same system that they had examined in their previous investigation [77], thus addressing the key issue of scale-up of the GAS recrystallization technique. Their results showed that the produced particles could be obtained reproducibly through a process that could also be scaled-up. Reverchon et al. [*42] used a pilot scale SAS process for micronizing amoxicillin to understand the effects of controlling parameters in larger scale. They mentioned that one of the most important aspects in the SAS process is the role played by the injection system. On the laboratory scale, Reverchon and coworkers [78] used a thin wall injector, while in the pilot scale they used a coaxial injection system plus a large nozzle. They found that different injection systems in terms of diameter and arrangement only slightly affected particle diameters and distributions of amoxicillin powders, whereas, no modification was detected in particle morphology. Recently, Jung et al. [79] studied the scaling-up of a SAS process by pulverizing a model molecule (inulin) from a NMP solution with CO2 as anti-solvent. In their study, they used three different-sized units (1: lab-scale pilot plant with a precipitation vessel of 0.5 l and a CO2

381

flow rate up to 5 kg/h; 2: a larger equipment with a precipitation vessel of 4 l and CO2 flow rate up to 20 kg/h; 3: a commercial scale pilot plant with a precipitation vessel of 50 l and CO2 flow rate up to 500 kg/h). Different important issues (atomization, particle collection, residual solvent stripping from the particles, and fluid purification and recycle) were considered for the scaling-up of the process. They compared the particle size distribution, residual solvent content, and recovery yield of these equipments. Their result showed the same particle size distribution and similar residual solvent contents for all three equipments while recovery yield increased with scale. Another study has recently been conducted by Papet et al. [80] for the scaling-up of a SAS process for precipitation of an active pharmaceutical ingredient (API) with CO2 as anti-solvent, and DMSO as solvent by designing a pilot-scale SAS process capable of producing one ton of API per year. The scaling-up factor between the two apparatuses was about 20. They compared the powders produced by the pilot-scale and lab-scale apparatuses. The dissolution rate of the powder in an aqueous solution of sodium dodecyl sulfate was considered as a criterion for comparison of the results obtained from the different apparatuses. Their results showed that the scaling-up of the SAS process is possible.

7. Conclusions Supercritical fluids offer a wide range of possibilities in the making of particles. While the concepts of GAS and other SCF processes are fairly straightforward, application to commercial processes requires a thorough understanding of the non-ideal behavior of solution expansion by SCF, and the operating variables that affect the rates of nucleation and crystal growth, as well as the physical form of the material. The gas anti-solvent precipitation experiments, which have been carried out for hundreds of systems on the laboratory scale, support the potential and the necessity of further investigation on the GAS and other SCF processes for particle design processes as replacement techniques for the conventional techniques such as jet milling. References The papers of particular interest have been highlighted as: * of special interest; ** of outstanding interest. [*1] M€ uller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy rationale for development and what we can expect for the future. Adv Drug Delivery Rev 2001;47:3.

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