These slides covered a brief introduction about super critical fluids and some of their applications in pharmaceutical field.

1. Sarah Aly Mohamed Omran

2. Content
1. Introduction to SCF
2. Applications of SCF
3. Collective summary of SCF techniques

3. States of the matter
Figure 1. Phase diagram of CO2 ( From Principles of
General Chemistry (v. 1.0).)

4. Introduction
 SCF is a solvent at a temperature and pressure above
its critical temperature and pressure (critical point).
 Critical temperature is the maximum temp. were the
liquid state could exist.
 Critical pressure is the minimum pressure needed to
liquify a solvent at critical temp.

5. Examples for SCF
 Critical temperatures and pressures of some
fluids:
Tc (oC) Pc (MPa)
Carbon dioxide 31.1 7.4
Water (power
generation)
374.1 22.1
Ethane 32.5 4.91
Propane 96.8 4.26
Methanol 240 7.95
Ethanol 243.1 6.39
Isopropanol 235.6 5.37

6. Advantages of SC-CO2
Cheap
Safe
Abundant
Nonflammable
Easily removed
Low Tc (31 oC) and Pc (73.8 bar)
i.e. low energy consumption
Disadvantage : nonpolar

7. Properties of SCF
 Density, diffusion coefficient and viscosity of
gaseous, supercritical and liquid CO2:
CO2
Density
(g cm-3)
Diffusion
(cm-2 s-1)
Viscosity
(g cm-1 s-1)
Gas 10-3 10-1 10-4
Supercritical
10-1-1
(liquid like)
10-4-10-3
(liquid like)
10-4-10-3
(gas like)
Liquid 1 <10-5 10-2

8.  Surface tension:

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10. How to utilize these properties?
 Density
 Could be tuned by changing the pressure and temperature
 Tunable solubility of a solute
 Gas like viscosities
 Accelerate the chemical reaction kinetics.
 Zero surface tension ,
 Good wetting of the surface to allow chemical reaction happen on
the surface
 Facilitates a better penetration of the reactants into a porous
structure.
 Exist due to adjusted pressure and temp.
 By releasing pressure,
 CO2 gas could be easily separated
 Its solubilizing capacity decrease, giving a dry end product

11. Properties of the end product
 Materials with superior properties such as
 Higher surface area,
 Better distribution of secondary material in matrix,
 Less agglomeration
 Better-defined nanostructures
(Compared to those obtained using conventional
solvents at ambient pressure.)

12. Traditional applications of SC-CO2
1. Extraction
2. Drying and Cleaning

13. 1-Extraction
 Since 1950's.
 Large scale extraction processes (150 commercial
process plants worldwide).
 Widely used in the food industry for the
decaffeination of coffee

14. EXTRACTION OF LIPIDS AND
ESSENTIAL OILS
 Disadv. Of conventional method:
1. Need large amount of highly pure and
hazardous solvents (flammable and toxic)
2. Time consuming
3. Altered flavour and fragrance in
hydrodistillation:
 Thermal degradation
 Hydrolysis
 Solubility of some compounds in water

15. Extraction technique
1. The material to be extracted is placed in a high
pressure vessel, which is heated and pressurized
above the critical point.
2. With SC-CO2 circulating, it extracts the desired
compounds from the solid material,
3. Passing to another vessel where the pressure is
reduced to separate the gas CO2 from the extracted
compounds.
4. After the separation, the gas CO2 is recirculated.

17. Important Parameters for SCF
extraction
1. Threshold pressure:
 minimum Pressure where solute become soluble
2. Max. pressure where solubility of solute reach its
max.
3. Knowledge of physical properties of solute
 Solubility in SC-CO2
 m.p., since liquid is better dissolved than solids

18. Solubility of solutes
 SC-CO2 is nonpolar solvent
 Its polarity is like liquid pentane (suitable for
lipophilic)
 Has polar C=O bond (materials with hydroxide,
carbonyl or fluoride groups are soluble).
 Water is not soluble in supercritical CO2,
 can be utilized to produce water-in-CO2 emulsion
as a nanoreactor for materials synthesis
 Polar molecules such as sugars and other inorganic
salts are not soluble

19. Co-solvent
 Miscible with SC-CO2
 Excellent solubility to the material of interest
 Used in small quantities (1-10%) to increase
polarity of SC-CO2.
 Example:
 Ethanol, methanol, isopropanol, acetone, hexane,
formic acid and acetic acid

20. 2-Drying and cleaning of organic
residuals
 In the micro-electro-mechanical systems (MEMS):
 .

21.  Organic solvents are trapped in the narrow gaps in
the MEMS device.
 Conventional drying by heating causes collapse.
 Zero surface tension of supercritical CO2 allowed
it to reach the valley of the narrow gaps, dry and
remove the residuals completely by dissolving
them without structural deformation

22. Advanced applications of SC-CO2
1. Particle and crystal engineering
2. Coating
3. Exfoliation and intercalation of layered materials
4. Water-in-co2 microemulsion as a nanoreactor
5. Liposome prparation
6. Drying proteins and peptides
7. Impregnation
8. Chromatography

23. 1-Particle and crystal
engineering
 Conventional process (milling, micronization,
spray drying, freeze drying) has:
1. Limited control over particle size, shape and
crystallinity
2. Multistep manufacturing process

24. Technique used: Supercritical
antisolvent (SAS)
1. Drug solution was sprayed (through nozzle)in a
closed pressurized container (containing SC-CO2)
2. Rapid difussion of solvent from the sprayed solution
droplets to SC-CO2
3. Ppt of drug
Requirment :
 Drug should be soluble in solvent but not in SC-
CO2
 Solvent should be miscible in SC-CO2

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26. Mechanism of ppt.:

28.  Figure 5: Antisolvent processed
substances. (a) Rifampicin
microparticles precipitated from
DMSO at 90 bar, 40◦C, and 10
mg/mL. Mag = 5.00 KX. (b)
Cefoperazone microparticles
precipitated from DMSO at 150
bar, 40◦C, and 50 mg/mL. Mag =
20.00 KX. ( c ) Bovine serum
albumin microparticles. Mag =
50.00 KX.
a
c
b

29.  Factors affecting P.S. and shape:
1. Pressure and temperature of SCF
2. Diameter of expansion nozzle
3. Type of solvent (ex. Purarin)
 Ethanol: needle like crystals
 Methanol: long colomn
 Acetone: long needles with brushes

30. 2-Coating
 Examples:
1. Coating of super hydrophobic papers
2. Coating in pharmaceutics

31. Ex. Coating of superhydrophobic
paper
 Coating randomly aligned flakes with the low
surface energy of AKD on paper
 Regarded as a new type of multifunctional material,
1. With easy-to clean property,
2. Bacterial adhesion reduction,
3. Water repellence,
4. Broadband anti-reflection,
5. Anti-icing,
6. Non-adhesive property.

32.  Technique used: RESS (rapid expansion of
supercritical solutions)
1. Solute is solubilized in a SC-CO2 either by
 applying quite high pressures and
temperatures
 Using extraction colomn
2. Then expanded to lower pressure or to
ambient conditions (through a nozzle).
3. Extreme high supersaturation due to quick
depressurization
4. Extremely fine particles are obtained

33. RESS flow sheet and Mechanism of
nucleation

35. Factors affecting P.S. And shape in RESS
 Pre and post expansion pressure and temp.
 Drug concentration, solubility.
 Cosolvent addition
 Length to diameter ratio of the nozzle

36. Coating of pharmaceuticals
 Purpose:
 Protect from rapid degradation
 In controlled drug release.
 Disadvantage of traditional method ( applying
coating solution/ dispersion to the exterior of a solid
dosage form)
*Residual
solvent
*Costly
*Environme
ntal concern
organic
solvent *Long drying
time
*Insolubility
of number of
polymers
Aqueous
solvent

37. Coating silica nanoparticles by
Eudragit polymer using SAS technique
1. The polymer (insol. in SC-CO2) was dissolved in
acetone,
2. Silica nanoparticles were suspended in the
polymer solution using ultrasonication.
3. Spraying the suspension in SC-CO2 (antisolvent)
through a nozzle.
4. The polymer in the droplet became saturated very
quickly due to the extraction of acetone from the
droplet, and the polymer started to gelate.

38.  Fig. 15 shows a schematic illustration of the encapsulation
process together with a resulted structure

39. 3-Exfoliation and intercalation of
layered materials
1. SCF penetrate easily into the layered structure.
2. Upon rapid depressurization, the CO2 expands to
gaseous state and further breaks the bonds to
separate the layers.
 For coating of layers:
 precursors could be initially dissolved in SC-CO2 and
diffuse into the layered structures.

41. 4-Water-in-CO2 microemulsion as
a nanoreactor

42. silver and copper nanoparticles
1. AOT (surfactant, amphiphilic) and the metal
precursors (soluble in water and insoluble in SC-
CO2)were dissolved in the water core.
2. After 30 min of stirring at 38 C and 200 atm in a
high pressure vessel, formation of water-in-CO2
microemulsion was visually observed.
3. reducing agent of NaBH3CN in an ethanol solution
was injected into the vessel to reduce Ag+ and Cu2+
into the elemental metal particles.

43.  Nanoreactor:
 restricting the chemical reactions in
the water-in-CO2 micelles.
 Advantage:
 particle size is restricted by the micelle
diameter which can be tuned by
adjusting processing parameters such as
scCO2 pressure, temperature, and water
to surfactant ratio.

44. Hollow inorganic spheres
1. Precursor are dissolved in SC-CO2 solution
2. mixed with water containing cetyltrimethyl-
ammonium bromide (CTAB) to form emulsion.
3. Hydrolysis reaction in the interface of scco2 and
water,
4. Resulted in hollow spheres of silica and titania.

45. 5-liposome preparation
 Disadv. Of conventional methods
1. Need large volume of organic solvents
2. Multistep
3. High energy consumption

46. Supercritical Assisted Liposome formation
(SuperLip) technique
 SC_CO2 (contain
phospholipids and
cholesterol)
1. depressurized
2. mixed with
sprayed water
nano
droplets(contain
bovine serum
albumin)
SC-CO2
PL+ CH
Water
liposome

47.  Fig. 6. A schematic
representation of the
mechanism proposed for
liposomes formation in
SuperLip process.

48. Advantage:
P.S.in nano range = 200 nm
Used organic solvent less than ethanol injection
method by 15 times
High encapsulation efficiencies for water soluble
drugs (85–90%)

49. 6- Drying proteins and peptides:
 Disadv. Of conventional freeze drying :
1. Time and energy consumption
2. Uncomplete recovery of protein due to
degradation during freeze and drying
process
 Example:
Lysozymes

50. Solution enhanced
dispersion by SCF (SEDS)
 Modifications on SAS
 using nozzle with 2
coaxial passage
 SCF used as
1) antisolvent
2) spray enhancer

51. 7- Impregnation
 Incorporation of drugs in polymeric matrix through
deposition or diffusion.
 Disadv. Of conventional method ( soaking polymer
in dispersion/solution containing drug):
 residual solvents.
 Adv. Of SCF:
1. No toxic solvents
2. Additional swelling and/or plasticizing effect on
polymer.

53. Example
 Cefuroxime Na
 Polymer: intraocular lense ( polymethyl methacrylate)

54. 8- SCF chromatography
 Mobile phase: SCF-CO2
 Modifiers: small amount of organic solvents to
improve solubility.
 Adv. Over conventional HPLC:
1. Faster and more efficient separation
2. High solubility of most pharmaceuticals in SCF
3. Easy and more economic recovery of purified
compounds ( CO2 evaporate as pressure decrease)
4. CO2 is cheap, greener, safe.

55. SCF technologies

56. Classification of SCF technology
 Depending on the way SCF-CO2 is being used.
1. As solvent for active substances (RESS, PGSS,
RESOLV, RESAS, DELOS)
2. As antisolvent for the precipitation of active
substances in organic solvent (GAS, ASES, PCA, SAS,
ASAIS, SEDS)

57. SCF as solvent
1. Rapid expansion of supercritical solution (RESS)
2. Prefiltration RESS (PF-RESS)
3. Particle formation from gas saturated solution
(PGSS)
4. Rapid expansion of SCF in to antisolvent (RESOLV)
5. Others

58. Rapid expansion of supercritical
solution (RESS)

59. Disadvantage of RESS
1. Low solubility of polar drug in SCF-CO2
1. Require large volumes of SCF
2. Increase cost of production
2. Difficulty in scale up due to
1. Particle aggregation
2. Nozzle blocKage
 Rapid expansion of SCF solution cause
cooling
3. Poor control over PDI

60. RESS with solid cosolvent (RESS-
SC)
 Properties of solid cosolvent (SC):
 Increase solubility of polar drugs
 High solubility in SCF
 Barrier for coagulation
 Removed easily from ppt by sublimation (has high
vapour pressure)
 Example:
 Menthol in production of phenytoin powder
 Benzoic acid in salicylic acid or phenanthrene
production.

61. Prefiltration RESS (PF-RESS)
 Use porous membrane instead of capillary nozzles
 Adv.:
 control P.S. and PDI
 Limitation:
 Clogging problems appeared

62. Particle formation from gas saturated
solution (PGSS)
1. Melt/suspend material (insoluble in SCF) in
solvent at given temp.
2. Introduce SCF to produce gas saturated melted
solution/ suspension
3. Depressurize through nozzle
 Adv:
 Substance need not to be soluble in SCF
 Decreased volume of solvent and SCF used

64. Rapid expansion of SCF in to liquid solvent
(RESOLV)
 Spraying SCF solution into aqueous medium ( may
contain aqueous polymers or surfactants for
stabilization)
 Adv. :
 stop particle growth
 Limitation:
 recovery problems from aqueous solvents.

66.  Figure 3.7 SEM images of
the ibuprofen nanoparticles
obtained with SDS (a), PEG
(b), and BSA (c) as
stabilization agents in
RESOLV.
a
b
c

67. SCF as antisolvent
1. GAS,
2. ASES or PCA or SAS
3. ASAIS,
4. SEDS
5. Others

68. GASEOUS ANTISOLVENT(GAS)
1. precipitator is partially
filled with the solution
of solute
2. SCF is pumped into
the vessel (from the
bottom)
 DISADV. :
 Uncontrolled PS

69. Supercritical antisolvent (SAS)
1. SCF is first pumped to the top of the high pressure
vessel until the system reaches a constant
temperature and pressure
2. Drug solution is sprayed above SCF through an
atomization nozzle.

70.  Disadv.:
 Particle agglomeration
 Modification:
1. Ultrasonic nozzles
2. Vibrating precipitation vessel

71. Ultrasonic nozzles
 Use sound waves for
droplet formation
( instead of inertial and
fractional forces)
 Advantages:
1. Intensive mixing of
solution with SCF.
2. Causes an increase in
mass transfer rate.
3. Allow the use of large
diameter nozzle.

72. Atomization of supercritical antisolvent
induced suspension (ASAIS)
1. antisolvent mixed with the solution to generate a
suspension in a small tube.
2. This suspension of particles is then sprayed into a
precipitator at atmospheric condition.
 Adv.:
 No need for high volume and high pressure
precipitator.
 very small to moderate antisolvent concentration is
required

73. Solution Enhanced Dispersion by
Supercritical Fluids (SEDS)
 Role of coaxial nozzle:
1. facilitate the dispersion
of drug solution by SCF,
(i.e.enhancing mass
transfer and formation
of fine particles )
2. allows intense mixing.

74. Conclusion
 SCF address many challenges facing drug delivery
1. Particle generation and processing
 Control P.S. and shape
 Clean
 Scalable
 One step process
2. Products range from dry powder to micro and
nano drug carriers
3. Could retain the biological activity of heat labile
pharmaceuticals ( proteins and antibiotics)

75. REFERENCES
 Applications of supercritical carbon dioxide in
materials processing and synthesis, Xiaoxue Zhang,
Saara Heinonen and Erkki Lev¨anen*
 Petrucci, Ralph H. General Chemistry: Principles and
Modern Applications. Upper Saddle River, N.J.:
Pearson/Prentice Hall, 2007.
 Liposomes preparation using a supercritical fluid
assisted continuous process, Islane Espirito Santo a,b,
Roberta Campardelli a, Elaine Cabral Albuquerque b,
Silvio Vieira de Melo b, Giovanna Della Porta a,
Ernesto Reverchon a

76. THANK YOU