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 g/ml solubility in 70s or 80s (0.01-0.1 mg/mL was considered low)*
Industry-wide increase in insoluble drug candidates** Solubilities of 0.1 g/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 g/ml solubility in 70s or 80s (0.01-0.1 mg/mL was considered low)*
Industry-wide increase in insoluble drug candidates** Solubilities of 0.1 g/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 g/ml solubility in 70s or 80s (0.01-0.1 mg/mL was considered low)*
Industry-wide increase in insoluble drug candidates** Solubilities of 0.1 g/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
Conventional Oral Deliverya Simplistic View
Disintegration Solubilization Precipitation
Absorption
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Deliverya Simplistic View
Disintegration Solubilization Precipitation
Absorption
pH?
Food?Native Surfactant?
Dilution?
Fluid Dynamics?
Conventional Oral Deliverya Simplistic View
Formulation Toolbox:Increase dissolution rate (improve wetting, disintegration time, surface area)Increase dissolution extent (supersaturation)
Conventional Oral Deliverya Simplistic ViewE
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Xtal + water
solution
For a mathematical treatment, see Jain and Yalkowsky, J Pharm Sci (2001) 90:2, 234-252
Conventional Oral Deliverya Simplistic ViewE
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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 Deliverya Simplistic ViewE
n
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r
g
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 Deliverya Simplistic ViewE
n
e
r
g
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
Todays 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) DensificationCompaction/
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
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for fixed T and P
PolymerAPI
Solid Dispersions Performance and Risk
Polymer selection defines this curve Process does not define this curve
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for fixed T and P
Amorphous apparent Solubility
PolymerAPI
Solid Dispersions Performance and Risk
unstable
amorphous-amorphous equilibrium
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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
TMTG
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Solid Dispersions Performance and Risk
liquid
sc liquid
crystal
glass (history 1)
TMTG
glass (history 2)
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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
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Temperature (C)Exo Down Universal V3.8B TA Instruments
PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
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50% Compound E/ 50% PVP-PVAc Copolymer (10oC/min; 5 cycles)
Example Screening Approach for Miscibility
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