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ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac and Professor Richard Holdich Department of Chemical Engineering, Loughborough University, Leicestershire, U.K. Innovations in encapsulation
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ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

Oct 16, 2020

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Page 1: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

ENCAPSULATION BY MEMBRANE EMULSIFICATION

Dr Marijana M. Dragosavac and

Professor Richard Holdich

Department of Chemical Engineering, Loughborough University, Leicestershire, U.K.

Innovations in encapsulation

Page 2: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 3: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

CONVENTIONAL MEMBRANES

Innovations in encapsulation

Page 4: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 5: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 6: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

STIRRING – DISPERSION CELL

Innovations in encapsulation

Page 7: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 8: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 9: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

Interfacial tension

Drop diameter

Shear stress Pore radius

t

gttt

3

481218 2224422ppp rrr

x++

=

STIRRING – DISPERSION CELL

Innovations in encapsulation

Page 10: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

STIRRING – DISPERSION CELL

Innovations in encapsulation

Page 11: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

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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

Page 13: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

coacervates dyed with blue food colouring:

SHEAR STRESS BY PULSING LIQUID FLOW

Innovations in encapsulation

Page 14: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 15: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

SHEAR STRESS ON THE MEMBRANE SURFACE OSCILLATING (AZIMUTHAL) SYSTEM

Innovations in encapsulation

Page 16: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

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1. COMPLEX COACERVATION O/W emulsion

Innovations in encapsulation

Please see poster: Alix Barton

Page 18: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 19: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 20: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 21: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

• 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

Page 22: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

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(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

Page 24: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 25: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

2. ANTICANCER DRUG ENCAPSULATION

Aim to encapsulate water soluble peptide

Innovations in encapsulation

Page 26: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 27: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 28: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 29: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

Page 30: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

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3. SILICA PARTICLES W/O emulsion

Aim to produce spherical silica particles

with high surface area and internal structure

Innovations in encapsulation

Page 32: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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

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4. SURFACTANT FREE PARTICLES O/W emulsion

Aim to produce encapsulated and functional particles

for photocatalysis

Innovations in encapsulation

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surfactant free

4. SURFACTANT FREE STABILISATION

Innovations in encapsulation

A Pickering emulsion (Ramsden)

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TiO2/oil

surfactant free

4. SURFACTANT FREE STABILISATION

Innovations in encapsulation

Page 36: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

5. YEAST ENCAPSULATION W/O emulsion

Aim to produce encapsulated particles

capable of drug delivery surviving gastric juices

Innovations in encapsulation

Page 37: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

5. YEAST ENCAPSULATION

Innovations in encapsulation

Please see poster: Serena Morelli

Page 38: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

§ 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

Page 39: ENCAPSULATION BY MEMBRANE EMULSIFICATIONformulation.org.uk/images/ie16/1010Richard Holdich - Encapsulation … · ENCAPSULATION BY MEMBRANE EMULSIFICATION Dr Marijana M. Dragosavac

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