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Solid dispersions

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  • 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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    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

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    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

  • G

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    0 21

    for fixed T and P

    PolymerAPI

    Solid Dispersions Performance and Risk

    Polymer selection defines this curve Process does not define this curve

  • G

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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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    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

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