Supercritical Fluids micronization techniques

Supercritical Fluids Supercritical Fluids Supercritical Fluids Supercritical Fluids micronization techniquesmicronization techniquesmicronization techniquesmicronization techniques

University of SalernoUniversity of SalernoDepartment of Chemical Engineering

University of University of TurkuTurkuDepartment of Biochemistry and Food Chemistry

Renata Adami Renata Adami Renata Adami Renata Adami PhD studentDept. Biochemistry and Food ChemistryUniversity of Turku [email protected]. Chemical and Food EngineeringUniversity of Salerno [email protected]

FINNISH CHEMICAL SOCIETY Compressed fluid technologies divisionCompressed fluid technologies divisionCompressed fluid technologies divisionCompressed fluid technologies divisionSeminar, Helsinki 23 November 2006

15.12.2006 Renata Adami

OutlineOutlineOutlineOutline

SCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesoSCF as a solventSCF as a solventSCF as a solventSCF as a solventoSCF as a soluteSCF as a soluteSCF as a soluteSCF as a soluteoSCF as a coSCF as a coSCF as a coSCF as a co----solventsolventsolventsolventoSCF as an antiSCF as an antiSCF as an antiSCF as an anti----solventsolventsolventsolvent

SAS micronization apparatusSAS micronization apparatusSAS micronization apparatusSAS micronization apparatus


Production of Production of Production of Production of micromicromicromicroand nanoparticlesand nanoparticlesand nanoparticlesand nanoparticles

products for aerosol1 µm < d < 5 µm

suspensions for injectiond < 500 nm

microparticlesmicroparticlesmicroparticlesmicroparticles

nanoparticlesnanoparticlesnanoparticlesnanoparticles

d < 200 nm directly to the organs

improvement of solubility characteristicsimprovement of solubility characteristicsimprovement of solubility characteristicsimprovement of solubility characteristics

SCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF as a solventSCF as a solventSCF as a solventSCF as a solventSCF as a soluteSCF as a soluteSCF as a soluteSCF as a soluteSCF as a coSCF as a coSCF as a coSCF as a co----solventsolventsolventsolventSCF as an antiSCF as an antiSCF as an antiSCF as an anti----solventsolventsolventsolvent



Spray-dryinglarge PSD

high Temperature

Jet-millinglarge PSD

compounds denaturation

Liquid Antisolvent Crystallization

large PSD

residual solvents

Traditional ProcessesTraditional ProcessesTraditional ProcessesTraditional ProcessesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques

SCF as a solventSCF as a solventSCF as a solventSCF as a solventSCF as a soluteSCF as a soluteSCF as a soluteSCF as a soluteSCF as a coSCF as a coSCF as a coSCF as a co----solventsolventsolventsolventSCF as an antiSCF as an antiSCF as an antiSCF as an anti----solventsolventsolventsolvent



gasgasgasgas----likelikelikelike

High High High High diffusivitydiffusivitydiffusivitydiffusivity

LowLowLowLow viscosityviscosityviscosityviscosity

liquidliquidliquidliquid----likelikelikelike

High densityHigh densityHigh densityHigh density

SupercriticalSupercriticalSupercriticalSupercritical FluidsFluidsFluidsFluids

Best control of PS PSDBest control of PS PSDBest control of PS PSDBest control of PS PSD




RRapidapidapidapid EExpansionxpansionxpansionxpansion of of of of SSupercriticalupercriticalupercriticalupercritical SSolutionolutionolutionolution

PParticles fromarticles fromarticles fromarticles from GGasasasas----SSaturated aturated aturated aturated SSolutionsolutionsolutionsolutions

RESSRESS

PGSSPGSS

SCF SCF SCF SCF asasasas a a a a solventsolventsolventsolvent

SCF SCF SCF SCF asasasas a solutea solutea solutea solute

®®

Supercritical Supercritical Supercritical Supercritical FluidsFluidsFluidsFluids basedbasedbasedbasedMicronization Micronization Micronization Micronization ProcessesProcessesProcessesProcesses




DDepressurizationepressurizationepressurizationepressurization of anof anof anof an EExpanded xpanded xpanded xpanded

LLiquidiquidiquidiquid OOrganicrganicrganicrganic SSolutionolutionolutionolution

DELOSDELOS

SSupercritical upercritical upercritical upercritical AAssisted ssisted ssisted ssisted AAtomizationtomizationtomizationtomizationSAASAA

CCarbon dioxidearbon dioxidearbon dioxidearbon dioxide AAssisted ssisted ssisted ssisted

NNebulization withebulization withebulization withebulization with aaaa BBubble ubble ubble ubble DDryerryerryerryerCANCAN--BDBD

SCF SCF SCF SCF asasasas a a a a cocococo----solventsolventsolventsolvent

®®

®®

®®

Supercritical Fluids basedSupercritical Fluids basedSupercritical Fluids basedSupercritical Fluids basedMicronization ProcessesMicronization ProcessesMicronization ProcessesMicronization Processes




SSupercritical upercritical upercritical upercritical AAntintintinti----SSolventolventolventolventSASSAS

SCF SCF SCF SCF asasasas anananan antiantiantianti----solventsolventsolventsolvent

GGas as as as AAntintintinti----SSolventolventolventolventGASGAS

AAerosol erosol erosol erosol SSolventolventolventolvent EExtractionxtractionxtractionxtraction SSystemystemystemystemASESASES

SSolutionolutionolutionolution----EEnhanced nhanced nhanced nhanced DDispersion by ispersion by ispersion by ispersion by SSupercritical fluidsupercritical fluidsupercritical fluidsupercritical fluidsSEDSSEDS

PPrecipitation with recipitation with recipitation with recipitation with CCompressed ompressed ompressed ompressed AAntintintinti----solventssolventssolventssolventsPCAPCA

SupercriticalSupercriticalSupercriticalSupercritical FluidsFluidsFluidsFluids basedbasedbasedbasedMicronization Micronization Micronization Micronization ProcessesProcessesProcessesProcesses




solubility of the compound in the SCF

morphology of the product depends on material structure and operative parameters

no use of organic solvents

limits for applications: many attractive substrates not enough soluble into the SCF

characteristicscharacteristicscharacteristicscharacteristics

RESSRESSRESSRESSSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




CO2CO2

pump

Active substance

Expansion vessel

EXTRACTION UNIT

PRECIPITATION UNIT

pump

Active substance

Expansion vessel

EXTRACTION UNIT

PRECIPITATION UNIT

pump

Active substance

Expansion vessel

EXTRACTION UNIT

PRECIPITATION UNIT





inorganic and organic compounds

pharmaceuticals

polymers, biopolymers

very fine particles (d=0.5-20 µm) withnarrow diameter distributions

microcapsules or microspheres of composite materials

productsproductsproductsproducts

CarbamazepineCarbamazepineCarbamazepineCarbamazepineCarbamazepineCarbamazepineCarbamazepineCarbamazepine

[P. M. Gosselin et al., 2003]

GriseofulvinGriseofulvinGriseofulvinGriseofulvinGriseofulvinGriseofulvinGriseofulvinGriseofulvin (SC(SC(SC(SC(SC(SC(SC(SC--------CHFCHFCHFCHFCHFCHFCHFCHF33333333)))))))) ββββββββ--------SitosterolSitosterolSitosterolSitosterolSitosterolSitosterolSitosterolSitosterol

[M. Türk et al., 2002]





solubility of SC-CO2in melted or liquid-suspended

substances

CO2as atomization vector and viscosity reducer

particles produced from a great variety of substances

limits: drug thermal stability up to melting conditions

difficulties in monitoring the PS


PGSSPGSSPGSSPGSS®®SCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




Saturation

Expansion

Product

CO2

Saturation

Expansion

Product (polymer)

CO2





inorganic and organic compounds

pharmaceuticals

microspheres 1->100 µmmicrocomposite particles

productsproductsproductsproducts

BaTiOBaTiOBaTiOBaTiOBaTiOBaTiOBaTiOBaTiO33333333

[Z. Novak et al. 2001]

TheophyllineTheophyllineTheophyllineTheophyllineTheophyllineTheophyllineTheophyllineTheophylline/HPO (/HPO (/HPO (/HPO (/HPO (/HPO (/HPO (/HPO (HydrogenatedHydrogenatedHydrogenatedHydrogenatedHydrogenatedHydrogenatedHydrogenatedHydrogenated PalmPalmPalmPalmPalmPalmPalmPalm Oil)Oil)Oil)Oil)Oil)Oil)Oil)Oil)

[M. Rodrigues et al. 2004]





limited solubility between SC-CO2and liquid solvent

efficient coating between the two phases

use of N2for maintenance of temperature during the

process

low temperature

atmospheric pressure

solvent: organic solvents, WATER


SAASAASAASAA®SCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




SAASAASAASAA®

2040

2040

20

2040

E. E. E. E. ReverchonReverchonReverchonReverchon SwissSwissSwissSwiss PatentPatentPatentPatent 1209/01, 20011209/01, 20011209/01, 20011209/01, 2001

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33333333

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44444444




productsproductsproductsproducts� micromicromicromicro andandandand submicro crystalline particlessubmicro crystalline particlessubmicro crystalline particlessubmicro crystalline particles

� micromicromicromicro and nanoand nanoand nanoand nano particlesparticlesparticlesparticles (100(100(100(100 nmnmnmnm ---- >5 >5 >5 >5 µµµµm)m)m)m)� inorganic compoundsinorganic compoundsinorganic compoundsinorganic compounds

� pharmaceuticalspharmaceuticalspharmaceuticalspharmaceuticalsNaClNaClNaClNaClNaClNaClNaClNaCl fromfromfromfromfromfromfromfrom HHHHHHHH22222222OOOOOOOO

TetracyclineTetracyclineTetracyclineTetracyclineTetracyclineTetracyclineTetracyclineTetracyclinefromfromfromfromfromfromfromfrom HHHHHHHH

22222222OOOOOOOO

RifampicinRifampicinRifampicinRifampicinRifampicinRifampicinRifampicinRifampicin fromfromfromfromfromfromfromfrom HHHHHHHH22222222OOOOOOOO

AluminumAluminumAluminumAluminumAluminumAluminumAluminumAluminum SulfateSulfateSulfateSulfateSulfateSulfateSulfateSulfatefromfromfromfromfromfromfromfrom HHHHHHHH

22222222OOOOOOOO

[E. Reverchon et al., 2003][E. Reverchon et al., 2003]

SAASAASAASAA®SCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




Batch OperationBatch OperationBatch OperationBatch OperationBatch OperationBatch OperationBatch OperationBatch Operation

SemicontinuousSemicontinuousSemicontinuousSemicontinuousSemicontinuousSemicontinuousSemicontinuousSemicontinuous OperationOperationOperationOperationOperationOperationOperationOperation

SAS processesSAS processesSAS processesSAS processes

Discontinuous for the solid phaseDiscontinuous for the solid phaseDiscontinuous for the solid phaseDiscontinuous for the solid phase

Continuous for the fluid phaseContinuous for the fluid phaseContinuous for the fluid phaseContinuous for the fluid phaseGas batch SASGas batch SASGas batch SASGas batch SAS

Liquid batch SASLiquid batch SASLiquid batch SASLiquid batch SAS

SASSASSASSAS

the solute insoluble in the antisolvent

the liquid solvent completely miscible in the supercritical antisolvent at the process conditions





CO 2

pump

Solution of active substance

particles

Expanded solution

CO 2

pump

Solution of active substance

particles

Expanded solution

Gas Gas Gas Gas Gas Gas Gas Gas batchbatchbatchbatchbatchbatchbatchbatch SASSASSASSASSASSASSASSAS

LiquidLiquidLiquidLiquidLiquidLiquidLiquidLiquid batchbatchbatchbatchbatchbatchbatchbatch SASSASSASSASSASSASSASSAS

precipitation precipitation precipitation precipitation occurs in the occurs in the occurs in the occurs in the liquid rich phaseliquid rich phaseliquid rich phaseliquid rich phase

precipitation occurs precipitation occurs precipitation occurs precipitation occurs in supercritical fluid in supercritical fluid in supercritical fluid in supercritical fluid rich phaserich phaserich phaserich phase

Batch SASBatch SASBatch SASBatch SAS

GASGASGASGASSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




liquid solution and supercritical anti-solvent are continuously delivered to the precipitation vessel P

CO 2

pump

nozzle

High pressure vessel

pump

P vent

Low pressure tank

P P

CO 2

nozzle

P P

SemiSemiSemiSemi----continuouscontinuouscontinuouscontinuous SASSASSASSAS

SAS SAS SAS SAS –––– ASES ASES ASES ASES –––– SEDS SEDS SEDS SEDS ---- PCAPCAPCAPCA

ASESASESASESASESASESASESASESASES

SAS SAS SAS SAS SAS SAS SAS SAS –––––––– SEDS SEDS SEDS SEDS SEDS SEDS SEDS SEDS --------PCAPCAPCAPCAPCAPCAPCAPCA

delivering in codelivering in codelivering in codelivering in co----current modecurrent modecurrent modecurrent mode

delivering in counterdelivering in counterdelivering in counterdelivering in counter----current modecurrent modecurrent modecurrent mode

11111111

33333333

22222222




• DMSODMSODMSODMSO

• NMPNMPNMPNMP

• MeOHMeOHMeOHMeOH

• EtOHEtOHEtOHEtOH

• AcetoneAcetoneAcetoneAcetone

• DichloromethaneDichloromethaneDichloromethaneDichloromethane

• EthylEthylEthylEthyl AcetateAcetateAcetateAcetate

UsualUsualUsualUsual SolventsSolventsSolventsSolvents

SASSASSASSAS

• MethyleneMethyleneMethyleneMethylene chloridechloridechloridechloride

• TolueneTolueneTolueneToluene

• CyclohexanoneCyclohexanoneCyclohexanoneCyclohexanone

• ButylButylButylButyl BromideBromideBromideBromide

• MEKMEKMEKMEK

• HexaneHexaneHexaneHexane

• THFTHFTHFTHF

• DMFDMFDMFDMF

OtherOtherOtherOther SolventsSolventsSolventsSolvents




ExplosivesExplosivesExplosivesExplosives improvementimprovementimprovementimprovement of of of of combustioncombustioncombustioncombustion processprocessprocessprocess

PolymersPolymersPolymersPolymers, , , , biopolymersbiopolymersbiopolymersbiopolymers chromatographychromatographychromatographychromatography, , , , adsorbentsadsorbentsadsorbentsadsorbents, , , , catalystcatalystcatalystcatalystsupportssupportssupportssupports, , , , drugdrugdrugdrug delivery systemdelivery systemdelivery systemdelivery system

PharmaceuticalPharmaceuticalPharmaceuticalPharmaceutical principlesprinciplesprinciplesprinciples improvementimprovementimprovementimprovement of of of of therapeutictherapeutictherapeutictherapeuticaction of action of action of action of drugsdrugsdrugsdrugs

ColoringColoringColoringColoring mattermattermattermatter, , , , superconductorssuperconductorssuperconductorssuperconductors, , , , catalystscatalystscatalystscatalysts

improvementimprovementimprovementimprovement of of of of coloringcoloringcoloringcoloring power, power, power, power, surfacesurfacesurfacesurface areasareasareasareas, , , , superconductingsuperconductingsuperconductingsuperconducting

propertiespropertiespropertiesproperties

ApplicationsApplicationsApplicationsApplications

SASSASSASSASSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




AcYAcY from DMSOfrom DMSO

[E. Reverchon et al., 1998, 2002]

GdAcGdAcGdAcGdAcGdAcGdAcGdAcGdAc from DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSO

Superconductor Superconductor Superconductor Superconductor precursorsprecursorsprecursorsprecursors





DextranDextranDextranDextranDextranDextranDextranDextranfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSO

PLLA from PLLA from PLLA from PLLA from PLLA from PLLA from PLLA from PLLA from Methylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene Cloride

[E. Reverchon et al., 2000]

LLLLLLLL--------PLA PLA PLA PLA PLA PLA PLA PLA from from from from from from from from Methylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene ClorideMethylene Cloride

[L.S. Tu at al., 2002]

BiopolymersBiopolymersBiopolymersBiopolymers





Tetracycline from NMPTetracycline from NMPTetracycline from NMPTetracycline from NMPTetracycline from NMPTetracycline from NMPTetracycline from NMPTetracycline from NMP

Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP Amoxicillin from NMP

RifampicinRifampicinRifampicinRifampicinRifampicinRifampicinRifampicinRifampicin from DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSOfrom DMSO

PharmaceuticalsPharmaceuticalsPharmaceuticalsPharmaceuticalsSASSASSASSAS

[E. Reverchon et al., 1999, 2002]




Ascorbic Acid Ascorbic Acid Ascorbic Acid Ascorbic Acid Ascorbic Acid Ascorbic Acid Ascorbic Acid Ascorbic Acid from EtOHfrom EtOHfrom EtOHfrom EtOHfrom EtOHfrom EtOHfrom EtOHfrom EtOH

[F. E. Wubbolts et al., 1999]

ParaParaParaParaParaParaParaPara--------Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid Hydroxybenzoic Acid from Methylene Chloridefrom Methylene Chloridefrom Methylene Chloridefrom Methylene Chloridefrom Methylene Chloridefrom Methylene Chloridefrom Methylene Chloridefrom Methylene Chloride

Lysozyme from Lysozyme from Lysozyme from Lysozyme from Lysozyme from Lysozyme from Lysozyme from Lysozyme from DMSODMSODMSODMSODMSODMSODMSODMSO

[P. York et al., 2000]

FoodFoodFoodFood additivesadditivesadditivesadditives

SASSASSASSAS

[L.S. Tu at al., 2002]




SAS SAS SAS SAS apparatusapparatusapparatusapparatus

SAS laboratory apparatusSAS laboratory apparatusSAS laboratory apparatusSAS laboratory apparatusUniversity of Salerno (Italy)University of Salerno (Italy)University of Salerno (Italy)University of Salerno (Italy)

SAS semiSAS semiSAS semiSAS semi----industrial apparatus industrial apparatus industrial apparatus industrial apparatus MTT MTT MTT MTT AgrifoodAgrifoodAgrifoodAgrifood Research FinlandResearch FinlandResearch FinlandResearch Finland

Liquid solution

CO 2 pump max 10 kg/h

pump

vent

CO 2

Inj e c tor of 20 0 micron

precipitator L/D ratio of 5 I.V. 0.5 dm 3

P

low pressure tank

11111111

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SAS SAS SAS SAS laboratorylaboratorylaboratorylaboratory----scalescalescalescale plantplantplantplant

University of Salerno (Italy)University of Salerno (Italy)University of Salerno (Italy)University of Salerno (Italy)




MTT MTT MTT MTT AgrifoodAgrifoodAgrifoodAgrifood Research Finland, Research Finland, Research Finland, Research Finland, JokioinenJokioinenJokioinenJokioinen (Finland)(Finland)(Finland)(Finland)

SAS pilotSAS pilotSAS pilotSAS pilot----scale scale scale scale plantplantplantplantSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniquesSCF and micronization techniques




for your attentionfor your attentionfor your attentionfor your attention


ReferencesReferencesReferencesReferencesP. M. Gosselin, R. Thibert, M. Preda and J. N. McMullen, Polymorphic properties of Polymorphic properties of Polymorphic properties of Polymorphic properties of micronizedmicronizedmicronizedmicronized carbamazepinecarbamazepinecarbamazepinecarbamazepine produced by RESS produced by RESS produced by RESS produced by RESS International Journal of Pharmaceutics (2003) 252 (1-2), 225-233J. Jung and M. Perrut, Particle design using supercritical fluids: Literature and pateParticle design using supercritical fluids: Literature and pateParticle design using supercritical fluids: Literature and pateParticle design using supercritical fluids: Literature and patent survey, nt survey, nt survey, nt survey, J Supercrit. Fluids, (2001) 20 (3), 179-219S. Moshashaee, M. Bisrat, R.T. Forbes, H. Nyqvist, P. York, Supercritical fluid processing of proteins. I: Supercritical fluid processing of proteins. I: Supercritical fluid processing of proteins. I: Supercritical fluid processing of proteins. I: LysozymeLysozymeLysozymeLysozyme precipitation from organic precipitation from organic precipitation from organic precipitation from organic solution.solution.solution.solution. Eur. J. Pharm. Sci. (2000), 11(3), 239-245.

Z. Novak, Z. Knez, I. Ban, M. Drofenik, Synthesis of barium Synthesis of barium Synthesis of barium Synthesis of barium titanatetitanatetitanatetitanate using supercritical CO2 drying of gels.using supercritical CO2 drying of gels.using supercritical CO2 drying of gels.using supercritical CO2 drying of gels. J Supercrit. Fluids (2001), 19(2), 209-215.

E. Reverchon, G. Della Porta, A. Di Trolio, S. Pace, Supercritical Antisolvent Precipitation of Nanoparticles of SupSupercritical Antisolvent Precipitation of Nanoparticles of SupSupercritical Antisolvent Precipitation of Nanoparticles of SupSupercritical Antisolvent Precipitation of Nanoparticles of Superconductor Precursors,erconductor Precursors,erconductor Precursors,erconductor Precursors,Ind. Eng. Chem. Res. (1998), 37(3), 952-958.

E. Reverchon, G. Della Porta, Production of antibiotic microProduction of antibiotic microProduction of antibiotic microProduction of antibiotic micro---- and and and and nanonanonanonano----particles by supercritical antisolvent precipitation,particles by supercritical antisolvent precipitation,particles by supercritical antisolvent precipitation,particles by supercritical antisolvent precipitation, Powder Tech. (1999), 106(1-2), 23-29.

E. Reverchon, Supercritical antisolvent precipitation of microSupercritical antisolvent precipitation of microSupercritical antisolvent precipitation of microSupercritical antisolvent precipitation of micro---- and and and and nanonanonanonano----particles,particles,particles,particles, J. Supercrit. Fluids (1999), 15(1), 1-21.

E. Reverchon, G. Della Porta, M.G. Falivene, Process parameters and morphology in amoxicillin micro and Process parameters and morphology in amoxicillin micro and Process parameters and morphology in amoxicillin micro and Process parameters and morphology in amoxicillin micro and submicrosubmicrosubmicrosubmicro particles generation by particles generation by particles generation by particles generation by supercritical antisolvent precipitation,supercritical antisolvent precipitation,supercritical antisolvent precipitation,supercritical antisolvent precipitation, J. Supercrit. Fluids (2000), 17(3), 239-248.

E. Reverchon, G. Della Porta, I. De Rosa, P. Subra, D. Letourneur, Supercritical antisolvent micronization of some biopolymers,Supercritical antisolvent micronization of some biopolymers,Supercritical antisolvent micronization of some biopolymers,Supercritical antisolvent micronization of some biopolymers, J. Supercrit. Fluids (2000), 18(3), 239-245.

E. Reverchon, SupercriticalSupercriticalSupercriticalSupercritical----Assisted Atomization To Produce MicroAssisted Atomization To Produce MicroAssisted Atomization To Produce MicroAssisted Atomization To Produce Micro---- and/or Nanoparticles of Controlled Size and Distribution,and/or Nanoparticles of Controlled Size and Distribution,and/or Nanoparticles of Controlled Size and Distribution,and/or Nanoparticles of Controlled Size and Distribution, Ind. Eng. Chem. Res. (2002), 41(10), 2405-2411.

E. Reverchon, I. De Marco, G. Della Porta, RifampicinRifampicinRifampicinRifampicin microparticles production by supercritical antisolvent precipimicroparticles production by supercritical antisolvent precipimicroparticles production by supercritical antisolvent precipimicroparticles production by supercritical antisolvent precipitation.tation.tation.tation. Int. J. Pharm. (2002), 243(1-2), 83-91.

E. Reverchon, I. De Marco, G. Della Porta, Tailoring of Tailoring of Tailoring of Tailoring of nanonanonanonano---- and microand microand microand micro----particles of some superconductor precursors by supercritical particles of some superconductor precursors by supercritical particles of some superconductor precursors by supercritical particles of some superconductor precursors by supercritical antisolvent precipitation,antisolvent precipitation,antisolvent precipitation,antisolvent precipitation, J. Supercrit. Fluids (2002), 23(1), 81-87.

E. Reverchon, G. Della Porta, Micronization of antibiotics by supercritical assisted atomizatiMicronization of antibiotics by supercritical assisted atomizatiMicronization of antibiotics by supercritical assisted atomizatiMicronization of antibiotics by supercritical assisted atomization,on,on,on, J. Supercrit. Fluids (2003), 26(3), 243-252.

E. Reverchon, Process for the production of micro and/or Process for the production of micro and/or Process for the production of micro and/or Process for the production of micro and/or nanonanonanonano particles,particles,particles,particles, PCT Int. Appl. (2003), 20 pp. WO 2003004142

E. Reverchon, A. Spada, Crystalline Microparticles of Controlled Size Produced by SupercCrystalline Microparticles of Controlled Size Produced by SupercCrystalline Microparticles of Controlled Size Produced by SupercCrystalline Microparticles of Controlled Size Produced by Supercriticalriticalriticalritical----Assisted Atomization,Assisted Atomization,Assisted Atomization,Assisted Atomization, Ind. Eng. Chem. Res. (2004), 43(6), 1460-1465.

M. Rodrigues, N. Peirico, H. Matos, E. Gomes de Azevedo, M.R. Lobato, A.J. Almeida, MicrocompositesMicrocompositesMicrocompositesMicrocomposites theophyllinetheophyllinetheophyllinetheophylline/hydrogenated palm oil /hydrogenated palm oil /hydrogenated palm oil /hydrogenated palm oil from a PGSS process for controlled drug delivery systems,from a PGSS process for controlled drug delivery systems,from a PGSS process for controlled drug delivery systems,from a PGSS process for controlled drug delivery systems, J Supercrit. Fluids (2004), 29(1-2), 175-184.L.S. Tu, F. Dehghani, N.R. Foster, Micronization and microencapsulation of pharmaceuticals using a Micronization and microencapsulation of pharmaceuticals using a Micronization and microencapsulation of pharmaceuticals using a Micronization and microencapsulation of pharmaceuticals using a carbon dioxide antisolvent.carbon dioxide antisolvent.carbon dioxide antisolvent.carbon dioxide antisolvent. Powder Tech (2002), 126(2), 134-149.

M. Turk, P. Hils, B. Helfgen, K. Schaber, H.J. Martin, M.A. Wahl, Micronization of pharmaceutical substances by the Rapid ExpansioMicronization of pharmaceutical substances by the Rapid ExpansioMicronization of pharmaceutical substances by the Rapid ExpansioMicronization of pharmaceutical substances by the Rapid Expansion of n of n of n of Supercritical Solutions (RESS): a promising method to improve biSupercritical Solutions (RESS): a promising method to improve biSupercritical Solutions (RESS): a promising method to improve biSupercritical Solutions (RESS): a promising method to improve bioavailability of poorly soluble pharmaceutical agents,oavailability of poorly soluble pharmaceutical agents,oavailability of poorly soluble pharmaceutical agents,oavailability of poorly soluble pharmaceutical agents, J Supercrit. Fluids(2002), 22(1), 75-84.

F.E. Wubbolts,O.S.L. Bruinsma, G.M. van Rosmalen, DryDryDryDry----spraying of ascorbic acid or acetaminophen solutions with supercspraying of ascorbic acid or acetaminophen solutions with supercspraying of ascorbic acid or acetaminophen solutions with supercspraying of ascorbic acid or acetaminophen solutions with supercritical carbon ritical carbon ritical carbon ritical carbon dioxide.dioxide.dioxide.dioxide. J Crystal Growth (1999), 198/199 (1), 767-772.

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Supercritical Fluids micronization techniques