Solid Dispersions
New Approaches and Technologies in Oral Drug DeliveryControlled Release Society; Rutgers, NJ
02 June 2009 Craig A. McKelveyMerck & 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)
• 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
* 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
+Image with permission of Sam Calagione, Dogfish Head Brewing Company, Milton, DE
Not a generally accepted delivery vehicle
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Delivery—a Simplistic View
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Delivery—a Simplistic View
Formulation Toolbox:Increase dissolution rate (improve wetting, disintegration time, surface area)Increase dissolution extent (supersaturation)
Conventional Oral Delivery—a Simplistic ViewE
nerg
y
Xtal + water
solution
For a mathematical treatment, see Jain and Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic ViewE
nerg
y
Formulation Toolbox:Make water a more desirable place for drug
- micellization- microemulsions
Xtal + water
solution
For a mathematical treatment, see Jain and Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic ViewE
nerg
y
Formulation Toolbox:Make water a more desirable place for drug
- micellization- microemulsions
Make the drug solid phase less desirable- neat amorphous - dissolved
Xtal + water
solution
For a mathematical treatment, see Jain and Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Delivery—a Simplistic ViewE
nerg
y
Formulation Toolbox:Make water a more desirable place for drug
- micellization- microemulsions
Make the drug solid phase less desirable- neat amorphous - dissolved
Xtal + water
solution
For a mathematical treatment, see Jain and Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
This option inherently introduces physical stability risk as more stable state is known to exist
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
US Patent 5,663,015
Spray dry onto substrate
1996J&JSporanox
Bloch et al., Pharm ActaHelv, 62, 1987
Process Unknown
1985Eli LillyCesamet
Spray Drying
Extrusion
Extrusion
Melt process; exact process unknown
Technology
Kaur et al., J Pharm Sci, 69, 1980
1975Pedinal PharmInc.
GrisPEG
Jan 2005 Arden House
1997PfizerRezulin
31 Oct 2005 Press Release
2005(sNDA)
AbbottKaletra
24 June 2005 Press Release
Ph IIIPfizerTorcetrapib
ReferenceYear Approved
CompanyProduct
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 feed
Extrusion(heat in) Cooling Milling
Solution Spray Drying (solvent out) Densification Compaction/
Encapsulation
These routes can be used for clinical manufacture, other analagousprocesses 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
ΔG
ibbs
Fre
e E
nerg
y
0 21
for fixed T and P
PolymerAPI
Solid Dispersions – Performance and Risk
⇒ Polymer selection defines this curve⇒ Process does not define this curve
ΔG
ibbs
Fre
e E
nerg
y
0 21
for fixed T and P
Amorphous apparent Solubility
PolymerAPI
Solid Dispersions – Performance and Risk
unstable
amorphous-amorphous equilibrium
ΔG
ibbs
Fre
e E
nerg
y
0 21
for fixed T and P
Amorphous apparent Solubility
1
Solubility PolymerAPI
Solid Dispersions – Performance and Risk
unstable
amorphous-amorphous equilibrium
crystal-amorphous equilibrium
Solid Dispersions – Performance and Risk
liquid
sc liquid
crystal
glass (history 1)
TMTG
glass (history 2)
Vol
ume
or E
ntha
lpy
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; 20032. A. Shanbhag et al., IJP (2008), 351, 209-218 3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. 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; 20032. A. Shanbhag et al., IJP (2008), 351, 209-218 3. V. Barillaro et al., J Combinatorial Chemistry (2008), 10:5, 637-6434. Mura et al., International Journal of Pharmaceutics (1995), 119, 71-79
-4
-2
0
2
4
Hea
t Flo
w (W
/g)
0 50 100 150 200 250 300
Temperature (°C)Exo Down Universal V3.8B TA Instruments
PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
-4
-2
0
2
4
Hea
t Flo
w (W
/g)
0 50 100 150 200 250 300
Temperature (°C)Exo Down Universal V3.8B TA Instruments
50% Compound E/ 50% PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
-4
-2
0
2
4
Hea
t Flo
w (W
/g)
0 50 100 150 200 250 300
Temperature (°C)Exo Down Universal V3.8B TA Instruments
70% Compound E/ 30% PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
Drug solubilizedin polymer
Drug particlesdispersed in
polymer
Drug-excipientgranules or
pasteExtrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Drug solubilizedin polymer
Drug particlesdispersed in
polymer
Drug-excipientgranules or
pasteExtrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
Drug solubilizedin polymer
Drug particlesdispersed in
polymer
Drug-excipientgranules or
pasteExtrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
Congealing
Encapsulation
Pelletization/Spheronization/Spray
Compaction
Tastemasked/modified
release pelletsCompaction
Post Extrusion Processing
CuttingCalenderingMulti-
laminate
Drug solubilizedin polymer
Drug particlesdispersed in
polymer
Drug-excipientgranules or
pasteExtrudate Composition
Potential Extrusion-Based Routes to Pharmaceutical Products
Polymeric films Injection molding Cylinders/Strands
Extrudate Macrostructure
Congealing
Encapsulation
Pelletization/Spheronization/Spray
Compaction
Tastemasked/modified
release pelletsCompaction
Post Extrusion Processing
CuttingCalenderingMulti-
laminate
TraditionalTablets
Capsules andPerformance Capsules
PerformanceTablets
Tablet-likedosage forms
Fast dissolve strips/Transdermal
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
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
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
Dry Feed: Could be combined or separate loss in weight or volumetric
Vacuum: removal of residual solvents/water
Wet/Dry Feed: Can pump slurries or solutions or stuff solid powders of actives and excipients
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
Die: Physically shape extrudate(e.g., rods, sheets, tubes)
Graphic courtesy Leistritz
Screws and Barrels are Modular
Flanged barrels, electrically heated and liquid cooled
Screws are assembled on high torque splined shafts
=> 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
Pressure Transducer
Feeder
Feed ThroatRaman + tNIRportsDie
Extrusion: Intermediate Scale (16 mm ThermoPrism)
Feed Stream #1Process Model
Feed Stream #2Process Model
Feed Stream #3Process Model
Real time mass feeder flow rate data at t=t0
Real time numerical convolution
Future outlet compositions at t=t0+τm
Predict the outlet composition one mean residence time in the future
Extruder: Predicting the Future
Slide courtesy Gregory Troup
0
10
20
30
40
50
60
70
80
90
100
14:45:36 14:52:48 15:00:00 15:07:12 15:14:24
API ModelSURF modelPOLY modelAPI NIRSURF NIRPOLY NIR
Model Predictive Process Monitoring
Slide courtesy Gregory Troup
Spray Drying
Spray Dried API/VA64
AtomizationGas
Evaporation of Solvent
Heat in
Hotterregion
Coolerregion
SprayDroplet
SpraySolution Hot
CoolProcessing Gas
Courtesy of G. Shi
• 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
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
Preparing Suspensions from Solid Dispersions
drug dissolved to form drug-excipient solution
drug particles (crystalline or amorphous) in excipient(s)-or-
milling, atomization, pellitization, etc.
particles
suspensionscompaction/encapsulation
Suspension Applications:•Ex-clinical studies (discovery, safety, etc.)•Human use (powder for constitution—e.g., sachet)
⇒ general use, pediatric, geriatric•Coating for other dosage form routes•Applications requiring metered/customized dose
e.g., Moser et al., American Pharmaceutical Review (2008), 11(6), 68-73
Suspension Application: Impact
Plasma Concentration Profile Following Oral Administration in Male Sprague-Dawley Rats
(Compound A; n=4)
Solid dispersion-based suspension (300 mpk)
Crystalline API suspended in 20% Vitamin E TPGS (1200 mpk)
e.g., Moser et al., American Pharmaceutical Review (2008), 11(6), 68-73
Pla
sma
Con
cent
ratio
n
Time
Suspension Application: Impact
Plasma Concentration Profile Following Oral Administration in Male Sprague-Dawley Rats
(Compound A; n=4)
Solid dispersion-based suspension (300 mpk)
Crystalline API suspended in 20% Vitamin E TPGS (1200 mpk)
4-16X750 mpk 10% PS80
200 mpk
D
2-6X300 mpk Methocel Suspension
100 mpk
C
67X100 mpk Imwitor 742:PS 80
100 mpk
B
2-8X1200 mpk 20% Vitamin E TPGS
300 mpk
A
Exposure increase
Reference formulation
SD susp. dose
Cpd
Cross-Project PK Data Summary
e.g., Moser et al., American Pharmaceutical Review (2008), 11(6), 68-73
Pla
sma
Con
cent
ratio
n
Time
Suspension Application: Route FlexibilityRaw Materials
FeedExtrusion(heat in)
Milling or Atomization
Solution/Suspension
Spray Drying (solvent out)
Use any process that reliably produces the desired phase state for the application
Suspension Application: Route Flexibility
Plasma Concentration Profile Following Oral Administration of Compound A Solid Dispersion(male beagle dogs; n=6; crossover; 50 mg dose)
Raw MaterialsFeed
Extrusion(heat in)
Milling or Atomization
Solution/Suspension
Spray Drying (solvent out)
Use any process that reliably produces the desired phase state for the application
Pla
sma
Con
cent
ratio
n
Time
Suspension Application: Route Flexibility
Plasma Concentration Profile Following Oral Administration of Compound A Solid Dispersion(male beagle dogs; n=6; crossover; 50 mg dose)
Raw MaterialsFeed
Extrusion(heat in)
Milling or Atomization
Solution/Suspension
Spray Drying (solvent out)
Use any process that reliably produces the desired phase state for the application
Key Considerations:• Particle size/density (suspension
stability)• Phase state desired• Phase stability in suspension• Formulation with tuneability solubility
(prevent premature solubilization)⇒ pH⇒ temperature⇒ non-aqueous vehicleP
lasm
a C
once
ntra
tion
Time
AcknowledgementsMichael LowingerTodd GibsonJeff CasselBhagwant RegeDavid PipkornWei XuCurt PanzerMike RiebeAmanda SinhaSami KaraborniLaman AlaniHenry WuAdam ProcopioMelanie MarotaBrit RudeenPatrick MarsacNarayan VariankavalBrett CooperGalen ShiKatie Kleissas
Celia CruzLuke SchenckSeth ForsterAdam ChenJennifer HoStephen WahnJohn HigginsJustin MoserSarah GeersKarim YounanHui XuZhen LiuVaraporn TreemaneekarnRobert MeyerPaul HarmonLi LiLixia CaiCindy StarbuckJeff KoFilippos KesisoglouGreg Troup