Hot melt extrusion has successfully emerged as an innovative manufacturing technology in pharmaceutical industry for the creation of amorphous solid dispersions (ASDs).
In this webinar you will learn about the potential of hot melt extrusion to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA) as a matrix polymer. We will provide an overview about different types of solid dispersions and their evolution in the pharmaceutical field. A brief introduction in hot melt extrusion processing will be given as well as actual formulation trends. You will get insights in potential down-stream options to create your final dosage form and you will gain ideas on how to speed up your formulation development.
A detailed background of PVA will be provided including its physical properties as well as its regulatory status. PVA is more than a polymer. Due to its amphiphilic structure it has the potential to improve the supersaturation of low soluble APIs and to prevent precipitation after release. This highlights the versatility of PVA as an advanced polymer for HME applications and we will guide you through our latest research activities so that you can leverage our knowledge to improve your formulations.
This webinar includes:
- The current status and further potential of HME in pharmaceutical industry
- Advantages of PVA in the field of ASDs: Solubility improvement, impact on supersaturation potential, stability data generated on sample formulations & downstream options
- Deep dive into latest research activities: Permeation studies with Caco-2 cell membranes, pH shift studies to investigate supersaturation potential, ongoing research activities to get to know a more detailed understanding of matrix systems and their intermolecular interactions
In this webinar, you will learn:
- which potential hot melt extrusion has, to overcome challenges in API solubility and bioavailability by using polyvinyl alcohol (PVA)
- why PVA is more than just a polymer
- how to create your final dosage form and speed up your formulation development
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Hot melt extrusion with PVA – solubility enhancement, supersaturation performance & formulation stability
1. Dr. Finn Bauer (Head of Solid Formulations R&D)
November 21th, 2018
2. Developing a single use adenovirus-based vaccine Webinar
The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.
5. 5
Importance of Solubility Enhancement
Solubility enhancement precedes bioavailability to support R&D success
A. Pandit, GlobalData 2009
6. Solubility of new APIs
Source: PharmaCircle, 2003 - 2011
(pharmacopoeial definition and categorization of solubility)
6
7. Solubility of new APIs
7
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
Data adapted from Benet et al. Journal of Pharmaceutical Sciences.
2013;102(1):34-42
8. Ensure Performance of Active Ingredients
Speed up
liberation
Increase
absorption
Solubility Permeability Other
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
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
8
• Solubility
• Permeability
9. 9
Increase Absorption
Speed up
liberation
Increase
absorption
Solubility Permeability Other
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
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
• Chemical approaches
• Physical approaches
10. 10
Strategies to Solubility Enhancement
Speed up
liberation
Increase
absorption
Solubility Permeability Other
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
• 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
11. 11
Strategies to Solubility Enhancement
Speed up
liberation
Increase
absorption
Solubility Permeability Other
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
• 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
12. What is Hot Melt Extrusion (HME)?
12
HME itself can be described as a process in which a material melts or softens
under elevated temperature and pressure and is forced through an orifice by
screws to produce a homogeneous solid dispersion.
Advantages of
HME
▪ Enhanced solubility
& bioavailability
▪ Controlled release
▪ Continuous
effective process
▪ Solvent-free
manufacturing
▪ Shaping to the final
dosage form
13. Types of Solid Dispersions
13
Visualization of possible types of solid dispersions related
to Dhirendra et al., 2009
System Eutectic
Amorphous
Precipitation
in Crystalline
Matrix
Continuous
Solid Solution
Discontinuous
Solid Solution
Substitutional
Solid Solution
Interstitial
Solid Solution
Glass Suspension Glass Solution
Matrix C C C C C C A A A
Drug C A M M M M C A M
Phase 2 2 1 2 1 or 2 2 2 2 1
A Amorphous
C Crystalline
M Molecular dispersed
Most solid dispersions are multi-phasic systems
14. The evolution of solid dispersions
14
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
Adapted from Vasconcelos et al. (2007) & Vo et al. (2013)
Advantage of Parteck® MXP
excipient as a surface active
polymer with potential for
controlled release
15. • HME is a thermal/mechanical process
• Thermal and mechanical stability of API
• Limited number of suitable polymers
• Suitable glass transition temperature (Tg)
• High thermal degradation temperature (Tdeg)
• Limited number of polymers are approved for pharmaceutical use
• Limited stability of API solid dispersion
Main Challenges of Hot Melt Extrusion
15
17. Introduction to PVA
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
Manufacture
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%)
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*
17
18. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
18
What Do Formulators Care about?
19. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
19
What Do Formulators Care about?
20. PVA – Loading Capacity and Solubility Enhancement
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
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
*Plasticizer required
20
Tm Breakdown of 67 BCS II and IV compounds
21. Solid Dispersion
API and PVA form a solid dispersion after extrusion
Solid Dispersion
DSC of extrudate PVA with 30 % indomethacin and crystalline APIDSC of indomethacin and PVA raw material
before HME after HME
API
API
PVA
PVA/API
21
22. Solubility Enhancement
22
✓ Solubility enhancement
due to high soluble matrix
(+20% compared to other
polymers)
✓ Rapid dissolution
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
23. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
23
What Do Formulators Care about?
24. Stability of Extruded Powder
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
Extrudates of model API show stable dissolution performance over 12 months
24
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
25. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
25
What Do Formulators Care about?
26. PVA for Hot Melt Extrusion (Basic Properties)
26
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
Melt Viscosity at
D=200s-1
Melt Viscosity at
D=1200s-1
345.3±7.8 Pa s 174.0±1.7 Pa s
Product Properties
Hydrolysis grade (%) 85-89
Solubility (%) (max. in
water)
33
Mass average molar mass
(Da)
approx. 32,000
pH-value (4 % / water) 5.0-6.5
28. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
28
What Do Formulators Care about?
29. Main Final Dosage Form for HME
Pelletizing
Direct shaping
Tablet
Tablet
Hot Melt
Extrusion
Milling
Capsule
Clickicon
toaddpicture
Hot Melt
Extrusion
Pelletizing
Direct shaping
Tablet
Tablet
Capsule
Milling
29
30. Immediate Release: Dissolution of Capsules
30
0
20
40
60
80
100
120
0 50 100 150 200 250 300 350 400
Drugrelease(%)
Time (min)
crystalline itraconazole
0.5mm Pellets in Capsule
1.5mm Pellets in Capsule
3.0mm Pellets in Capsule
Immediate release of itraconazole:PVA capsule
formulations
Dissolution method: FDA-recommended conditions for itraconazole, 900 mL SGF,
37 °C, 100 rpm, 100 mg itraconazole, N=3
Pellets in Capsule
3 mm 1.5 mm <0.5 mm
Simple manufacturing process, simple composition
Fast track to preclinical and clinical testing
32. Sustained Release: Direct-Shaped Tablets
32
0,00
20,00
40,00
60,00
80,00
100,00
120,00
0 50 100 150 200 250 300 350 400
Dissolution(%)
Time (min)
Dissolution of itraconazole direct-shaped tablets
0.1M HCL without ethanol
0.1M HCL with 10% ethanol
0.1M HCL with 20% ethanol
0.1M HCL with 40% ethanol
Crystalline itraconazole
Dissolution method: FDA-recommended conditions for itraconazole, 900 mL, 37 °C, 100 rpm, 200 mg itraconazole, N=6
No dose dumping in up to 40 % ethanol (FDA method)
33. Comparison to Marketed Solid Dispersion Products
33
PVA capsule:
PVA
HPMC (Capsule)
Marketed product A
using hot melt
extrusion
Colloidal SiO2
Crospovidone
Hydrogenated
vegetable oil
HPMC
MCC
Lactose
Mg Stearate
PEG
Talc
TiO2
Marketed product B
using spray drying
Glucose Syrup
Hypromellose
Indigo carmin
Macrogol 20000
Starch
Sucrose
Titan dioxide
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%
Crystalline itraconazole
Marketed product A
Marketed product B
PVA capsule
Highly simplified formulations with PVA
Time (min)
34. 34
HighSolubilityLowSolubility
Immediate Release (IR) Sustained Release (SR)
Final formulation benefits:
• Variety of final dosage forms to cover
various targeted release kinetic
• Low drug dilution (due to high API load)
• Directly shaped tablets exhibit:
• Alcohol resistance
• High Strength = Abuse Deterrent
Capsule
or direct
compression
tablet
Direct
compression
tablet
Crystalline API
Extrudateswith
PVA
One Extrudate – Three Formulation Options
Direct shaped
tablet
Marketed Tablet
Marketed Capsule
Highly flexibility with PVA
35. Solubility
enhancement
High drug load
(>20 %)
Broad API
range
Stability
Physical
properties
(easy to use)
Flexibility in
drug release
kinetic
No reaction
with API
35
What Do Formulators Care about?
36. Improved Supersaturation
36
High potential for improving the supersaturation of low soluble APIs
pH Shift Assessment of Itraconazole Extrudates
Improved
supersaturation
▪ Parteck® MXP excipient
is able to delay the
precipitation of low
soluble APIs
▪ Linked to its unique
structure
▪ Clear advantage
versus competitor
polymers
37. In vitro Solubility and Permeability
37
by courtesy of Absorption
Systems LLC, Exton, PA
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
38. In vitro Solubility and Permeability
38
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
~ 10-fold increase of itraconazole in solution in the donor well.
Translates to…
Concentration of itraconazole in donor wellConcentration of itraconazole in donor well
Crystalline Itraconazole Itraconazole - PVA Extrudate
39. In vitro Solubility and Permeability
39
20- to 50-fold increased concentration in the receiver well
Concentration of itraconazole in receiver wellConcentration of itraconazole in receiver well
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
Crystalline Itraconazole Itraconazole:PVA Extrudate
40. How does it work?
40
Info
▪ Two-dimensional 1H/1H Nuclear
Overhauser Effect Spectroscopy
(NOESY)
▪ Amphiphilic structure of PVA
provides unique characteristics
▪ Interactions between PVA
backbone and remaining non
hydrolyzed acetate groups with
aromatic structures of APIs can
provide a stabilizing effect
41. Molecular Dynamic Simulation
41
Info
▪ Molecular interactions
between Indomethacin
and a simplified PVA
matrix
▪ Hydrogen bonds as well
as apolar interactions
▪ PVA takes a dedicated
conformation surrounding
the model drug substance
and providing a stabilizing
effect
42. Can you combine Parteck® MXP excipient with other polymers?
42
The addition of Parteck®MXP excipient can improve
the performance of your formulation
43. Future Trends
43
Due to its unique mechanical properties Parteck® MXP excipient
is perfectly suitable for 3D Printing applications
Evaluation of Parteck® MXP excipient in 3D Printing technology
Research paper submitted:
Title: “Application of 3D printing technology and quality by design approach for development of age-
appropriate pediatric formulation of baclofen”
Main Author: Ketan Patel
Co-Authors: Siddhant C Palekar; Pavan Kumar Nukala; Saurabh M Mishra; Thomas Kipping
Award winning poster presentation:
45. Simple
Simple synthetic polymer
Flexibility in release kinetics & easy to use
Soluble
Increased solubility over broad range of APIs
High solubilization capacity
Stable
High degradation temperature (Tdeg)
Stabilization of supersaturation and support of permeation
Parteck® MXP excipient – Benefits at a Glance
PVA is a thermostable polymer which is suitable for hot melt extrusion
and can formulate poorly water-soluble APIs into a stable amorphous
solid dispersion, and therefore improve the solubility of APIs.
45
47. CPhI "Excellence in Excipients" Award 2018
Parteck®
MXP was
recognized by
the CPhI,
winning the
"Excellence in
Excipients"
award 2018.
47
48. References
Benet, L.Z. (2013). The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug
disposition ssification system) in drug development. JPharmSci.102(1):34-42
Dhirendra, K., Lewis, S., Udupa, N. & Atin, K. (2009). Solid dispersions: a review. Pak. J. Pharm. Sci., 22(2):234-46
Pandit, A. (September 10, 2009). Cutting edge water-based Nanotechnology ind rug development. Addressing key
challenges in predictability, solubility, toxicity, stability and intellectual property. Webinar retrieved from:
https://www.scribd.com/
Vasconcelos, T., Sarmento, B., Costa, P. (2007). Solid dispersions as strategy to improve oral bioavailability of poor
water soluble drugs. Drug Discovery Today 12(23), 1068-75.
Vo, C.L., Park, C., Lee B.J. (2013). Current trends and future perspectives of solid dispersions containing poorly
water-soluble drugs. European Journal of Pharmaceutics and Biopharmaceutics 85(3, Part B), 799-813.