Hot melt extrusion with PVA: A new opportunity for challenging APIs

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Hot melt extrusion
with PVA – A new
opportunity for
challenging APIs
Dr. Thomas Kipping
22.08.2019, Darmstadt

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

Agenda
1
2
3
Introduction
Hot melt extrusion
process
Solubility enhancement
with PVA
4
5
Molecular interactions
Case studies with final
formulations
6 Screening tools for hot
melt extrusion
7 Summary

Importance of solubility enhancement
Hot melt extrusion with PVA – A new opportunity for challenging APIs – August 20195
Hot melt extrusion with polyvinyl alcohol
A. Pandit, GlobalData 2009
New molecular entities are becoming larger, more lipophilic and therefore
less soluble

Distribution of oral
immediate-release
drugs on the market
NME percentages from a
data set of 28,912
medicinal chemistry
compounds
New molecular entities are becoming larger, more lipophilic and therefore
less soluble

7
Speed up
liberation
Increase
absorption
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Type of dosage form
• Disintegration time
• Tissue targeting
• Protein binding
• Avoid the first
pass effect
• Reduce
enzymatic bio-
transformation
• Increase
circulation
lifetime
• Increase size
• Solubility
• Permeability

Speed up
liberation
Increase
absorption
Solubility Permeability Other
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Protein binding
• Avoid the first
pass effect
• Reduce
enzymatic bio-
transformation
• Increase
circulation
lifetime
• Increase size
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
• Chemical approaches
• Physical approaches

Speed up
liberation
Increase
absorption
Solubility Permeability Other
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Protein binding
• Avoid the first
pass effect
• Reduce
enzymatic bio-
transformation
• Increase
circulation
lifetime
• Increase size
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
Chemical
approaches
Physical
approaches
• Salt formation
• Prodrug
formation
• Particle size reduction
• Complexation
• Drug carriers
• Solid form modification
• Solid dispersion

Types of solid dispersions – an evolution
Soliddispersions First generation Crystalline carriers Urea & sugars
Second generation Polymeric carriers
Known polymers for
HME
Third generation
Mixture of surfactants &
polymers
Surfactants
Novel strategies:
Carriers provide
surfactant activity
and/ or self-
emulsifying
capabilities
Mixture of polymers
Fourth generation
Controlled release solid
dispersion
Release modifying
polymers
Vasconcelos et al. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today. 2007;12(23):1068-75
Info
Great advantage of
Parteck® MXP as a surface
active polymer with
potential for controlled
release

Introduction to Polyvinyl alcohol
Polyvinyl alcohol (PVA) is a fully synthetic polymer.
History
 Polyvinyl alcohol was first
described in 1915 by
F. Klatte
 In 1956 approval of the
first drug product
containing PVA
Manufacturing
 Step 1: Polymerization of
vinyl acetate to polyvinyl
acetate.
 Step 2: Hydrolysis to
polyvinyl alcohol
Applications
 PVA has a long history of
use in various applications
in the food, cosmetic and
pharmaceutical industries
1 2 3
(*Ph. Eur.: hydrolysis grade greater than 72.2%; USP: hydrolysis grade between 85 and 89%;
JPE: hydrolysis grade between 78 and 96%)
4 Monographs
• Only polyvinyl alcohol with
a hydrolysis rate between
85 – 89 % fulfills the
requirements of all three
major pharmacopeias: USP,
Ph. Eur. and JPE*

Product characteristics
Product Properties
Bulk density (g/mL) 0.53±0.02
Tapped density (g/mL) 0.74±0.02
Particle size (D50) (μm) 60-80
Loss on drying (%) <3.0
Angle of repose (°) 35
Tg
(by DSC)
Tm
(by DSC)
Td
(by TGA)
40-45 °C 170 °C >250 °C
Temperature
Melt Viscosity
D=200 (s-1)
Melt Viscosity
D=1200 (s-1)
210 °C 702 Pa*s 283 Pa*s
230 °C 345 Pa*s 174 Pa*s
Product Properties
Hydrolysis grade (%) 85-89
Solubility (%) (max. in water) 33
Mass average molar mass approx. 32,000
pH-value (4% / water) 5.0-6.5

Hot melt extrusion technology
Potential
Expert opinion:
“The continuous advancements in
pharmaceutical manufacturing
technologies and formulation
design development, along with
the many applications and
advantages of HME, demonstrate
that HME has the potential to
become one of the most prominent
pharmaceutical formulation
processing technologies of the 21st
century.”
- Tiwari et al. 2016
Twin screw extrusion process involves heating, mixing and melting of an
API together with a polymeric carrier

Melt properties
▪ Thermoplastic polymer
▪ Pseudo-plastic viscosity behavior: Shear thinning
▪ Parteck® MXP loves shear forces!
The higher the shear forces the easier will be the
process resulting in
▪ Enabling of high throughput rates
▪ Improve down-streaming
▪ Optimized melt flow through die channels
▪ Extended process ranges

Hot melt extrusion technology
Exemplary process conditions for Parteck® MXP: Optimized particle
properties assure a constant process
80 20190190 190190

Solubility
enhancement
with PVA

Perspective of the formulator
Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No
interaction
with API

PVA loading capacity and solubility enhancement
API BCS II&IV Tm of API
Loading
Capacity
Solubility
Enhancement
(max.)
Ibuprofen* 78 °C > 30 % 2 x
Cinnarizine 118-122 °C < 20 % 10 x
Indomethacin 151 °C > 50 % 3 x
Ketoconazole 146 °C > 35 % 17 x
Naproxen 152 °C > 30 % 4 x
Atorvastatin 159-160 °C > 55 % 154 x
Itraconazole 167 °C > 30 % 80 x
Carbamazepine 204 °C > 30 % 2 x
Telmisartan* 260 °C > 15 % 35 x
3%
10%
27%
24%
15%
21%
< 100°C
100°C-130°C
130°C-160°C
160°C-200°C
200°C-240°C
>240°C
Tm Breakdown of 67 BCS II and IV compounds: Sarah Shugarts and
Leslie Z. Benet, The Role of Transporters in the Pharmacokinetics of
Orally Administered Drugs, Expert Review, Pharmaceutical Research,
Vol. 26, No. 9, September 2009
*Plasticizer required

Creation of solid dispersions –what is the aim?
Amorphous
system
Homogenous
Distribution
Prolonged
Supersaturation

Solubility enhancement
0
20
40
60
80
100
0 50 100 150 200
Dissolution(mg/L)
Time (min)
Crystalline itraconazole Itraconazole:PVA Extrudate
Itraconazole:Marketed Polymer 1 Extrudate Itraconazole:Marketed Polymer 2 Extrudate
Itraconazole:Marketed Polymer 3 Extrudate
Conditions: FDA-recommended conditions for itraconazole, 900 mL SGF, 37 °C,
100 rpm, 100 mg itraconazole, 30 % drug load
✓ Solubility enhancement
due to high soluble
matrix
✓ Rapid dissolution

Molecular interactions: Solid state characterization
Outcome
Homogenous distribution
confirmed by uniform 1H
T1 relaxations
Correlation of PVA
backbone to aromatic parts
of API can be observed
HETCOR, MAS@12kHz, ct 1.5ms
Take trace at d13C 69.6 ppm and project the
associated 1H correlations

Molecular interactions: Interactions in solutions
Info
Two-dimensional 1H/1H
Nuclear Overhauser Effect
Spectroscopy (NOESY)
Interactions between PVA
backbone and remaining
non hydrolyzed acetate
groups with aromatic
structures of APIs can
provide a stabilizing effect

Molecular dynamic simulation
Info
Molecular interactions between
Indomethacin and a simplified
PVA matrix
PVA takes a dedicated
conformation enabling an
interaction between PVA
backbone and aromatic
structures of the API
High probability for hydrogen
bond formation

Versatile downstream options
Pelletizing
Tablet
Hot Melt
Extrusion
Milling
Capsule
Clickicon
toaddpicture
Hot Melt
Extrusion
Pelletizing
Direct
shaping
Tablet
Tablet
Capsule
Milling
Film
extrusion
Filament
production3D
Printing

Immediate release: Dissolution of capsules
Immediate release of itraconazole: PVA capsule
formulations
Pellets in Capsule
0
20
40
60
80
100
120
0 20 40 60 80 100 120 140 160 180
Drugrelease(%)
Time (min)
crystalline itraconazole
0.5mm Pellets in Capsule
Dissolution method: FDA-recommended conditions for itraconazole, 900 mL SGF,
37 °C, 100 rpm, 100 mg itraconazole, N=3
Simple manufacturing process, simple composition
Fast track to preclinical and clinical testing

Controlled release: Direct compression tablets
Dissolution of compressed tablets based on milled itraconazole: PVA
(FDA-recommended conditions for itraconazole, 900 mL SGF, 37 °C, 100 rpm, formulated
extrudate with 30 % drug load; N=3)
Tablet 1 Tablet 2 Tablet 3 Tablet 4
Extrudate (%) 50 50 50 60
Microcrystalline cellulose (%) 10 10 10 10
K2CO3 (%) - - 14.75 10
NaCl (%) 14.75 14.75 - -
Magnesium stearate (%) 0.5 0.5 0.5 0.5
Lactose (%) 16.25 16.25 16.25 11
Silica (%) 1 1 1 1
Crospovidone (%) 7.5 7.5 7.5 7.5
Compressed force (kN) 15 10 10 10
Tmax (min) 15 30 60 120 0
10
20
30
40
50
60
70
80
90
0 30 60 90 120
Drugrelease(%)
Time (min)
Tablet 1
Tablet 2
Tablet 3
Tablet 4
Crystalline
itraconazole
Single polymer, single extrudate, many dissolution kinetic options

Sustained release: Direct-shaped tablets
No dose dumping in up to 40 % ethanol (FDA method)
0
20
40
60
80
100
120
0 50 100 150 200 250 300 350 400
Dissolution(%)
Time (min)
0.1M HCL without ethanol
0.1M HCL with 10% ethanol
Crystalline itraconazole
Dissolution of itraconazole direct-shaped tablets

Comparison to marketed products based on solid dispersions
Highly simplified formulations with PVA
PVA capsule:
PVA
HPMC (Capsule)
Marketed product B
using spray drying
Glucose Syrup
Hypromellose
Indigo carmin
Macrogol 20000
Starch
Sucrose
Titan dioxide
Marketed product A
using hot melt
extrusion
Colloidal SiO2
Crospovidone
Hydrogenated vegetable
oil
HPMC
MCC
Lactose
Mg Stearate
PEG
Talc
TiO2
Dissolution method: FDA recommended conditions for itraconazole, 900 mL SGF,
37 °C, 100 rpm, 100 mg itraconazole, 30 % drug load
0
20
40
60
80
100
0 20 40 60 80 100 120
Dissolution%
Time (min)
Crystalline
itraconazole
Marketed product A
Marketed product B

Stability of extruded powder
Extrudates of model API show stable dissolution performance over 12 months
API
Storage
Conditions
Time Results*
Itraconazole
(30% loading,
powder)
Low: 2-4 °C
Room: 25 °C,
60% humidity
Accelerated:
40 °C, 75%
humidity
12 M
Stable under all
conditions
*Stability assessments: DSC, repeat dissolution, HPLC; samples were stored in closed container
Repeat dissolution of itraconazole
extrudate after 12 months storage
0
20
40
60
80
100
120
0 50 100 150 200
Dissolution(mg/L)
Time (min)
Crystalline Itraconazole
Extrudate at T=0
Extrudate at 12 M, 2-4°C
Extrudate at 12 M, 25°C, 60% rH
Extrudate at 12 M, 40°C, 75% rH
Conditions: FDA-recommended conditions for itraconazole, 900 mL SGF, 37 °C, 100 rpm,
100 mg itraconazole, 30 % drug load

In vitro Solubility and Permeability
Overview
 Measurements performed using
in vitro dissolution and
absorption system (iDAS)
 Caco-2 cell monolayer
separating the donor and
receiver wells
 Donor well measurements to
determine dissolution of the API
 Receiver well measurements to
determine flux/absorption of
the API across the biological
membrane
by courtesy of Absorption
Systems LLC, Exton, PA
Donor Receiver
Caco-2 cell monolayer

Conditions: Milled extrudates itraconazole: PVA, 30 % drug load. Measurement made using iDAS permeability system,
Donor buffer: HBSSg, pH 6.5, Receiver buffer: HBSSg, pH 7.4, containing 4.5% BSA modified SGF, 37 °C, stirring
Concentration of itraconazole in donor wellConcentration of itraconazole in donor well
Crystalline Itraconazole Itraconazole - PVA Extrudate

20- to 50-fold increased concentration in the receiver well
Concentration of itraconazole in receiver wellConcentration of itraconazole in receiver well
Crystalline Itraconazole Itraconazole - PVA Extrudate
Conditions: Milled extrudates itraconazole: PVA, 30 % drug load. Measurement made using iDAS permeability system,
Donor buffer: HBSSg, pH 6.5, Receiver buffer: HBSSg, pH 7.4, containing 4.5% BSA modified SGF, 37 °C, stirring

Screening tools for hot melt extrusion
General motivation for screening tools
▪ Low amount of drug substances available at early development stages (mg range)
▪ Selecting the right polymer / API combination is crucial at early project stages
▪ Performance evaluations provide key advantage compared to competitors
Actual status
▪ Solvent film casting is the most prominent screening method:
▪ Polymers and targeted drug substance are dissolved in a suitable solvent which is then removed
Limitations
▪ Strong deviation from later HME process resulting in limited predictability
▪ Method in most cases not well applicable for water soluble polymers
▪ -> Increased risk of non ideal polymer selection

Heating
25 – 230 °C
at 30 °C/Min
Isothermal 3 Min at 230 °C
Cooling
230 – 25 °C
at 30 °C/Min
Evaluation via Differential
Scanning Calorimetry (DSC)
using a simplified heating
program
Fill physical mixture of API and
polymer directly in the DSC pan,
target weight: 25 mg (100 µL pan)
Close the DSC pan
Initiate dedicated heating program
Remove cover of DSC pan -> further
analysis

Direct comparison hot melt extruded formulation vs. DSC screening method
Model compound; Ketoconazole, drug loading 20%
HME Formulation DSC Screening

Heating 25 – 230 °C
Isothermal 3-5 Min at 230 °C
Cooling 230 – 25 °C
Evaluation via Vacuum
compression molding
(VCM) using a simplified
heating program
Insert physical
mixture
(Polymer & API)
Apply vacuum &
compress the
mixture
Initiate the
heating program
including
isothermal step
Defined cooling to
room temperature

Direct comparison hot melt extruded formulation vs. VCM screening method
Model compound; Ketoconazole, drug loading 20%
HME Formulation VCM Screening

Summary
✓ Both technologies DSC as well as VCM can be used to predict formulation
performance at small scale
✓ Both optimized screening technologies are easy applicable & simple to use
✓ DSC method can be easily established on existing equipment
✓ VCM method can be implemented to gain a deeper understanding of your
formulation and it offers the potential to apply an extended analytical
evaluation (DSC, PXRD, advanced dissolution testing)

Summary
1
2
3
Formulation flexibility & Solubility enhancement
▪ Increased solubility over a broad range of different APIs
▪ Enhanced supersaturation & prolongation of the supersaturated state
▪ Flexible down-stream options & release kinetics
Polymer characteristics
▪ Simple synthetic polymer
▪ Particle characteristics and melt viscosity & optimized for hot
melt extrusion
4
Molecular interactions
▪ As an amphiphilic molecule PVA can also stabilize rather lipophilic
molecular structures
▪ Deep understanding of molecular interactions is important for polymer
selection
Novel screening approaches
▪ Melt based screening tools can enhance formulation development
already in early stages
▪ Improved screening can increase success rate for new APIs

Dr. Thomas Kipping
thomas.kipping@emdgroup.com
contact
Thank You for Your Attention!
The vibrant M, SAFC 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.
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Learn more about Parteck® MXP Excipient for Hot Melt Extrusion by
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Hot melt extrusion with PVA: A new opportunity for challenging APIs

Hot melt extrusion with PVA: A new opportunity for challenging APIs

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