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Particle Size Analysis for Pharmaceutical Homogenization Process Development

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Guest speaker Dr. Daniel Huang of Novartis joins HORIBA Scientific (http://www.horiba.com/particle) to speak about homogenization process development. …

Guest speaker Dr. Daniel Huang of Novartis joins HORIBA Scientific (http://www.horiba.com/particle) to speak about homogenization process development.

High-pressure homogenization has been used to prepare emulsions in a broad range of industries. Particle size distribution and emulsion stability are two key properties of the system essential to a successful downstream application. In this study, Daniel and his colleagues have investigated the effects of process conditions on droplet size and coalescence rate of the emulsion systems.

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  • 1. Particle Size Analysis for HomogenizationProcess DevelopmentDaniel HuangNovartis PharmaceuticalsHoriba SeminarSeptember 20, 2012
  • 2. Outline Background Study Objective Equipment Operating Principles Emulsion Preparation Process Instrument for Evaluation Laboratory Study Results Summary
  • 3. Pulmonary Drug Delivery Product Life Cycle Dose Aerodynamics Formulation Chemical/Physical Stability Dispersability Solid-state properties Particle Process control Excipients Engineering Scale up UserPatient’s needsReproducible Technology Powder ProcessingEasy to use & reliable Synthesis Aerosol Delivery Fine powders Low mass, tight RSD Filling & Remain dispersable Billions/year Packaging
  • 4. Methods to Produce Fine Particles for Pharmaceutical Applications Molecule Spray Drying SCF Lyophilization Crystallization Attrition / Jet MillingEmulsion SolutionBased BasedPulmoSphere® Fine ParticlesTechnology (MMAD ~ 1-5 mm)
  • 5. Novartis PulmoSphere Technology  Manufacture of a Fluorocarbon-in-Water Emulsion  Excipients primarily composed of phospholipids Drug substance • Perfluorocarbons added as a Heat processing aid H2O • Removed in the process Heat Stage I I Blowing agent removal Blowing agent Drop radius
  • 6. Manufacture of PulmoSphere Particles Heat Stage I Water Emulsion Water loss + Drug H2O & particle formation FC Homogeneous droplet Heat Stage II Atomization Blowing agent removal Homogeneous droplet Blowing agent Drop radius Drying suspension solution Hot air drying Collection Cyclone or filter collection
  • 7. PulmoSphere Particle Characteristics Particle Physical Properties • Hollow and porous • Surface roughness • Low density Particle Performance Attributes • Flowability • Dispersibility • Aerodynamic
  • 8. Particle Size Analysis for Homogenization Process  The objective of this study is to develop a robust homogenization process for making pharmaceutical emulsions by evaluating droplet size distribution Homogenization is a fluid mechanical process that involves the subdivision of droplets or particles into nanometer or micron sizes to create a stable emulsion or dispersion for further processing. This technology is one of most efficient means for size reduction.
  • 9. Criteria for Evaluating High-Pressure Homogenizers Mean Particle Size Particle Size Distribution Emulsion Stability Cycle Time CIP/SIP Capability Scale Up Capability Routine Operation Maintenance
  • 10. High-Pressure Homogenizer Systems High-pressure homogenizers generally consist of a high-pressure pump, mostly in the form of a one- to three-piston plunger pump which can be electrically or pneumatically actuated, an interaction assembly, and a cooling unit. High-pressure interaction assembly can be subdivided into three different types: Types Manufacturers • Radial Diffusers/Valves - Avestin, APV, Niro… • Nozzle Aggregates - BEE, Kombi-Blende… • Counter-jet Dispergators - Microfluidics, Bayer, Nanoject…
  • 11. Homogenization Principles High-pressure processing equipment for reducing droplet or suspension particle size primarily involves four mechanisms: • Shear - is caused by elongation and subsequent breakup of droplets, due to acceleration of a liquid • Turbulence - is caused by high velocity fluid resulting in chaotic motion to tear apart the globules • Impact - is caused by impinging of pressurized fluid on a hard surface breaking globules into smaller droplets • Cavitation - is caused by an intense pressure drop, leading to formation of vapor bubbles in the liquid, which implode causing shock waves in the fluidHomogenizers, available from different manufacturers operate based oncombination of these mechanical forces
  • 12. Process and Product Parameters  Processes • Configuration (gap, length, shape, and size) • Pressure drop • Residence time • Cooling efficiency (temperature control)  Product • Concentration • Viscosity (ratio and individual) • Interfacial tension (surfactant amount and adsorption rate) • Coalescence rate (Gibbs elasticity) • Temperature sensitivity
  • 13. Equipment for Evaluation - Microfluidics Microfluidics: M-110EH • Microfluidics combines high flow with high-pressure, scalable fixed-geometry interaction chambers that impart high shear rates to product formulations • The entire product experiences identical processing conditions, producing the desired results, including: uniform particle and efficient droplet size reduction
  • 14. Emulsion Preparation Process Aqueous phase prepared with lipid surfactant Addition of modifier Pre-mix: Oil phase is slowly added to aqueous phase while mixing with a high-speed rotor/stator mixer High pressure homogenization
  • 15. Process Parameters Evaluated  Pressure Drop  Configuration  Number of Passes  Temperature Control
  • 16. Desirable Quality Attributes Mean Particle Size • Less than 0.8 micron (fine emulsion) Polydispersity • RSD Less than 10% (narrow distribution) Emulsion Stability • Less than 10-20% change in particle size or particle size distribution over extended period of time (long hold time)
  • 17. Instrumentation Used For Evaluation  Instrument for determining emulsion size • Photo sedimentation – CPS • Dynamic light scattering – Malvern Zetasizer • Static light scattering – Horiba LA-950  Criteria for choosing particle size analyzer • Wide dynamic range • Broad applications • Accuracy and precision • Short cycle times (sample prep, measurement, and cleaning) • Ease of operation and maintenance • Regulatory compliance • At-line/on-line application
  • 18. Instrument for Particle Size Analysis  Emulsion Sizing • Horiba LA-950 • Laser light scattering technique • Mie theory • 0.01 – 3000 micron • Good reproducibility • Fill, auto-alignment, blank, measurement, and rinse in less than 60 seconds
  • 19. Microfluidics Study Chambers G10Z and F20Y Pressures 15 and 25 kpsig Passes 1-5 Z - Type Y - Type
  • 20. Microfluidics - G10Z at 15 kpsig 24.00 x50 (μm) 22.00 Coarse 8.23 20.00 Pass 1 0.36 18.00 Pass 2 0.27 Pass 3 0.27 16.00 Pass 4 0.27 14.00 Pass 5 0.27Mean q(%) 12.00 10.00 8.00 Coarse emulsion Pass 1 6.00 Pass 2 4.00 Pass 3 Pass 4 2.00 Pass 5 0.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm)
  • 21. Microfluidics - G10Z at 25 kpsig 24.00 x50 (μm) 22.00 Coarse 8.32 20.00 Pass 1 0.29 18.00 Pass 2 0.26 Pass 3 0.26 16.00 Pass 4 0.27 14.00Mean q(%) Pass 5 0.27 12.00 10.00 8.00 Coarse Emulsion Pass 1 6.00 Pass 2 4.00 Pass 3 Pass 4 2.00 Pass 5 0.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm)
  • 22. Microfluidics - F20Y at 15 kpsig 24.00 x50 (μm) 22.00 Coarse 9.52 20.00 Pass 1 0.38 Pass 2 0.26 18.00 Pass 3 0.25 16.00 Pass 4 0.26 14.00 Pass 5 0.25Mean q(%) 12.00 10.00 Coarse Emulsion 8.00 Pass 1 6.00 Pass 2 Pass 3 4.00 Pass 4 2.00 Pass 5 0.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm)
  • 23. Microfluidics - F20Y at 25 kpsig 24.00 x50 (μm) 22.00 Coarse 10.04 20.00 Pass 1 0.28 18.00 Pass 2 0.28 Pass 3 0.27 16.00 Pass 4 0.27 14.00Mean q(%) Pass 5 0.27 12.00 10.00 8.00 Coarse Emulsion Pass 1 6.00 Pass 2 4.00 Pass 3 Pass 4 2.00 Pass 5 0.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm)
  • 24. Microfluidics Study – Effects of Temperature Control Temperature Control Zones Cooling • Interaction Chamber Jacket • Auxiliary Processing Module (APM) Outlet • Cooling Jacket Inlet Reservoir Intensifier APM Pump Pressure Interaction Gauge Chamber
  • 25. Microfluidics Study – Effects of TemperatureControl Interaction - Chamber APM Cooling Jacket Interaction Chamber - + + APM ++ +++ Cooling Jacket + Interaction Chamber + Exit Line + Cooling Jacket = ++
  • 26. Microfluidics Study – Temperature Control of APMand Cooling Jacket Particle Size, Micron PressureCondition Chamber Pass 1 Pass 2 kpsig x10 x50 x90 x10 x50 x90 1 G10Z 15 0.26 0.39 0.62 0.19 0.26 0.35 2 G10Z 20 0.21 0.29 0.40 0.19 0.25 0.33 3 G10Z 25 0.20 0.27 0.37 0.19 0.26 0.34 4 F12Y 15 0.22 0.31 0.44 0.19 0.26 0.35 5 F12Y 20 0.19 0.27 0.37 0.19 0.26 0.34 6 F12Y 25 0.19 0.26 0.36 0.19 0.26 0.33
  • 27. Microfluidics – F12Y at 15 kpsig with OptimizedCooling x10 x50 x90 25 1 Pass 0.22 0.31 0.44 2 Passes 0.19 0.26 0.35 Two Passes 20 One Pass 15Mean, q% Coarse Emulsion 10 5 0 0.01 0.10 1.00 10.00 100.00 Diameter, Microns
  • 28. Microfluidics – F12Y at 25 kpsig with OptimizedCooling x10 x50 x90 25 1 Pass 0.19 0.26 0.36 2 Passes 0.19 0.26 0.33 20 Two Passes Coarse Emulsion One Pass 15Mean, q% 10 5 0 0.01 0.10 1.00 10.00 100.00 Diameter, Microns
  • 29. Emulsion Stability Studies Time Homogenizer Sample Point x10 x50 x90 Mean Mode Homogenized Avestin C-50 Emulsion Pass #3 0 Ave 0.18 0.26 0.38 0.35 0.25 Homogenized Avestin C-50 Emulsion Pass #3 24hrs Ave 0.19 0.28 0.41 0.35 0.28 Homogenized Avestin C-50 Emulsion Pass #3 96hrs Ave 0.22 0.32 0.59 0.46 0.31 Microfluidics Homogenized M-110EH Emulsion Pass #1 0 Ave 0.19 0.27 0.39 0.33 0.27 Microfluidics Homogenized M-110EH Emulsion Pass #1 24hrs Ave 0.20 0.29 0.42 0.34 0.28 Microfluidics Homogenized M-110EH Emulsion Pass #1 96hrs Ave 0.23 0.32 0.49 0.39 0.32 Microfluidics Homogenized M-110EH Emulsion Pass #2 0 Ave 0.19 0.26 0.35 0.27 0.27 Microfluidics Homogenized M-110EH Emulsion Pass #2 24hrs Ave 0.18 0.25 0.35 0.26 0.26 Microfluidics Homogenized M-110EH Emulsion Pass #2 96hrs Ave 0.20 0.28 0.38 0.29 0.28
  • 30. Emulsion Study Summary  High precision and reproducible data from Horiba LA-950 particle size analyzer provide the critical information for evaluating different equipment and processing conditions.  Both Y and Z types interaction chambers from Microfluidics produce emulsions with fine size and fairly uniform distribution. Y type is slightly more efficient than Z type.  Cooling study using Microfluidics demonstrates that immediate quench of the processed emulsions is a critical process parameter to control the emulsions stability.  When employing new cooling strategy, Microfluidics F12Y interaction chamber is able to produce fine and single-mode emulsions in less than two passes.
  • 31. Acknowledgements Jeff Weer* Thomas Tarara* Jamshed Ghandhi Dan Miller Vidya Joshi Omar Ruiz Vinh Pham *”Improved Lung Delivery from a Passive Dry Powder Inhaler Using an Engineered PulmuSphere Powder”, S. Duddu et al, Pharmaceutical Research, Vol. 19, No. 5, May 2002
  • 32. Novartis Particle Engineering Technology PulmoSphere SEDS PulmSol Dropmeter