Chemistry Reference
In-Depth Information
The parameter
σ
is the solubility relative to maximum theoretical concentration,
η
is the
rate of mass transfer relative to the rate of transport through the GI, and
ζ
is the rate of
permeation relative to the rate of transport through the GI.
This model is illustrated by Figure 7.2. Figure 7.2a depicts a simulated absorption
model, using
first-order absorption, that applies over a wide dose range (100
-
800mg).
As Figure 7.2b re
ects, the bioavailability of a theoretical soluble material (
σ
>>
1) is
σ
1). Imagine starting
from the upper left of a graph and traversing from left to right; one crosses contours of
constant fraction absorbed (%
F
a
) at a nearly perpendicular angle. If one were to instead
begin from the lower-left corner, the contours of constant %
F
a
are nearly parallel, and
therefore dif
more sensitive to dissolution rate than an insoluble material (
cult to bisect. As a comparison of the four panels indicates, permeability
affects the spacing of the contours such that a highly permeable compound is more
sensitive to dissolution rate and solubility than a low-permeability compound.
7.2.2 Preparing and Characterizing an Amorphous Dispersion:
Spray Drying and Glass Transition
Once absorption and the relative contributions of dissolution and permeability are
adequately understood, subsequent discovery stage work
—
which includes preclinical
formulation development
requires a group to have the desired physical form of the API
in hand. If the target product pro
—
le (see Section 7.1) calls for a crystalline compound,
and the solubility of the molecule
s crystalline form (or forms) allows it, then various,
extensive solid form studies should be done. These studies would determine whether any
other substance could cocrystallize with the API to form a salt, solvate, clathrate, or
cocrystal, and would attempt to induce form, or polymorph, changes in the neat API.
Although it is not currently possible to know whether all potential polymorphs have been
discovered, a rigorous polymorph screen substantially derisks later development
'
—
and
even commercialization. Ritonavir
an HIV protease inhibitor developed by Abbott that
suddenly began converting to an alternate, less soluble form in the commercial manu-
facturing plant and had to be redesigned [23]
—
—
is an example of how tragic such an event
can be for the patients affected.
However, if the strategic decision has been made to move forward with an amor-
phous dispersion, the next step is to prepare it
in other words, to render a crystalline
drug amorphous and keep it that way. Several options exist for producing an amorphous
dispersion at laboratory scale, including melt quenching, rotovapping, and simply
grinding it. (These options are discussed in detail by our colleagues in Chapter 10.)
For the examples described in this chapter, we used spray drying.
Spray drying produces an amorphous dispersion, but two important considerations
remain. To a greater or lesser degree, they represent con
—
icting priorities. First, a spray-
dried dispersion generally retains some amount of residual solvent. Since spray drying
solvents tend to be organic substances that are unacceptable above trace levels in a
human or animal formulation, a secondary drying step is necessary to gently remove it.
Second, the SDD, however, could be a metastable state with higher free energy than a
crystalline form; hence, the dispersion will, on some timescale, revert to the crystalline
state. The kinetics of this recrystallization in the solid state can be temperature dependent.
