Amorphous Solid Dispersions: Application Of Spray Drying Formulations For Discovery Toxicology Studies - Mengwei Hu, Merck & Co.

1. Amorphous Solid Dispersions:
Application Of Spray Drying
Formulations For Discovery
Toxicology Studies
Mengwei Hu, James Ormes and Jiang Chang
Merck & Co.

2. 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
2

3. 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 can be significantly improved
– Dissolution rate by formulation strategies
– 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
3

4. 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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5. 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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6. 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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7. Spray Drying Process
Atomization Spray
Gas Hot
Solution Credit: Galen Shi
Processing Gas Cool Evaporation
of Solvent
Spray
Droplet
Heat in
Hotter
region
Cooler
region Spray Dried Drug/Polymer
• 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)
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8. How Spray Dried Amorphous Solid Enhances Drug
Exposure
Free Energy Solvated Drug G
G
Amorphous Drug
Crystalline Drug
• Amorphous state has higher free-energy No crystal lattice to break 
Higher Thermodynamic Solubility
• Fine particle size  Large surface area  Improved Kinetic Dissolution
Amorphous solid dispersion is particularly useful for
compounds with high crystal lattice energy
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9. Polymer Excipients in Spray Drying
Free Energy Amorphous Drug
Amorphous Drug
w/Polymer Better Solubility
Low Stability
Better Solubility Crystalline Drug
Better Stability
Poor Solubility Patrick Marsac with permission
Stable
•Polymers stabilize the
amorphous state of the drug.
•Enhance super-saturation of
the drug upon dissolution by
preventing nucleation.
Dina Zhang with permission
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10. 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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11. 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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12. Scaled Down Process
•ProCepT Microspray Drying
system provides capabilities of Feed Solution
small batch size to Drying
Gas
accommodate limitation of Inlet
+
compound availability in Heater
Discovery space:
Drying
 Batch size: 0.25 – 4000 mL Chamber
 Particle size range: 2- 75 microns
 Processing yield: ~85% for 25 mg of
product
Cyclone
+ Collection Connecting
Vessel Tube
Information provided by ProCepT
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13. 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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14. Platform Vehicle and Vehicle Selection
• 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.
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15. 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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16. Case Study #1: Using Spray Dried Amorphous Solid
Dispersion Of Compound A For Discovery Toxicology Studies
Rodent PK
16.00
Challenge: Identify a formulation PEG/Tw een (200 mpk)
20% TPGS (200 mpk)
strategy to provide exposure Nanoformulation (100 mpk)
Spray Dried Amorphous (100 mpk)
despite the poor solubility 12.00
(<0.001 mg/mL in SGF and
FaSSIF). 8.00
Spray dried
amorphous solid
AUC
dispersion
In rodents the spray dried formulation
amorphous solid dispersion 4.00
formulation significantly improve
exposure relative to alternative 0.00
formulation strategies. 0 4 8 12 16 20 24
Time (hr)
J. Ormes, J. Chang, D. Leung, E. Kwong, F. Li
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17. Case Study #2: Using Solid Dispersion Formulation to
Enhance Oral Exposure and Resolve Polymorphism Issues
• Challenges:
1. The compound exhibited polymorphism with numerous crystalline
phases (>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
M. Hu, J. Ormes, J. Chang, E. Kwong, A. Bak, C. Alleyne, S. Lohani
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18. 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.
Cmax AUC(0-x) Exposure Physical Stability
PK 100 mpk in Rat Tmax (h)
(μM) (μMh) Multiple (in vehicle)
Conventional
Formulation
48 2 611 127x unstable
(partially
solubilization)
Nanosuspension
21.5 2 254 53x unstable
(wet milling)
Amorphous Solid
Dispersion 43.8 2.3 686 143x stable
(spray drying)
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19. Summary
• 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.
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20. Acknowledgement
Dennis Leung Justin Moser
Fangbiao Li Mike Lowinger
Candice Alleyne Caroline McGregor
Sachin Lohani Dina Zhang
Vincent Tong Elise Miller
Lina Liu Davida Krueger
Timothy Rhodes Elizabeth Kwong
Patrick Marsac Allen Templeton
Annette Bak Michael Kress
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