Pharmaceutical Manufacturing Handbook: Production and

1274 NANOTECHNOLOGY IN PHARMACEUTICAL MANUFACTURING
of a stable suspension with the smallest particle size requires a high nucleation rate
but low growth rate. Both process rates are dependent on temperature and supersaturation.
The optimum temperature for nucleation might lie below that for growth.
A high - supersaturation condition is achieved by adding small amounts of a water -
miscible organic solution of the drug to the nonsolvent (water) under rapid mixing,
which leads to spontaneous nucleation. At high - supersaturation levels, the crystal
habit or external appearance is changed to a needlelike or dendritic morphology.
These crystals are easily broken, forming new smaller nuclei. Rapidly grown crystals
tend to be more imperfect and often incorporate impurities and dislocations. This
effect is more pronounced for fl exible molecules that have many degrees of freedom
[19] . The presence of stabilizing surfactants is generally necessary to assist in forming
submicrometer particles, and hydrophilic groups in the surfactants lead to rapid
wetting of the high - surface - area particles in aqueous media, for example, in the case
of oral administration. It is well known that the unprotective surfaces of nanoparticles
show a high energy that leads to particle agglomeration. Therefore, the
nanoparticles must be protected by, for example, steric hindrance and electrostatic
pulsion. In the case of itraconazole (ITZ) nanosuspension manufacturing, a mixture
solution of ITZ and Poloxamer (P407) in THF at room temperature was mechanically
injected into a P407 aqueous solution at 3 ° C. Magnetic stirring was utilized to
enhance heat and mass transfer. Nanosuspensions containing sub - 300 - nm particles
were obtained with drug loads as high as 86% [60] .
Top - down methods are also commonly used to manufacture nanosuspensions,
including wet milling and homogenization. In pearl/ball milling, the active agent, in
the presence of surface stabilizer(s), is comminuted by milling media. Particle size
is determined by stress intensity and the number of contact points. The drug macrosuspensions
are poured into a milling container containing milling pearls from,
for example, glass, zircon oxide or special polymers such as hard polystyrene derivatives.
The drugs are ground to nanocrystals between the pearls. The nanosus pension -
derived products, Rapamune (sirolimus tablets) and Emend (aprepitant capsules),
were approved by the FDA and launched in 2000 and 2003, respectively. They are
manufactured by Elan ’ s NanoCrytal technology using a proprietary wet - milling
technique. A general problem of pearl mills is potential erosion of materials from
the milling pearls leading to product contamination. A polymer as substitution may
minimize erosion. Scaling up with pearl mills is possible; however, there is a certain
limitation in the size of the mill due to its weight. Up to about two - thirds of the mill
volume are the pearls lead to heavy weight of the machinery, thus limiting the
maximum batch size [127] .
Homogenization can be divided into two types. One is the forcing of a suspension
under pressure through a narrow - aperture valve (microfl uidization). The other is
high - pressure homogenization of particles in water or other media (piston gap).
Microfl uidization is a jet stream principle. The suspension is accelerated and passes
a specially designed homogenization chamber with a high velocity. In the Z - type
chamber, the suspension changes the direction of its fl ow a few times, leading to
particle collision and shear forces, while in the Y - type chamber, the suspension
stream is divided into two streams colliding frontally. Sometimes it is necessary to
pass through the microfl uidizer many times to minimize particle size [127] .
In piston - gap homogenization, suspension contained in a cylinder passes a very
thin gap with an extremely high velocity. Bubbles of water vapor are produced for