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

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



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

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



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

    • Amorphous Solid Dispersions:Application Of Spray DryingFormulations For DiscoveryToxicology StudiesMengwei Hu, James Ormes and Jiang ChangMerck & Co.
    • 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
    • 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
    • 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) 4
    • Challenges In Discovery Toxicology FormulationDevelopment (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 5
    • 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 6
    • Spray Drying Process Atomization Spray Gas Hot Solution Credit: Galen ShiProcessing 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) 7
    • 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 DissolutionAmorphous solid dispersion is particularly useful forcompounds with high crystal lattice energy 8
    • 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 theamorphous state of the drug.•Enhance super-saturation ofthe drug upon dissolution bypreventing nucleation. Dina Zhang with permission 9
    • Integrate Amorphous Solid Dispersion in the Drug Discovery ProcessChallenges:• 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 10
    • 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 11
    • 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 12
    • Characterization of Spray-Dried Amorphous SolidDispersion• 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 13
    • 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. 14
    • 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 15
    • Case Study #1: Using Spray Dried Amorphous Solid Dispersion Of Compound A For Discovery Toxicology Studies Rodent PK 16.00Challenge: 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 andFaSSIF). 8.00 Spray dried amorphous solid AUC dispersionIn rodents the spray dried formulationamorphous solid dispersion 4.00formulation significantly improveexposure relative to alternative 0.00formulation strategies. 0 4 8 12 16 20 24 Time (hr)J. Ormes, J. Chang, D. Leung, E. Kwong, F. Li 16
    • 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 17
    • Case Study #2: Using Solid Dispersion Formulation toEnhance 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) 18
    • 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. 19
    • AcknowledgementDennis Leung Justin MoserFangbiao Li Mike LowingerCandice Alleyne Caroline McGregorSachin Lohani Dina ZhangVincent Tong Elise MillerLina Liu Davida KruegerTimothy Rhodes Elizabeth KwongPatrick Marsac Allen TempletonAnnette Bak Michael Kress 20