1. Grinding Aids for Nano-milling using a Stirred Media Mill Center for Particulate & Surfactant Systems (CPaSS) IAB Meeting Columbia University, New York 20 th April, 2009 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

2. Industrial Relevance (Liversidge, Toxic Path, 2008) - increased bioavailability - lower effective dosage - can maintain crystallinity - does not require organic solvents - allows more facile scale up Poorly water soluble commercial powders are frequently milled to smaller sizes to improve performance Sub-micron and nano suspensions of API have many advantages: Nano-milling using Stirred media mill : 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) e.g. active pharmaceutical ingredients[API], agrochemicals, minerals, pigments

3. Background 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 Known parameters in Media/attrition milling: media size, type and loading grinding aid(s) concentration grinding rate and time Nano milling: increased particle-particle interactions agglomeration ( spontaneous and forced) competes with comminution

4. Objective 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. To investigate the effect of grinding aids (surfactant/ polymer) on milling efficiency and dispersion of insoluble material (charge) in Stirred Media Milling. Proposed Hypothesis Preventing slippage by promoting enough adhesion of charge (e.g., API) to media The grinding aid(s) can increase milling efficiency by : Media Stabilizing milled material; prevent re-agglomeration- maximize comminution Optimizing rheology and tribology Slippage Weak adhesion Media Surfactant

5. Research Methods/ Techniques Selected System Experimental Stirred media mill: Ibuprofen, Itraconazole, others Pluronics (i.e., F-68, F-127), Tweens, other Generally Regarded As Safe (GRAS) surfactants Insoluble materials: Grinding Aid: API characterization: Particle size distribution, morphology, crystallinity Particle–Particle Interactions: Atomic Force Microscopy (AFM) studies Employ Design of Experiments to develop a correlation between process parameters and milling performance. Union Process 1S attrition mill Media : Kodak polymeric media (500  m – 50  m); Polystyrene 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: 5 o C

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

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

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

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

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 Milling efficacy is reduced at higher RPM Media Load 60% ( net volume) API-F68 25% ( void volume) 1 2 3 1 2 3

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

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