Solid Dispersions

New Approaches and Technologies in Oral Drug Delivery

Controlled Release Society; Rutgers, NJ
02 June 2009
Craig A. McKelvey
Merck & Co., Inc.
 Today
• Solid dispersions: motivation and definition
• Solid dispersion preparation
– Performance and risk
– Screening drugs and excipients
– Extrusion
– Spray drying
• Applications and Performance
– In vitro
– Preclinical
 Oral Delivery of Insoluble Drugs: Motivation
for New Approaches
• Practically no marketed drugs with less than 10 μg/ml solubility in 70’s
or 80’s (0.01-0.1 mg/mL was considered low)*
• Industry-wide increase in insoluble drug candidates**
• Solubilities of 0.1 μg/mL not uncommon
– 500,000 mL water to dissolve 50 mg dose

* Recent Advances in the Application of Solid Dispersions for Poorly Water-Soluble Drugs, 2004 AAPS and
Simonelli Conference, A.T.M. Serajuddin (Novartis)
** For example Cambridge Health Institute Issue 15:1, “Adapting to Change in Technology and Markets”,
Christopher A. Lipinski (Pfizer)
 Oral Delivery of Insoluble Drugs: Motivation
for New Approaches
• Practically no marketed drugs with less than 10 μg/ml solubility in 70’s
or 80’s (0.01-0.1 mg/mL was considered low)*
• Industry-wide increase in insoluble drug candidates**
• Solubilities of 0.1 μg/mL not uncommon
– 500,000 mL water to dissolve 50 mg dose

1000 pints+ 125 full stomachs

* Recent Advances in the Application of Solid Dispersions for Poorly Water-Soluble Drugs, 2004 AAPS and
Simonelli Conference, A.T.M. Serajuddin (Novartis)
** For example Cambridge Health Institute Issue 15:1, “Adapting to Change in Technology and Markets”,
Christopher A. Lipinski (Pfizer)
+Image with permission of Sam Calagione,

Dogfish Head Brewing Company, Milton, DE

 Oral Delivery of Insoluble Drugs: Motivation
for New Approaches
• Practically no marketed drugs with less than 10 μg/ml solubility in 70’s
or 80’s (0.01-0.1 mg/mL was considered low)*
• Industry-wide increase in insoluble drug candidates**
• Solubilities of 0.1 μg/mL not uncommon
– 500,000 mL water to dissolve 50 mg dose

1000 pints+ 125 full stomachs

Not a generally accepted delivery vehicle

* Recent Advances in the Application of Solid Dispersions for Poorly Water-Soluble Drugs, 2004 AAPS and
Simonelli Conference, A.T.M. Serajuddin (Novartis)
** For example Cambridge Health Institute Issue 15:1, “Adapting to Change in Technology and Markets”,
Christopher A. Lipinski (Pfizer)
+Image with permission of Sam Calagione,

Dogfish Head Brewing Company, Milton, DE

Conventional Oral Delivery—a Simplistic View

Disintegration Solubilization Precipitation

Absorption
Conventional Oral Delivery—a Simplistic View

Dilution? pH?
Disintegration Solubilization Precipitation

Native Surfactant? Food? Fluid Dynamics?

Absorption
Conventional Oral Delivery—a Simplistic View

Dilution? pH?
Disintegration Solubilization Precipitation

Native Surfactant? Food? Fluid Dynamics?

Absorption
Formulation Toolbox:
ÖIncrease dissolution rate (improve wetting, disintegration time, surface area)
ÖIncrease dissolution extent (supersaturation)
Conventional Oral Delivery—a Simplistic View

solution
Energy

Xtal + water

For a mathematical treatment, see Jain and

Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic View

Formulation Toolbox:
Ö Make water a more desirable place for drug
- micellization
solution
- microemulsions
Energy

Xtal + water

For a mathematical treatment, see Jain and

Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic View

Formulation Toolbox:
Ö Make water a more desirable place for drug
- micellization
solution
- microemulsions
Energy

Xtal + water
Ö Make the drug solid phase less desirable
- neat amorphous
- dissolved

For a mathematical treatment, see Jain and

Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic View

Formulation Toolbox:
Ö Make water a more desirable place for drug
- micellization
solution
- microemulsions
Energy

Xtal + water
Ö Make the drug solid phase less desirable
- neat amorphous
- dissolved

This option inherently introduces physical stability risk

as more stable state is known to exist

For a mathematical treatment, see Jain and

Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
 Solid Dispersion: Definition
• Common jargon
– Solid solutions
– Amorphous formulations
– Physically stabilized
– High energy state
• Today’s presentation: focused on solid solutions of API,
polymer(s), and/or compatabilizers
 Solid Dispersions: Products
Product Company Year Technology Reference
Approved
GrisPEG Pedinal Pharm 1975 Melt process; Kaur et al., J
Inc. exact process Pharm Sci, 69,
unknown 1980
Cesamet Eli Lilly 1985 Process Bloch et al.,
Unknown Pharm Acta
Helv, 62, 1987
Sporanox J&J 1996 Spray dry onto US Patent
substrate 5,663,015

Rezulin Pfizer 1997 Extrusion Jan 2005

Arden House

Kaletra Abbott 2005 Extrusion 31 Oct 2005

(sNDA) Press Release
Torcetrapib Pfizer Ph III Spray Drying 24 June 2005
Press Release
 Today
• Solid dispersions: motivation and definition
• Solid dispersion preparation
– Performance and risk
– Screening drugs and excipients
– Extrusion
– Spray drying
• Applications and Performance
– In vitro
– Preclinical
 Solid Solution Preparation
• Most processes to make solid solutions involve the formation of a
true solution followed by quenching
– Cooling
– Solvent removal
• Other processes include mechanical activation, precipitation
techniques, etc.

Ingredient Extrusion
Cooling Milling
feed (heat in)

Spray Drying Compaction/

Solution Densification
(solvent out) Encapsulation

These routes can be used for clinical manufacture, other analagous

processes can be used for screening (e.g. batch solvent casting)
 Solid Solution Preparation
• Process should result in homogeneous glass
– Notion that one process is universally superior suspect
– Processes can be interchangeable
– Impact of inhomogeneity likely dramatic
• Sample history will lead to different relaxation states
– Quench rate, mechanical stress, conditioning
– May impact kinetics of physical stability
 Solid Dispersions – Performance and Risk

1 0 2

Δ Gibbs Free Energy

⇒ Polymer selection defines this curve
⇒ Process does not define this curve

API Polymer

for fixed T and P

 Solid Dispersions – Performance and Risk

1 0 2

Δ Gibbs Free Energy

unstable

amorphous-
amorphous equilibrium

API Amorphous Polymer

apparent Solubility
for fixed T and P
 Solid Dispersions – Performance and Risk

1 0 2

Δ Gibbs Free Energy

unstable

amorphous-
amorphous equilibrium
1 crystal-amorphous
equilibrium

API Amorphous Solubility Polymer

apparent Solubility
for fixed T and P
Solid Dispersions – Performance and Risk

liquid
Volume or Enthalpy

sc liquid

glass

crystal

TG TM
Solid Dispersions – Performance and Risk

liquid
Volume or Enthalpy

sc liquid

glass (history 1)
glass (history 2)

crystal

TG TM
 Screening
• Monomers or liquid oligomer surrogates of polymers1
• High throughput solvent casting2,3
• Cyclical DSC of blends or manually solvent cast4

1. Breitenbach et al., US Patent 6599931; 2003

2. A. Shanbhag et al., IJP (2008), 351, 209-218
3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-643
4. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79
 Screening
• Monomers or liquid oligomer surrogates of polymers1
• High throughput solvent casting2,3
• Cyclical DSC of blends or manually solvent cast4

1. Breitenbach et al., US Patent 6599931; 2003

2. A. Shanbhag et al., IJP (2008), 351, 209-218
3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-643
4. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79
 Example Screening Approach for Miscibility
4

2
Heat Flow (W/g)

-2

PVP-PVAc Copolymer (10oC/min; 5 cycles)

-4
0 50 100 150 200 250 300
Exo Down Temperature (°C) Universal V3.8B TA Instruments
 Example Screening Approach for Miscibility
4

2
Heat Flow (W/g)

-2

50% Compound E/ 50% PVP-PVAc Copolymer (10oC/min; 5 cycles)

-4
0 50 100 150 200 250 300
Exo Down Temperature (°C) Universal V3.8B TA Instruments
 Example Screening Approach for Miscibility
4

2
Heat Flow (W/g)

-2

70% Compound E/ 30% PVP-PVAc Copolymer (10oC/min; 5 cycles)

-4
0 50 100 150 200 250 300
Exo Down Temperature (°C) Universal V3.8B TA Instruments
Potential Extrusion-Based Routes to Pharmaceutical Products
Drug particles Drug-excipient
Drug solubilized
dispersed in granules or
in polymer
polymer paste
Extrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Drug particles Drug-excipient
Drug solubilized
dispersed in granules or
in polymer
polymer paste
Extrudate Composition

Polymeric films Injection molding Cylinders/Strands

Extrudate Macrostructure
Potential Extrusion-Based Routes to Pharmaceutical Products
Drug particles Drug-excipient
Drug solubilized
dispersed in granules or
in polymer
polymer paste
Extrudate Composition

Polymeric films Injection molding Cylinders/Strands

Extrudate Macrostructure

Pelletization/Spheronization/Spray Congealing
Multi- Calendering
Cutting laminate
Taste
masked/modified
release pellets
Compaction
Compaction Encapsulation
Post Extrusion Processing
Potential Extrusion-Based Routes to Pharmaceutical Products
Drug particles Drug-excipient
Drug solubilized
dispersed in granules or
in polymer
polymer paste
Extrudate Composition

Polymeric films Injection molding Cylinders/Strands

Extrudate Macrostructure

Pelletization/Spheronization/Spray Congealing
Multi- Calendering
Cutting laminate
Taste
masked/modified
release pellets
Compaction
Compaction Encapsulation
Post Extrusion Processing

Fast dissolve strips/ Tablet-like Performance Capsules and Traditional

Transdermal dosage forms Tablets Performance Capsules Tablets
Oral Dosage Forms
=> Transdermal, ocular, sub-cutaneous inserts, biomedical devices, implants possible
 Selected Examples Highlighting
Processing Flexibility

Screw and Barrel Modularity: Feed, vacuum, mixing,

heating/cooling, and compression locations/duration can be easily
modified to suit application
Graphic courtesy Leistritz
 Selected Examples Highlighting
Processing Flexibility

Dry Feed: Could be combined

or separate loss in weight or
volumetric

Wet/Dry Feed: Can pump slurries

or solutions or stuff solid powders
of actives and excipients

Screw and Barrel Modularity: Feed, vacuum, mixing,

heating/cooling, and compression locations/duration can be easily
modified to suit application
Graphic courtesy Leistritz
 Vacuum: removal of
residual solvents/water Selected Examples Highlighting
Processing Flexibility

Dry Feed: Could be combined

or separate loss in weight or
Die: Physically volumetric
shape extrudate
(e.g., rods, sheets, tubes)

Wet/Dry Feed: Can pump slurries

or solutions or stuff solid powders
of actives and excipients

Screw and Barrel Modularity: Feed, vacuum, mixing,

heating/cooling, and compression locations/duration can be easily
modified to suit application
Graphic courtesy Leistritz
 Screws and Barrels are Modular

Screws are assembled on Flanged barrels, electrically

high torque splined shafts heated and liquid cooled

=> Provides process flexibility from a single instrument

Pictures courtesy Leistritz

 Extrusion: Small Scale
• Recirculating extruders
– Moderate amount of API
– Generally conical screw design with no aggressive mixing
– Some models have capability to estimate viscosity
– Manual operation (slow)

Pharmalab mixer (5-10 g batch size)

Image with permission from Thermo

Fisher Scientific
 Extrusion: Intermediate Scale
(16 mm ThermoPrism)
Feeder

Raman + tNIR Pressure Feed Throat

Die ports Transducer
 Extruder: An Inside Look

Material Feed
Die End

Kneading
Paddles
 Extruder: Predicting the Future
Real time mass Real time Future outlet
feeder flow rate numerical compositions at
data at t=t0 convolution t=t0+τm

Feed Stream #1
Process Model

Feed Stream #2
Process Model

Feed Stream #3
Process Model

Predict the outlet composition one mean residence time in the future
Slide courtesy Gregory Troup
 Model Predictive Process Monitoring
100

90

80

70

60 API Model
SURF model
POLY model
50
API NIR
SURF NIR
40 POLY NIR

30

20

10

0
14:45:36 14:52:48 15:00:00 15:07:12 15:14:24

Slide courtesy Gregory Troup

 Spray Drying
Atomization Spray
Gas Hot
Solution

Processing Gas Cool Evaporation

of Solvent
Spray
Droplet

Heat in

Hotter
region

Cooler
region Spray Dried API/VA64

• Liquid feed of drug, polymer, and/or surfactants (solution or suspension)

• Atomize liquid feed to generate droplets
• Dry droplets to generate amorphous solid particles
• Collect product by cyclone & bag filter
Courtesy of G. Shi
Spray drying equipment

Niro SD Micro
Image with permission of GEA
Pharma Systems-Niro Inc.
 Today
• Solid dispersions: motivation and definition
• Solid dispersion preparation
– Performance and risk
– Screening drugs and excipients
– Extrusion
– Spray drying
• Applications and Performance
– In vitro
– Preclinical
Quality Testing: Dissolution
(Compound E; in capsule)
 Preparing Suspensions from Solid
Dispersions
drug dissolved to form drug particles (crystalline or
-or-
drug-excipient solution amorphous) in excipient(s)

milling,
atomization,
pellitization,
Suspension Applications:
etc.
• Ex-clinical studies (discovery, safety, etc.)
• Human use (powder for constitution—e.g., sachet)
⇒ general use, pediatric, geriatric
particles • Coating for other dosage form routes
• Applications requiring metered/customized dose

compaction/
suspensions encapsulation
e.g., Moser et al., American Pharmaceutical
Review (2008), 11(6), 68-73
 Suspension Application: Impact
Plasma Concentration

Solid dispersion-based suspension (300 mpk)

Crystalline API suspended in 20%

Vitamin E TPGS (1200 mpk)

Time

Plasma Concentration Profile Following Oral

Administration in Male Sprague-Dawley Rats
(Compound A; n=4)
e.g., Moser et al., American Pharmaceutical
Review (2008), 11(6), 68-73
 Suspension Application: Impact

Cpd SD Reference Exposure

susp. formulation increase
Plasma Concentration

dose
A 300 1200 mpk 20% 2-8X
mpk Vitamin E
Solid dispersion-based suspension (300 mpk) TPGS
B 100 100 mpk 67X
mpk Imwitor 742:PS
Crystalline API suspended in 20% 80
Vitamin E TPGS (1200 mpk) C 100 300 mpk 2-6X
mpk Methocel
Suspension
D 200 750 mpk 10% 4-16X
Time mpk PS80

Plasma Concentration Profile Following Oral

Cross-Project
Administration in Male Sprague-Dawley Rats
PK Data Summary
(Compound A; n=4)
e.g., Moser et al., American Pharmaceutical
Review (2008), 11(6), 68-73
 Suspension Application: Route Flexibility
Raw Materials Extrusion Milling or Use any process that
Feed (heat in) Atomization reliably produces the
Solution/ Spray Drying desired phase state for
Suspension (solvent out) the application
 Suspension Application: Route Flexibility
Raw Materials Extrusion Milling or Use any process that
Feed (heat in) Atomization reliably produces the
Solution/ Spray Drying desired phase state for
Suspension (solvent out) the application
Plasma Concentration

Time
Plasma Concentration Profile Following Oral
Administration of Compound A Solid Dispersion
(male beagle dogs; n=6; crossover; 50 mg dose)
 Suspension Application: Route Flexibility
Raw Materials Extrusion Milling or Use any process that
Feed (heat in) Atomization reliably produces the
Solution/ Spray Drying desired phase state for
Suspension (solvent out) the application

Key Considerations:
Plasma Concentration

• Particle size/density (suspension

stability)
• Phase state desired
• Phase stability in suspension
• Formulation with tuneability solubility
(prevent premature solubilization)
⇒ pH
⇒ temperature
⇒ non-aqueous vehicle
Time
Plasma Concentration Profile Following Oral
Administration of Compound A Solid Dispersion
(male beagle dogs; n=6; crossover; 50 mg dose)
 Acknowledgements
Michael Lowinger Celia Cruz
Todd Gibson Luke Schenck
Jeff Cassel Seth Forster
Bhagwant Rege Adam Chen
David Pipkorn Jennifer Ho
Wei Xu Stephen Wahn
Curt Panzer John Higgins
Mike Riebe Justin Moser
Amanda Sinha Sarah Geers
Sami Karaborni Karim Younan
Laman Alani Hui Xu
Henry Wu Zhen Liu
Adam Procopio Varaporn Treemaneekarn
Melanie Marota Robert Meyer
Brit Rudeen Paul Harmon
Patrick Marsac Li Li
Narayan Variankaval Lixia Cai
Brett Cooper Cindy Starbuck
Galen Shi Jeff Ko
Katie Kleissas Filippos Kesisoglou
Greg Troup