Nanocrystals: Production, Cellular Drug Delivery, Current and Future Products - Intracellular Delivery: Fundamentals and Applications - page 418

4.2 Bead Milling

Scale up of the bead mill in a discontinuous production is only feasible to a
limited extend, because the weight of the beads (density zirconium oxide:
approx. 6 g/mL ( Zirconium dioxide - Wikipedia )) would lead to a too high
weight of the mill. It needs to be also considered that about 70% of the mill
volume is filled by beads, leaving only about 30% volume for adding the mac-
rosuspension. A relatively high mill weight results compared to a low volume of
suspension for processing. Therefore the continuous process is applied in phar-
maceutical industry. The suspension is passed multiply through the mill (Fig. 2 ,
middle). Very often, with just one passage a mean diameter in the nanometer
range is obtained. The number of passages depends on the product requirements.
About three to four passages are typically required to obtain a mean diameter
below 500 nm. To minimize the content of crystals >1 mm (e.g. for i.v. inject-
ables) about six to ten passages are needed. Typically after 10 passages, latest
15 passages very often the maximum dispersivity is reached. The perfectness of
the crystals increases with decreasing size because the crystals break preferen-
tially at their imperfections. At maximum dispersivity the energy is not suffi-
cient to break these more perfect crystals. Therefore additional passages do not
lead to further size reduction. On the contrary additional energy input can pro-
mote aggregation because the energy put in cannot be used any more for size
reduction. This energy is now available to overcome the repulsive forces between
crystals and to aggregate them.

4.3 High Pressure Homogenization

Homogenizers with a homogenization capacity of 1,000 L/h and more are
commercially available. This is very favourable for large scale production and
can compensate the need of 10 or even 20 passages through the homogenizer
(= homogenization cycles) for the product. Compared to other equipment, the
homogenizers are relatively low cost. To accelerate the process, four homogenizers
can be placed in line, one passage through this line is equivalent to four homo-
genization cycles. The pumping velocity of the four homogenizers is electronically
coordinated (Fig. 2 , lower). Assuming a batch size of about half a ton, roughly
500 L, and ten production cycles on a homogenizer line with 1,000 L/h per homo-
genizer, one passage through this line is equivalent to four cycles and takes 30 min
homogenization time. For the equivalence of ten cycles 1 h and 15 min are required,
plus preparation and cleaning time.
Important for the output is also the solid concentration of the suspension to
be processed. For both bead milling and homogenization concentrations in the
range 10-20% are in most cases processable without sincere problems. With the bead
mill sometimes concentrations up to about 40% are processable (depending on
particle size of the starting material, affecting the viscosity). However, more