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![Page 1: The Formation of an Interpolymer Complex in Supercritical Carbon Dioxide and its Application in the Encapsulation of Probiotics Presented at the CSIR R&I.](https://reader030.fdocuments.in/reader030/viewer/2022012902/56649c925503460f9494cadc/html5/thumbnails/1.jpg)
The Formation of an Interpolymer Complex in Supercritical Carbon Dioxide and its Application in the Encapsulation of Probiotics
Presented at the CSIR R&I Conference
Materials Science and Manufacturing
Dr. Sean Moolman
Polymers, Ceramics and Composites
27 February 2006
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Slide 2 © CSIR 2006 www.csir.co.za
Structure of talk
• Supercritical fluidsWhat are they & what makes them
special?
• ProbioticsWhat is it & why do we want to
encapsulate it?
• Polymers and scCO2
Love/hate relationship!
• Interpolymer complexesA potential solution!
• The CSIR technologySo how do we do it?
• Results(Does it actually work?!)
• ConclusionsWhere to from here?
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Supercritical fluids
What are they & what makes them special?
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Slide 4 © CSIR 2006 www.csir.co.za
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Slide 5 © CSIR 2006 www.csir.co.za
Comparison of typical values of physico-chemical properties for a liquid, gas and supercritical fluid
Material stateDiffusivity
[cm2/s]Viscosity [Pa.s] Density [kg/m3]
Liquid 10-5 10-3 1000
Supercritical fluid 10-3 10-5 300
Gas 10-1 10-5 1
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Slide 6 © CSIR 2006 www.csir.co.za
Supercritical carbon dioxide
Most commonly used supercritical fluid, because:• Non-toxic & non-flammable• Inert – cannot be oxidised• Relatively mild supercritical conditions (31.0 ºC, 73.8 bar)• Inexpensive• Easy separation by depressurization & no residual solvent• Environmentally benign (zero net effect – already
produced by many industries, e.g. beer production)
But:• SCF processing relatively expensive, therefore higher
value add applications(Commercially used in e.g. decaffeination, hops extraction)
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Slide 7 © CSIR 2006 www.csir.co.za
CO2 Total Solubility Parameter - Experimental vs. Calculated
0
2
4
6
8
10
12
14
16
18
1 10 100 1000
Pressure (bar)
Hil
deb
ran
d p
aram
eter
(M
Pa
0.5)
Exp. 31 ºC
LW 31 ºC
Hansen 31 ºC
Adjusted molar vol.
Calculation base values:LW: dd = 16.6 dp = 5.3 dh = 5.7 MPa0.5
Hansen: dd = 15.3 dp = 6.9 dh = 4.1 MPa0.5
Tref = 25 ºC, Pref = 1655 bar, Vref = 3.61E-5 m3/mol
Adjusted Vref = 4.15E-5 m3/mol, Pref = 606 bar
Temperature = 31 ºC
Hansen
LW
Adjusted
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Probiotics
What is it & why do we want to encapsulate it?
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Slide 9 © CSIR 2006 www.csir.co.za
Bacteria & the human body
• No. of bacteria 20 times more than no. of cells!
• Large intestine – 1010 – 1011 bacteria / g intestinal contents; 400 – 500 species
• Up to 1.5 kg of bacteria!
• Friendly bacteria – help promote digestion, aid in absorption of nutrients
• Pathogens – responsible for digestive problems (diarrhoea, etc.)
(From Holzapfel et al. 1998. Overview of gut flora andProbiotics. Int. Jnl. Food Microb. 41:85-101)
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Slide 10 © CSIR 2006 www.csir.co.za
Probiotics - definitions
• Live microbial cultures fed by mouth and surviving transit through the large intestinewhere they colonise the system (Frost andSullivan, 2000; Saarela et al., 2000)
• A preparation of or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora by implantation or colonization, in a compartment of the host and by that, exert beneficial effects on host health (Schrezenmeir and de Vrese, 2001)
• Live microorganisms which when administered in adequate amounts confer a health benefit on the host (FAO/WHO, 2001).
• Most commonly Lactobacillus and Bifidobacterium
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Slide 11 © CSIR 2006 www.csir.co.za
Potential benefits of probiotics as supplement or in functional foods
• Prevention and treatment of diarrhoea caused by rotavirus, especially in children
• Immune system enhancement• Reducing some allergic reactions\• Treating and preventing respiratory infections, especially
in children• Decreased faecal mutagenicity• Decrease in the level of pathogenic bacteria• Decreased faecal bacterial enzyme activity• Prevention of the recurrence of superficial bladder cancer• The restoration of the correct balance of natural microflora
after stress, antibiotic treatment, alcohol use and chemotherapy
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Slide 12 © CSIR 2006 www.csir.co.za
Problems with putting probiotics in food products…
• Lactobacillus – microaerophilic & Bifidobacterium – anaerobic, thus sensitive to OXYGEN…
• Short shelf-life…→ encapsulation?
• Encapsulation difficult because the bacteria also sensitive to HEAT and SOLVENTS
• Also sensitive to the aggressive GASTRIC environment
• Thus a ‘soft’ encapsulation method required – perhaps supercritical CO2-based? (no solvent, low temp., no oxygen)
• Enteric release would be advantageous (i.e. protection in stomach, release in intestines)
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Polymers and scCO2
Love/hate relationship!
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Slide 14 © CSIR 2006 www.csir.co.za
Polymers and scCO2
• High-pressure CO2 can depress polymer Tg and/or melting point of polymers and improve processing…
• However, many polymers have insufficient solubility in or compatibility with scCO2 to enable processing at mild pressures and temperatures
Graphs from: Kirby CF, McHugh MA. 1999. Phase Behaviour of Polymers in Supercritical Fluid Solvents. Chem. Rev. 99:565-602.
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Slide 15 © CSIR 2006 www.csir.co.za
Approaches to overcome low affinity between polymers and scCO2
Approach Elaboration Limitations
Polymer design Incorporation of "CO2-philic" functional
groups in new polymers
Need FDA approval for new polymers
Surfactants The addition of CO2-soluble surfactants Need FDA approval for surfactants
Cosolvents The addition of a cosolvent such as methanol or ethanol to increase the solvation power of scCO2
Reintroduces requirement for use of a solvent - many actives are sensitive to solvents
Mixtures of SCFs The use of a second supercritical fluid to enhance polymer processability
No obvious second supercritical fluid with desired combination of properties (low/no toxicity, low critical temperature & pressure, low cost, etc.)
Gas anti-solvent (GAS) technique
Use scCO2 as an anti-solvent to extract
the solvent from a sprayed polymer solution and thus precipitate the polymer
Reintroduces requirement for use of a solvent - many actives are sensitive to solvents
Use low molar mass and low polarity polymers
These polymers are more amenable to scCO2 processing.
These polymers generally have low mechanical integrity and/or barrier properties
Use fats / waxes for encapsulation
Fats, waxes and oils are generally soluble in scCO2
Limited flexibility with regards to properties
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Interpolymer complexes
A potential solution!
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Slide 17 © CSIR 2006 www.csir.co.za
What are interpolymer complexes?
“Non-covalent interaction between two or more polymers through forces such as ionic forces, hydrophobic interactions, hydrogen bonding and Van der Waals forces”
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Slide 18 © CSIR 2006 www.csir.co.za
Proven, proprietary CSIR technologies based on interpolymer complexes…
• Controlled release drug delivery systems• Barrier coating for packaging applications
0
20
40
60
80
100
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
PMVE-MA as wt fraction of (PVOH + PMVE-MA)
No
rmal
ized
vis
cosi
ty
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0.05
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
Gantrez content
OT
R (
cm3 @
stp
/bo
ttle
/day
)
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Slide 19 © CSIR 2006 www.csir.co.za
Desired properties of polymers for encapsulation system
• scCO2-processable (soluble / plasticizable)
• pH-dependent release in intestinal tract
• Complementary (form interpolymer complex)
• FDA approved for food or pharma
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The CSIR technology
So how do we do it?
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Slide 21 © CSIR 2006 www.csir.co.za
Polymer system
Vinyl pyrrolidone repeat unit Vinyl acetate repeat unit
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Slide 22 © CSIR 2006 www.csir.co.za
SCF processing unit
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Slide 23 © CSIR 2006 www.csir.co.za
SCF processing unit
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Slide 24 © CSIR 2006 www.csir.co.za
Important parameters
• Temperature, pressure
• Back pressure in product chamber
• Nozzle configuration (e.g. capillary vs. orifice)
• Processing aids
• Stirrer design
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Results
(Does it actually work?!)
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Slide 26 © CSIR 2006 www.csir.co.za
Plasticization of PVP and PVAc-CA
PVP
PVAc-CA
2000 – 3000 g/mol
45 000 g/mol
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Slide 27 © CSIR 2006 www.csir.co.za
Formation of interpolymer complex in scCO2
PVAc-CA
Complex
PVP
Carbonyl absorption band
acetate absorption band overlapping with two carbonyl stretching modes of the free and self-associated carboxylic acid groups
1664 cm-1
1681 cm-1
0
1
2
3
4
5
6
7
8
9
Mo
istu
re a
bso
rpti
on
(%
)
PVP:PVAc-CA PVP-VAc:PVAc-CA PEO-PPO-PEO:PVAc-CA
Moisture absorption, 72 hours, 60% RH, 30 ºC
Dry blend scCO2-processed
24 h, 30 ºC, 60% RH
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Slide 28 © CSIR 2006 www.csir.co.za
Product particles containing B. lactis
Particle size (µm)
0.1 1 10 100 1000 10000
No
rma
lize
d v
olu
me
dis
trib
utio
n
0
20
40
60
80
100PVP:PVAc-CA 0.25:0.75GMS:PVP:PVAc-CA0.75:0.0625:0.1875
Sauter meandiameter 168 µm
Sauter meandiameter 6.9 µm
3.0E+12 3.0E+12
9.3E+10
0.0E+00
5.0E+11
1.0E+12
1.5E+12
2.0E+12
2.5E+12
3.0E+12
Via
ble
cel
l co
un
t (c
fu/g
)
Control SCF-encapsulated Spray-dried
Survival of B. longum through encapsulation process
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Slide 29 © CSIR 2006 www.csir.co.zaTime (hr)
0 5 10 15 20 25
% o
f enc
apsu
late
d dr
ug r
elea
sed
0
20
40
60
80
100
pH 6.8 bufferpH 1.2 buffer
pH-dependent release of indomethacin
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Slide 30 © CSIR 2006 www.csir.co.za
Dissolution/swelling of encapsulated B. longum
Freeze-dried control
SCF encapsulated
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Slide 31 © CSIR 2006 www.csir.co.za
Shelf-life improvement
*Cui et al. 2000. Survival and stability of bifidobacteria loaded in alginate poly-l-lysine microparticles. Internat. J. of Pharmaceutics 210:51-59
Bb12 (B. lactis ) survival after 7 weeks
1.0E+06
1.0E+07
1.0E+08
1.0E+09
1.0E+10
1.0E+11
1.0E+12
1.0E+13
1.0E+14
Bb12 - RT PL3/129 - RT Bb12 - 4 ºC PL3/129 - 4 ºC Bb12 - RH PL3/129 - RH B. bifidum inalginate-
polylysine, 4ºC*
Sample / conditions
Bac
teri
a su
rviv
al (
cfu
/g)
RH = Humidity cabinet, 30 ºC, 60% RH RT = Room temperature, dessicated 4 ºC = 4 ºC, dessicated
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Slide 32 © CSIR 2006 www.csir.co.za
SGJ & SIF results – vs time
1.E+08
1.E+09
1.E+10
1.E+11
1.E+12
1.E+13
1.E+14
-1 1 3 5 7
Time (h)
Via
ble
ce
lls (
cfu
/g)
Bb-46 controlEncapsulated - pelletEncapsulated - supernatantEncapsulated - total
Beforeexperiment
Simulated gastric juice
(HCl, pepsin, saline, pH 2)
Simulated intestinal f luid(KH2PO4, NaOH, pancreatin, pH 6.8)
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Slide 33 © CSIR 2006 www.csir.co.za
Summary of B. longum results - final counts
1.E+06
1.E+07
1.E+08
1.E+09
1.E+10
1.E+11
1.E+12
1.E+13
Via
ble
bac
teri
a (c
fu/g
)
Controls (cfu/g)
Encapsulated (cfu/g)
Controls (cfu/g) 2.25E+08 1.16E+07 1.16E+07 1.21E+08 1.07E+10 2.05E+08
Encapsulated (cfu/g) 3.29E+09 1.35E+08 1.52E+09 9.45E+08 1.52E+12 1.20E+09
Normal system
Normal system + Pluronic
Normal system
Normal system -
low er press.
Normal system +
GMS
Normal + GMS + gelatin
Counts after exposure to simulated gastric juice and simulated intestinal fluid
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Conclusions
Where to from here?
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Slide 35 © CSIR 2006 www.csir.co.za
Conclusions
• Can form interpolymer complexes in scCO2
• Can process these interpolymer complexes in scCO2, without complexation inhibitor
• Can successfully encapsulate drugs and bacteria using PVP:PVAc-CA and the PGSS system, with minimal damage to bacteria
• PVP:PVAc-CA interpolymer complex insoluble in acidic environments, but swells & releases in alkaline environments
• SCF-encapsulated B. longum has improved survival through gastric environment compared to controls
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Slide 36 © CSIR 2006 www.csir.co.za
Further work
• Investigate other applications (e.g. oral vaccines)
• Improve shelf-life performance / testing methodology
• Shelf-life trials with subsequent SGJ-SIF testing
• Trials on SHIME system (Gent University – Belgium)
• Atomistic simulation to investigate optimum stoichiometric ratios
• Culture B. bifidum and determine effect of SCF-based encapsulation
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Slide 37 © CSIR 2006 www.csir.co.za
Acknowledgements
• Project team:• Philip Labuschagne, Dr. Thilo van der Merwe (CSIR)• Mapitsi Thantsha, Prof. Eugene Cloete (UP)
• IDC (joint investment)• DST (funded first supercritical fluid reactor system)