Solid Dispersions - Merk.pdf

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

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

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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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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