Chemistry Reference
In-Depth Information
Solid dispersion produced by either process (melting or solvent evaporation) can
yield similar bioavailability and physical stability as long as both processes yield a
homogeneous amorphous dispersion with appropriate
final powder particle size. How-
ever, HME can often yield nonhomogeneous amorphous dispersion that will likely
underperform due to incomplete dissolution of the compound. Either the high melting
temperature of the compound or the low solubility of the compound in the molten
polymer during the HME process can result in crystallization or phase separation when
the melt cools. Also, the creation of the amorphous state in spray drying happens very
quickly and at lower temperature, so the API and polymers are exposed to less heat for
less time. Finally, the process can be repeated with minimal loss: if a sample is only
incompletely converted to an amorphous material and some crystalline content remains,
that sample can readily be redissolved and spray dried again. Spray drying also has
several advantages over other evaporation methods (coprecipitation [24
-
26], super-
critical
fluids [27,28], etc.); most notably, it is highly scalable. During discovery, small-
scale spray dryers can handle samples on the order of a few hundred milligrams; later in
development, material can be spray dried at a rate of tens of kilograms per hour.
The spray drying process does have several drawbacks, though. As scale changes, so
does particle size (PS)
so some adaptation will still be necessary. Second, and exactly
the opposite of HME, the bulk density (BD) of a spray-dried dispersion (SDD) is
generally low. As a result, powder handling is dif
—
ne
particles, which both pose a safety issue (a potential inhalation hazard) and lower the
harvested yield. For the spray drying process, desired particle size and bulk density can
be achieved to render
cult; also, the material creates
flowable solid dispersion. Alternatively, another process, such as a
dry or wet granulation step, may be necessary to increase density and
flowability before
encapsulating or compressing the dispersion into tablets. Also, the design space is
somewhat limited by the requirement that the API and polymer both be suf
ciently
soluble in the same spray drying solvent system. And because of the amount of solvent
vaporized during the process (in addition to the cost of large quantities of nitrogen), spray
drying is somewhat more costly than other methods of amorphization and requires
certain measures to ensure that the vaporized solvents do not escape signi
cantly into the
environment.
Finally, the freshly sprayed dispersion will contain some residual spray drying
solvent, which poses two dif
culties. First, since the solvents used are generally organic,
they are acceptable only at very low levels in a material meant to be dosed in humans.
Second—as our colleagues discuss in some detail in Chapter 7—any moisture in the
dispersion plasticizes the material, increasing its molecular mobility and increasing the
likelihood that the amorphous dispersion will nucleate and recrystallize. (This plastici-
zation is re
ected quantitatively in the material
'
is glass transition temperature, or
T
g
,
which represents the points at which sudden or
“
catastrophic
”
crystallization is likely to
occur; residual moisture lowers the
T
g
.)
One
final consideration in selecting a melting or solvent evaporation technique is the
way in which that technique may constrain the eventual choice of delivery mechanism
downstream. HME creates extrudate, which can be dosed in capsules or even simply by
itself. However, while an extrudate can be formed into a tablet as well, this approach is
not ideal: the material needs to be rendered less dense, as unadulterated extrudates are
