PVA for sustained release: theory and practice

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
PVA for sustained
release: theory and
practice
Gudrun Birk
20th August 2020

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1
2
3
Introduction
Challenges of sustained
release formulations
Application of different
technologies
4 Conclusion

Introduction
Topic #1 Person Date

Introduction
Why Modified Oral Release?
Webinar - PVA for sustained release | 20.08.20205
Drivers for modified release
Reducing side-effects
• Therapeutic efficacy
• Prolonging action
• Optimizing performance
• •
Life-cycle management
• Minimizing variability
• • Challenging API
Bypassing IP hurdle
Improving patient compliance •

21
Introduction
Sustained Release Approaches
Matrix systemsFunctional coatings
Rate controlling step: diffusion of dissolved drug through
coating; membrane-controlled
 Benefits
 Performance adjustable (coating type, layer thickness, pores)
 ‟Delayed“ release possible
 Drawbacks
 Additional process step  costs 
 Batch-to-batch consistency (layer/pore homogeneity)
 Risk of dose dumping
 Crushing/division of tablet by patient (dose adjustment)
 Gaps in coating layer
 pH variability in gastrointestinal tract
 Potential for alcohol-induced dose dumping
Rate controlling step: diffusion of dissolved drug through
matrix or by slow matrix erosion; matrix-controlled
 Benefits
 Performance adjustable (polymer type, grades thereof,
quantity)
 Generally lower risk of dose dumping
 Dosage forms divisible (dose adjustment)
 Drawbacks
 Polymers usually used are naturally derived  quality and
performance variabilities
 Potential for alcohol-induced dose dumping, depending on
polymer type
 One single polymer does not suit all drugs

Introduction
Main Challenges
1 Dose dumping - unintended, rapid drug release in a short period of time of the entire
amount or a significant fraction of the drug contained in a modified release dosage form
2
3
4
5
Batch-to-batch consistency of formulation components
Process cost efficiency – which technology is suitable and most efficient?
API dependent release kinetics – which formulation is suitable?
Flexible modification of release profile – how can the profile adapted?

Parteck® SRP 80
Synthetic PVA for Sustained Release
2 Established solutions to-date
such as cellulose based polymers
 Naturally derived products
 Batch to batch consistency
 Consistent quality of the excipient supports
Quality by Design and helps to minimize risks in
development and manufacture
 Batch to batch variability
 Challenges in formulation and production
processes
 May affect release performance of final product
 Inconsistent excipient quality poses a challenge
to Quality by Design implementation
Parteck® SRP 80 supports a consistent final product quality
1 Parteck® SRP 80
S(sustained) R(release) P(polyvinyl alcohol)
80(mean particle size in µm)
 Fully synthetic and chemically defined product

Material PVA 40-88
Bulk density 0.51 - 0.58 g/ml
Tapped density 0.70 - 0.77 g/ml
Angle of repose 32°- 37°
Mean particle size (laser diffraction Dv50) 60 – 100 µm
(target ~ 80 µm)
Surface (nitrogen adsorption BET) 0.3 - 0.5 m²/g
Pore volume (nitrogen adsorption BET) not detectable
Loss on drying (3h, 105°C) ≤ 5.0%
Processability
Material Characteristics
 Optimized particle size
for direct
compressibility
 Optimized particle size
for drug dissolution
 Compliant with Ph.
Eur., USP, JPE
monographs
 Emprove® Program

Processibility
Amount in % (w/w)
Active ingredient 5 – 50
Parteck® SRP 80 > 20
Microcrystalline cellulose 0 - 60
Silicon dioxide, highly dispersed 0.25 – 1.50
Parteck® LUB MST 0.25 – 0.75
TOTAL 100
The Parteck® SRP 80 content of the formulation
should not be less than 20 % (w/w), otherwise
gel forming will be inhomogeneous.
Parteck® SRP 80 is designed for the formulation of sustained release oral dosage forms,
and is well suitable for direct compression processes.
General Formulation with Parteck® SRP 80

Efficiency -
Direct
cOmpression

Cost efficiency
Direct Compression
1 Parteck® SRP 80
Suitable for direct compression
2 Main competitors
Typically complex, multiple-step processes
Granulation
(Dry/Wet)
Tablet
Mixing
Wetting
Granulation
Drying
Sieving
Mixing
Compression
Direct compression
Tablet
Mixing
Compression
Coating
Tablet
Coated tablet
Granulation or
direct
compression
Coating
Multiparticulates
Tablet / Capsule
Mixing
Wetting
Drying
Filling into
capsule or
tabletting
process
Extrusion
Spheronization
Substantial process cost savings through simple and economic process

Cost efficiency
Process Costs: Wet Granulation vs. Direct Compression
Wet granulation
Potential reduction of 6 additional steps
Total cost reduction up to 75%**
Compression to tablets
1. Weighing of ingredients
2. Blending of ingredients
TOTAL
Direct compression
0.4 – 1.00 €/kg
0.2 – 1.50 €/kg
0.6 – 2.50 €/kg
Process cost
(€/kg)*
1. Weighing of ingredients
2. Blending of ingredients
3. Prep. granulation fluid
4. Granulation
5. Wet sieving
6. Drying process
7. Dry sieving process
8. Add. of external phase
TOTAL
0.4 – 1.00 €/kg
0.2 – 1.50 €/kg
0.5 – 0.75 €/kg
1.0 – 2.00 €/kg
0.3 – 0.70 €/kg
1.5 – 3.00 €/kg
0.3 – 0.70 €/kg
0.3 – 0.70 €/kg
4.7 –10.35 €/kg
Process cost
(€/kg)*
*process cost was estimated based on available production data and own experience
**depending on the formulation process
Reproduced with modifications from Lammens, R. F. (2014). "Maximizing Roller Compaction
Efficiency with the Proper Excipients Selection." webinar

15 Webinar - PVA for sustained release | 20.08.2020
Direct compression
Amount
[mg]
Amount
[%]
Function
Propranolol HCl 160.00 32.0 Model API
Parteck® SRP 80 335.00 67.0
Sustained
release
polymer
SiO2, highly
dispersed
2.50 0.50 Flow regulator
Parteck® LUB MST 2.50 0.50 Lubricant
Total 500.00 100
57
131
181
0
200
400
600
800
0
100
200
10 20 30
EjectionForce[N],s(rel)
TabletHardness[N],s(rel)
Compression Force [kN]
Parteck® SRP 80 example formulation,
tablet hardness [N]
Parteck® SRP 80 example formulation,
ejection force [N]
Tableting Performance
The example formulation with Parteck® SRP 80 shows high compressibility and low
ejection forces over a vast range of compression forces.

Direct compression
Uniformity of Tablets
Parameter 10 kN 20 kN 30 kN
Average
weight [mg]
498.4 499.8 500.5
Standard
deviation [mg]
4.0 2.4 2.3
1.9
1.2
1.1
0.0
0.5
1.0
1.5
2.0
10 20 30
AcceptanceValue(AV)
Compression force [kN]
SRP 80 + Propranolol x HCl
AV < 15 acc. to pharmacopoeia
AV = (M-X) + ks
M=X, k=2.4 (n=10), s=standard dev.
Uniformity requirements of pharmacopoeia met by direct compressible
formulation.

Various tablet hardness
Release Performance
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22
%ofPropranololHCldissolved
Time [h]
10 kN, PP pH 6.8 20 kN, PP pH 6.8 30 kN, PP pH 6.8
Constant in-vitro
release behavior
over a broad range
of compression
forces
Dissolution procedure:
USP Apparatus 2 (Paddle Apparatus),
900 mL phosphate buffer pH 6.8, 50 rpm, 37 °C; n=3

Sustained release dosage forms are intended to release the drug in desired concentrations for a prolonged
period of time. Therefore, they must contain larger amounts of the drug than single-dose formulations.
Dose dumping is defined as
‟unintended, rapid drug release in a short period of time of the entire amount or a significant fraction of the
drug contained in a modified release dosage form“.*
Dose dumping
Ensuring Safety and Consistency
 tampering
 grinding/crushing
 dose division
 pH / food effect  dissolved in or taken
with alcoholic beverages
The dose dumping risk needs to be overcome to ensure patient safety and therapeutic
effect *definition based on EMA draft guideline EMA/CPMP/EWP/280/96 Corr1 and Meyer, R. J. and A. S.
Hussain (2005). Awareness Topic: Mitigating the Risks of Ethanol Induced Dose Dumping from Oral
Sustained/Controlled Release Dosage Forms. FDA’s ACPS Meeting, U.S. Department of Health and
Human Services, Food and Drug Administration.

Different media
Dose Dumping
Robust
performance at
different pH
values, no dose
dumping
900 mL phosphate buffer pH 6.8 / HCl 0.1 M, 50 rpm, 37 °C; n=3
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22
Time [h]
20 kN, PP pH 6.8 pH 6.8 20 kN, HCl 0.1 M

0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22
Time [h]
20 kN HCl 0.1M
20 kN HCl 0.1M/EtOH 95/5 Vol.-%
Presence of alcohol
Dose Dumping
Robust in-vitro
release behavior
confirmed in
presence of
alcohol, no dose
dumping
900 mL HCl 0.1 M/ x Vol. % EtOH, 50 rpm, 37 °C; n=3

Propranolol
Confirmation with Various Model Drugs
Diltiazem
Caffeine
Acetaminophen
Amount
[%]
Amount
[%]
Function
API
1. Caffeine, Diltiazem,
Paracetamol
22.5
Model API
2. Propranolol, Theophyllin 32.0
Parteck® SRP 80 76.5 67.0
Hydrophilic matrix
polymer
SiO2, highly dispersed 0.5 0.5 Flow regulator
Parteck® LUB MST 0.5 0.5 Lubricant
Total 100 100
API dependent release kinetics
Theophylline

API dependent release kinetics
Confirmation with Various Model Drugs
Retardation of release confirmed for various APIs
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16
%APIdissolved
Time [h]
Propranolol, PO4 pH 6.8 Theophylline, PO4 pH 6.8
Diltiazem; PO4 pH 7.2 Caffeine, PO4 pH 6.8
Acetaminophen, PO4 pH 7.2
900 mL medium, 37°C, 50rpm, n=3
131
230
151
120 116
0
50
100
150
200
250
300
20
Tablethardness[N]
Propranolol x HCl Theophylline Diltiazem x HCl
Caffeine Acetaminophen

Flexible
Modification of
Release Profile

Flexible modification of release profile
Change in Composition – Addition of Mannitol
Component
SRP 80
Amount [%]
SRP 80/M 200 (1/1)
Amount [%]
SRP 80/M 200 (2/1)
Amount [%]
SRP 80/M 200 (1/2)
Amount [%]
Parteck® SRP 80 67 32.75 43.7 21.65
Mannitol DC (Parteck® M 200) - 32.75 21.8 43.35
Model drug Propranolol 32 32 32 32
SiO2 0.5 0.5 0.5 0.5
Magnesium stearate
(Parteck® LUB MST)
0.5 2 2 2.5 *
* Running roughly occured so that
more lubricant was needed
 Premix of Parteck® SRP 80 and filler
 Addition of other components (including API)
 Addition of lubricant
 Mixing for 5 min, 46 rpm after each step
 Compression of tablets (500 mg, 11 mm, 10/20/30 kN)

Flexible modification of release profile
Modification of Release Profile
The release profile can be modified by addition of mannitol as pore former.
51
124
162
51
93
120
38
86
97
81
144 143
0
50
100
150
200
10 20 30
Tablethardness[N]
Parteck® SRP80 Parteck® SRP80/Mannitol 1/1
Parteck® SRP80/Mannitol 2/1 Parteck® SRP80/Mannitol 1/2
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14 16 18 20
Dissolution[%]
Time [h]
Parteck® SRP80
Parteck® SRP80/Mannitol 1/1

Application of
different
technologies

 Simple process only requiring
mixing step(s) – stable,
homogeneous mixture is a
prerequsite
 Compressibility and dissolution
performance confirmed with
various model drugs
 Process comprises several
steps – granulation and mixing
– no liquid is applied
 ‟Pre“-compaction possibly
affects compressibility,
impact on dissolution not
expected
 Complex process using liquid
– stable API mixtures are
achieved, compressibility could
be improved
 Performance of PVA 40-88
challenging, specific process
beneficial?
Granulation
Application of different technologies
Direct compression Dry granulation Wet granulation

Dry Granulation
Components
Amount
mg/tablet %
Internal phase
Parteck® SRP 80 335 67
Model drug (Ascorbic
acid)
160 32
External phase
SiO2 highly dispersed 2.5 0.5
Parteck® LUB MST 2.5 0.5
• Roller compactor RCC 100x20, powtec Maschinen und Engineering GmbH,
Remscheid, Germany
• Smooth roller surface, roller speed 3 rpm, compaction pressure adjusted by
screw speed and roller gap; resulting compaction pressure 75 bar
• Integrated 1.25mm oscillating sieve with 50 rpm, 75 bar

Peformance in Dry Granulation
Tablet hardness acceptable, in comparison to DC process reduced.
Dissolution performance comparable to DC tablets.
207
121
0
50
100
150
200
250
300
20
Tablethardness[N]
SRP80, DC SRP80, RC 75 bar
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Dissolution[%]
Time [h]
SRP80, DC SRP80, RC 75 bar
900 mL, Phosphatpuffer pH 2,7 (Titriplex III), 37°C, 50rpm

 5/10/20/30% water
 139 rpm
 0.5 kg batches
 10/30/50% water
 150 rpm
 2 kg batches
 10 % water/25% PVA 40-88
solution (4%)
 Temperature 70 °C
 1 kg batches
Wet Granulation
Low shear (LS) High shear (HS) Fluidized bed (FB)
Physical mixture of PVA 40-88 (74.75%) and model drug (Ascorbic acid, 25.25%)
prepared, granulation solution added.
MST/SiO2 (0.5 % each) added to final tableting mixture.

Performance of Wet Granulation Process
The granulation process is challenging due to the stickiness of the product.
Granules
Before drying
After drying/sieving
High shear Fluidized bed

Tableting Performance
0
50
100
150
200
250
300
10 20 30
Tablethardness[N]
DC, MW LS, 1% H2O LS, 5% H2O LS, 10% H2O LS, 20% H2O
LS, 30% H2O HS, 10% H2O HS, 30% H2O HS, 50% H2O HS, 15% H2O,
tray
HS, 15% H2O,
fluid
FB, H2O FB, PVA sol.
Components
Amount [%]
%
Internal phase
Parteck® SRP 80 74.0
Model drug (Ascorbic
acid)
25.0
External phase
SiO2 highly dispersed 0.5
Parteck® LUB MST 0.5
500 mg, 11 mm, facetted,
Single punch Korsch EK0

Dissolution Performance
0
20
40
60
80
100
120
0 1 2 3 4 5 6 7 8 9 10 11 12
Dissolution[%]
Time [h]
DC MW LS, 1% H2O LS, 5% H2O LS, 10% H2O LS, 20% H2O
LS, 30% H2O HS, 10% H2O HS, 15% H2O,
tray
HS, 15% H2O,
fluid
HS, 30% H2O
HS, 50% H2O FB, H2O FB, PVA sol.
900 mL, Phosphatpuffer pH 2,7 (Titriplex III), 37°C, 50rpm
Process (type/parameter) does not significantly affect product performance.
Tableting performance is slightly worse compared to direct compression, dissolution
not affected by granulation.

Conclusion and
Summary

Adressing main challenges
Parteck® SRP 80 for Sustained Release
1
Robust release performance – No dose dumping
- over a broad range of compression forces
- at different pH
- in presence of alcohol
2
3
4
5
Batch-to-batch consistency – Fully synthetic and chemically-defined product
Process cost efficiency – designed for direct compression being most efficient process.
Application in dry granulation as alternative process.
API dependent release kinetics – Sustained release performance confirmed for many
different APIs
Flexible modification of release profile – Achieved by modifying the formulation composition,
e.g. adding mannitol

daniel-
joseph.price@milliporesigma.com
gudrun.birk@milliporesigma.com
Daniel Joseph Price
Gudrun Birk
The vibrant M and Parteck are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates.
All other trademarks are the property of their respective owners. Detailed information on
trademarks is available via publicly accessible resources.
© 2020 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

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