Pharmaceutical Manufacturing Handbook: Production and

Tensile strength (Pa)
14
12
10
8
6
4
2
0
Aerosil 300
Aerosil R 812
Aerosil 200
Aerosil R 805
Printex 95
Titanium dioxide P 25
Aluminum oxide C
Titanium dioxide T 805
Primary particle diameter (nm)
POWDER CHARACTERISTICS 915
Aerosil OX 50
Printex G
Printex 25
0 10 20 30 40 50 60
FIGURE 12 Correlation of tensile strength with primary particle size of glidant.
this correlation was further improved when some outlying glidant (Aserosil 200 and
300 and Printex 25) were excluded ( R 2 values of 0.1287 – 0.8616).
If a powder consisting of two materials both having identical physical properties
is mixed for a suffi cient time, random mixing will eventually be achieved. Unfortunately,
most pharmaceutical powders consist of mixtures of materials with differing
physical properties, such as size, shape, density, and surface area, leading to segregation
among particles, where particles of similar properties tend to collect together
in part of the powder. When segregating powders are mixed, as the mixing time is
extended, the powders appear to unmix. The differences in particle size are the most
important for segregation in pharmaceutical powders. One exception to overcome
segregation is ordered mixing rather than random mixing. When one component of
a powder mix has a very small particle size (less than 5 μ m) and the other is relatively
large, the fi ne powder may coat the surface of the larger particles, and the adhesive
forces will prevent segregation, known as ordered mixing. This ordered mixing
makes the powders produce greater homogeneity than by random mixing. The percolation
of fi ne particles is also a factor. If the particles sizes are quite different, the
smaller particles can drop easily and move to the bottom of powder, resulting in
segregation. This segregation process can occur whenever movement of particles by
vibration, shaking, and pouring takes place.
6.1.4.7 Particle Size Reduction (Micronization and Milling)
Mechanical attrition, that is , high - energy ball milling of powders, is a nonequilibrium
processing method that has generated the reduced particle size and the formation
of physically metastable materials. It can be used to modify materials by refi ning
the microstructure, homogenizing the composition, extending solid solubility, creating
matastable crystalline phases, or producing metallic glass. High - energy ball
milling is both a processing method to reduce particle size and a route to the physical
synthesis of metastable materials. Early in product development, when only
small amounts of drug are available, comminution (grinding/mixing) may be carried
out with a mortar and pestle. For lager batches, ball milling or micronization can be