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Grinding Aids for Nano-milling using a Stirred Media Mill

Grinding Aids for Nano-milling using a Stirred Media Mill. P. Sharma 1 , S. Brown 1 , H. El-Shall 1,2 and B. Moudgil 1, 2. 1 Particle Engineering Research Center, 2 Department of Materials Science and Engineering, University of Florida.

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Grinding Aids for Nano-milling using a Stirred Media Mill

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  1. Grinding Aids for Nano-milling using a Stirred Media Mill P. Sharma1, S. Brown1, H. El-Shall1,2 and B. Moudgil1, 2 1Particle Engineering Research Center, 2Department of Materials Science and Engineering, University of Florida Center for Particulate & Surfactant Systems (CPaSS) IAB Meeting Columbia University, New York 20th April, 2009

  2. Industrial Relevance • Poorly water soluble commercial powders are frequently milled to smaller sizes to improve performance e.g. active pharmaceutical ingredients[API], agrochemicals, minerals, pigments • Nano milling is a relatively new field: transform existing products into new patentable entities e.g. ~ 40% of active substances are poorly water soluble providing opportunities (Lipinski Am Pharm Rev 2002) • Sub-micron and nano suspensions of API have many advantages: -increased bioavailability -lower effective dosage (Liversidge, Toxic Path, 2008) • Nano-milling using Stirred media mill : -can maintain crystallinity - does not require organic solvents - allows more facile scale up

  3. Background • Known parameters in Media/attrition milling: • media size, type and loading • grinding aid(s) concentration • grinding rate and time Nano milling: • increasedparticle-particle interactions • agglomeration ( spontaneous and forced) competes with comminution • Major knowledge gaps exist for • nano milling : • current selection criteria for grinding • aids is empirical ( Lu et. al. J. Mater. Sc. 2006; • Cho et. at. J. Mat. Sci. 2001) Role of fundamental surfactant/polymer interactions with the media and milled material interfaces for nano-milling has not been explored

  4. Objective To investigate the effect of grinding aids (surfactant/ polymer) on milling efficiency and dispersion of insoluble material (charge) in Stirred Media Milling. Proposed Hypothesis The adsorption/ desorption behavior of grinding aids on charge & media influences interparticle interactions (e.g., adhesion, friction) and plays a critical role in determining the efficiency/effectiveness of particle size reduction and dispersion in stirred media milling. The grinding aid(s) can increase milling efficiency by : Weak adhesion • Preventing slippage by promoting enough adhesion of charge (e.g., API) to media Media Media • Stabilizing milled material; prevent • re-agglomeration- maximize comminution Surfactant • Optimizing rheology and tribology Slippage

  5. Research Methods/ Techniques Selected System Ibuprofen , Itraconazole , others Insoluble materials: Grinding Aid: Pluronics (i.e., F-68, F-127), Tweens, other Generally Regarded As Safe (GRAS) surfactants Stirred media mill: Union Process 1S attrition mill Media : Kodak polymeric media (500 mm – 50 mm); Polystyrene Experimental API characterization:Particle size distribution, morphology, crystallinity Particle–Particle Interactions: Atomic Force Microscopy (AFM) studies Milling conditions: Stir rate: 400- 3000 rpm Media loading: 60-80 % net volume Ibuprofen + F-68 slurry: 20-50% void volume API: 20-50% of slurry (by mass) Temperature: 5oC Employ Design of Experiments to develop a correlation between process parameters and milling performance.

  6. Ibuprofen: Characterization 500 mm Optical microscopy shows polydisperse, rod shaped particles

  7. Ibuprofen: Characterization Particle Size Distribution of Ibuprofen in F-68, before milling Number Average Volume Average Mean: Number ~ 6.5mm; Volume ~ 240 mm

  8. Particle – Particle Force Spectroscopy • ~10 micron Ibuprofen Particle attached to the end of a cantilever and used to measure interaction forces with an opposing micron-sized particle. Cantilever Cantilever Ibuprofen –Ibuprofen Interactions ibuprofen • In water • In F-68 solution ibuprofen polymeric media Ibuprofen – Polymeric Media Interactions • In water • In F-68 solution

  9. Influence of F68 on Ibuprofen-Ibuprofen Interactions Approaching Force Curves F68 Solution • A repulsive steric barrier appears with F68 addition : • helps reduce aggregation DI Water Retracting (pull-off) Force Curves F68 Solution • Pull-off forces are also reduced F68 addition: • helps grinding efficacy DI Water

  10. Influence of Loading Force on Ibuprofen Pull-off Forces Particle-particle adhesion increases with increasing load Energy loss to deaggregation likely increases with higher impact forces ( stirring rates)

  11. Preliminary results: Effect of stirring speed 1 2 3 Media Load 60% ( net volume) 3 1 API-F68 25% ( void volume) 2 Milling efficacy is reduced at higher RPM

  12. SEM Media Load 60% ( net volume) API-F68 25% ( void volume) RPM 800 Sub- 100nm particles are observed in SEM

  13. Summary • Preliminary studies show correlation between particle-particle interactions and milling efficacy • F-68 Reduces Ibuprofen-Ibuprofen adhesion • Force measurements and milling experiments indicate optimal mechanical milling conditions e.g. stirring rates, particle impact force Future Studies • Explore other GRAS surfactants/polymers for nano-milling of Ibuprofen • Employ design of experiments approach to establish grinding aid – milling performance correlations • Correlate force measurements with energy calculations in milling • Expand current study to other materials.

  14. Deliverables • Better understanding of the factors that influence nano-milling and dispersion • Significance of grinding aid adsorption • Influence of particle–particle interactions • Develop selection criteria of grinding aids for nano-milling of water insoluble compounds. Acknowledgements Industry Members Battistini,Matthew R; PERC Singh, Amit: PERC Hahn, Megan; PERC

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