Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 415

However, this should not lead to the conclusion that bottom up processes are not
industrially viable! On the contrary, they might be the basis for the third generation
of drug nanocrystals/amorphous drug nanoparticles. By precipitation very small
sizes (<<100 nm) are accessible, which are not or only very difficult to access
by top down technologies. They are of high interest especially for intracellular
delivery because they can be internalized by endocytosis/pinocytosis, that means by
many cells in the body and not only by macrophages.

3.2 Top Down Processes - First Generation Nanocrystals

In the top down processes one starts from a larger size unit and reduces the size
to the nanometer range. Typically wet milling processes are applied. They can be
differentiated in low energy milling and high energy milling processes, i.e. bead
(pearl, ball) milling and high pressure homogenization. They are used for production
of nanocrystals which can be referred to as the first generation: NanoCrystal ® ,
DissoCubes ® and NANOEDGE ® .
The NanoCrystals ® are produced by bead milling (Liversidge et al. 1992 ).
A macrosuspension of the drug powder is fed to a bead mill, containing small hard
milling beads (e.g. 0.2-0.4 mm diameter, made from zirconium oxide or hard poly-
styrene). The beads are moved by an agitator or by rotating the milling chamber itself,
and the drug crystals are ground between the moving beads (Merisko-Liversidge
2002 ). The system can be discontinuous (mill filled with complete batch), or conti-
nuous by pumping macrosuspension through the mill. The lab scale milling process
typically lasts a few hours, relatively low energy is applied for a longer time.
In the high energy process of homogenization (DissoCubes ® (Müller et al.
1999 )) the macrosuspension is passed through the homogenizer (piston-gap, jet
stream) at pressure of 1,500 bar and higher. Typically 10-20 passes through the
homogenizer need to be applied. In the first generation, the dispersion medium of
the macrosuspension was water, cavitation was considered as major cause for size
reduction. In the NANOEDGE ® process, a pre-step of precipitation is performed,
then the precipitated suspension is exposed to a high energy step, typically high
pressure homogenization (Kipp et al. 2003 ). In a further development, precipitation
can be performed in a counter flow process (Kipp et al. 2005 ).

3.3 Top Down Processes - Second Generation Nanocrystals

In further developments, the nanocrystal production was improved regarding:

- running of process (e.g. less homogenization cycles, production of final dosage

forms)
smaller particle sizes (<100 nm) -

- physical properties of nanosuspension (improved physical stability, long-term

and against electrolytes).