Biomedical Engineering Reference
In-Depth Information
Special properties of nanocrystals are an increased saturation solubility c
s
and an
increased surface area A, both leading to an increased dissolution velocity dc/dt
according to the Noyes-Whitney equation (Buckton and Beezer
1992
). The increase
in saturation solubility leads to increased concentration gradients at biological
barriers and membranes (e.g. gut wall, skin, barriers such as blood-brain barrier),
and subsequently to increased penetration into or permeation across (Keck and
Müller
2010
). The increased dissolution velocity has advantages, but implies the
problem that the nanocrystals might be dissolved before reaching the cellular target.
How to deal with this problem is discussed below. Another important feature is the
adhesiveness to surfaces. Identical to any other nanomaterial, nanocrystals stick to
surfaces due to increased interaction of their large surface with substrates. This
adhesion process is very reproducible, and the reason for better pharmacological
performance, e.g. minimized variation in bioavailability when using nanocrystals as
delivery system (Liversidge and Conzentino
1995
; Liversidge and Cundy
1995
).
The physical background of the nanocrystal properties is described in detail in
(Müller et al.
2003
).
3
Process Technology
3.1
Bottom Up Processes
In a bottom up process, one starts from a small unit and in the process the size is
increased. In case of nanocrystals one starts from a molecular solution of the
drug, the molecules are aggregated to form particles in the nanometer size range.
Practically in most of these processes we have a classical precipitation. A solvent
containing the drug is added to a non-solvent. The solvent can be water, or organic
solvents, the non solvent can be fluids miscible with the solvent (e.g. ethanol,
acetone) or even supercritical fluids, typically carbon dioxide.
The so called hydrosols by Sucker are generated by classical precipitation, they
are crystalline (List and Sucker
1988
). Applying special precipitation conditions
leads to amorphous nanoparticles, a process developed by Auweter and co-workers
at BASF Germany. Food products on the market based on this technology are
carotenoid powders (Auweter et al.
2002
). In the pharmaceutical area, amorphous
precipitation is performed by Soliqs for its product NanoMorph. There is quite a
variety of other precipitation methods described in the literature, e.g. high-gravity
controlled precipitation technology (Chen et al.
2009
) and flash nanoprecipitation
(Bénet et al.
2002
; Johnson et al.
2006
). Also a number of supercritical fluid pro-
cesses is applicable, which would actually require a review on their own. Therefore
it is referred to (Byrappa et al.
2008
).
Controlled precipitation is a little bit tricky to run, costly because solvents might
need to be removed, solvent residues need to be controlled, with regard to many aspects
more complex than some top down processes. This is the reason why there are no
currently marketed pharmaceutical products for therapy made with this technology.
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