Biomedical Engineering Reference
In-Depth Information
This was achieved by using combination processes, but also varying the dispersion
medium. Water was replaced by non-aqueous dispersion media, or water mixtures
(Nanopure
®
, Müller et al. (
2000
)). Oily nanosuspensions can directly be filled into
capsules for oral delivery. Combination processes optimize in a first step the drug
material to be more fragile in the second step of high pressure homogenization, or
to yield more physically stable nanocrystals. Combinations are:
H42:
spray-drying of drug solution and subsequent homogenization (Möschwitzer
2005
)
H69:
precipitation of suspension just before entering or in the cavitation zone of the
homogenizer (Müller and Möschwitzer
2007
)
H96:
lyophilisation
of
drug
solution
and
subsequent
homogenization
(Möschwitzer and Lemke
2007
)
CT:
bead milling followed by homogenization (Petersen
2006
)
These different technologies are unified under the trade name smartCrystal
®
by
Soliqs/Germany, offered as a toolbox of different processes for tailor-making of
nanocrystals.
4
Process Scale Up
Lack of scale up ability is one of the reasons for the failure of interesting
nanocarriers - feasible on lab scale - to enter the market. First of all, the process
itself needs to be scaleable, secondly the process needs to be able to be qualified
and validated, the production lines have to be regulatorily acceptable, and of course
cost-effective (sufficient capacity per hour, limited manpower required for process,
yield, costs of excipients). The costs of the production line are less critical, because
it is a unique investment. Below the processes are discussed possessing from
our point of view presently highest commercial potential, being already used in
products or being closest to products. Therefore the supercritical processes are not
considered.
4.1
Precipitation
Precipitation itself is basically a simple process when the precipitation condi-
tions are established. Critical can be the scale up, because precipitation velocity
is quite different on lab scale (e.g. 1 L volume) or on large scale in a 1,000 L
container. Mixing of solvent and non-solvent is much faster in a small volume.
The Ostwald-Mier region is passed very fast, which yields small crystals. A major
development step, easing the scale up tremendously, is the static blenders. Precipi-
tation takes place within the small volume of the static blender, being of similar size
than the lab scale beaker. Lab scale conditions are imitated on large scale production.
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