supercritical fluid technology

supercritical fluid technology

1. Supercritical and Subcritical
Fluid Technology in Drug Delivery
1
By:RajeshL. Dumpala
(B.Pharm, M. Pharm.) PhD. ( Pursuing)
Research Scientist,
Alembic Research Centre. Vadodara
E.Mail:[email protected]

2. List of Abbreviations
Supercriticalfluid(SF)
SupercriticalCarbondioxide(SC-CO
2)
RapidExpansionofSupercriticalSolution(RESS)
RapidExpansionofaSupercriticalSolutionintoaLiquid
Solvent(RESOLV)
TheGasAnti-solvent(GAS)
ParticlesbyCompressedAntisolvent(PCA)
SupercriticalAntisolvent(SAS)
2

3. List of Abbreviations
AerosolSolventExtractionSystem(ASES)
SolutionEnhancedDispersionbySupercriticalFluids
(SEDS)
ParticlesfromGas-SaturatedSolutions/Suspensions(PGSS)
DepressurizationofanExpandedLiquidOrganicSolution
(DELOS)
ContinuousPowderCoatingSprayingProcess(CPCSP)
CarbondioxideAssistedNebulizationwithaBubbleDryer
(CAN-BD)
SupercriticalFluid-AssistedAtomization(SAA)
3

4. Introduction
4
CRITICAL
TEMPERATURE
Ifthetemp.iselevated
sufficiently,avalueis
reachedabovewhichitis
impossibletoliquefya
gasirrespectiveofthe
pressureapplied.
Thistemp.abovewhicha
liquidcannolongerexist,
isknownasCRITICAL
TEMPERATURE
CRITICAL PRESSURE
Thepressurerequiredto
liquefyagasatit’s
criticaltemperatureisthe
CRITICAL PRESSURE,
whichisalsothehighest
vapourpressurethatthe
liquidcanhave.

5. Introduction
5
SFs are GASES/LIQUIDS
that are at temperatures
and pressures above their
critical point.
Possess properties of both
liquid and gas.
Density as of liquid
Flow properties as of gas
Useful for thermolabile
material
SFs is dense but highly
compressible, particularly
near the SCF region

6. Commonly used SC material
6

7. 7
Phase diagram of CO
2
Why CO
2is
preferred over
other
materials?
Inexpensiveness
Non-flammability
Non-toxicity
Recyclability
Environment benignity
GRAS
HYDROPHOBIC

8. Processing using supercritical fluids
8
Operations where the SCF acts as a solvent
(RESS, RESOLV);
Operations where the SCF acts as an antisolvent
(GAS, SAS, PCA, ASES, SEDS);
Particles from a gas-saturated solutions (PGSS,
DELOS, CPCSP);
CO
2-assisted spray-drying (CAN-BD, SAA).

9. SCF TECHNIQUES FOR PARTICLE ENGINEERING
Precipitation from supercritical
solutions composed of
supercritical fluid and solute
Precipitation from solutions
using SCFs or compressed
gases as antisolvents
Precipitation from Gas
Saturated Solutions (PGSS)
RESS
PCA
SAS
ASES
GAS SEDS

10. The Rapid Expansion of Supercritical Solution
Process
Mechanism
Saturation of
SCF with
substrate(s)
Depressurizing
the solution
throughheated
nozzle
Rapid
nucleation of
the
substrate(s)
Product
10

11. RESS Equipment
Process
Variables
Pre-expansion
Temperature
Capillary length
Spraying
Distance
Pressure
Solute Solubility
Aggregation
11

12. Rapid Expansion of a Supercritical Solution into a
Liquid Solvent Process
12
This technique is usedin order to minimize the
particles aggregation during the jet expansion.
Step 2
Depressurization of SC solution in to water at
room temp.(ctg. Polymers and Surfactants for
stabilization of nanosupension)
Step 1
Mixing of SC-CO
2and solute mixture to generate
supersaturated solution.

13. The Gas Anti-solvent
Mechanism
Step 3
Solute precipitates in microparticles
Step 2
Mixing, expansion and supersaturation of solution mixture
Step 1
Antisolvent Solution of Active Substance
13

14. GAS Equipment
14
Process
variables
Rateof
additionof
antisolvent
Temperature
andpressure
inprecipitator
Solvent

15. Particles by Compressed Antisolvent and
Supercritical Antisolvent
15
IntheParticlesbyCompressedAntisolvent(PCA)and
SupercriticalAntisolvent(SAS),theCO
2(supercriticalfor
SAS,orsubcriticalforPCA)isfirstpumpedinsidethe
high-pressurevesseluntilthesystemreachesthefixed
pressureandtemperature,then,theorganicsolutionis
sprayedthroughanozzleintotheSCFbulkdetermining
theformationoftheparticlesthatarecollectedonafilter
atthebottomofthevessel

16. 16
Process
variables
Rateof
additionof
antisolvent
Temperature
andpressure
inprecipitator
Solvent
SAS/PCA Equipment

17. Aerosol Solvent Extraction System Process
Mechanism
Spraying of
active substance
& solvent
mixture
Compressed
SCF (CO2)
Dissolution into
the liquid
droplets due to
large volume
expansion
Sharp rise in the
supersaturation
within the liquid
mixture
Formation of
small &
uniform
particles
Step 1
Step 2
Step 3
17

18. ASES Equipment
Process
Variables
Temperature
Liquid solution
pressure
Operating
vessel pressure
18

19. Solution Enhanced Dispersion by Supercritical
Fluids process
Mechanism
Active
substance
solution
Spontaneous
contact of liquid
solution & SCF
Simultaneous
spraying of
SCF
Particle
precipitation
19

20. SEDS Equipment
Process
Variables
Type of nozzle
Pressure
Temperature
20

21. Advantages
Itcanbeusedforthewater-solublecompounds
•Proteins
•Peptides,byintroducingorganicsolvent(Binary
system)
Suitableforscaling-up
Highlycontrolled&reproducibletechnique
ManufacturingaccordingtoGMPrequirement
21
Solution Enhanced Dispersion by Supercritical
Fluids process

22. 22
Schematic
representation
oftheGAS,SAS,
ASES,PCA,and
SEDSprocesses
andtheirbasic
operational
principles.

23. Particles from Gas-Saturated Solutions/Suspensions
Process
Mechanism
SCF (CO2) is
dissolved in
solution or melt of
solid
Expansion of
gas saturated
solution
Generation of
solid particles or
liquid droplets
23

24. PGSS Equipment
Process
Variable
Pressure
Temperature
24

25. Thisprocessisdesignedformakingparticlesof
materialsthatabsorbsupercriticalfluidathigh
concentrations
Thetechniquecanbeusedforformationof
microsphereswithanembeddedsubstance
Highlysuitableforpolymerpowderproduction,
particularlyforcoatingapplications
25
Particles from Gas-Saturated Solutions/Suspensions
Process

26. Depressurization of an Expanded Liquid Organic
Solution Process
26
TheCO
2expandsinanautoclavewhereanorganic
solutionofthesolutetobemicronizedisdispersed
Ternarymixturesolute–solvent–compressedgasis
depressurizedbyrapidreductionofthesystempressureto
atmosphericconditions
Thetemperaturedropisthedrivingforcethatcausesthe
nucleationandprecipitationofthedrug
TheCO
2doesnotactasanantisolvent,butasaco-
solventtonebulizeandcooltheorganicsolution
Theprocessisnotnecessarilysupercritical,infactthe
operativepressuredoesnotexceedthecriticalpointofthe
CO
2/solventmixture

27. Continuous Powder Coating Spraying Process
27
CPCSP,themaincomponents(binderandhardener)
aremeltedinseparatedvesselstoavoida
prematureinteractionwiththepolymer
Themoltenpolymerisfedintoastaticmixer,and
homogenizedwithcompressedcarbondioxide.
Thedifferentcomponentsareintensivelymixedand
theformedsolutionexpandedthroughanozzleinto
aspraytower.

28. Carbon dioxide Assisted Nebulization with a Bubble
Dryer
28
Thenear-criticalorsupercriticalCO
2andthesolution
arepumpedthroughanearzerovolumetogive
risetoanemulsionwhichexpandsthroughaflow
restrictorintoadryingchamberatatmospheric
pressuretogenerateaerosolsofmicrobubblesand
microdropletsthataredriedbyafluxofwarm
nitrogen

29. Supercritical Fluid-Assisted Atomization
29
InthecaseofSAA(SupercriticalFluid-Assisted
Atomization)thesupercriticalCO
2andthesolutionare
mixedintoavesselloadedwithstainlesssteelperforated
saddlewhichassuresalargecontactsurfacebetween
liquidsolutionandtheSCF;thenthemixtureissprayedin
aprecipitatoratatmosphericpressureunderaflowofhot
N
2.
ThemaindifferencebetweenCAN-BDandSAAprocesses
isrepresentedbythemixingpartoftheequipmentand,
therefore,bytheextentofsolubilizationoftheSC-CO
2in
theliquidsolution.

30. Process Role of
supercritical
fluid
Role of
organic
solvent
Mode of phase
separation
1. RESS Solvent Co-solvent Pressure/temper
ature-induced
2. GAS/ SAS Antisolvent Solvent Solvent-induced
3. ASES Antisolvent Solvent Solvent-induced
4. SEDS Antisolvent/disp
ersing agent
Solvent/non-
solvent
Solvent-induced
5. PGSS Solute _ Pressure/temper
ature/solvent-
induced
Table 1 : Summary of available Supercritical fluid technology
30
Particle Formation Processes With Supercritical
Fluid

31. Application of Supercritical Fluid
31
DRUG DELIVERY
Particle and Crystal Engineering (Size
Reduction and Solid State Chemistry)
Particle Coating
Particulate Dosage Form
Cyclodextrin Inclusion Complexes
Extrusion
Liposomes Preparation
Microspheres

32. Other Application of Supercritical Fluid
32
Sterilization
Solvent Removal
Extraction
Supercritical and Subcritical Chromatography

33. Particle and Crystal
Engineering (Size
Reduction and Solid
State Chemistry)
33
DRUG DELIVERY

34. ParticledesignofAPIsisimportantfor
Makingsoliddosageformswithsuitable
physicochemicalproperties
Controlbiopharmaceuticalproperties
Maximizetheefficiencyandminimizethe
requireddosage
34
Particle Design & Its Importance

35. Standard Micronization
Processes
Supercritical Fluid
Based Techniques
Multiple-stepprocesses
Difficulttocontrol
Mechanical stress
leadstodamage
Increased surface
energyleadsto
adhesion and
agglomeration
Single step process
Easy to control
No mechanical stress
Little or no adhesion
& agglomeration
Standard Micronization Processes Vs
Supercritical Fluid Based Techniques
35

37. Particle Formation Processes With Supercritical
Fluid
Requirementsofanidealparticleformation
process
Operateswithrelativelysmallquantitiesof
organicsolvent(s)
Molecularcontrolofprocess
Singlestep,scalableprocessforsolvent-free
finalproduct
37

38. 38
Abilitytocontroldesiredparticleproperties
Suitableforwiderangeofchemicaltypesof
therapeuticagentsandformulationexcipients
Capabilityforpreparingmulti-component
system
GMPcompliantprocess
Particle Formation Processes With Supercritical
Fluid

39. Advantages
Supercritical fluid based techniques
mildoperatingtemperatures
singlestepprocess
recoveryandrecycleoffluid
greentechnology
solventfreeproducts
39

40. SEM images of nabumetone
(a) Before RESS process (b) After RESS process
40
Advantages

41. Comparison of particle size and dissolution rate
Mean particle size= 32.6 µm (original)K
W= 0.0217 min
-1
(original)
Mean particle size= 3.3 µm (processed) K
W= 0.0749 min
-1
(Processed)
41
Advantages

42. Crystallization
42


43. Crystallization
43
Salmeterolxinafoate
Habitmodificationtoobtainlowbulkdensity
particleswaspossiblebychangingtheoperating
conditions
Attractivefeatures
Improvingperformanceofdrypowderinhaler
Powderflow
Reducethesurfacefreeenergy
Smoothsurfaceofparticle

44. Polymorphism
44
Pseudopolymorph
Two types of polymorph
Enantiotropic
Monotropic
Metastable to stable.
New polymorph of Fluticasone propionate is prepared by the
SEDS technique.
Particle size & shape is controlled by SEDS.
New polymorph exhibit improved drug delivery characteristics in
a metered dose inhaler.

45. Polymorphism
45
Anequimolarmixtureof
carbamazepinepolymorphs
IandIIIwasprocessed
withsupercriticalCO
2to
obtainacrystallographically
purephase.
Ithasbeenprovedthat
the suspension in
supercriticalCO
2leadsto
analmostquantitative
conversionofformIinto
formIII.
SF Treatment %Form III
0 47.9
6 88.3
9 90.6
23 91.2
48 94.7

46. Particle coating
46
DRUG DELIVERY

47. Particle coating
47
Conventionalcoatingprocessusesorganicsolvents
Useofaqueoussolutions;butitincreasesdrying
timeduetolatentheatofvaporizationofthewater
Lowtemperature&pressureallowstocoatsensitive
materiallikePROTIEN
Paraffinirregularlyshapedparticlesofbovineserumalbumin
(BSA)andinsulin
Proteinparticleswerecoatedwithtrimyristin(Dynasan
®
114)
andGelucire
®
50-02,twoglyceridemixtureswithamelting
pointof45and50
◦
C

48. Particulate Dosage Form
1. Cyclodextrin Inclusion
Complexes
48
DRUG DELIVERY

49. Cyclodextrin(CD) Inclusion Complexes
49
CDsarecyclicOligosaccharidecanabletoinclude
aguestmoleculeintotheirhydrophobicinternal
cavityeitherfullyorpartially.
Improvedphysico-chemical&organolepticproperties
Example:Asuccessfulcomplexation(94%inclusion
yield)betweenpiroxicamandβ-cyclodextrin(β-CD)
wasobtainedby.Theinclusionexperimentswere
performedbykeepingaphysicalmixtureofβ-CD
andpiroxicamfor6hincontactwithCO
2at150
◦Cand15MPawithouttheuseoforganicsolvents.

50. Particulate Dosage Form
2. Extrusion
50
DRUG DELIVERY

51. Extrusion
51
CapabilityofSC-CO
2toplasticizepolymersatlow
temperaturecanbeexploitedintheextrusion
process
SC-CO
2canbothchangetherheologicalproperties
ofthematerial,andbehaveasanexpansionagent.
ThedissolutionofalargeamountofSC-CO
2
determinesapolymerexpansionandviscosity
reduction.Theviscosityreductionresultsinlower
mechanicalconstraintsanddecreasestherequired
operatingtemperature,thusallowingprocessingof
thermolabilecompounds.

52. Extrusion
52
Examples
ExtrusionofPVP-VA(polyvinylpyrrolidone-co-vinyl
acetate),Eudragitandethylcellulose,inwhich
pressurizedCO
2wasinjectedataconstantpressure
rate.Thespecificsurfaceareaandtheporosityof
thepolymersincreasedaftertreatmentwithcarbon
dioxide,eventuallyresultinginenhancedpolymer
dissolutioninwater.

53. Particulate Dosage Form
3. Liposomes
53
DRUG DELIVERY

54. Liposomes
54
Thepreparationofliposomesformulationonindustrial
scaleisstillamajorissuemainlyduetotheneed
ofthelargeamountoforganicsolventsandthe
highenergyconsume.
The 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
(POPC)andcholesterolweredissolvedin
supercriticalcarbondioxidemodifiedwithethanol.
Rapidexpansionofthesupercriticalsolutionintoan
aqueousphasecontainingamarkerresultsinthe
formationofliposomesencapsulatingthemarker.

55. 55

56. Particulate Dosage Form
4. Microspheres and
Microprticles
56
DRUG DELIVERY

57. Microspheres and Microprticles
57
Particleswithirregulargeometry,composedofan
activesubstanceinformofaggregatesor
molecularlydispersedsolidembeddedintoamatrix.
Theyarecalled‘microspheres’.
Particleswithsphericalgeometry,composedofa
coreofactivesubstancesurroundedbyasolid
polymericorproteicshell.Theyarecalled
‘microcapsules’.

58. Microspheres and Microprticles
58
MicroparticlesbytheRESSco-precipitationofadrug
(lovastatin)andabiodegradablepolymer(poly(D,l-lactic
acid)(DL-PLA)).Theco-precipitationofthepolymerandthe
drugledtoaheterogeneouspopulationofmicroparticles
consistingofmicrospherescontainingasinglelovastatin
needle,largerspherescontainingseveralneedles,
microsphereswithoutprotrudingneedlesandneedles
withoutanypolymercoating.
Formationofmicrospheresofflavonesandapolymer
(Eudragit-100orPEG6000)bysprayingatatmospheric
pressure,asuspensionofflavonoidsinasupercritical
solutionofthepolymerandaco-solvent.

59. Microspheres and Microprticles
59
Aprocesscalledpolymerliquefactionusing
supercriticalsolvation(PLUSS).
Thecarrierisapolymerthatissaturatedwith
carbondioxideundersupercriticalconditions,causing
polymerswellingandliquefactionatatemperature
muchbelowitsglasstransitionorfusion
temperature.
Theactive-carriermixtureisatomizedthrougha
nozzleintoalowpressurevessel,leadingto
microcapsules,asclaimedontheexampleofIBDV
vaccineinsidepolycaprolactone(MW4000).

60. Limitations
Poorsolubilityofpharmaceuticalingredientsinsupercriticalfluids
Difficulttoscale-up
Particleaggregation
Nozzleblockage
Whenco-solventsareusedadvantageofgreentechnologyis
lost
N
2Oandlighthydrocarbonsarehazardousandlessenvironment
friendly
60

61. 61

62. 62