Grinding Aids for Nano-milling using a Stirred Media Mill

Center for Particulate & Surfactant Systems (CPaSS)IAB Meeting

Columbia University, New York 20th April, 2009

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

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

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

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

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 rpmMedia loading: 60-80 % net volumeIbuprofen + F-68 slurry: 20-50% void volumeAPI: 20-50% of slurry (by mass)Temperature: 5o

C

500 m

Ibuprofen: Characterization

Optical microscopy shows polydisperse, rod shaped particles

Ibuprofen: Characterization

Particle Size Distribution of Ibuprofen in F-68, before milling

Mean: Number ~ 6.5m; Volume ~ 240 m

Number Average

Volume Average

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

-60nN

-50

-40

-30

-20

-10

0

10

Fo

rce

(n

N)

1.0µm0.80.60.40.20.0

Piezo Displacement (m)

10nN

5

0

-5

-10

Fo

rce

(n

N)

1.0µm0.80.60.40.2

Piezo Displacement (m)

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 CurvesF68 Solution

DI Water

•Pull-off forces are also reduced F68 addition:

helps grinding efficacy

Influence of Loading Force on Ibuprofen Pull-off Forces

35nN

30

25

20

15

10

5

0

Ad

hes

ion

Fo

rce

10-10

2 4 6 8

10-9

2 4 6 8

10-8

2 4 6 8

10-7

Applied Load (N)

Particle-particle adhesion increases with increasing load

Energy loss to deaggregation likely increases with higher impact forces ( stirring rates)

Preliminary results: Effect of stirring speed

Milling efficacy is reduced at higher RPM

Media Load60% ( net volume)

API-F6825% ( void volume)

0

2

4

6

8

10

12

1 10 100 1000

Num

ber;

Vol

ume

%

Particle diameter ( microns)

2000 rpm Number AvIbuprofen in F-68 Number Av2000 rpm Volume AvIbuprofen in F-68 Volume Av800 rpm Volume Av800 rpm Numer Av

1

2

3

1

2

3

Sub- 100nm particles are observed in SEM

SEM

Media Load60% ( net volume)

API-F6825% ( void volume)

RPM800

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.

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 MembersBattistini,Matthew R; PERCSingh, Amit: PERC Hahn, Megan; PERC