ENCAPSULATION BY MEMBRANE EMULSIFICATION
Dr Marijana M. Dragosavac and
Professor Richard Holdich
Department of Chemical Engineering, Loughborough University, Leicestershire, U.K.
Innovations in encapsulation
PRESENTATION LAYOUT
§ Produce drops (convert to encapsulated particles)
§ Membrane surface, what makes a good membrane?
§ Membrane emulsification – shear and size
§ Examples – from drops to particles, includingsurfactant free drops and yeast encapsulation
Innovations in encapsulation
CONVENTIONAL MEMBRANES
Innovations in encapsulation
NO SHEAR STRESS ON THE MEMBRANE SURFACE
Kosvintsev et al. 2008
TOP VIEW
MEMBRANE EMULSIFICATION
D50=200 µm Scaling up – possible Productivity – high
Hydrophilic membrane
Innovations in encapsulation
SHEAR STRESS ON THE MEMBRANE SURFACE
Movements of continuous phase: § STIRRING § CROSS FLOW § PULSING THE CONTINUOUS PHASE
Movements of the membrane: § VIBRATION (axial oscillation) § ROTATION § AZIMUTHAL (TORSIONAL)
Innovations in encapsulation
STIRRING – DISPERSION CELL
Innovations in encapsulation
13 38 68 105 146 dynes/cm2
Particle diameter, microns.
Am
ount
in g
rade
, %.
0
10
20
30
40
1 10 100 1000
D(v,90): 104D(v,10): 73D(v,50): 87Span: 0.36
drop is very low, due to the membrane design, the shear is low and emulsification conditions are gentle
pressure
STIRRING – DISPERSION CELL
Innovations in encapsulation
caF - Capillary force
Fca MEMBRANE
dF - Drag force
),,( max dpd drfF t=
),( pca rfF g=2
2
max 29 p
ddp rddd -÷
øö
çèæ= ptgp
dca FF =
2rp
Fb Fd
Dispersed phase
Continuous phase
FORCE BALANCE MODEL
dhwt 1825.0max transr=
Kosvintsev et al. 2008
Dragosavac et al. 2008 dd=f(rp, tmax, g)
Innovations in encapsulation
Interfacial tension
Drop diameter
Shear stress Pore radius
t
gttt
3
481218 2224422ppp rrr
x++
=
STIRRING – DISPERSION CELL
Innovations in encapsulation
STIRRING – DISPERSION CELL
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OSCILLATION AXIAL SYSTEM
Continuous phase
DOES CHANGE WITH TIME AND IT DOES NOT CHANGE OVER THE MEMBRANE AREA
Dis
pers
ed p
hase
Dispersed phase
Holdich R. G. et. al. 2010
Time
Shea
r str
ess
t max
- t max
SHEAR STRESS ON THE MEMBRANE SURFACE
t
Shear stress ( )aff ,,max ht =
Innovations in encapsulation
Holdich R. G. et. al. 2010
Time
Shea
r str
ess
t max
- t max
t
Continuous phase
Dispersed phase Dispersed phase
Shear stress ( )aff ,,max ht =
PULSING THE LIQUID FLOW
SHEAR STRESS ON THE MEMBRANE SURFACE
Piacentini. et. al. 2014
Innovations in encapsulation
coacervates dyed with blue food colouring:
SHEAR STRESS BY PULSING LIQUID FLOW
Innovations in encapsulation
Oscillating Membrane Emulsification
• Pharma / high value – Current capacity: 4 kg/hour,
• FMCG market
– Current capacity: 100 kg/hour,
SHEAR STRESS ON THE MEMBRANE SURFACE OSCILLATING (AZIMUTHAL) SYSTEM
Innovations in encapsulation
SHEAR STRESS ON THE MEMBRANE SURFACE OSCILLATING (AZIMUTHAL) SYSTEM
Innovations in encapsulation
EXPERIMENTAL RESULTS
FORMULATIONS 1. COMPLEX COACERVATION
2. POLYMER PARTICLES FOR DRUG DELIVERY
3. INORGANIC SILICA PARTICLES
4. SURFACTANT FREE STABILISATION
Innovations in encapsulation
5. YEAST ENCAPSULATION
1. COMPLEX COACERVATION O/W emulsion
Innovations in encapsulation
Please see poster: Alix Barton
1. COMPLEX COACERVATION O/W emulsion
Motivation for the work: Currently batch production High polydispersity of the product and usually too big droplet size Need for pig gelatine alternative
Innovations in encapsulation
1. Drop production in hydrocolloids solution
2. Coacervation (phase separation) implying the formation of a coacervate phase – pH adjustment
3. Wall formation by aggregation of the hydrocolloid around droplets of the emulsified hydrophobic material – time, room temperature
4. Wall-hardening, which is generally achieved by cross-linking the hydrocolloid forming the wall
1. COMPEX COACERVATION
Innovations in encapsulation
1. COMPLEX COACERVATION – Oil encapsulation
LIQUID CRYSTALS
Dragosavac 2012, Unpublished material
Fast cooling
Slow cooling
ENCAPSULATION OF ESSENTIAL OILS
Dragosavac 2012, Unpublished material
ENCAPSULATION OF PARAFFIN OIL
Optimising drying methods – longer storage
Innovations in encapsulation
• ROOM TEMPERATURE - less energy compared to alternative gelatine types and
• New possibilities for encapsulation of VOLATILE COMPOUNDS
• Increased CONSUMER consent for religious or diet reasons and health safety
WHY FISH GELATINE? FISH GELATINE CAPSULES
1. COMPLEX COACERVATION – Oil encapsulation
Piaccentini et al., 2013 ITM-CNR @ University of Calabria, Rende
Innovations in encapsulation
100 µm 100 µm
100 µm 100 µm
(a) (b)
(c) (d)
(a) 30:70; (b) 40:60; (c) 80:20; and (d) 50:50.
DIFFERENT RATIOS OF FG:GA FOR MICROCAPSULES
FG:GA
ROOM TEMPERATURE
Piaccentini et al., 2013
Innovations in encapsulation
(a)
100 µm 100 µm
(c)
(b)
(d)
100 µm 100 µm
Freeze dried particles (to enable future volatile compound encapsulation) Silica particles added to produce free flowing particles
OIL ENTRAPMENT
Piaccentini et al., 2013
Innovations in encapsulation
DISPERSION CELL, PULSING & VIBRATING SYSTEMS
0
50
100
150
200
250
300
0 5 10 15 20 25
Med
ian
part
icle
dia
met
er /
µm
Shear Stress / Pa
Stirred cell (FG:GA=50:50 w/w)
Pulsating system (FG:GA=50:50 w/w; a=1.6mm)
Eq. 1 IT(measured)=12.2mN/m (FG:GA=50:50 w/w)MODEL Vibrating system (FG:GA=50:50 w/w; a=1.6 mm)
Dispersed phase: Sunflower oil Continuous phase: Fish gelatine (FG) and Gum Arabic (GA)
Piaccentini et al., 2013 Flux through the pulsed membrane up to 30 L h-1
1. COMPLEX COACERVATION
20 µm MEMBRANE
Innovations in encapsulation
2. ANTICANCER DRUG ENCAPSULATION
Aim to encapsulate water soluble peptide
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2. Poly (D,L-Lactic-Glycolic Acid): PLGA
§ FDA approved biocompatibility § Complete degradation § Current applications:
§ Anticancer drug carrier § Human growth deficiency treatments § Protein and gene delivery § Scaffolds for bone repairing § Suture material
Secondary emulsion W/O/W
Innovations in encapsulation
2. ANTICANCER DRUG ENCAPSULATION O/W & W/O/W
Motivation for the work: Currently batch production Low uniformity of the produced particles using conventional emulsification methods, expensive losses of product Need for higher encapsulation efficiency Anticancer drug - extremely expensive & shear/temperature sensitive
Innovations in encapsulation
2. ENCAPSULATION OF WATER SOLUBLE PEPTIDE USING BIODEGRADABLE POLYMER
1. Dispersion phase – polymer (PLGA) mixed with DCM (volatile oil phase)
2. Mixing the peptide with previously prepared dispersion phase
3. Injecting through the membrane into 1% PVA solution
4. DCM will evaporate from the particles leaving only peptide within the spherical PLGA particles
SOLVENT EVAPORATION
Innovations in encapsulation
O/W EMULSIONS
2. ENCAPSULATION OF WATER SOLUBLE PEPTIDE USING BIODEGRADABLE POLYMER
W/O/W EMULSIONS
HPLC - ENCAPSULATION EFFICIENCY (EE) OF PEPTIDE POLYMER
CONCENTRATION (%) EE (%)
COSOLVENT METHOD (O/W)
10 40
20 50
W/O/W 10 70
20 85 Dragosavac 2012,
Unpublished material
Commercially available 14 day kit
(~1g particles/ 70mg peptide)
~200£
üCancer treatment
Innovations in encapsulation
G. Gasparini et. al, 2010, Colloids and Surfaces B: Biointerfaces
O/W EMULSIONS
W/O/W EMULSIONS
2. ENCAPSULATION OF WATER SOLUBLE PEPTIDE USING BIODEGRADABLE POLYMER
W/O/W emulsions
encapsulation efficiency
close to 100%
Innovations in encapsulation
3. SILICA PARTICLES W/O emulsion
Aim to produce spherical silica particles
with high surface area and internal structure
Innovations in encapsulation
5% Sodium silicate 1M H2SO4
Final solution had
pH=3.5
2% Span 80 in
Kerosene
Oil phase
Hydrophobic membrane
Pore size 15 µm Pore spacing 200
µm
Dispersion Cell
3. SILICA PARTICLES SILICA PARTICLES WITH D50=40µm AFTER DRYING
100 µm 20 µm
200 nm 1 µm 100 nm
SEM at Loughborough Materials Characterization Centre
Commercial spherical
silica
1g ~ 100 £
0.2 0.4 0.6 0.8 1.00
100
200
300
400
500
600
700
1 2 3 40
0.5
1.0
1.5
2.0
Amou
nt N
2 sorb
ed /
cm3 g
-1
Relative pressure / -
Adsorption Desorption
Diffe
rent
ial p
ore v
olum
e /
cm3 g
-1
Pore diameter / nm
0.2 0.4 0.6 0.8 1.00
100
200
300
400
500
2 4 6 8 10 12 14 160
0.5
1.0
1.5
2.0
2.5
Am
ount
N2 so
rbed
/
cm3 k
g-1
Relative pressure / -
Adsorption Desorption
Diffe
rent
ial p
ore v
olum
e /
cm3 g
-1
Pore diameter / nm
WATER ACETONE
AGING OF THE HYDROGEL IN DIFFERENT SOLVENTS
Spec. surface area - 750 m2 g-1
Av. pore size - 1.3 nmSpec. surface area - 320 m2 g-1
Av. pore size - 6 nm
Na2SiO3 (aq)+ H2SO4 (aq)→ SiO2 (s) + Na2SO4 (s)+H2O (aq)
Innovations in encapsulation
4. SURFACTANT FREE PARTICLES O/W emulsion
Aim to produce encapsulated and functional particles
for photocatalysis
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surfactant free
4. SURFACTANT FREE STABILISATION
Innovations in encapsulation
A Pickering emulsion (Ramsden)
TiO2/oil
surfactant free
4. SURFACTANT FREE STABILISATION
Innovations in encapsulation
5. YEAST ENCAPSULATION W/O emulsion
Aim to produce encapsulated particles
capable of drug delivery surviving gastric juices
Innovations in encapsulation
5. YEAST ENCAPSULATION
Innovations in encapsulation
Please see poster: Serena Morelli
§ Low energy process § Low pressure process § Formulation is still key § Small-scale through to production § Variety of shear techniques: § Mainly stirred cell and oscillation/pulsation
§ Good for multiple emulsions and continuous production § Small & large drop: encapsulation and functionalised particles § Good encapsulation of shear/temperature sensitive compounds
WHY MEMBRANE EMULSIFICATION?
Innovations in encapsulation
Micro / Nano – Materials Engineering Group,
Prof. Richard G. Holdich Dr Marijana M. Dragosavac Dr Goran T. Vladisavljevic
Visiting researchers: Emma Piaccentini, CNR Italy,
Alessandra Imbrognio, CNR Italy Miguel Angel Suarez Valdes, UNIDAV, Spain
Current Research Students & PostDocs:
Serena Morelli, Alix Barton,
Rahimah Othman, Konstantin Loponov…
ACKNOWLEDGEMENTS
Funding:
TSB Micropore Technologies Ltd. UK
For the membranes:
Microchannel Array Engineering Team, National Food Research Institute, Tsukuba, Japan.
Prof. Mitsutoshi Nakajima
http://www.micropore.co.uk/
Innovations in encapsulation