Amorphous Solid Dispersions: Application Of Spray Drying Formulations For Discovery Toxicology Studies

Mengwei Hu, James Ormes and Jiang Chang Merck & Co.

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Presentation Outline

• Challenges in Discovery toxicology formulation development

• General concept of spray dried amorphous solid dispersions

• Integration of spray drying technology in Discovery space

• Case studies of applications of amorphous solid dispersion for Discovery toxicology studies

• Summary

• Acknowledgement

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Challenges In Discovery Toxicology Formulation Development

• Requirement of higher oral exposure (except for oncology programs) to ensure safety margin:

– Exposures can be limited by• Compound specific properties:

–Solubility–Dissolution rate–Permeability–GI tract stability–First pass effect

• Formulation specific properties:–Maximum feasible dose: limited by feasible concentration,

dosing volume and daily allowed amount of excipients–Release rate

can be significantly improved by formulation strategies

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Challenges In Discovery Toxicology Formulation Development (continued)

• Prefer solution/suspension formulation– Easiness for dosing especially for rodent species

– Easiness for body weight adjustment

– Besides bioperformance, need to address:• Dosability:

– uniformity, viscosity and syringability

• Stability:

– Physical stability: polymorphism, disproportionation, particle size distribution, pH shift, agglomeration and gelling

– Chemical stability: chemical degradation (hydrolysis, oxidation,compatibility with excipients and photostability)

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Challenges In Discovery Toxicology Formulation Development (continued)

• Narrower choices of excipients– To ensure clear read out of toxicity caused by API.

– Excipients with similar toxicity concern as the API have to be avoided.

– Wider choices for short term study. However, line of sight for long term toxicology study is critical.

– Full knowledge of species specific toxicity of excipients is essential.

– Maximum daily allowed amount of excipients has to be established.

– Concern specific to the therapeutic area: • Example: using lipid based formulations for lipid modifying agents

• Short development time for toxicology formulations

• Limited availability of API

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Toxicology Formulation Strategies

• Solubilization– Ionization by pH adjustment– Salt– Cosolvent– Surfactant– Complexation– Lipid based formulation

• Increase dissolution rate through particle size reduction– Micronization– Nanoparticle

• Improve solubility by converting API to amorphous state and maintaining it at amorphous state (amorphous solid dispersion)

– Hot melt extrusion or melt quenching techniques– Spray drying

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Spray Drying Process

• Mix up liquid feed containing drug, polymer, and optional surfactants in a solution or suspension.• Atomize liquid feed to generate desired droplet formation• Dry droplets (fast drying rate) to generate amorphous, solid particles (from solution)• Collect product from processing gas stream (e.g cyclone & bag filter)

Spray Dried Drug/Polymer

AtomizationGas

Evaporation of Solvent

Heat in

Hotterregion

SprayDroplet

SpraySolution Hot

CoolProcessing Gas

Coolerregion

Credit: Galen Shi

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How Spray Dried Amorphous Solid Enhances Drug Exposure

• Amorphous state has higher free-energy No crystal lattice to breakHigher Thermodynamic Solubility

• Fine particle size Large surface area Improved Kinetic Dissolution

Amorphous solid dispersion is particularly useful for compounds with high crystal lattice energy

Free Energy

Crystalline Drug

Amorphous Drug

GSolvated Drug

G

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Polymer Excipients in Spray Drying

•Polymers stabilize the amorphous state of the drug.

•Enhance super-saturation of the drug upon dissolution by preventing nucleation.

Free Energy

Crystalline Drug

Amorphous DrugAmorphous Drug

w/Polymer

Poor SolubilityStable

Better SolubilityLow Stability

Better SolubilityBetter Stability

Dina Zhang with permission

Patrick Marsac with permission

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Integrate Amorphous Solid Dispersion in the Drug Discovery Process

Challenges:

• Aggressive timeline requires fast turn-around– Rely on high throughput screening and platform approaches

• API supply limitations at various stages of Discovery space– Scaled down process for batch preparation, characterization and

analysis

• Cross-functional collaboration is required– High throughput screening– Formulation preparation– Characterization and analysis– Troubleshooting – Scale up

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Screening For Solvents and Polymers

• Solvent Selection is based on solubility (> 10 mg/mL) and compatibility• Acetone, MeOH, EtOH, IPA, t-BuOH, EtOAc, IPOAc, Toluene, HOAc,

MEK, THF, DCM plus mixing with H2O (up to 25%)

• Polymer Selection• Solvent casting screening in 96-well plate• Polymers: HPMCAS (LF, MF, HF), HPMCP (HP-55), PVP-PVAc(Kollidone

VA64) PVP (Kollidone 90F), Eugragit (L100) and etc.• Surfactants (optional) to further enhance solubility• A small amount of film is formed and characterized by microscopy and

PXRD• Kinetic solubility of dispersed film in FaSSIF

Shanbhag, A. et. al.,International Journal of Pharmaceutics, 351, 209-218 (2008)Moser, J. D. et. al.. American Pharmaceutical Review, Sep/Oct, 2008

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Scaled Down Process

•ProCepT Microspray Drying system provides capabilities of small batch size to accommodate limitation of compound availability in Discovery space:

Batch size: 0.25 – 4000 mL Particle size range: 2- 75 microns Processing yield: ~85% for 25 mg of

product

Information provided by ProCepT

Drying GasInlet

+ Heater

Feed Solution

Cyclone + Collection

Vessel

Drying Chamber

Connecting Tube

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Characterization of Spray-Dried Amorphous Solid Dispersion

• Physical characterization: mDSC, PXRD and TGA

• Chemical characterization: assay and impurity profile

• Solid state stability

• In-use stability in suspending vehicle

• Redisperse study in SGF and FaSSIF

• Maximum feasible concentration determination

• Confirm exposure enhancement by pharmacokinetic studies

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• Platform vehicle:

Suspending agent + Acidifying agent + Wetting agent

• Key Considerations:– Visual wetting, stirability/suspendability/syringability, at low and high

dose (MFC)

– Physically and chemically stable for at least 4 hours

– Well-dispersed and uniform suspension

– Maximum feasible concentration

– Acidifying agent prevents API released from the pH sensitive polymer to ensure in-use physical stability

– Low amount of surfactant is added as a wetting agent but may promote solubilization/dissolution of the API and hence may promote crystallization.

Platform Vehicle and Vehicle Selection

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Limitations of Spray Dried Amorphous Solid Dispersion Formulation

• Solubility and compatibility in organic solvents

• Drug loading limitations (Maximum Feasible Concentration concerns)

• Complexity of workflow in fast-paced Discovery space

• Additional work of scaling up for GLP toxicology studies

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Challenge: Identify a formulation strategy to provide exposure despite the poor solubility (<0.001 mg/mL in SGF and FaSSIF).

In rodents the spray dried amorphous solid dispersion formulation significantly improve exposure relative to alternative formulation strategies.

Case Study #1: Using Spray Dried Amorphous Solid Dispersion Of Compound A For Discovery Toxicology Studies

0.00

4.00

8.00

12.00

16.00

0 4 8 12 16 20 24

PEG/Tw een (200 mpk)20% TPGS (200 mpk)Nanoformulation (100 mpk)Spray Dried Amorphous (100 mpk)

Time (hr)

AU

C

Rodent PK

Spray dried amorphous solid dispersion formulation

J. Ormes, J. Chang, D. Leung, E. Kwong, F. Li

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• Challenges:

1. The compound exhibited polymorphism with numerous crystallinephases (>20) identified and physical phase instability in the conventional formulation

2. The compound exhibited a >30x decrease in solubility from amorphous phase upon identification of a high melting crystalline form (decline from > 0.600 ug/mL to 0.017 ug/mL).

3. Discovery toxicology formulation had to be developed within two weeks to meet program timeline

Case Study #2: Using Solid Dispersion Formulation to Enhance Oral Exposure and Resolve Polymorphism Issues

M. Hu, J. Ormes, J. Chang, E. Kwong, A. Bak, C. Alleyne, S. Lohani

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Case Study #2: Using Solid Dispersion Formulation to Enhance Oral Exposure and Resolve Polymorphism Issues

• Spray Dried formulation provided a physically stable formulation which overcame solubility concerns to provide sufficient exposure for discovery toxicology studies without timeline delay.

unstable53x254221.5Nanosuspension

(wet milling)

stable143x6862.343.8Amorphous Solid

Dispersion

(spray drying)

unstable127x611248

Conventional Formulation

(partially solubilization)

Physical Stability (in vehicle)

Exposure Multiple

AUC(0-x)(μMh)

Tmax (h)Cmax (μM)PK 100 mpk in Rat

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• Spray dried amorphous solid dispersion is a powerful tool for enhancing bioavailability and providing stable amorphous platform formulations in Discovery:

– Spray Drying enables compounds with poor solubility to achieve sufficient oral exposures

– Spray dried amorphous solid dispersion also simplifies formulation strategy for compounds displaying complex polymorphism.

• By utilizing solvent casting screening, scaled down process and platform approach, spray-dried amorphous solid dispersion becomes a feasible formulation strategy in Discovery when API is limited and timeline is short.

Summary

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Acknowledgement

Dennis Leung

Fangbiao Li

Candice Alleyne

Sachin Lohani

Vincent Tong

Lina Liu

Timothy Rhodes

Patrick Marsac

Annette Bak

Justin Moser

Mike Lowinger

Caroline McGregor

Dina Zhang

Elise Miller

Davida Krueger

Elizabeth Kwong

Allen Templeton

Michael Kress