Particle Size Analysis for Homogenization Process Development
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The seminar presented by Daniel Huang discussed the development of a robust homogenization process for manufacturing pharmaceutical emulsions used in pulmonary drug delivery systems. It emphasized the importance of controlling particle size and distribution for stability and performance, explored the mechanisms involved in high-pressure homogenization, and detailed the results of laboratory studies on emulsion stability and processing conditions. Key findings included the effectiveness of microfluidics technology in producing fine emulsions with uniform distribution and the critical role of cooling strategies in maintaining emulsion stability.
Particle Size Analysis for Homogenization Process Development
- 1. Daniel Huang HORIBA Seminar February 22, 2018 Particle Size Analysis for Homogenization Process Development
- 2. Outline Background Study Objective Homogenization Equipment Operating Principles Emulsion Preparation Process Instrument for Particle Size Evaluation Laboratory Study Results Summary
- 3. Micro- and Nano- Particulate Systems Micro- and nano- suspensions and emulsions are commonly used in pharmaceutical, chemical, and consumer products. The control of the size and its distribution of these small- scale materials is important to their stability and performance during applications. Today, I am going to give you an example of how we developed a homogenization process for manufacturing pharmaceutical emulsions used in a pulmonary drug delivery system.
- 4. Pulmonary Drug Delivery Product Life Cycle Formulation Filling & Packaging Aerosol Delivery Aerodynamics Dispersability Process control Scale up Dose Chemical/Physical Stability Solid-state properties Excipients Patient’s needs Reproducible Easy to use & reliable Fine powders Low mass, tight RSD Remain dispersable Billions/year Powder Processing Particle Engineering
- 5. Lyophilization Attrition / Jet Milling Fine Particles (MMAD ~ 1-5 µm) Molecule SCF CrystallizationSpray Drying Emulsion Based Solution Based Methods to Produce Fine Particles for Pharmaceutical Applications PulmoSphere® Technology
- 6. PulmoSphere Particle Characteristics Particle Physical Properties • Hollow and porous • Surface roughness • Low density Particle Performance Attributes • Flowability • Dispersibility • Aerodynamic
- 7. Atomization Drying Collection Homogeneous droplet Drop radius Emulsion Homogeneous droplet Hot air drying Cyclone or filter collection H2O Heat Blowing agent Heat Stage I Water loss & particle formation Stage II Blowing agent removal FC Water + Drug Manufacture of PulmoSphere Particles suspension solution
- 8. Novartis PulmoSphere Technology Manufacture of a Fluorocarbon-in-Water Emulsion Excipients primarily composed of phospholipids • Perfluorocarbons added as a processing aid • Removed in the process Drug substance Drop radius H2O Heat Blowing agent Heat Stage I I Blowing agent removal
- 9. 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.
- 10. 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
- 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 fluid Homogenizers, available from different manufacturers operate based on combination of these mechanical forces
- 12. 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
- 13. 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
- 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 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm) Meanq(%) Coarse emulsion Pass 1 Pass 2 Pass 3 Pass 4 Pass 5 x50 ( m)μ Coarse 8.23 Pass 1 0.36 Pass 2 0.27 Pass 3 0.27 Pass 4 0.27 Pass 5 0.27
- 21. Microfluidics - G10Z at 25 kpsig 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm) Meanq(%) Coarse Emulsion Pass 1 Pass 2 Pass 3 Pass 4 Pass 5 x50 ( m)μ Coarse 8.32 Pass 1 0.29 Pass 2 0.26 Pass 3 0.26 Pass 4 0.27 Pass 5 0.27
- 22. Microfluidics - F20Y at 15 kpsig 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 0.010 0.100 1.000 10.000 100.000 Meanq(%) Diameter(µm) Coarse Emulsion Pass 1 Pass 2 Pass 3 Pass 4 Pass 5 x50 ( m)μ Coarse 9.52 Pass 1 0.38 Pass 2 0.26 Pass 3 0.25 Pass 4 0.26 Pass 5 0.25
- 23. Microfluidics - F20Y at 25 kpsig 0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 0.010 0.100 1.000 10.000 100.000 Diameter (µm) Meanq(%) Coarse Emulsion Pass 1 Pass 2 Pass 3 Pass 4 Pass 5 x50 ( m)μ Coarse 10.04 Pass 1 0.28 Pass 2 0.28 Pass 3 0.27 Pass 4 0.27 Pass 5 0.27
- 24. Microfluidics Study – Effects of Temperature Control Inlet Reservoi r Intensifier Pump Pressure Gauge Interaction Chamber Cooling Jacket Outlet Temperature Control Zones • Interaction Chamber • Auxiliary Processing Module (APM) • Cooling Jacket Outlet APM
- 25. - Interaction Chamber APM Cooling Jacket Interaction Chamber - + + APM ++ +++ Cooling Jacket + Microfluidics Study – Effects of Temperature Control Interaction Chamber + Exit Line + Cooling Jacket = ++
- 26. Microfluidics Study – Temperature Control of APM and Cooling Jacket Conditio n Chambe r Pressur e kpsig Particle Size, Micron Pass 1 Pass 2 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 Optimized Cooling 0 5 10 15 20 25 0.01 0.10 1.00 10.00 100.00 Diameter, Microns Mean,q% One Pass Two Passes Coarse Emulsion x10 x50 x90 1 Pass 0.22 0.31 0.44 2 Passes 0.19 0.26 0.35
- 28. Microfluidics – F12Y at 25 kpsig with Optimized Cooling 0 5 10 15 20 25 0.01 0.10 1.00 10.00 100.00 Diameter, Microns Mean,q% Coarse Emulsion One Pass Two Passes x10 x50 x90 1 Pass 0.19 0.26 0.36 2 Passes 0.19 0.26 0.33
- 29. Emulsion Stability Studies Homogenizer Sample Time Point x10 x50 x90 Mean Mode Avestin C-50 Homogenized Emulsion Pass #3 0 Ave 0.18 0.26 0.38 0.35 0.25 Avestin C-50 Homogenized Emulsion Pass #3 24hrs Ave 0.19 0.28 0.41 0.35 0.28 Avestin C-50 Homogenized Emulsion Pass #3 96hrs Ave 0.22 0.32 0.59 0.46 0.31 Microfluidics M-110EH Homogenized Emulsion Pass #1 0 Ave 0.19 0.27 0.39 0.33 0.27 Microfluidics M-110EH Homogenized Emulsion Pass #1 24hrs Ave 0.20 0.29 0.42 0.34 0.28 Microfluidics M-110EH Homogenized Emulsion Pass #1 96hrs Ave 0.23 0.32 0.49 0.39 0.32 Microfluidics M-110EH Homogenized Emulsion Pass #2 0 Ave 0.19 0.26 0.35 0.27 0.27 Microfluidics M-110EH Homogenized Emulsion Pass #2 24hrs Ave 0.18 0.25 0.35 0.26 0.26 Microfluidics M-110EH Homogenized 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.
Editor's Notes
- #5: To provide a pulmonary insulin delivery system that is safe, effective, and above all reproducible, We took an Integrated “systems solution” approach, driven by user needs to create the PDS We developed RT stable macromolecule powders which dissolve rapidly upon landing in the lung to release their drug payload. We pioneered particle engineering via spray drying to create dispersible powders of very small aerodynamic size and scaled it up. We invented unprecedented powderfilling technology where we now meter 1 mg doses of fine powders at RSDs less than 3%, leave the powder uncompressed and dispersible, and have scaled it up to billions of fills per year. Finally we created a device and packaging system that is easy to use, and reliably delivers aerosol drug.
- #7: 0.02-0.3 g/cc Range confirmed by Tom Tarara