Review Particle design using supercritical ï¬‚uids: Literature and

Journal of Supercritical Fluids 20 (2001) 179–219

Review

Particle design using supercritical fluids: Literature andpatent survey

Jennifer Jung, Michel Perrut *SEPAREX-LAVIPHARM 5, rue Jacques Monod 54250, Champigneulles, France

Received 21 November 1999; received in revised form 10 October 2000; accepted 28 December 2000

Abstract

As particle design is presently a major development of supercritical fluids applications, mainly in the pharmaceuti-cal, nutraceutical, cosmetic and specialty chemistry industries, number of publications are issued and numerouspatents filed every year. This document presents a survey (that cannot pretend to be exhaustive!) of publishedknowledge classified according to the different concepts currently used to manufacture particles, microspheres ormicrocapsules, liposomes or other dispersed materials (like microfibers):

RESS: This acronym refers to ‘Rapid Expansion of Supercritical Solutions’; this process consists in solvating theproduct in the fluid and rapidly depressurizing this solution through an adequate nozzle, causing an extremely rapidnucleation of the product into a highly dispersed material. Known for long, this process is attractive due to theabsence of organic solvent use; unfortunately, its application is restricted to products that present a reasonablesolubility in supercritical carbon dioxide (low polarity compounds).

GAS or SAS: These acronyms refer to ‘Gas (or Supercritical fluid) Anti-Solvent’, one specific implementation beingSEDS (‘Solution Enhanced Dispersion by Supercritical Fluids’); this general concept consists in decreasing the solventpower of a polar liquid solvent in which the substrate is dissolved, by saturating it with carbon dioxide in supercriticalconditions, causing the substrate precipitation or recrystallization. According to the solid morphology that is wished,various ways of implementation are available:

GAS or SAS recrystallization: This process is mostly used for recrystallization of solid dissolved in a solvent withthe aim of obtaining either small size particles or large crystals, depending on the growth rate controlled by theanti-solvent pressure variation rate;

ASES: This name is rather used when micro- or nano-particles are expected; the process consists in pulverizing asolution of the substrate(s) in an organic solvent into a vessel swept by a supercritical fluid;

SEDS: A specific implementation of ASES consists in co-pulverizing the substrate(s) solution and a stream ofsupercritical carbon dioxide through appropriate nozzles.

PGSS: This acronym refers to ‘Particles from Gas-Saturated Solutions (or Suspensions)’: This process consists in

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J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219180

dissolving a supercritical fluid into a liquid substrate, or a solution of the substrate(s) in a solvent, or a suspensionof the substrate(s) in a solvent followed by a rapid depressurization of this mixture through a nozzle causing theformation of solid particles or liquid droplets according to the system.

The use of supercritical fluids as chemical reaction media for material synthesis. Two processes are described:thermal decomposition in supercritical fluids and hydrothermal synthesis.

We will successively detail the literature and patents for these four main process concepts, and related applicationsthat have been claimed. Moreover, as we believe it is important to take into account the user’s point-of-view, we willalso present this survey in classifying the documents according three product objectives: particles (micro- or nano-)of a single component, microspheres and microcapsules of mixtures of active and carrier (or excipient) components,and particle coating. © 2001 Elsevier Science B.V. All rights reserved.

Keywords: Particle design; supercritical fluids; literature and patent

Fig. 1. RESS equipment concept.

1. Part 1: Rapid expansion of supercriticalsolutions (RESS)

1.1. Concept

As presented on Fig. 1, the Rapid Expansion ofSupercritical Solutions consists in saturating asupercritical fluid with the substrate(s), then de-pressurizing this solution through a heated nozzleinto a low pressure chamber in order to cause anextremely rapid nucleation of the substrate(s) inform of very small particles — or fibers, or filmswhen the jet is directed against a surface — thatare collected from the gaseous stream.

The pure carbon dioxide is pumped to thedesired pressure and preheated to extraction tem-perature through a heat exchanger. The supercrit-ical fluid is then percolated through the extractionunit packed with one or more substrate(s), mixedin the same autoclave or set in different auto-

claves in series. In the precipitation unit, thesupercritical solution is expanded through a noz-zle that must be reheated to avoid plugging bysubstrate(s) precipitation.

The morphology of the resulting solid materialboth depends on the material structure (crystallineor amorphous, composite or pure, …) and of theRESS parameters (temperature, pressure drop,distance of impact of the jet against the surface,dimensions of the atomization vessel, nozzle ge-ometry, ….) [6–9,11,24,25,29,31,36,40,46,56,61].It is to be noticed that the initial investigationsconsisted in ‘pure’ substrates atomization in orderto obtain very fine particles (typically of 0.5–20�m diameter) with narrow diameter distribution,meanwhile the most recent publications are re-lated to mixture processing in order to obtainmicrocapsules or microspheres of an active ingre-dient inside a carrier.

J. Jung, M. Perrut / J. of Supercritical Fluids 20 (2001) 179–219 181

This concept can be implemented in relativelysimple equipment although particle collectionfrom the gaseous stream is not easy. But theapplications are limited as most attractive sub-strates are not soluble enough into the supercriti-cal fluid to lead to profitable processes: aco-solvent may be used to improve this solubility,but it shall be eliminated from the resulting pow-der, what is not simple and cheap. Nevertheless,we think that RESS should always be consideredat first, as it is much less costly to use thanSAS/SEDS, … when it works!

1.2. History

There is no doubt that the basic concept ofRESS was first described by the pioneers Hannayand Hogarth [1], … 120 years ago: ‘When thesolid is precipitated by suddenly reducing pres-sure, it is crystalline, and may be brought down asa ‘snow’ in the gas, or on the glass as a ‘frost’, …’!As stated by Krukonis in 1981 [3], ‘Maybe we canuse this phenomenon as a way of tailoring the sizeand size distribution of difficult-to-comminute or-ganic materials’.

However, this concept was really understoodand developed after the pioneering works ofKrukonis [4] and especially the Battelle Instituteresearch team [6-9,11] that described and modeledthe flow pattern and nucleation process.

1.3. Patents

In fact, very few patents has been filed onRESS apparatus or applications:� Smith of Battelle Institute [6,11] patented in 1983

processes and apparatus for depositing a film ofsolid material on a surface, or forming a finepowder of solid material, according to the RESSconcept. This was the result of a very detailedresearch work on pulverization of supercriticalfluids or mixtures [7] published later. This patentdetails several types of nozzles. Two systems arecited as examples: polystyrene in pen-tane:cyclohexanol (98:2) mixture, and silica inwater.

� A German patent [2] filed in 1979 might also beconsidered as a RESS application: Best et al.

claimed production of very fine crystals of sev-eral carotenoids using several fluids and co-sol-vents; however, the expansion of thesupercritical solutions is not operated exactly asin RESS, but after dispersion of these solutionsinto an aqueous colloidal matrix that is furtherdepressurized to atmospheric pressure.

� In 1991, Leibovitz of Hewlett-Packard [18]patented a process using supercritical carbondioxide for producing highly accurate and ho-mogeneous powder mixture used in high qualityceramic superconductors formation.

� In 1990, Sievers [16] developed a method, calledsupercritical fluid transport chemical deposition(SFT-CD), for deposition of films fromlipophilic precursors, which are dissolved in asupercritical fluid. The solution is caused torapidly expand through a restrictor forming avapor or dense aerosol, which is directed ontoa heated surface where thermally induced sur-face reactions take place. A variety of metal andmetal oxide thin films, including Pd, Cu, Al, Cr,In, Ag, YBa2Cu3O7−x, have been deposited bythis method using various supercritical solvents,such as, diethylether, pentane, acetone, N2O andCO2 [17,21].

� In two other patents [28,32] filed first in 1992,Sievers described a new method using supercrit-ical fluids for delivery of pharmaceutical agentsdirectly to the lung. The physiology active soluteis dissolved into a suitable supercritical fluid,aerosolized by rapid expansion of the resultingsupercritical solution through a nozzle and di-rectly administered to a subject via inhalation.Production of particles of diameter lower than6.5 �m is claimed using this supercritical fluiddrug delivery (SFDD) technique. Claim 1 of theEuropean patent [28] is broader than the USPatent claims [32] and does not refer to drugdelivery, but rather only the preparation of amedicament by RESS for aerosol delivery.

� In 1996, Mishima [35] claimed the formation ofpolymeric microcapsules by a process calledrapid expansion from supercritical solution witha non solvent (n-RESS). A polymer dissolved inthe supercritical fluid containing a co-solvent issprayed at atmospheric pressure. The co-solventhas to be chosen in order to increase the polymer


solubility into the supercritical fluid but must bea non solvent of the polymer at atmosphericpressure to avoid particles agglomeration. Mi-crocapsules formation is claimed by making asuspension of active principle in the supercriticalsolution of polymer. In further publications[41,58], Mishima described the encapsulation of3-hydroxyflavone with Eudragit E-100 orPolyethylene glycol 6000, using the process de-scribed in this patent.

� Combes et al. [38] patented in 1997 a process forpreparing toner additive sub-micronic wax par-ticles by expanding a heated supercritical solu-tion of wax. Polypropylene and polyethyleneparticles formation is described using differentsupercritical solvents: ethane, propane, butane,pentane, isobutane, carbon dioxide andchlorodifluoromethane.

� In the pharmaceutical field, Godinas et al. [45]used the RESS process for preparing suspen-sions of sub-micron particles of water-insolubledrugs. The water-insoluble drug is dissolved ina compressed gas solvent with a surface modifierand the resulting solution is expanded into anaqueous solution containing a second surfacemodifier. This process leads to stabilizedaqueous suspensions of water-insoluble drugswith a particle size of 50–2000 nm and a narrowsize distribution. Formation of a fine suspensionof fenofibrate with a mean particle size of 200nm, by expanding a solution containing fenofi-brate, Lipoid-80 and Tween-80 in water, isclaimed. An other example describes the expan-sion of a carbon dioxide solution of cyclosporineand Tween-80 into an aqueous dispersion of eggphospholipid and mannitol that leads to atranslucent aqueous suspension of about 23 nmparticle size.

� In 1998, A. Bausch et al. [44] claimed a techniquewhere a biologically active compound is dis-solved under elevated pressure in a compressedgas, liquid or supercritical fluid containing asurface modifier or in compressed dimethyletheroptionally containing a surface modifier. In aspecial embodiment, the resulting solution isthen rapidly expanded thereby precipitating thedissolved compound. The formation of twoactive principle powders is described. Tetrahy-

drolipstatin particles formation with an averageparticle size of 1.5 �m is claimed by dissolvingthe active principle and a surface modifier (Brij,96) in supercritical CO2 and expanding thesolution in water. Particles of a second activeprinciple, Saquinavir, is also described: a super-critical dimethylether solution of the active anda surfactant (aerosol OT or Brij, 96) is expandedin water and leads to particles of diameter 1–3�m, depending on the conditions.

1.4. Publications

As shown on the following Table 1, manypublications are related to atomization of pharma-ceutical products, either to obtain very fine parti-cles, or microcapsules of an active into acarrier/excipient.

Moreover, micronic particles are typically ob-tained with the RESS process, but some examplesreport nanometric particles formation using appro-priate nozzles (benzoic acid [39] or cholesterol [49]).

It is to be noticed that only few examples werepublished on application of RESS to microspheresgeneration. For example, Debenedetti [22] suc-ceeded in encapsulating an anticholesterol druginto PLA, or more recently, Mishima [41, 58]reported the formation of microspheres of flavonesembedded in an excipient.

1.5. Future de�elopment

RESS is a very attractive process as it is simpleand relatively easy to implement at least at smallscale when a single nozzle can be used; however,extrapolation to a significant production size re-quires either a multi-nozzle system or use of aporous sintered disk through which pulverizationoccurs, in both the cases, particle size distributionis not easy to control, and may be much wider thanin the case of a single nozzle. Moreover, particleharvesting is complex, as it is in any process leadingto very small particles.

But, the most important limitation of RESSdevelopment lies in the too low solubility of com-pounds in supercritical fluids, what precludes pro-duction at acceptable costs, as, in most cases, useof a co-solvent to increase solubility in the fluid isnot feasible.


Table 1Compounds atomized with the RESS processa

Substrates Results and observations ReferencesSupercriticalfluid

Polymers and biopolymersKrytoxdiamide of CO2 Droplet size: from 0.6 to 4.5 �m with an Chernyak, 2000 [54]

average size of 2.8 �mhexamethylene (KRYTOX)Chlorodifluoro- Powder or fibers depending on the conditions Lele, 1992 [24]Polycaprolactonemethane

�0.1-�m-diameter particles or 1-�m-diameterPentanePoly(carbosilane) Matson, 1987 [7,8]fibers of 80–160 �m lengthFormation of a stable aqueous latex withCO2 Shim, 2000 [59]Poly(2-ethylhexyl acrylate)particles of diameter: 2–5 �m

Poly(heptadecafluorodecyl- CO2 Particle size: 0.1–5 �m Blasig, 2000 [52]acrylate)

Spherical and ‘cornflakes’ particles with aCO2Poly-l-lactic acid (l-PLA) Tom, 1991 [19]length of 4–10 �mVariety of morphology: microparticles of 10–25CO2+1 wt.% Tom, 1991 [19]

acetone �m (T=15–37°C), dendrites of up to 100 �m(50°C)0.5–1.0 �m-diameter particles or 1-�m diameterPropane Matson, 1987 [7,8]Poly(methylmethacrylate)fibers of 100–1000 �m length

Chlorodifluoro- Powder or fibers depending on the conditions Lele, 1992 [24]methane

Agglomerated spheres (each sphere of 0.5 �mPropane Matson, 1987 [7,8]Poly(phenyl sulfone)diameter)Small fibers of diameter 1–5 �mPolypropylene Krukonis, 1984 [4]CO2

0.5–1.0 �m-diameter spheres or 1 �m-diameterPentane Matson, 1987 [8]fibers of 100–1000 �m length

Pentane Petersen, 1987 [9]Pentane Petersen, 1987 [9]PolystyrenePentane 20-�m diameter spheres or 1-�m diameter Matson, 1987 [8]

fibers of 100–1000 �m lengthPentane+2% Particle size: 0.3 �m with extremely narrow Smith, 1983 [6]

size distributioncyclohexanolPoly(vinyl chloride), KI 7 �m diameter spheresEthanol Matson, 1987 [7]

Inorganic and organic materialsFormation of a silver film after reaction atAcetone Hansen, 1992 [21]AgI600°CFormation of a silver film after reaction atDiethyl etherAg triflate Hansen, 1992 [21]600°CFormation of an aluminium film after reactionPentane Hansen, 1992 [21]Al(hfa)3

at 680°CFormation of a Al2O3 film after reaction atN2O Hansen, 1992 [21]100°CChange in morphology from 20-�m hexagonalAnthracene Nagahama, 1997 [42]CO2

particles to 45-�m dendritic particles with anincrease in the dilutionTablets of size: 5–20 �mCO2 Subra, 1998 [48]Particle size with a capillary nozzle: 2–8 �mCO2 Domingo, 1997 [39]Benzoic acidWith a sintered nozzle: 0.2–0.3 �mSpherical particles with diameter: 20–40 �m Peirico, 1998 [47]CO2

Particle size: 0.5–1.1 �mCO2 Turk, 1999 [50]Trifluoro- Particle size: 0.4–1.4 �m Turk, 1999 [50]methane


Table 1 (Continued)

Supercritical fluidSubstrates Results and observations References

Particle size: 2–7 �mBenzoic Acid Krober, 2000 [57]CO2

Tablet-like core with sprouting needles Subra, 1998 [48]Caffeine+anthracene CO2

Formation of a chromium film after reactionAcetone Hansen, 1992 [21]Cr(acac)3

at 800°CN2OCr(hfa)3 Formation of a Cr2O3 film after reaction at Hansen, 1992 [21]

100°CPentaneCu(oleate)2 Formation of a copper film after reaction at Hansen, 1992 [21]

740°CFormation of a copper film after reaction atN2OCu(thd)2 Hansen, 1992 [21]700°CFormation of a CuO film after reaction atN2O Hansen, 1992 [21]100°C5 �m agglomerates or 0.5–0.3 �m-diameterGeO2 Matson, 1987 [7]Waterspheres depending on preexpansiontemperature

In(acac)3 CO2 Formation of an indium film after reaction at Hansen, 1992 [21]600°C

Naphtalene CO2 45°C/220 bar � particle size: 30–135 �m Mohamed, 1989 [13,14]Matson, 1987 [7]55°C/350 bar � Particle size: 4–38 �m Particle

size: 0.5–3 �mNi(thd)2 Formation of a nickel film after reaction atPentane Hansen, 1992 [21]

600°CParticle size: 0.3–1 �mCO2 Sievers, 1993 [28]Oil Blue N (organic dye)A supercritical ammonia/Pb(NO3)2 solution is Sun, 2000 [60]AmmoniaPbSexpanded in a solution of NaS in ethanol toproduce PbS nanoparticles with an averageparticle size of 4 nm

Pd(tod)2 Formation of a palladium film after reaction atPentane Hansen, 1992 [21]Hybertson, 1991 [17]600°C

CO2Phenanthrene Particle size: 5 �m Shaub, 1991 [20]Particle size: 10–25 �mCO2 Nagahama, 1997 [42]

CO2 Particle size 1–5 �m Domingo, 1997 [39]CO2Phenanthrene+Anthracene Particle composed of homogeneous crystals Nagahama, 1997 [42]

Product morphology: �1.0-�m thick film andWater Matson, 1987 [7]SiO2

0.1–0.5 �m diameter spheresFormation of a SiO2 film after reaction atN2O Hansen, 1992 [21]Si(OC2H5)4

100°C20-�m agglomeratesSiO2, KI Matson, 1987 [7]WaterFormation of an yttrium film after reaction atN2OY(thd)3 Hansen, 1992 [21]687°C

PentaneY(thd)3+Cu(thd)2 Formation of a (Yba2Cu3O7−x) film after Hansen, 1992 [21]reaction at 800°C

+Ba5(thd)9(H2O)3OHParticle size: 0.1 �mEthanol Matson, 1987 [7]ZrO(NO3)2

Zr(tfa)4 Diethyl ether Formation of a zyrconium film after reaction Hansen, 1992 [21]at 600°C

Pharmaceutical compoundsAspirin CO2 Capillary nozzle: 2–5 �m Domingo, 1997 [39]Caffeine CO2 Needles of size: 3–5 �m Subra, 1998 [48]

Particle size: 0.3–0.5 �mCO2 Krober, 1999/2000 [49,57]CholesterolParticle size: 2–3 �m Sievers, 1993 [28]

CO2+EtOH Sievers, 1993 [28]Dipalmitoylphosphatidyl-Choline (DPPC)

Particle size: less than 1 �m Krukonis, 1984 [4]�-estradiol CO2


Table 1 (Continued)

Substrates Supercritical fluidResults and observations References

CO2+ethanol Polymeric microspheres with flavone coresFlavone and Mishima, 1997 [41]Particle size: 10 �m3-Hydroxyflavone+PEG

CHF3 Reverchon, 1995 [33]GriseofulvinPeirico, 1998 [47]Hydrogenated palm oil CO2

CO2+Ethanol The 3-hydroxyflavone is coated thoroughly by3-Hydroxyflavone+Eudragit Mishima, 2000 [58]the polymerE-100Capillary nozzle: less than 2 �mIbuprofen CharoenchaitrakoolCO2

1999-2000, [51,53]Lazaroid compound U-74389F Sievers, 1993 [28]CO2+EtOHLecithin CO2 Particle size: 1 �m Krukonis, 1984 [4]Lidocaine CO2 Particle size around 100 nm with spherical shape Frank, 2000 [55]

Particle size: 0.1–1 �mCO2 Mohammed, 1989 [14]MevinolinCO2+5 wt.% Particle size: 10–50 �m Larson, 1986 [5]MeOH

Particle size: 1–3 �mNifedipin Stahl, 1988 [12]CO2

Microspheres containing needles of lovastatinPLA+lovastatin Debenedetti, 1993 [22]CO2

CO2 Kim, 1996 [34]PLA+naproxenPLA+pyrene Debenedetti, 1994 [30]CO2

Particle size: 2–5 �mCO2 Coffey, 1988 [10]ProgesteroneSalicylic acid Varying conditions, a wide range of particlesCO2 Reverchon, 1993 [26,27]

were obtained: particles with diameters from 1to 5 �m and length from 1 to 170 �m

CO2 Capillary nozzle: 2–5 �m Sintered nozzle: 1–2 Domingo, 1997 [39]�mWhisker-like crystalsStigmasterol Ohgaki, 1990 [15]CO2

Testosterone CO2 Particle size: 2–5 �m Coffey, 1988 [10]Needles of length 4–12 �m and diameter: 0.9 �mCO2 Subra, 1996 [37]Theophyllin

CO2 Particle size: 1–2 �m Hybertson,1993 [23]�-tocopherolSievers, 1993 [28,32]

Particle size: 5–50 �m Peirico, 1998 [47]CO2Tropic acid ester

a Abbreviations used. thd, bis(2,2,6,6-tetramethyl-3,5-heptanedionato); acac, tris(2,4-pentandionato); hfa, tris (1,1,1,5,5,5-hex-afluoro-2,4-pentanedionato); tfa: tetrakis(1,1,1-trifluoro-2,4-heptanedionato); tod, bis(2,2,7-trimethyl-3,5-octanedionato).

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[40] C. Domingo, F.E. Wubbolts, R. Rodriguez-Clemente, G.M.van Rosmalen, Rapid Expansion of Supercritical TernarySystems : Solute+Cosolute+CO2. The 4th InternationalSymposium on Supercritical Fluids, 11–14 May, Sendai(Japan), 1997, 59–62.

[41] K. Mishima, K. Matsuyama, H. Uchiyama, M. Ide,Microcoating of Flavone and 3-Hydroxyflavone with Poly-mer Using Supercritical Carbon Dioxide. The 4th Interna-tional Symposium on Supercritical Fluids, 11–14 May,Sendai (Japan), 1997, 267–270.

[42] K. Nagahama, G.T. Liu, Supercritical Fluid Crystallizationof Solid Solution. The 4th International Symposium onSupercritical Fluids, 11–14 May, Sendai (Japan), 1997,43–46.

[43] J. Robertson, M.B. King, J.P.K. Seville, D.R. Merrifield,P.C. Buxton, Recrystallisa-tion of Organic Compoundsusing Near Critical Carbon Dioxide. The 4th InternationalSymposium on Supercritical Fluids, 11–14 May, Sendai(Japan), 1997, 47–50.

[44] A. Bausch, P. Hidber, Patent EP 9902316, WO 9952504,1998.

[45] A. Godinas, I.B. Henriksen, V. Krukonis, K.A. Mishra,G.W. Pace, G.M. Vachon, Patent US 0089852, 1998 andWO 9965469, 1999.


[46] H. Ksibi, Effect of Small Capillaries on the Hydrody-namic Conditions in the RESS Process. Proceedings ofthe 5th Meeting on Supercritical Fluids, Tome 1; M.Perrut, P. Subra (Eds.), ISBN 2-905-267-28-3, 23–25March, Nice (France), 1998, 319–324.

[47] N.M. Peirico, H.A. Matos, E. Gomez de Azevedo, Pro-duction of Drug-Biocompatible Polymer Microsize Com-posites by RESS with Supercritical CO2. Proceedings ofthe 5th Meeting on Supercritical Fluids, Tome 1; M.Perrut, P. Subra (Eds.) ISBN 2-905-267-28-3, 23–25March, Nice (France), 1998, 313–318.

[48] P. Subra, P. Boissinot, S. Benzaghou, Precipitation ofPure and Mixed Caffeine and Anthracene by Rapid Ex-pansion of Supercritical Solutions. Proceedings of the 5thMeeting on Supercritical Fluids, Tome 1; M. Perrut, P.Subra (Eds.), ISBN 2-905-267-28-3, 23-25 March, Nice(France), 1998, 307–312.

[49] H. Krober, U. Teipel, H. Krause, Formation of Submi-cron Particles by Rapid Expansion of Supercritical Solu-tions. GVC-Fachausschu� ‘High Pressure ChemicalEngineering’, 3–5 March, Karlsruhe (Germany), 1999,247–250.

[50] M. Turk, B. Helfgen, S. Cihlar, K. Schaber, Experimentaland Theoretical Investigations of the Formation of SmallParticles from the Rapid Expansion of Supercritical Solu-tions (RESS). GVC-Fachausschu� ‘High Pressure Chemi-cal Engineering’, 3–5 March, Karlsruhe (Germany), 1999,243–246.

[51] M. Charoenchaitrakool, F. Dehghani, N.R. Foster, Mi-cronisation of Ibuprofen Using the Rapid Expansion ofSupercritical Solutions (RESS) Process. CISF 99, fifthConference on Supercritical Fluids and their applications,13–16 June, Garda (Italy), 1999, 485–492.

[52] A. Blasig, C.W. Norfolk, M. Weber, M.C. Thies, Process-ing Polymers by RESS: The Effect of Concentration onProduct Morphology. Proceedings of the 5th Interna-tional Symposium on Supercritical Fluids, 8-12 April,Atlanta (USA), 2000.

[53] M. Charoenchaitrakool, F. Dehghani, N.R. Foster, Mi-cronization by RESS to enhance the Dissolution Rates ofPoorly Water Soluble Pharmaceuticals. Proceedings ofthe 5th International Symposium on Supercritical Fluids,8–12 April, Atlanta (USA), 2000.

[54] Y. Chernyak, R.K. Franklin, J.R. Edwards, R.D. Gould,J.M. DeSimone, R.G. Carbonell, Delivery of Perfluoro-polyether Coatings from Homogeneous Solution in CO2

by the Rapid Expansion of Supercritical Solution (RESS)Process. Proceedings of the 5th International Symposiumon Supercritical Fluids, 8–12 April, Atlanta (USA),2000.

[55] S.G. Frank, C. Ye, Small particle formation and dissolu-tion rate enhancement of relatively insoluble drugs usingrapid expansion of supercritical solutions (RESS) process-ing. Proceedings of the 5th International Symposium onSupercritical Fluids, 8–12 April, Atlanta (USA), 2000.

[56] D.M. Ginosar, W.D. Swank, R.D. McMurtrey, W.J.Carmack, Flow-Field Studies of the RESS Process. Pro-

ceedings of the 5th International Symposium on Super-critical Fluids, 8–12 April, Atlanta (USA), 2000.

[57] H. Krober, U. Teipel, H. Krause, The Formation of SmallOrganic Particles Using Supercritical Fluids. Proceedingsof the 5th International Symposium on Supercritical Flu-ids, 8–12 April, Atlanta (USA), 2000.

[58] K. Mishima, K. Matsuyama, S. Yamauchi, H. Izumi, D.Furudono, Novel Control of Crystallinity and CoatingThickness of Polymeric Microcapsules of Medicine byCosolvency of Supercritical Solution. Proceedings of the5th International Symposium on Supercritical Fluids, 8–12 April, Atlanta (USA), 2000.

[59] J. Shim, M.Z. Yates, K.P. Johnston, Latexes Formed byRapid Expansion of Polymer/CO2 Suspensions into Wa-ter. Proceedings of the 5th International Symposium onSupercritical Fluids, 8–12 April, Atlanta (USA), 2000.

[60] Y.P. Sun, R. Guduru, F. Lin, T. Whiteside, Preparationof Nanoscale Semiconductors through the Rapid Expan-sion of Supercritical Solution (RESS) into Liquid Solu-tion. Proceedings of the 5th International Symposium onSupercritical Fluids, 8–12 April, Atlanta (USA), 2000.

[61] M. Weber, M.C. Thies, Improving the Prediction ofParticle Sizes in RESS. Proceedings of the 5th Interna-tional Symposium on Supercritical Fluids, 8–12 April,Atlanta (USA), 2000.

2. Part 2: Supercritical anti-solvent and relatedprocesses (GAS/SAS/ASES/SEDS)

2.1. Concept

In this process, the supercritical fluid is used asan anti-solvent that causes precipitation of thesubstrate(s) dissolved initially in a liquid solvent.

The solute is recrystallized from solution in oneof the three ways.� In the first method, a batch of solution is

expanded several-fold by mixing with a densegas in a vessel (Fig. 2). Due to the dissolutionof the compressed gas, the expanded solventhas a lower solvent strength than the puresolvent. The mixture becomes supersaturatedand solute precipitates in microparticles. Thisprocess has been called gas anti-solvent (GAS)or supercritical anti-solvent 1 (SAS) recrystal-

1 Note: It is to be noticed that the term ‘supercritical’ maybe improper in regard with its exact meaning according tothermodynamic definition; it would be more accurate to use ‘afluid at supercritical pressure’, or ‘at a pressure over its criticalpressure’.


lization. As shown on Fig. 2, the precipitator ispartially filled with the solution of active sub-stance. CO2 is then pumped up to desiredpressure and introduced in the vessel, prefer-ably from the bottom to achieve a better mix-ing of the solvent and anti-solvent. After aholding time, the expanded solution is drainedunder isobaric conditions to wash and cleanthe precipitated particles.

� The second method involves spraying the solu-tion through an atomization nozzle as finedroplets into compressed carbon dioxide (Fig.3). The dissolution of the supercritical fluidinto the liquid droplets is accompanied by alarge volume expansion and, consequently, areduction in the liquid solvent power, causing asharp rise in the supersaturation within theliquid mixture, and the consequent formationof small and uniform particles.The supercriticalfluid is pumped to the top of the high pressurevessel by a high pressure pump. Once the sys-tem reaches steady state (temperature and pres-sure), the active substance solution isintroduced into the high pressure vesselthrough a nozzle. To produce small liquiddroplets in the nozzle, the liquid solution ispumped at a pressure higher (typically �20

bar) than the vessel operating pressure. Parti-cles are collected on a filter at the bottom ofthe vessel. The fluid mixture (supercritical fluidplus solvent) exits the vessel and flows to adepressurization tank where the conditions(temperature and pressure) allow gas-liquidseparation. After collection of a sufficientamount of particles, liquid solution pumping isstopped and pure supercritical fluid continuesto flow through the vessel to remove residualsolvent from the particles. This spray processhas been called aerosol solvent extraction sys-tem (ASES) process.

� The third method, known as solution enhanceddispersion by supercritical fluids (SEDS) wasdeveloped by the Bradford University [18] inorder to achieve smaller droplet size and in-tense mixing of supercritical fluid and solutionfor increased transfer rates. Indeed the super-critical fluid is used both for its chemical prop-erties and as ‘spray enhancer’ by mechanicaleffect: a nozzle with two coaxial passages al-lows to introduce the supercritical fluid and asolution of active substance(s) into the particleformation vessel where pressure and tempera-ture are controlled (Fig. 4). The high velocityof the supercritical fluid allows to break up the

Fig. 2. GAS/SAS equipment concept.


Fig. 3. ASES equipment concept.

Fig. 4. SEDS equipment concept.


solution into very small droplets. Moreover,the conditions are set up so that the supercriti-cal fluid can extract the solvent from the solu-tion at the solution at the same time as it meetsand disperses the solution. Similarly, a variantwas recently disclosed by University of Kansas[31], where the nozzle design leads to sonicwaves development leading to very tiny parti-cles around 1 �m.These three processes, thatcan lead to micro-/nano-particles, are adequatefor processing solids which are difficult to dis-solve into supercritical fluids (RESS is impossi-ble), or are sensitive to high shear stress such aspeptides or proteins [12,20,45,51]. Moreover,addition of a carrier (often a polymer) to theactive solution can lead to the formation ofactive substance-loaded micro-/nano-spheres.

2.2. History

The origin of the GAS process is the statementthat the absorption of a gas in a liquid occurswith an expansion of the liquid. In particular,when a solution is expanded sufficiently by a gas,the liquid phase is no longer a good solvent forthe solute and nucleation occurs. As far as 1954,in its pioneering work on binary and ternarysystems involving liquid carbon dioxide, Francis[1] clearly stated the GAS concept: ‘CO2 exerts ademixing or precipitating effect’ and ‘the precipi-tation action (of CO2) is recognized in at leastseven patents’. McHugh et al. [2,3] used a gaseousanti-solvent to reduce the lower critical solutiontemperature of polymer solutions to concentratepolymers. Then, Gallagher et al. [6] demonstratedthat the rate of addition of a gas anti-solvent maybe programmed to control crystal morphology,size, and size distribution over a wide range. Theyapplied this property to recrystallize difficult-to-handle explosives. It seems that powder genera-tion through dispersion of a liquid solution into asupercritical fluid firstly appeared in a patent ap-plication of Schmitt [5] filed in 1988.

2.3. Patents

� Krukonis et al. [7] patented a method for recrys-tallizing solid materials using a new technique:

the GAS process. Supercritical fluids had al-ready been investigated for nucleation process(RESS), but the solid to be recrystallized had tobe soluble in the supercritical fluid. In the GASprocess, the supercritical fluid is used as ananti-solvent for processing solids that are insol-uble in supercritical fluids. The process exploitsthe ability of gases or supercritical fluids todissolve in organic liquids and to lower thesolvent power of the liquid for the solid insolution, thus causing the solid to precipitate.The near critical or supercritical fluid is intro-duced in a vessel containing an organic solventin which the solid to be crystallized is dissolved,causing intimate mixing of the fluid and theliquid and resulting in liquid expansion andparticles precipitation. This patent was the re-sult of a detailed work about recrystallization ofan extremely sensitive explosive (RDX).In asecond patent [9], filed in 1992, the GAS processis used for the crystallization and the separationof two explosives; RDX and HMX.

� In 1988, Schmitt [5] patented a variant of theGAS process, the solid to be finely divided isdissolved in the liquid carrier and then injectedto a volume of anti-solvent sufficient to precip-itate the solid. In this process, the injection ofthe solution in the anti-solvent leads to a highanti-solvent/liquid solution ratio compared withthe GAS process. As a result, contacting, mix-ing and diffusion occur on a fast time scale andthe solid precipitates out of the mixture as smallparticles. If contacting was operated at a slowerrate (such as in GAS process where anti-solventis slowly added to the solution), then largersized particles of precipitated solid would form.This patent described the basis of the ASES, butno specific system for liquid injection is claimed.Triamcinolone particles of diameter 5–10 �mfrom THF solution were processed.

� In 1987, Fischer and Muller [4] patented aprocess in which a solution containing an activesubstance and a carrier is contacted with asupercritical fluid, leading to particles forma-tion consisting of microspheres of carrier inwhich are imbedded the active substance. Thepatent discloses a number of ways in which thefluids can be contacted with one another and


describes the formation of particles during orafter the contact step.

� Later, Debenedetti et al. [8] patented a processfor the formation of protein particles, based onthe ASES process. A protein solution is in-jected at the top of a crystallizer through alaser-drilled platinum disc to produce a finespray. Catalase and insulin particles were ob-tained with 1–5 �m size.

� The Bradford University [18] patented the pro-duction of very fine particles using the SEDStechnique previously described. Formation ofvery fine particles of salmeterol xinafoate,cobaltous nitrate and nickel chloride hexahy-drate with controlled shape is claimed. Butthey noticed that preparation of particles ofsugars or proteins is problematic. Lactose, forexample, has very low solubility in conven-tional organic solvents. But it dissolves readilyin water, which is not soluble in supercriticalfluid. The same problem arises with proteins.Although solutions of such proteins in organicsolvents can be prepared, it is generally unde-sirable to do so because of the risk of theprotein unfolding and denaturing. Therefore,the Bradford university patented another pro-cess [21] which allows to maintain thesemolecules in a favorable environment untilrapid processing with modified supercriticalcarbon dioxide.

� The process is quite similar to the previousone. As shown on Fig. 5, it is based on theco-introduction, through a nozzle with three

coaxial passages into a particle formation ves-sel, of:

A solution or suspension of active substancein solvent 1.A solvent 2, miscible with solvent 1 andsoluble in the supercritical fluid.A supercritical fluid.

� The dispersion of the active substance solution(in solvent 1) and solvent 2, and the extractionof these two solvents occur simultaneously. Atthe point where the active substance solutionand solvent 2 are introduced, hydrogen-bond-ing and/or similar interactions are formed be-tween both solvents. The two solvents are thenextracted together by the supercritical fluid.

� This process differs from the tee method ofSievers et al., described in Part 3, because theoutlet of the Bradford nozzle is still pressurizedand enters a chamber with the supercriticalfluid, while the Sievers nozzle is decompressedrapidly to atmospheric pressure and uses noorganic solvents.

� This process was used to prepare particles ofsugars (lactose, maltose, threhalose, sucrose)with aqueous solution of sugar/(ethanol ormethanol)/supercritical CO2 systems and parti-cles of proteins with aqueous solution ofprotein/ethanol/supercritical CO2 system [21].Moreover, Sloan et al. [46] used this processwith two model proteins, lysozyme and trypsin.SEDS-processing of both model proteins re-sulted in reduced particle size with improvedsize distribution. Lysozyme was processedwithout loss of enzymatic activity (95%) whereas 40% of the trypsin activity was recoveredafter similar processing.

� A more recent process patented by BradfordParticle Design [52] allows particle formationof lipophilic substances and low polarity mate-rials with a special anti-solvent process. Inconventional GAS/SAS methods, the supercrit-ical fluid expands an organic solution of theactive, decreasing its solvent power and causingthe active precipitation. In this new process,the supercritical fluid expands another super-critical solvent, pure or modified with a co-sol-vent, in which the active principle is dissolved,producing fine particles of the active. This pro-Fig. 5. Three coaxial-passages nozzle.


cess cannot be considered as RESS becauseparticle formation is not due to a pressurereduction but to the second supercritical fluidaction. Ibuprofen particles were obtained withthis process by mixing supercritical nitrogenwith a supercritical solution of ibuprofen incarbon dioxide.The micronization of otherlipophilic substances (salicylic acid, ketoprofen,salmeterol xinafoate and nicotinic acid) is alsodescribed.

� More recently, Subramaniam et al. [31,47,65]patented a process and apparatus for particleprecipitation and coating using near-criticaland supercritical anti-solvents. The contactstep between a solution or suspension of asolute and the supercritical fluid anti-solvent ismade so as to generate high frequency sonicwaves, which will break the solution into ex-tremely small droplets. Special nozzles are usedto create high frequency sonic waves: an ener-gizing gas stream is injected through a passage-way perpendicular to the dispersion of theliquid by the supercritical solvent. This energiz-ing gas stream generates high frequency wavesthat break up the fluid dispersion and generatesextremely small droplets leading to the finalparticles. The energizing gas can be the same asthe anti-solvent or can be selected from agroup consisting of air, oxygen, nitrogen, he-lium, carbon dioxide, propane, butane, isobu-tane, trifluoromethane, nitrous oxide, sulfurhexafluoride and mixtures thereof. Formationof very small particles on the order of 0.1–10�m is claimed. The invention also includessupercritical coating techniques that we willexamine later in this paper. Recrystallization offour substances (hydrocortisone, poly(D,L-lac-tide-glycolide), ibuprofen and camptothecin) isdescribed.

� Pallado et al. [23] described a process forpreparing nanospheres composed of a biocom-patible polysaccharidic polymer by precipita-tion in a anti-solvent. These spheres are used asvehicling agents or carriers in the preparationof pharmaceutical compositions. The biocom-patible polysaccharide polymer is dissolved inan appropriate solvent and contacted with aflow of supercritical fluid that expands the

solution causing particles precipitation. Loadedmicrospheres can be produced by adding theactive principle to the polymer solution. Mi-croparticles of acyl esters of hyaluronic acids(HYAFF-11, HYAFF-11-p75, HYAFF-7), acrosslinked polysaccharide of hyaluronic acid(ACP), an ester of alginic acid, an ester ofpectinic acid, were prepared. The formation ofloaded microspheres is also described: calci-totin/HYAFF particles, GranulocyteMacrophage Colony Stimulating Factor (GM-CSF)/HYAFF particles, Insulin/HYAFFparticles.

� Anderson et al. [33] patented the formation ofsmall and sterile particles of prednisolone ace-tate using the ASES process.

� In 1998, Manning [39] patented a process forparticle production using the ASES process. Atrue solution of a pharmaceutical substance isprepared in an organic solvent in which thesubstance is not normally soluble, by forming ahydrophobic ion-pair complex involving thesubstance and an amphiphilic material. Thissolution is then sprayed into a compressedsupercritical fluid. To obtain micro-encapsu-lated products, a biodegradable polymer maybe added to the solution. Pulverization of in-sulin-SDS complex is described in this patent.

� In 1998, Bausch et al. [34] described a processfor the manufacture of a pulverous preparationof a (sub)micron-sized biologically active com-pound. The compound is first dissolved underelevated pressure in a compressed gas, liquid orsupercritical fluid containing surface modifieror in compressed dimethylether optionally con-taining a surface modifier. In a special embodi-ment, the resulting solution is sprayed into anantisolvant phase optionally containing a sur-face modifier. According to claim 11, the anti-solvent phase can be water or compressedcarbon dioxide.

2.4. Publications

As shown on Table 2, numerous publicationsshow that the SAS/GAS process (and its variants)has been used to recrystallize many differentproducts (explosives, polymers, pharmaceuticals,

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Table 2Compounds atomized with the GAS/SAS/ASES/SEDS processesa

Supercritical ReferencesProcessSubstrates (solvent) Results and observationsfluid

Explosi�esProduction of void-free particles Particle Gallagher, 1992 [9,10]GASCyclotrimethylenetri-nitramine (RDX) CO2

sizes depending on the conditions: from(acetone or cyclohexanone)200 to 1 �m

�-HMX (acetone) Cai, 1997 [24]Particle size: 2–5 �mCO2 GASCO2 GAS Particle size: 65 �m�-HMX (acetone) Forter-Barth, 1999 [56]

Forter-Barth, 1999 [56]CO2�-HMX (g-butyrolactone) GAS Particle size: 90 �mNitroguanidine (NMP or DMF) Gallagher, 1989 [6]CO2 GAS Particle size: a few microns Different

shapes were obtained during the testsLim, 1998 [38]NTO (DMF or DMSO or methanol) CO2 Variety of shapes (sphere, cube,GAS

spherical agglomerate) of sizes 0.5–20�m depending upon the conditions

Polymers and biopolymersCO2 GAS Particle size: 0.8 �m Pallado, 1996 [23]ALAFF (ester of alginic acid) (DMSO)

Reverchon, 1999 [54]Particle size: 0.1–0.2 �mASESDextran (DMSO) CO2

Pallado, 1996 [23]Ester of pectinic acid (DMSO) CO2 GAS Particle size: 0.7 �mReverchon, 1999 [61]Spherical microparticles of diameterCO2 ASESHPMA (poly(hydroxypropyl

0.1–0.2 �mmethacrylamide)) (DMSO)Particle size: 1 �m Pallado, 1996 [23]HYAFF 7 (ethyl ester of hyaluronic CO2 GAS

acid) (DMSO)Benedetti, 1993 [11] Reverchon, 1999Particle size: 0.3–10 �mHYAFF 11 (hyaluronic acid ethyl ester) CO2 ASES[54](DMSO)Pallado, 1996 [23]GAS Particle size: 0.6 �mPallado, 1996 [23]HYAFF 11 p75 (DMSO) CO2 GAS Particle size: 0.8 �mReverchon, 1999 [54,61]ASES Spherical particles with a maximumCO2Inulin (DMSO)

diameter of 5 �mPLA (acetone) Chou, 1997 [25]CO2 Brittle solid similar to the startingASES

materialParticle size: 1–10 �m Particle size: 1–2 Bleich, 1993 [13] Reverchon, 1999 [61]PLA (methylene chloride) CO2

�mCO2+N2 SEDS Particle size: 10 �mDL-PLA (n.a.) Ghaderi, 1999 [68]

Particle size: 10 �m Ghaderi, 1999 [68]DL-PLG (n.a.) SEDSCO2+N2

CO2 GAS Particle size: 50 nm Dillow, 1997 [26]PLGA (acetone)Johnston, 1994 [19]Polyacrylonitrile (DMF) ASESCO2 Formation of microfibrilles

CO2+N2 SEDS Particle size: 25–85 �mPolycaprolactone (n.a.) Ghaderi, 1999 [68]Poly(methacrylated sebacic anhydride) Owens, 1999 [67]ASESCO2 A high powered ultraviolet source

allows photopolymerisation. Particle(methylene chloride)size: 1–5 �m

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ASES Particle size: 0.1–20 �mCO2 Dixon, 1993 [14]Polystyrene (toluene)CO2 SEDS Particle size: 0.5 �m Hanna, 1998 [36]Polystyrene (toluene)

Inorganic and organic materials: coloring matters, catalysts, superconductors…GAS Yeo, 2000 [84]Particle size: 1–5 �mCO2Ammonium Chloride (DMSO)

Yeo, 2000 [84]Barium Chloride (DMSO) Particle size: 7–9 �m with cubic shape orGASCO2

needle-like crystals depending on theconditionsSpheres of diameter between 1 and 10 �mCO2 ASESBronze Red (ethanol) Hong, 2000 [76]depending on experimental conditionsSpheres or needles of diameter between 3 Hong, 2000 [76]ASESCO2Bronze Red (acetone)and 15 �m depending on the conditions

CO2 ASES Particle size: 100–300 nmBuckminster-fullerene (toluene) Chattopadhyay, 2000 [71]Hanna, 1994 [18]CO2Cobaltous nitrate (acetone) SEDS Free-flowing pink powder

CO2Epoxy powder (acetone or methyl ethyl Heater, 1998 [37]Without surfactant: agglomerates withASESpluronic R-17: separated particles withketone)uniform spherical morphology

Wubbolts, 1997 [32]GAS and ASESHydroquinone (acetone) CO2 GAS: agglomerates of size 500 �m ASES:needle and prismatic shaped particles ofsize 50–100 �mVery fine free-flowing powder Hanna, 1994 [18]Nickel Chloride hexahydrate (absolute SEDSCO2

ethanol)CO2 GAS Particle size: 160–540 �mPhenanthrene (toluene) Berends, 1994 [16]

Particle size: down to 0.6 �m Gao, 1997 [27]Red Lake C pigment Pigment Yellow 1 GASCO2

Pigment Blue 15 (acetone)CO2 ASES Particle size: 0.1–0.3 �mSamarium acetate (DMSO) Reverchon, 1997 [29,44]CO2 SEDS Particle size: 0.2 �mSamarium acetate (water+methanol) Hanna, 1998 [36]

Hanna, 1998 [36]Particle size: 0.3 �mSEDSSilver nitrate (methanol) CO2

CO2 ASES Reverchon, 1998 [42]Superconductor precursorsCO2 Ballons formed by submicronic elementsYttrium acetate (DMSO) ASES Reverchon, 1997 [29,43] Muhrer, 2000

[78]CO2 ASES Particle size: 0.08–0.13 �mZinc acetate (DMSO) Reverchon, 1997 [30,63]

Pharmaceutical compoundsGilbert, 2000 [75]Acetaminophen (ethanol) SEDSCO2 Particle size: 6–8 �m

Particle size: 50–500 nmSEDS Bustami, 2000 [70]CO2+EthanolAlbumin (water)Liang, 2000 [77]CO2 GAS n.a.7-aminocephalo-sporanic acid (acetone and

water)Reverchon, 1999 [57,64]CO2Amoxicillin (NMP) ASES Particle size: 0.2–0.8 �m

CO2+ethanol SEDS Activity of processed antibody: 45% Sloan, 1999 [58]Antibody Fab fragment (water)Antibody Fv fragment (water) CO2+ethanol Sloan, 1999 [58]SEDS Activity of processed antibody: 3%

CO2 ASES Particle size: 1–10 �m Weber, 1999 [55]Ascorbic acid (ethanol)

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Particle size: platelet morphology of 2–10GAS Cocero, 2000 [72]CO2�-carotene (ethyl acetate)�m size

Debenedetti, 1992 [8]ASESCatalase (ethanol-water 90:10) Particle size: 1 �mCO2

Process ReferencesSubstrates (solvent) Results and observationsSupercriticalfluidCO2 ASES Particle size: 1–10 �mChloramphenicol (ethanol) Weber, 1999 [55]

Cu2(indomethacin)4 (DMF)2 (DMF) GAS Warwick, 2000 [83]CO2 Slow expansion: rhombic crystals of 50�m size Fast expansion: crystals of 20 �msize

CO2 Thiering, 1998 [49]p-HBA (methanol) GAS ASES GAS: Particle size: 1–2 �m ASES: 0.1–1.0�m

Schmitt, 1995 [22]Particle size: 5 �mHydrocortisone acetate (DMF) ASESCO2

CO2 ASES Particle size: 1 �mInsulin (ethanol-water 90:10) Debenedetti, 1992 [8]CO2+Ethanol SEDS Particle size: 50–500 nm Bustami, 2000 [70]Insulin (water)CO2 Yeo, 1993 [15] Thiering, 2000 [80, 1,82]Particle size [15]: �4 �m Particle sizeInsulin (DMSO or DMF) ASES

[80,81,82]: 1.4–1.8 �mThiering, 2000 [80,81,82]CO2Insulin (Methanol) GAS Particle size: 0.2–0.7 �m

Insulin (Ethyl acetate) Thiering, 2000 [80,81,82]Particle size: 0.3–0.7 �mCO2 GASCO2 GAS Particle size: 0.05–0.3 �m Thiering, 2000 [80,81,82]Insulin (Ethanol)

Thiering, 2000 [80,81,82]NH3Insulin (water) GAS Particle size: 0.2–0.3 �mHanna, 1994 [18]SEDSCO2+ethanol�-lactamase (water)

Lactose (water) Hanna, 1995 [21] Palakodaty, 1998 [40]SEDS Particle morphology depends on theCO2 andmethanol nozzle Particle size: 3.0–10.5 �mCO2 ASESLecithin (ethanol or hexane) Weber, 1999 [59]

D. Amaro-Gonzalez, 2000 [69]Particle size: 0.2–0.6 �mASESLobenzarit disodium (water) CO2+EthanolSEDSLysozyme (water) Sloan, 1998 [46] Bustami, 2000 [70]Particle size [46]: 0.78 �m Activity ofCO2+ethanol

processed enzyme: 95% Particle size [70]: Gilbert, 2000 [75]500 nm Particle size [75]: 0.5–5 �mParticle size: 0.05–0.2 �mGAS Thiering, 2000 [80,81,82]CO2Lysozyme (DMSO)

CO2+DMF Thiering, 2000 [80,81,82]GASLysozyme (DMSO) Particle size: 0.1 �m(30% vol.)CO2+Ethanol Thiering, 2000 [80,81,82]GASLysozyme (DMSO) Particle size: 0.02–0.04 �m(30% vol.)

Thiering, 2000 [80,81,82]Particle size: 0.05 width×0.25 lengthGASCO2+acetic acidLysozyme (DMSO)(8% vol.)CO2+water GAS Particle size: 0.05–0.07Lysozyme (Ethanol) Thiering, 2000 [80,81,82]

Thiering, 2000 [80,81,82]CO2Lysozyme (Methanol) GAS Particle size: 0.01–0.05 �mNH3 GAS Particle size: 0.05–0.2 �m Thiering, 2000 [80,81,82]Lysozyme (Water)

Maltose (water) Hanna, 1995 [21]CO2+absolute SEDS Result: free-flowing white powderethanol

Bustami, 1999 [66]CO2 ASES Particle size: 10–50 �mMefenamic acid (methanol or ethanol oracetone)

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219196Table 2 (Continued)


ASES Particle size: 5 �mCO2 or ethane Schmitt, 1995 [22] Muhrer, 2000 [78]Methylprednisolone (tetrahydrofuran)Thiering, 2000 [80,81,82]GASMyoglobin (DMSO) Particle size: 0.03–0.4 �mCO2

CO2 GASMyoglobin (Methanol) Particle size: 0.05–0.3 �m Thiering, 2000 [80,81,82]Chou, 1997 [25]ASES Needles-like crystals with diameter 1 �mCO2Naproxen (acetone)

and length 1 mmHanna, 1998 [36]CO2Nicotinic acid (absolute ethanol) SEDS Particle size: 0.4–0.75 �mWeber, 1999 [55]ASESParacetamol (ethanol) Particle size: 1–10 �mCO2

Phospholipids (chloroform or ethanol) CO2 Magnan, 1999 [53,60]ASES Spherical particles of size: 1–40 �mSloan, 1999 [58]CO2+ethanol SEDS Activity of processed plasmids: 10%Plasmid DNA pSVb with no protectant

(water)Sloan, 1999 [58]CO2+ethanol SEDS Activity of processed plasmids: 75%Plasmid DNA pSVb with protectant

(water)Particle size: 1 �m Anderson, 1998 [33]ASESCO2Prednisolone acetate (acetone)

Bustami, 2000 [70]CO2+ethanolRhDNase (water) SEDS Particle size: 50–500 nmSalbutamol(methanol+acetone) Hanna, 1998 [36]Particle size: 0.5 �mCO2 SEDS

CO2 ASES Particle size: 1–10 �m Hanna, 1994 [18] Hanna, 1998 [35]Salmeterol xinafoate (methanol or acetone)Salmeterol xinafoate (acetone or methanol) Hanna, 1998 [36]SEDSCO2 With acetone: platelet particles with

methanol: needles-like particlesParticle size: 0.1–20 �m Jaarmo, 1997 [28]ASESCO2Sodium cromoglicate (methanol)

Hanna, 1995 [21]CO2+absolute SEDS Result: free-flowing white powderSucrose (water)ethanolCO2 ASES Particle size: 0.6–0.8 �mTetracycline (NMP) Reverchon, 1999 [57,64], 2000 [79]

Result: free-flowing white powder Hanna, 1995 [21]SEDSTrehalose (water) CO2+absoluteethanol

Trypsin (HCl 1mM) Sloan, 1998 [46]SEDSCO2+ethanol Particles size: 1.53 �m Activity ofprocessed enzyme: 36%Particle size: 1–10 �mASESCO2 Weber, 1999 [55]Urea (ethanol)

MicrocompositesPallado, 1996 [23]GASCalcitonin+HYAFF (DMSO) Particle size: 0.5–1 �mCO2

Particle size: 1–2 �m Elvassore, 2000 [73]CO2Chimotrypsin-AOT+PLA (methylene ASESchloride)

Chloramphenicol and urea (ethanol) GAS Weber, 1998 [50]CO2

Composite particles of 50–150 nm with aCO2Copper-, Barium- and Yttrium acetate Weber, 1999 [55]ASESunique homogeneous distribution of each(ethanol)of the elements

Pallado, 1996 [23]GMCSF+HYAFF (DMSO) CO2 GAS Particle size: 0.5–1 �mp-HBA (methanol)+PLGA (acetone) Sze Tu, 1998 [48]SEDSCO2 Crystals of p-HBA coated with a layer of

PLGA microspheresSze Tu, 1998 [48]CO2 Fibrous network of drug and polymerSEDSp-HBA (methanol)+PLA (methylene

mixturechloride)

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Table 2 (Continued)

Results and observations ReferencesSubstrates (solvent) Supercritical Processfluid

Ghaderi, 1999 [68]Hydrocortisone + CO2+N2 SEDS Particle size: 10–60 �mPoly(DL-lactide-co-glycolide):copolymercomposition 50:50 (n.a.)

Insulin+HYAFF (DMSO) Particle size: 0.4 �mCO2 GAS Pallado, 1996 [23]CO2 Elvassore, 2000 [73]ASESInsulin-lauric acid conjugate+PLA Particle size: 1–5 �m

(methylene chloride)Particle size: 1–5 �m Elvassore, 2000 [73]Insulin+PLA (methylene CO2 ASES

chloride+DMSO 50%)Particle size:1–2 �m Elvassore, 2000 [73]Lysozyme+PLA (methylene ASESCO2

chloride+DMSO 50%)Particle size: 5 �m Chou, 1997 [25]ASESCO2Naproxen+PLA (acetone)

GASCO2 Weber, 1998 [50]Paracetamol and ascorbic acid (ethanol) By variation of the composition, theproduct changed from needle-likecrystals (10 �m) to large tubes (length30–100 �m, diameter 2 �m) coveredwith prismatic crystals (�1 �m)

CO2PLA+clonidine HCl (dichloromethane) ASES Hollow spheres of diameter: 100 �m Schwarz Pharma, 1987 [4]Bleich, 1994 [17]ASESPLA+hyoscine (butylbromide) Particle size �20 �mCO2

Hanna, 1994 [18]Fine white powderCO2Salmeterol SEDSxinafoate+hydroxypropyl-cellulose(acetone)

a Abbreviations used AOT, dioctylsulfosuccinate; DMF, N,N-dimethyl formamide; DMSO, dimethylsulfoxide; GMCSF, granulocyte macrophage colony stimulatingfactor; n.a., non available; NMP, N-methyl 2-pyrrolidone; NTO, 3-nitro-1,2,4.-triazole-5-one; p-HBA, para-hydroxybenzoic acid; PLGA, poly(lactide-co-glycolide);PLA, poly(L-lactic acid); DL-PLG, Poly(DL-lactide-co-glycolide):copolymer composition 50:50.


coloring materials, …) in order to make finepowders or microspheres of an active embeddedinto a carrier (see details on microspheres below).It is to be noticed that Reverchon [41,62] andFoster et al. [74] published reviews about super-critical anti-solvent precipitation applications.


There is no doubt that anti-solvent processeshave a bright future, especially for drug deliverysystems, as they permit to monitor the propertiesand composition of the particles with a greatflexibility and for almost any kind of compounds!Nevertheless, scale-up is presently foreseen onlyfor high-value specialty materials (pharmaceuti-cals, cosmetics, superconductors…) with produc-tions ranging from a few kilograms to a fewhundreds kilograms per day.

Regarding intellectual property, this complexsituation may lead to some limitations of processapplications until it will be cleared so as to ensurethat no patent infringement is to be feared bypotential users.

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[83] B. Warwick, F. Dehghani, N.R. Foster, Synthesis, Purifi-cation and Micronisation of Pharmaceuticals Using the

Gas Antisolvent Technique. Proceedings of the 5th Inter-national Symposium on Supercritical Fluids, 8–12 April,Atlanta (USA), 2000.

[84] S.D. Yeo, J.H. Choi, T.J. Lee, Crystal formation of BaCl2and NH4Cl using a supercritical fluid antisolvent. Journalof Supercritical Fluids, 16, 2000, 235–246.

3. Part 3: Particles from gas-saturatedsolutions/suspensions (PGSS)

3.1. Concept

As the solubilities of compressed gases in liq-uids and solids like polymers are usually high, andmuch higher than the solubilities of such liquidsand solids in the compressed gas phase, the pro-cess consists in solubilizing supercritical carbondioxide in melted or liquid-suspended sub-stance(s), leading to a so-called gas-saturated so-lution/suspension that is further expandedthrough a nozzle with formation of solid particles,or droplets (Fig. 6).

Typically, this process allows to form particlesfrom a great variety of substances that need notto be soluble in supercritical carbon dioxide, espe-cially with some polymers that absorb a largeconcentration (10–40 wt.%!) of CO2 that eitherswells the polymer or melts it at a temperaturemuch below (�10–50°C) its melting/glass transi-tion temperature [3,4,45]. This process can also beused with suspensions of active substrate(s) in apolymer or other carrier substance leading tocomposite microspheres.

Fig. 6. PGSS equipment concept.


3.2. History

In 1979, Best et al. [1] described a procedure forpreparing very finely divided carotenoids usingsupercritical gases. Crystalline substrates were dis-solved in a mixture of supercritical gas and en-trainer. The solution was then dispersed in acolloidal matrix before being decompressed result-ing in active precipitation into the matrix. Itseems to us that the mixture carotenoids, super-critical gas and entrainer leads to a gas-saturatedsolution that is further expanded. It is clear thatthis process cannot be considered as PGSS as thesolution is not decompressed through a nozzle butthe patent can be considered as anterior art of thisprocess.

But the basis of the PGSS technique was de-scribed later by Graser [2] who patented a processto prepare pigments by crystallizing finely milledcrude organic pigments. Recrystallisation is car-ried out in a solvent at high temperatures andunder atmospheric or higher pressure. In particu-lar cases, solvents are under supercritical pres-sures. Moreover, to isolate the formed pigments,the authors described different processes like dis-tillation or ‘forcing the conditioning mixturethrough a valve by means of an inert gases’ thatwould ‘isolate the pigment by a type of spraydrying’.

3.3. Patents

In fact, many patents were filed for processesthat can be considered to use the PGSS concept:� Many patents describe the use of supercritical

carbon dioxide as a viscosity reducing materialin spray applications of different products(paint, adhesives, plastic additives, …). Inthose patents, the solid material is suspended ina liquid carrier and mixed with a supercriticalsolvent. The mixture is then sprayed onto asubstrate to form a coating. The most ad-vanced applications are related to paint appli-cation (UNICARB® process[5,6,7,9,10,11,14,17,20,21,28,37] from UnionCarbide, or a similar process from Nordson[8,13,18]), and dry paint production with a verylarge production unit developed by Ferro

[23,27,32]. Powder coating production was alsopatented by Morton [35,38], Nippon Paint [19]and Otefal Spa. [24]. The process developed byUnion Carbide and Nordson involves the useof supercritical carbon dioxide both as an at-omization vector and as a solvent. Smooth andhigh-quality coatings without defects or bub-bles are attained with this technology. More-over, a drastic reduction of volatile organiccompounds (VOC’s) release is claimed from 30to 70%. In 1991, Kishimoto [12] developed aprocess in order to obtain a quick-drying andpollution-free adhesive without using a largequantity of dispersion medium. The adhesive isprepared by compression, under high pressures,of an adhesive prepolymer and carbon dioxideand sprayed onto a surface.

� In the VAMP™ process [27,32] developed byFerro, supercritical fluid is used as a processingaid for powder coating formulation and atom-ization. The supercritical fluid, mixed with thepowder coating raw materials (resins, harden-ers, fillers and additives), swells the resins andthe polymers resulting in better additives dis-persion. Several distinct advantages leading toimproved product quality have been demon-strated: low temperature and low shear forces,low molecular weight products, superior glosscontrol, better hiding, excellent color control.

� In 1995, Weidner et al. [26] patented a processfor preparing particles and powders using whatthey called the PGSS technique. A supercriticalfluid is dissolved into a melted substance or asuspension of a substance in order to make agas-saturated solution. This mixture is thenexpanded through a nozzle and solid particlesare formed due to the sharp temperature de-crease caused by fluid expansion.

� Also in 1995, Sievers et al. [25] patented a newCO2-assisted aerosolization process, related toPGSS, that permits the use of any compoundthat is water-soluble. The active substance isdissolved into an aqueous solution, which ismixed under pressure with supercritical CO2,forming an emulsion. The supercritical emul-sion flows through a restrictor and is rapidlydecompressed to form an aerosol. Because CO2

is one of the most soluble gases in water (1.6


mole% at 63°C and 100 bar), its use enhancesthe expansion process.Several variants of thistechnique have been described. A schematicrepresentation of the continuous CO2-assistednebulization process is presented on Fig. 7. Thesupercritical CO2 and the active substance solu-tion are mixed in a low-dead-volume (�1 �l)mixing tee. The mixture is then depressurizedthrough a restrictor to form an aerosol (Fig.

8).To obtain dry particles, the aerosol dropletsare directed into a high temperature furnacewhere they are desolvated [39,42]. Particle sizecan be controlled by varying the concentrationof the precursor solution, and other aerosoliza-tion parameters (temperature, pressure, flowrates and restrictor diameter).In fact, it is notclear that fluid dissolution does happen duringthe extremely short contact time in this tee,

Fig. 7. Schematic representation of the continuous nebulization process.

Fig. 8. The ‘mixing tee’.


Fig. 9. Particles formation with static nebulization process[25].

cal effect caused by high velocity expansion ofthe two-phase mixture, but, according to Siev-ers [43], CO2 solubility is so high in aqueousmedia that even within this short contact time,some dissolution happens and improves disper-sion; according to this author, it is proven bytwo observations: Aqueous droplets becomeacidic due to CO2 dissolution and dispersion isnot at all as efficient when CO2 is substitutedby nitrogen or air at similar pressure. Never-theless, there is no doubt that saturation is farfrom reached and this process cannot be explic-itly considered as a PGSS application. Con-seguently it is difficult to understand how thissystem differs from conventional aerosol tech-nology, known from many decades.Moreover,it is to be noticed that this clever-because sosimple and inexpensive!- method to obtain par-ticles of water-soluble products may lead toproblems when applied on large scale due tothe sharp temperature decrease caused by car-bon dioxide depressurization (possible ice for-mation), although this problem is far lesscritical than for the RESS process as the heatto dry the droplets is provided by an inert gas(generally nitrogen) after the aerosol is formedand moved away from the nozzle into theatomization vessel [25,39,41,42]. Indeed, the teeand the restrictor are usually heated to 50–100°C to avoid restrictor obstruction due tothe Joule-Thomson effect [25,42].A staticmethod according to the PGSS concept is alsodescribed in the same patent [25]: The super-critical fluid is introduced under pressure in avessel containing the solution. The mixture isthen decompressed through the restrictor (Fig.9). Moreover Sievers et al. describes a portabledevice composed of a canister equipped with aseptum, containing an immiscible mixture of asupercritical fluid and a solution (suspension)of a substance, and a threaded cap equippedwith a puncturing pin and a restrictor (Fig. 10).In operation, the cap is screwed down onto thecanister until the puncturing pin ruptures theseptum, releasing the mixture. The rapid pres-sure release causes the formation of an aerosolcomprising fine particles (�6.5 �m). More-over, the development of pocket-type of drug

Fig. 10. Portable device using static nebulization process [25].

although the equipment used by Sievers [25]may lead to phase mixing not only in thecapillary after the tee but also inside the liquidsolution tubing due to liquid pump strokes.Obviously, dispersion results from a mechani-


delivery system according to this concept is farfrom easy due to consumer acceptance andprotection (risk of canister explosion).

� Karasawa [30] patented in 1997 a method ofpulverizing solid particles using supercriticalfluids. The solid particles are suspended in afluid in a supercritical state. The suspension isexpanded through a jet to form particles. It is

claimed that a major advantage of this methodis to avoid agglomeration of the processedparticles.

3.4. Publications

The PGSS process can be applied in variousfields ranging from inorganic powders to pharma-ceutical compounds as shown in Table 3.

Table 3Compounds atomized with the PGSS processa

Substrates Supercritical fluid Results and observations References

Inorganic and organic materialsn.a. Cole, 1989 [6]CO2AdhesivesAerosolization of an aqueous solution Sievers, 1999 [39]CO2Benzoic acid

Sievers, 1999 [39]Aerosolization of an aqueous solutionGlucose CO2

Particle size: 20–50 �m Novak, 1993 [15]Glycerides CO2

CO2 Aerosolization, dehydration and pyrolysis of a metal acetate or nitrateMetal oxides Sievers, 1999 [39]aqueous solution

Phosphors Aerosolization, dehydration and pyrolysis of an aqueous solutionCO2 Xu, 1998 [40]Xu, 1997 [34](Y2O3:Eu)

n.a. Prince, 1993 [16]Plastic additives CO2

Polyethyleneglyc CO2 Particle size: 150–400 �m Weidner, 1996ol [29]

CO2Powder coating n.a. Mandel, 1997[31]Weidner, 1999Particle size: 1–30 �mPowder coating CO2

[44]CO2Powder lacquer n.a. Kieser, 1998 [36]

Spinels CO2 Aerosolization, dehydration and pyrolysis of an aqueous solution Xu, 1998 [40](Co3−xMxO4,M=Fe, Cr)

PharmaceuticalsCO2 Sievers, 1998,Aerosolization of an aqueous solution Particle size: 0.69 �mAlbuterol

2000 [39,46]sulfateAerosolization of an aqueous solutionAlkaline Sievers, 1999 [41]CO2

phosphataseAerosolization of an aqueous solution Particle size: 1 �mCromolyn Sievers, 1998,CO2

sodium 2000 [39,46]DL-alanine Aerosolization of an aqueous solution Particle size: 0.3–0.5 �mCO2 Sievers, 1995 [25]Glucose oxidase CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]Glutathione CO2 Aerosolization of an aqueous solution Sievers, 1999 [41]

Sievers, 1999 [41]Horseradish CO2 Aerosolization of an aqueous solutionperoxidase

Aerosolization of an aqueous solutionCO2 Sievers, 1995 [25]Na2Fe(DTPA)CO2Nifedipine Particle size: 15.4 �m Weidner, 1994

[22]CO2 Sievers, 1999 [41]RhDNase Aerosolization of an aqueous solution Particle size: �3 �m

Sievers, 1998 [39]Aerosolization of an aqueous solution Particle size: 1–2 �mTobramycin CO2

a n.a non available.


Moreover, it is possible to form microsphereswhen a suspension of the active substance into acarrier is saturated by supercritical carbon dioxideprior to atomization, as claimed by Shine andGelb [33] in a recent patent of a process calledpolymer liquefaction using supercritical sol�ation(PLUSS). The main interest of this process is thatit is not necessary that the carrier/polymer and theactive substance are soluble in the supercriticalfluid, what opens wide fields of applications. Themixture of the core material and the encapsulatingpolymer is supplied with a supercritical fluid capa-ble of swelling the polymer under a temperatureand a pressure sufficient to maintain the fluid in asupercritical state. The pressure is then rapidlyreleased what results in solidification of the poly-mer around the core material to formmicrocapsules.


Particle design using the PGSS concept is al-ready widely used at large scale, at the differencewith other process concepts presently under devel-opment yet. The simplicity of this concept, lead-ing to low processing costs, and the very widerange of products that can be treated (liquiddroplets or solid particles from solid material orliquid solutions or suspensions) open wide av-enues for development of PGSS applications, notonly for high-value materials but also perhaps forcommodities, in spite of limitations related to thedifficulty to monitor particle size.

Recently, many patents were successivelygranted. Most are related to paint application(pulverization of suspensions to make coatings)and powder coating manufacture (combination ofchemical reaction and pulverization of a suspen-sion); more surprisingly, the basic PGSS processpatent filed in 1995 [26] for formation of solidparticles from polymer or solid substances hasbeen successfully granted in Europe and recentlyin the US. Moreover, a patent for aerosol drugdelivery [25] was also granted, describing severaldifferent processes and apparatus: The ‘tee’ pro-cess and equipment although it is not clear thatpulverization is not caused only by the mechanicaleffect of gas expansion well known for long, and

a portable device for static nebulization usingRESS or PGSS concepts.

References

[1] W. Best, F.J. Muller, K. Schmieder, R. Frank, J. Paust,German Patent 2 943 267 (BASF AG), 1979.

[2] F. Graser, G. Wickenhaeuser, Patent US 4,451,654, Sep-tember 20, 1982.

[3] I.S. Liau, M.A. Mc Hugh, Supercritical Fluid Technology,Elsevier Science Publishers, Amsterdam, 1985, 415.

[4] R.G. Wissinger, M.E. Paulaitis, J. Polym. Sc.: Part BPolymer Phys. 25, 1987, 2497.

[5] H.F. Bok, K.L. Hoy, K.A. Nielsen (Union Carbide),Patent US 5 057 342, 1989.

[6] T.A. Cole, K.A. Nielsen (Union Carbide), Patent US 5066 522, March 22, 1989.

[7] C.W. Glancy, D.C. Busby (Union Carbide), Patent US89/327 274, 1989. European Patent EP 388 915, 1990.

[8] D.R. Hastings, J.A. Hendricks (Nordson Corporation),Patent US 89/416855, 1989. European Patent 421 796,1990.

[9] K.A. Nielsen (Union Carbide), Patent US 5 009 367, 1989.[10] K.A. Nielsen, C.W. Glancy (Union Carbide), Patent US

89/327 484, 1989. European Patent EP 0 388 923, 1990.[11] C. Lee, K.L. Hoy, M.D. Donohue (Union Carbide),

Patent US 4 923 720, 1990.[12] Y. Kishimoto (Matsushita Electric Ind. Co. Ltd.), Patent

JP 5132656, 1991.[13] L.B. Saidman, J.C. Smith (Nordson Corporation), Patent

US 91/723468, 1991. European Patent EP 520728, 1992.[14] J.W. Taylor, J.N. Argyropoulos, J.J. Lear (Union Car-

bide), Patent US 91/676 547, 1991. European patent EP506067, 1992.

[15] Z. Novak, P. Senvar-Bozic, A. Rizner, Z. Knez, Particlesfrom Gas Saturated Solution — PGSS. I Fluidi Super-critici e Le Loro Applicazioni. E. Reverchon, A. Schiraldi(Eds.), June 20–22, Ravello, 1993, 231–238.

[16] W.D. Prince, G.E. Keller, W.A. Fraser, P.S. Leung,Patent EP 590 647, September 29, 1993.

[17] D.C. Busby, M.D. Donohue, C.W. Glancy, K.A. Nielsen(Union Carbide), Patent US 5 290 603, 1994.

[18] K.J. Coeling, S.E. Mayer, J.W. Messerly, L.B. Saisman,J.C. Smith (Nordson Corporation), European Patent EP595521, 1994.

[19] K. Mishima, S. Yamaguchi, T. Moriyasu (Nippo Paint CoLtd), JP 8113652, 1994.

[20] K.A. Nielsen (Union Carbide), Patent US 5 290 604, 1994.[21] W.D. Prince, G.E. Keller, W.A. Fraser, P.S. Leung

(Union Carbide), US Patent 5 308 648, 1994.[22] E. Weidner, Z. Knez, Z. Novak, PGSS (Particles from

Gas Saturated Solutions) — A New Process for PowderGeneration. Proceedings of the 3rd International Sympo-sium on Supercritical Fluids, Tome 3; G. Brunner, M.Perrut (Eds.), ISBN 2-905-267-23-8, 17–19 October,Strasbourg, 1994, 229–234.


[23] F. Mandel (Ferro Corp.), US Patent 5 399 597, 1995.[24] G. Mura, S. Pozzoli (Otefal Spa.), Patent EP 0 661 091,

1995.[25] R.E. Sievers, U. Karst, European Patent 0 677 332, 1995.

US Patent 5,639,441, 1997.[26] E. Weidner, Z. Knez, Z. Novak, European Patent EP 0

744 992, February 1995 PatentWO 95/21688, July 1995.[27] F.S. Mandel, C.D. Green, A.S. Scheibelhoffer (Ferro

Corp.), US Patent 5 548 004, 1996.[28] K.A. Nielsen, C.W. Glancy (Union Carbide), US Patent 5

509 959, 1996.[29] E. Weidner, R. Steiner, Z. Knez, Powder Generation from

Polyethyleneglycols with Compressible Fluids. High Pres-sure Chemical Engineering, P. Rudolf von Rohr, and C.Trepp (Eds.), Elsevier Science, 1996.

[30] Y. Karasawa, Patent DE 19640027, 1997.[31] F. Mandel, Manufacturing of Powder Coatings via the

Utilization of Supercritical Carbon Dioxide. The 4th In-ternational Symposium on Supercritical Fluids, May 11–14, Sendai, Japan, 1997, 493–497.

[32] F. Mandel (Ferro Corp.), Patent US 5 993 747, 1997.[33] A. Shine, J. Gelb, Patent WO 98/15348, 1 October, 1997.[34] C. Xu, B. Watkins, R.E. Sievers, X. Jing, P. Trowga, C.S.

Gibbons, A. Vecht, Submicron-sized Spherical YttriumOxide based Phosphors Prepared by Supercritical CO2-as-sisted Aerosolization and Pyrolysis. Appl. Phys. Lett., 71(12) 1997, 1643–1645.[35] A.T. Daly, O.H. Decker, R.Wursthorn, F.R. Honda (Morton Company), US Patent5 766 522, 1998.

[36] M. Kieser, O. Stahlecker, Patent DE 19707051, 1998.[37] K.A. Nielsen, J.N. Argyropoulos, B.E. Wagner (Union

Carbide), US Patent 5 716 558, 1998.[38] A.T. Daly, N.B. Shah, G.D. Correll, K.R. Wursthorn

(Morton Company), US Patent 5 708 039, 1998.[39] R.E. Sievers, B.A. Miles, S.P. Sellers, P.D. Milewski, K.D.

Kusek, P.G. Kluetz, New Process for Manufacture ofone-micron Spherical Drug Particles by CO2-assistedNebulization of Aqueous Solutions. Proceedings fromRespiratory Drug Delivery IV Conference, Hilton Head,South Carolina, 3–8 May, 1998, 417–419.

[40] C.Y. Xu, R.E. Sievers, U. Karst, B.A. Watkins, C.M.Karbiwnyk, W.C. Andersen, J.D. Schaefer, C.R. Stoldt,Supercritical Carbon Dioxide Assisted Aerosolization forThin Films Deposition, Fine Powder generation, andDrug Delivery, Chapter 18 in Green Chemistry: Frontiersin Benign Chemical Synthesis and Processes, P.T. Anastasand T.C. Williamson (Eds.), Oxford University Press,Oxford, 1998, 313–335.

[41] R.E. Sievers, U. Karst, P.D. Milewski, S.P. Sellers, B.A.Miles, J.D. Schaefer, C.R. Stoldt, C.Y. Xu, Formation ofAqueous Small Droplet Aerosols Assisted by Supercriti-cal Carbon Dioxide. Aerosol Science and Technology, 30,1999, 3–15

[42] R.E. Sievers, S.P. Sellers, K.D. Kusek, G.S. Clark, B.J.Korte, CO2-Activated Nebulization and ‘Bubble’ SprayDrying to Form Fine (1–5 �m) Particles of Proteins andsmall Molecules for Inhalation Drug Therapy. Confer-ence on Drug Delivery, Breckenbridge, July, 1999.

[43] R.E. Sievers, Private conversation, October, 1999.[44] E. Weidner, M. Petermann, K. Blatter, H.U. Simmrock,

Manufacture of Powder Coatings by Spraying of GasSaturated Melts. Proceedings of the 6th Meeting on Su-percritical Fluids, Chemistry and Materials; M. Poliakoff,M.W. George, S.M. Howdle (Eds.), ISBN 2-905-267-30-5,10–13 April, Nottingham, 1999.

[45] E. Gulari, C.W. Manke, Rheological Properties of Ther-moplastics Modified with Supercritical Gases. Proceed-ings of the 5th International Symposium on SupercriticalFluids, April 8–12, Atlanta (USA), 2000.

[46] R.E. Sievers, P.D. Milewski, S.P. Sellers, B.A. Miles, B.J.Korte, K.D. Kusek, G.S. Clark, B. Mioskowski, J.A.Villa, Supercritical and Near-critical Carbon Dioxide As-sisted Low Temperature Bubble Drying. Proceedings ofthe 5th International Symposium on Supercritical Fluids,April 8–12, Atlanta (USA), 2000.

4. Part 4: Reactions in supercritical media leadingto particle formation

Over the past decade, supercritical fluids havereceived considerable attention as solvent for thesynthesis of a number of ceramics and closelyrelated oxide materials. These new applicationshave been developed in order to improve thecharacteristics of the obtained powders, such aschemical homogeneity or structural properties.Contrarily to the previously described processes(RESS, SAS, PGSS) where only physical transfor-mation occurs, the supercritical fluid is here usedfor chemical transformation of the materials, asdescribed for the two different processes presentedhere below.

4.1. Thermal decomposition with a supercriticalsol�ent

Precursors are thermally decomposed in a su-percritical media; at the end of the reaction, su-percritical solvent is depressurized and thesolvent, turned to gas phase, separates from theparticles which remain in a highly divided state.

The advantage of processing in a supercriticalmedia is that high nucleation rate and low crystal-growth rate can be achieved, leading to ultra fineparticles formation. Moreover, the high density ofthe supercritical fluid avoids aggregation prob-lems encountered in liquid-solid separation stepsof conventional wet chemistry processes [8-10].


Table 4Compounds obtained by thermal decomposition on supercritical media

Results and observationsSubstrates (precursor) ReferencesSupercritical fluid

Ceria and Yttria co-doped Yin, 1997 [23]MethanolZirconia/Aluminacomposites

Znaidi, 1998 [24]MethanolChromium oxide powder Synthesis of nanometricpowders with various surface(Cr(III)acetylacetonate orareas depending on conditionsCr(III)acetate hydroxide)

Pessey, 1999 [27]Cu CO2+ethanol Average particle size: 1 �m(Cu(hexafluoroacetyl-acetonate)2)

Fe3O4 (Fe(acetylacetonate)3) Particle size: 1 �mCO2+ethanol Pessey, 1999 [27]Ga2O3 (Ga(acetylacetonate)3) Particle size: 0.5 �mAmmoniac Pessey, 1999 [27]

Spherical particles of diameter:Ethanol Barj, 1992 [8] Chhor, 1992MgAl2O4 (Mg(Al(O-secBu)4)0.5-2 �m [9]

CO2+ethanol Particle size: 0.5–2 �m Chhor, 1995 [15] Znaidi,MgO (Magnesium chelate oracetate) 1996 [20]

Oxide silica compound CO2+water Different structures: fibers, Papet, 1998 [25](Tetraethoxysilane) spherical powders

TiO2 (Ti(O-iC3H7)4) Spherical particles of diameter:Ethanol Barj, 1992 [8] Chhor, 1992[9]0.5–2 �m

TiO2 (Ti(O-iC3H7)4) Pommier, 1994 [13]CO2+isopropanolGourinchas, 1996 [18]

TiO2 (Ti(O-iC3H7)4) CO2+water Spherical particles of diameter: Papet, 1998 [25] Papet, 1999[26]0.1-1 �m

CO2+aqueous solution ofTiO2 (Ti(O-iC3H7)4) Spherical particles of diameter: Tadros, 1996 [19]0.1-2 �msurfactant (Zonyl FSJ)

CO2+waterZirconia powder (zirconium Papet, 1998 [25]butoxide)

When the thermal stability of the precursordoes not allow dissolution in the supercriticalfluid, a variant process can be used: a sol-gelreaction is conducted at high pressure and hightemperature, followed by supercritical drying.Fine powders (diameter: 50 nm) can be obtainedusing this process [12].

4.2. Patents

� Yamanis [5] (Allied-Signal Inc.) patented acontinuous process for production offine particulate ceramics, in 1989. Con-tinuous production of a fine ceramic powderby drying at supercritical conditions is de-scribed.

� More recently, Sarrade et al. [22] (CEA-Com-missariat a l’Energie Atomique) patented aprocess where the organic precursors are con-

tacted with supercritical CO2 (31–100°C, 300–500 bar) to form metallic and silicon oxides. Asimple decompression of the reaction mixtureallows separation and recovery of the finalproducts. Manufacture of particles of variousoxides (titanium, aluminum, magnesium, thal-lium, silicon, barium, beryllium, and zirco-nium) is claimed.

4.3. Publications

As shown in Table 4, numerous publicationsare related to thermal decomposition.

4.4. Synthesis using supercritical fluid as areactant

In this process, supercritical fluid is used as asolvent and a reactant. The processes described in


Table 5Compounds synthesized using a supercritical reactant

Supercritical fluidSubstrates (precursor) ReferencesResults and observations

AlOOH (Al(NO3)3) Water Particle size: 100-600 nm Hexagonal, rhombic or Adschiri, 1992, 1994needle shape [6,7,11]

Water Octahedral particles of size: 300 nm Adschiri, 1994 [11] Hakuta,CeO2 (Ce(NO3)4)1997 [21]

Water Adshiri, 1992, 1994 [6,7,11]Octahedral particles of size: 50 nmCo3O4 (Co(NO3)2)Cr2O3 Water Yoshimura, 1980 [2]

Hirano, 1976 [1]AmmoniacCu3N Pessey, 1999 [27]

Adshiri, 1992, 1994 [6,7,11]WaterFe2O3 (Fe(NO3)3, Spherical particles of size: 50 nmFeCl2 or Fe2(SO4)3)

Fe3O4 Water Adshiri, 1992, 1994 [6,7,11]Spherical particles of size: 50 nm(Fe(NH4)2

H(C6H5O7)2)AmmoniacGaN Doradzijnski, 1995 [16]

HfO2 Water Particle size: 20–30 nm Toraya, 1982 [3,4]LaCrO3 Water Yoshimura, 1980 [2]

Hirano, 1976 [1]WaterNiO (Ni(NO3)2) Rod-like particles of size: 100 nm Adshiri, 1994 [11]WaterTiO2 (TiSO4 or TiCl4) Prismatic particles of size: 20 nm Adshiri, 1992, 1994 [6,7,11]

Adshiri, 1992, 1994 [6,7,11]Spherical particles of size: 10 nmZrO2 (ZrOCl2) Water

reaction rate leads to ultra fine powder formation.Moreover, this technique avoids crushing and cal-cination steps used in conventional processes. Butfiltration, washing and drying are still necessary,and corrosion problems associated with supercrit-ical water have to be considered.

4.5. Patents

� In 1995, Nissan Chemical Industries [14]patented a process for fine particles of bariumferrite formation by heat-treating an aqueoussolution comprising an iron compound, a bar-ium compound and an alkaline substance. De-composition of the precursors leads to finebarium ferrite particles. A more general patentwas filed in 1996 [17] concerning fine metaloxide particles production using the sameprocess.

� Recently, Yamasaki [28] patented a methodand an apparatus for continuous hydrothermalsynthesis. A heated material slurry is mixedwith a sub- or supercritical aqueous liquid andpulverized, reducing the particle size of thematerial slurry, before hydrothermal reaction.

patents and publications generally use supercriti-cal water; however, supercritical ammoniac is alsoreported.

Hydrothermal synthesis has been used for mi-croparticles or large crystals elaboration:

For large crystals formation, the material is firstdissolved in sub- or supercritical water. Becauseof thermal convection, the material moves tocolder regions where a seed allows crystal growth.This operation can last up to several months forlarge crystals (10 cm) formation. Using this pro-cess, inorganic monocrystals (oxides, sulfides …)can be prepared at lower temperature thanconventional.

For oxide powders formation, low-cost precur-sors (oxides, hydroxides or salts...) are first dis-solved in water, sometimes with ore-formingagents (halides or alkali hydroxides); and the solu-tion is introduced into a reactor operated at su-percritical conditions.

This method has a potential to adjust the direc-tion of crystal growth, morphology, particle sizeand size distribution, because of the controllabil-ity of thermodynamics and transport propertiesby pressure and temperature. In addition, high


4.6. Publications

Table 5 gathers publications concerningparticles production using a supercritical reactant.

References

[1] S. Hirano, S. Somiya. Journal of the American CeramicSociety, 59 (11–12), 1976, 534.

[2] M. Yoshimura, S. Somiya. Am. Ceram. Soc. Bull., 59 (2),1980, 246.

[3] H. Toraya, M. Yoshimura, S. Somiya. Communicationsof the American Ceramic Society, 65 (5), 1982, C–72.

[4] H. Toraya, M. Yoshimura, S. Somiya. Communicationsof the American Ceramic Society, 65 (9), 1982, C-159-160.

[5] J. Yamanis, US Patent 4 845 056, 1989.[6] T. Adshiri, K. Kanazawa, K. Arai. Journal of the Ameri-

can Ceramic Society, 75 (4), 1992, 1019–1022.[7] T. Adshiri, K. Kanazawa, K. Arai. Journal of the Ameri-

can Ceramic Society, 75 (9), 1992, 2615–2618.[8] M. Barj, J.F. Bocquet, K. Chhor, C. Pommier. Journal of

Materials Science, 27, 1992, 2187.[9] K. Chhor, J.F. Bocquet, C. Pommier. Materials Chem-

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Pommier. Ann. Chim. Fr, 17, 1992, 55.[11] T. Adshiri, S. Yamane, S. Onai, K. Arai, Hydrothermal

Synthesis of Metal Oxide Fine Particles in SupercriticalWater. Proceedings of the 3rd International Symposiumon Supercritical Fluids, Tome 3; G. Brunner, M. Perrut(Eds.), ISBN 2-905-267-23-8, October 17-19, Strasbourg,1994, 241-247.

[12] A. Lefevre, L. Znaidi, K. Chhor, J.F. Bocquet, C. Pom-mier. Proceedings of the 3rd International Symposium onSupercritical Fluids, Tome 3; G. Brunner, M. Perrut(Eds.), ISBN 2-905-267-23-8, October 17-19, Strasbourg,1994, 309.

[13] C. Pommier, K. Chhor, J.F. Bocquet. Silicates Industriels,3 (4), 1994, 141.

[14] K. Arai, T. Ajiri, S. Yuki, I. Ota, US Patent 5 433 878,1995.

[15] K. Chhor, J.F. Bocquet, C. Pommier. Materials Chem-istry and Physics, 40, 1995, 63.

[16] R. Doradzijnski, J. Garczynski, L. Sierzputowski. ActaPhysica Polonica A, 88, 1995, 833–836.

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Pommier. The Journal of Supercritical Fluids, 9, 1996,222.

[19] M.E. Tadros, C.L.J. Adkins, E.M. Russick, M.P. Young-man. The Journal of Supercritical Fluids, 9, 1996, 172.

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[21] Y. Hakuta, H. Terayama, S. Onai, T. Adshiri, K. Arai,Hydrothermal Syntesis of CeO2 Fine Particles in Super-critical Water. The 4th International Symposium on Su-percritical Fluids, May 11–14, Sendai, Japan, 1997,255–258.

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[24] L. Znaidi, C. Pommier, A New Process for NanometricChromium(III) Oxide Powder Synthesis in SupercriticalAlcohol. Proceedings of the 5th Meeting on SupercriticalFluids, Tome 2; M. Perrut, P. Subra (Eds.), ISBN 2-905-267-28-3, March 23–25, Nice, 1998, 913–918.

[25] S. Papet, S. Sarrade, A. Julbe, M. Carles, C. Guizard, AnInnovative Method for Ceramic Oxide Synthesis fromAlkoxide Precursors in Supercritical CO2 Media. Proceed-ings of the 5th Meeting on Supercritical Fluids, Tome 2;M. Perrut, P. Subra (Eds.), ISBN 2-905-267-28-3, March23–25, Nice, 1998, 855–860.

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5. Part 5: Composite micro-spheres/capsules

5.1. Introduction

Research, development, and sales of drug-deliv-ery systems are increasing at a rapid pacethroughout the world. This trend will intensifyalong the next decade in the pharmaceutical in-dustry as lower costs and higher efficiency will bedemanded; many efficient drugs have to be refor-mulated to allow control of delivery location andrate, the active substance being distributed di-rectly to the target to enhance the treatment effi-ciency and reduce the doses and relatedside-effects; this is of particular importance for


long-term treatments (cancer, chronic diseases,…), vaccination or delivery of very fragile activedrugs as microencapsulation allows to enhancematerial stability. Similar objectives are alsoaimed in other areas, like agrochemicals, cosmet-ics, food ingredients, xerocopy or carbonless copypaper.

5.2. Definition and description of compositemicroparticles

Microparticles have a variety of structures (Fig.11):� Particles with irregular geometry, composed of

an active substance in form of aggregates ormolecularly dispersed solid embedded into amatrix. They are called ‘microspheres ’;

� Particles with spherical geometry, composed ofa core of active substance surrounded by asolid polymeric or proteic shell. They are called‘microcapsules ’.There is no universally accepted size classifica-

tion of these particles. However, many workersclassify spheres/capsules smaller than 1 �m asnano-spheres/capsules and those larger than 1000�m as macro-spheres/capsules. Commercial mi-cro-spheres/capsules typically have a diameter be-tween 3 and 800 �m and contain 10–90 wt.%carrier/core. A wide range of materials has beenembedded/encapsulated, including adhesives,agrochemicals, live cells, active enzymes,flavors, fragrances, pharmaceuticals, and inks.Most carrier/shell materials are natural or syn-thetic organic polymers, but fats and waxes arealso used.

5.3. Composite microparticles production usingsupercritical fluids

The three processes previously described can beused to produce composite microparticles, rathermicrospheres than microcapsules, and liposomes.On the other hand, supercritical fluids are uniquevectors of impregnation of porous particles withsubstrates as they exhibit a very high diffusivityand variable solvent power that permits to carrysubstrate inside pores where it is precipitated byrapid depressurization.

Fig. 11. Structure of the different microparticles.

Production of microcapsules will be describedin the next chapter dealing with particle coating.

5.3.1. RESS process (rapid expansion ofsupercritical solution)

This process is composed of two phases: activesubstance and carrier extraction with supercriticalCO2 and atomization of the supercritical solution.This technique is of great interest as an alternativemethod to conventional size-reduction methodsand a novel route to solvent-free drug loadedmicrospheres. But its use is limited because of thelow solubility of most of the polymers and thera-peutic drugs in supercritical fluids.

Examples� Debenedetti et al. [2] obtained microparticles

by the RESS co-precipitation of a drug (lovas-tatin) and a biodegradable polymer (poly(D,l-lactic acid) (DL-PLA)).The co-precipitationof the polymer and the drug led to a heteroge-neous population of microparticles consistingof microspheres containing a single lovastatinneedle, larger spheres containing severalneedles, microspheres without protrudingneedles and needles without any polymercoating.

� Mishima [7,9,17] described the formation ofmicrospheres of flavones and a polymer (Eu-dragit-100 or PEG 6000) by spraying at atmo-spheric pressure, a suspension of flavonoids ina supercritical solution of the polymer and aco-solvent.

5.3.2. PGSS process (particles from gas-saturatedsolutions)

It is possible to form microspheres when asuspension of the active substance into a carrier is


saturated by supercritical carbon dioxide prior toatomization. The main interest of this process isthat it is not necessary that the carrier/polymerand the active substance are soluble in the super-critical fluid, what opens wide fields ofapplications.

Example: Shine and Gelb [10] recently filed apatent of a process called polymer liquefactionusing supercritical solvation (PLUSS). The carrieris a polymer that is saturated with carbon dioxideunder supercritical conditions, causing polymerswelling and liquefaction at a temperature muchbelow its glass transition or fusion temp-erature. The active-carrier mixture is atomizedthrough a nozzle into a low pressure vessel, lead-ing to microcapsules, as claimed on the exampleof IBDV vaccine inside polycaprolactone (MW�4000).

5.3.3. SAS (supercritical anti-sol�ent) processAn active substance and a carrier dissolved or

suspended in an organic solvent are sprayed to-gether or separately in an anti-solvent. The anti-solvent expands the solvent(s) that leads tomicroparticles formation.

Examples:� Schwarz Pharma patented a process [1] for

microspheres formation in which a solutioncontaining an active substance and a carrier iscontacted with a supercritical fluid. The result-ing supercritical solution is depressurised whatleads to particles formation. The patent dis-closes a number of ways in which the fluids canbe contacted with one another and describesthe formation of particles during or after thecontact step.

� This technique was used to prepare PLA-mi-crospheres loaded with 0.1% of clonidine.

� Elvassore [16] described the formation ofprotein-polymer microcapsules by supercriticalanti-solvent techniques. Homogeneous protein/polymer mixtures were contacted with super-critical carbon dioxide in order to producemicrospheres with diameter ranging from 1 to5 �m and containing around 80% of protein.Different procedures were used to have a betterprotein dissolution in the polymer solution (hy-drophobic ion pairing, protein conjugation to

acylic moieties or solubilization in solvent mix-tures). Production of PLA microparticles con-taining insulin, lysozyme and chimotrypsin isclaimed.

� Chou and Tomasko [8] studied GAS crystal-lization of a pharmaceutical (naproxen) and abiodegradable polymer (poly-Lactic acid). Theresults from GAS studies showed very smallspherical particles composed of a naproxencore surrounded by a polymer shell.

� Pallado [6] described formation of loadedpolysaccharidic micro-/nano-spheres using theGAS process. Three active principles calci-tonin, insulin and granulocyte macrophagecolony stimulating factor were embedded inHYAFF microspheres.

� Sze Tu et al. [11] used the ASES technique forthe coprecipitation of a model drug, parahy-droxybenzoic acid (p-HBA) with thebiodegradable polymers, poly(lactide-co-glycol-ide) (PLGA) and poly(l-lactic acid) (PLA) aspresented on Fig. 12. A multiple nozzle assem-bly arranged coaxially was designed for theco-introduction of the drug and polymer solu-tions (Fig. 13). In this configuration, solutionsare expanded at a much faster rate than in theconventional ASES process since minute vol-umes of the solution continually dispersed bythe nozzle suddenly enter a region of highanti-solvent concentration. The rapid expan-sion causes the solid to precipitate out of solu-tion almost instantaneously. In this case,supercritical fluid is used only for its anti-sol-vent properties. Coprecipitation of the p-HBAand PLGA resulted in the formation of p-HBAparticles coated with the polymer microspheres.The coprecipitation of p-HBA with PLA re-sulted in the formation of a product where thedrug and polymer were incorporated togetherin a fibrous network.

5.3.4. SEDS (solution enhanced dispersion bysupercritical fluids) process

As describer earlier, in this process patented bythe Bradford University [4,5], the supercriticalfluid is used both for its chemical properties andas ‘spray enhancer’ by mechanical effect. Twotypes of nozzles can be used:


Fig. 12. Process flowsheet by Sze Tu et al. [11].

� A nozzle with two coaxial passages allows tointroduce the supercritical fluid and a solutioncontaining more than one substance to formmicro-spheres/capsules.

� A nozzle with three coaxial passages is used tointroduce three different fluids to form micro-spheres/capsules (Fig. 14): supercritical fluid-solution of a substance 1-solution of asubstance 2.Hanna et al. described in this patent [4] the

preparation of particles of salmeterol xinafoatewith a polymer matrix. Two separated solutionsof the active substance and the polymer (hydrox-ypropylcellulose) in acetone were prepared andco-introduced with supercritical CO2 in a precipi-tator using a three-passage nozzle. Analyses confi-rmed the inclusion of the product into thepolymer matrix material.� Liposomes: Liposomes are spherical vesicles

consisting of one to several bilayers of phos-pholipids entirely enclosing an aqueous vol-ume. Due to their similarity to naturalmembranes, and their ability to entrap andrelease many substances, liposomes are consid-ered as useful drug carriers in intravenous ap-plications. In most existing preparationmethods, the phospholipids are first dissolvedin a organic solvent (diethylether, chloroform,methanol …) and after various preparationsteps, brought into contact with an aqueousphase, whereby the liposomes are formed spon-

taneously. The methods have drawbacks suchas residual toxic organic solvent and low en-capsulation efficiency.Frederiksen and al. [3]developed a new method for preparation ofliposomes suitable to encapsulate a water-solu-ble substance, where supercritical carbon diox-

Fig. 13. Nozzle principle [11].

Fig. 14. Schematic representation of a nozzle with three coax-ial process.


Fig. 15. Process flowsheet by Frederiksen et al. [3].

ide modified with ethanol replaces the organicsolvents used in other techniques. The 1-palmi-toyl-2-oleoyl-sn-glycero-3-phosphocholine(POPC) and cholesterol were dissolved in su-percritical carbon dioxide modified with etha-nol.Rapid expansion of the supercriticalsolution into an aqueous phase containing amarker results in the formation of liposomesencapsulating the marker (Fig. 15). Liposomeshave an average size of approximately 40–50nm.In 1998, Ma [12] described a method forliposoluble medicinal liposome production. Af-ter dissolution of a phospholipid, cholesterinand a liposoluble drug in critical or supercriti-cal carbon dioxide, the pressure is slowly re-leased until the carbon dioxide density becomeslower than that of liposoluble drug. The car-bon dioxide is then quickly released and adispersing liquid is loaded into the vessel.Through immersion and stirring, a liposomecoated with the liposoluble medicine is formed.

� Powder impregnation: Supercritical fluid-solu-ble substrates can be easily impregnated insideporous media as demonstrated by many inves-

tigators using various matrixes like polymers,wood, paper, … Domingo et al. [15] used thisprocess to prepare controlled drug delivery sys-tems. In this work, zeolite, several amorphousmesoporous inorganic matrices (silica gel, alu-mina and florisil) and a polymeric matrix (am-berlite) have been impregnated with variousthermally labile organic compounds (benzoicacid, salicylic acid, aspirin, triflusal, ketopro-fen) by diffusion from saturated supercriticalcarbon dioxide solutions.It is of special interestto combine on-line supercritical fluid extractionand impregnation when extract is difficult tohandle, in form of a very viscous liquid orpasty solid; this is generally the case whennatural products are processed, leading to ole-oresins or ‘concretes’, especially for nutraceuti-cals production that are often finally wished inform of powder for further incorporation intotablets. Majewski and Perrut [13] recentlypatented a process that is claimed to lead to anhomogeneous distribution of substrate into theexcipient and is illustrated by kava-kava ex-traction with on-line impregnation of thekavalactones-rich extract into maltodextrine.


� The Concentrated Powder Form technology:According to Weidner [14], powdery agglomer-ates with unusual high liquid concentrations ofup to 90 wt.% can be obtained by spraying gassaturated solutions and admixing a solid car-rier material with the spray. One function ofthe gas, which must be at least partially solublein the liquid is to generate small droplets.These droplets may infiltrate porous substratesor may agglomerate solid, non-porous materi-als. Infiltration and agglomeration is promotedby the expanding gas which causes an intensivemixing between liquid and solid substrate. Theformed powders are then separated by sedi-mentation, centrifugal forces or filters. A basicflow scheme of a continuously operated plant isgiven in Fig. 16.The powder formation andliquid loading was tested for several combina-tions of liquids (extracts of celery, oregano,laurel, pepper, ginger, nutmeg, basil, tumeric,paprika, rosemary, lemon oil, strawberryaroma, cheese aroma, butter fat, �-tocopherol,whiskey and vinegar) and solid carriers (silica,maize starch, waxy maize starch, potato starch,cellulose, maltodextrin, powdered spices, citric

acid, powdered sugar, titanium dioxide, sodiumchloride, polymers and emulsifiers).

References

[1] W. Fischer, B. Muller, Patent EP 0 322 687, 17 December,1988.

[2] P. Debenedetti, J.W. Tom, S.D. Yeo, G.B. Lim, Applica-tion of Supercritical Fluids for the Production of Sus-tained Delivery Devices. Journal of Controlled Release,24, 1993, 27–44.

[3] L. Frederiksen, K. Anton, B.J. Barrat, P. Van Hoogevest,H. Leuenberger. Proceedings of the 3rd InternationalSymposium on Supercritical Fluids, Tome 3; G. Brunner,M. Perrut (Eds.), ISBN 2-905-267-23-8, 17–19 October,Strasbourg, 1994, 235–240.

[4] M. Hanna, P. York, Patent WO 95/01221, 1994.[5] M. Hanna, P. York, Patent WO 96/00610, 1995.[6] K. Mishima, S. Yamaguchi, H. Umemoto, Patent JP

8-104830, 1996.[7] P. Pallado, L. Benedetti, L. Callegaro, Patent WO 96/

29998, 1996.[8] Y. Chou, D. Tomasko. The 4th International Symposium

on Supercritical Fluids, 11-14 May, Sendai, Japan, 1997,55–57.

[9] K. Mishima, K. Matsuyama, H. Uchiyama, M. Ide,Microcoating of Flavone and 3-Hydroxyflavone withPolymer Using Supercritical Carbon Dioxide. The 4th

Fig. 16. Flow scheme of the CPF-process [14].


International Symposium on Supercritical Fluids, 11–14May, Sendai (Japan), 1997, 267–270.

[10] A. Shine, J. Gelb, Patent WO 98/15348, 1 October, 1997.[11] L. Sze Tu, F. Dehghani, A.K. Dillow, N.R. Foster.

Proceedings of the 5th Meeting on Supercritical Fluids,Tome L., M. Perrut, P. Subra (Eds.), ISBN 2-905-267-28-3, 23–25 March, Nice, 1998, 263–270.

[12] S. Ma (Dalian Medicine Inst.), Patent CN 1221607, 1998.[13] W. Majewski, M. Perrut, Patent FR 99.12005, 27 Septem-

ber, 1999.[14] E. Weidner, Powder Generation by high pressure Spray

Processes. GVC-Fachausschub ‘High Pressure ChemicalEngineering’, 3–5 March, Karlsruhe (Germany), 1999,225-230.

[15] C. Domingo, J. Garcia-Carmona, J. Llibre, R. Rodriguez-Clemente, Impregnation of porous supports by solutediffusion from SC-CO2. A way of preparing controlleddrug delivery systems. Proceedings of the 6th Meeting onSupercritical Fluids, Chemistry and Materials; M. Poli-akoff, M.W. George, S.M. Howdle (Eds.), ISBN 2–905-267-30-5, 10–13 April, Nottingham, 1999, 101–107.

[16] N. Elvassore, A. Bertucco, P. Caliceti, Production ofProtein-Polymer Micro-Capsules by Supercritical Anti-Solvent Techniques. Proceedings of the 5th InternationalSymposium on Supercritical Fluids, 8–12 April, Atlanta(USA), 2000.

[17] K. Mishima, K. Matsuyama, S. Yamauchi, H. Izumi, D.Furudono, Novel Control of Crystallinity and CoatingThickness of Polymeric Microcapsules of Medicine byCosolvency of Supercritical Solution. Proceedings of the5th International Symposium on Supercritical Fluids, 8–12 April, Atlanta (USA), 2000.

6. Part 6: Particle coating

Supercritical carbon dioxide can be used to coatparticles of active substance, which have the de-sired size, with a coating agent. Severalprocesses are under investigation and develop-ment, depending on the size of the particles(nano-particles to tablets) and nature of the coat-ing. The precipitation methods previously de-scribed (RESS, SAS, PGSS and thermaldegradation) can be used for particle coating;however, RESS can only be used when the coat-ing is soluble in the supercritical fluid. It is to benoticed that an organic solvent is introducedwhen SAS is employed and may lead to presenceof residual solvent in the tablets and VOC emis-sion; and PGSS is not always possible, dependingon the interactions coating-fluid and fusion tem-perature of the coating.

6.1. Tablets coating

� Ciba-Geigy [1] patented a process for tabletscoating using supercritical fluid. In fact, thetablets are coated by classical means, using asolution of coating agent in an organic solvent,and then subjected to extraction with a super-critical fluid leading to tablets with a residualsolvent content of 0.01–0.001% by weight.However, this method is not generally applica-ble as the active component may be extractedor altered during this solvent stripping.

� Separex is presently developing a processderived from classical coating equipment inorder to avoid organic solvent use and to re-duce coating duration. This process, accordingto a pending patent [12], is founded on thepulverization of the coating agent(s) suspensioninto a supercritical fluid.

6.2. Particles coating

The precipitation methods previously described(RESS, SAS, PGSS and thermal decomposition)can be used for particle coating, and mostprocesses are derived from the Wurster processwhere coating agent is atomized onto fluidizedparticles:� Subramaniam et al. [2] patented a special case

of ASES process for spraying the coating solu-tion into the supercritical fluid so as to gener-ate high frequency anti-solvent sonic waves.According to the described implementation, thesolution of the coating agent is sprayed with aspecific system into a closed precipitation vesselcontaining the anti-solvent. Simultaneously, aturbulent fluidized flow of the core particles iscreated within the precipitation vessel. Condi-tions are maintained so that the anti-solventrapidly depletes the solvent and precipitates thecoating agent on the core material.

� Kobe Steel Ltd. [3] patented a process relatedto the RESS concept for microparticles forma-tion and coating. Primary microparticles areformed by rapid decompression of a supercriti-cal solution of the core material. These parti-cles are mixed with a supercritical solution ofthe coating agent and depressurized to form


microcapsules. Coating with multiple layerscan be achieved using this process. Applica-tions of this process are limited as the corematerial and the coating agent have to besoluble in a supercritical fluid.

� Krause et al. [5,6] patented a process for theapplication of a coating agent dissolved insupercritical fluid onto fine substrate particles(of diameter less than 100 �m) moving in afluidized bed. Very smooth and regular coat-ings can be achieved with this process relatedto RESS concept.

� Sunol [4,7] used a different process for coatingpolymeric thin films on particles. The methodinvolves a recirculation system that includesdissolution of the polymer into the supercriticalsolvent and coating the particles through atemperature swing operation in the fluidizedbed of particles. This system has been testedwith hydroxyl-terminated polybutadiene(HTTB) as coating polymer and particles ofsalt (30–500 �m). The film thickness was aslow as 0.2 �m.

� The Centre de Microencapsulation d’Angers,now called Mainelab (France) patented twoprocesses [8–10]:1. In the first method, [8,10] the coating agent

is solubilised into supercritical carbon diox-ide. In a stirred vessel, active substanceparticles are dispersed into the supercriticalsolution. By changing the pressure and thetemperature, the solubility of the coatingagent in the supercritical fluid can be re-duced so that it can precipitate on the parti-cles. Microcapsules of active substance arecollected after depressurization. This pro-cess allows to have a good control of thestructure (composition, thickness) of themicrocapsule without using organic sol-vents. This process was used to encapsulatesubstances such as: dyes, antibiotics, vita-mins, proteins. Coating agents must be sol-uble in supercritical carbon dioxide such aswaxes, glycerides, alcohols, fatty acids andesters.

2. The second method [9] used a suspension ofactive substance in a solution of a slightlypolar polymer (insoluble in liquid or super-

critical -carbon dioxide) in an organic sol-vent. This suspension is contacted withsupercritical carbon dioxide so that the or-ganic solvent is solubilized in such a man-ner that there is coacervation of the coatingpolymer onto the particles. Microcapsulesare collected after decompression.

These techniques, proven at lab-scale, are inter-esting even if extrapolation to industrial-scale re-mains to be demonstrated.� Wakayama [13] developed in 1999 a coating

process in which a supercritical solution of areaction precursor is brought into contact witha substrate in the presence with a reactioninitiator. The reaction between the precursorand the initiator leads to the formation of acoating product onto the substrate.

� More recently, Pessey et al. [11] (ICMCB-Insti-tut de Chimie de la Matiere Condensee deBordeaux) patented a process for surfaces coat-ing including particles coating. ‘Core-shell’structures production is claimed. The supercrit-ical fluid is introduced in the high-pressure cellcontaining the coating material and the parti-cles. Pressure and temperature are regulated toobtain thermal decomposition of the coatingmaterial. The coated powder is then collectedafter decompression and temperature decreaseof the system. Coating of nickel particles (di-ameter, 5 �m) with copper is described. Coat-ing of permanent magnet SmCo5 with copperusing the same method is further described[14].

References

[1] L.T. Heit, J.M. Clevenger, Patent EP 0 412 053, 1991.[2] B. Subramanian, S. Said, R.A. Rajewski, V. Stella, Patent

WO 97/31691, 1997.[3] Kobe Steel Ltd, Patent J 05057166, 1993.[4] A.K. Sunol, Patent US 0062332, 1997.[5] H. Krause, M. Niehaus, U. Teipel, Patent DE 19711393,

1998.[6] M. Niehaus, U. Teipel, H. Krause, W. Weisweiler, Coat-

ing of Particles in a Fluidized Bed using SupercriticalCarbon Dioxide. Proceedings of the 5th Meeting onSupercritical Fluids, Tome 1; M. Perrut, P. Subra (Eds.),International Society for the Advancement of Supercriti-cal Fluids, 23–25 March, Nice, 1998, 361–367.


Table 6Generation of mono-constituent particles

Available AdvantagesSubstrate is substantially soluble in Drawbackssupercritical fluid process

Yes Particle size monitoring Low solubility of most complexRESSmolecules(sub-micronic and micronic

particles)No organic solvent use High fluid consumption

Thermal Ultrafine particles Only used for metal, silicon andmetal oxidesdegradation

No organic solvent useAnti-solventNo Particle size monitoring Organic solvent use

(sub-micronic and micronicparticles)

Difficult fluid/solvent separationand fluid recyclingMedium to large volume ofpressurized equipment

Low fluid consumptionPGSS Impossible to producesub-micronic particles and tomonitor particles size

Low to medium pressureSmall volume of pressurizedequipment

[7] A.K. Sunol, J. Kosky, M. Murphy, E. Hansen, J. Jones,B. Mierau, S. Sunol, Supercritical Fluid Aided Encapsula-tion of Particles in a Fluidized Bed Environment. Pro-ceedings of the 5th Meeting on Supercritical Fluids, Tome1; M. Perrut, P. Subra (Eds.), International Society forthe Advancement of Supercritical Fluids, 23–25 March,Nice, 1998,409–412.

[8] J.P. Benoit, H. Rolland, C. Thies, V. Van de Velde, PatentEP 0 706 821, 1996, WO 96/11055, 1996.

[9] J.P. Benoit, J. Richard, C. Thies, Patent FR 2 753 639,1996, WO 96/13136, 1998.

[10] J. Richard, C. Thies, V. Gajan, J.P. Benoit, A NovelSolvent-Free Process to Prepare Drug Delivery Systems,Paper for Club Heterochimie CRIV, Paris, 14 October,1998.

[11] V. Pessey, F. Cansell, B. Chevalier, F. Weill, J. Etourneau,French Patent FR 9904175, 1999.

[12] Sanofi, Pending patent, 1999.[13] H. Wakayama, Patent WO 99 10167, 1999.[14] V. Pessey, R. Garriga, F. Weill, B. Chevalier, J.

Etourneau, F. Cansell, Core-Shell Materials Elaborationin Supercritical Media. Proceedings of the 5th Interna-tional Symposium on Supercritical Fluids, 8–12 April,Atlanta (USA), 2000.

7. Conclusion: how to choose a process of particledesign?

From this literature review, the reader may bepuzzled by the process variety and complexity,and need some help to optimize the route to thedesired particles. Even if this may be subjected tocriticism, we would try to summarize the problemin Table 6 for mono-constituent particles produc-tion and Table 7 for composite particles produc-tion, with advantages and drawbacks of eachtechnique.

To choose a process for particle design, the firstthing to consider is the solubility of the substrateand, when used, of the matrix, in the supercriticalfluid. The choice between different methods willthen be made considering the desired particle size,shape and structure, processing costs and produc-tion scale. For particle generation, RESS applica-tion must be considered at first, even if substrate


Table 7Formation of composite microparticles

Matrix RemarksAvailable processSubstrate Type ofsolubilitysolubility particles

produced

RESS Microspheres Particle size monitoring Very fewYesYessubstrates and coatings are bothsoluble in supercritical fluids

Supercritical impregnationYes Microspheres No change in particle geometry. CanNobe operated on-line downwardextraction at large scale

Liposomes-RESS processNo LiposomesYesRESS Fluidized-bed coating Microcapsules Very few coatings are soluble in

supercritical fluidsPolymer coacervation onto Microcapsules Impossible to apply at large scalesubstrate particlesCoating using thermal Microcapsules Dedicated to metal precursorsdecomposition

Many types of nozzles available forNo Anti-solvent processes (GAS,No MicrospheresASES, SEDS) or particle size and shape monitoring Use

microcapsules of organic solvent(s) Difficult organicsolvent/ fluid separation

Anti-solvent Fluidized-bed Microcapsules Difficult solvent/ fluid separationcoatingPGSS process Microspheres ‘Large’ particles generation Large scale

developmentCPF process Microspheres Continuous process that can be

operated at large scale

.

(and matrix) solubility is very often too low tolead to a profitable process. Then, anti-solventprocesses are to be considered especially for phar-maceutical applications as they allow to controlparticle size, shape and structure on a very widerange from nano-particles to micro-particles orspheres, even if they lead to high processing costsand are difficult to operate at large scale, mean-while PGSS processes should be preferred forlarger particles and lower-value material.

It also appears from this review that industrialproperty is complex with many patents pending,in spite of many anterior published works. Thismay refrain many companies to use these verypromising techniques that offer new excitingsolutions.

We would not conclude this work without

stressing on the difficulties of particle harvestingand handling downward the formation process, asit would be of no interest to generate particles ifcollection is not possible in conditions where theyare needed: in most cases as a dry powder, in fewcases in form of a suspension in a liquid in whichthey are totally insoluble. This is a difficult chal-lenge in most cases!

Acknowledgements

The authors thank Professors Gerd Brunner,Ernesto Reverchon and Robert Sievers for fruitfuldiscussions about this work and the EuropeanUnion for financial support (Brite-Euram pro-gramme BRPR-CT98-0765).

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