Chemistry Reference
In-Depth Information
dispersion is ingested, what happens next represents a race of sorts between two
processes: the solvent-mediated phase transition by which the metastable form recrys-
tallizes, and the absorption of the API into the systemic circulation. Hence, the speed of
absorption
—
which, as mentioned in Section 7.1.3, is inherent to a given scaffold and is
dif
determines the length of time a formulation
needs to resist recrystallizing in suspension. Some degree of precipitation
in vivo
is even
acceptable
cult to alter by formulation approaches
—
as long as the process is slower than absorption.
As we discussed in Section 7.2.3, the stability of the compound in aqueous
suspensions of differing pH is studied during suspension formulation development,
as preparation for preclinical
in vivo
work. For these studies, our group uses ITC. To
compare this figure with absorption, we first derive the rate constant for the drug's
permeation of the small intestinal wall. Given the surface area of the small intestinal
mucosa (a known quantity for a given species), as well as the jejunal permeability
(estimated for correlation with
in vitro
permeability), the rate constant is the product of
the surface area and permeability divided by the volume of
—
fluid in the stomach
(generally 250 ml for humans). If the ratio of the permeation rate constant to the
in vivo
precipitation rate
—
determined by ITC
—
is much greater or much less than 1,
the stability of that formulation is clearly suf
cient, respectively. If, on the
other hand, the two parameters differ by an order of magnitude or less, a more detailed
model will be required
cient or insuf
one that takes account of, for instance, the likelihood that a
given drug molecule will be a substrate of active transporters that take up substances
from the intestinal lumen.
—
7.3.4 Storage Stability
Finally, the development phase is when our group assesses how readily a dispersion can
be stored at time frames relevant to commercial manufacture, distribution, and dosing.
This assessment consists of a mixture of modeling and empirical studies.
First, to predict behavior upon storage, we return our attention to the glass transition
temperature, or
T
g
, of the dispersion. Since the
T
g
of a multicomponent amorphous
system is generally somewhere between the
T
g
of each component, the addition of a
polymer
antiplasticizes
the dispersion: antithetically to the plasticizing effects of a
residual solvent, the polymer reduces molecular mobility and thereby slows the initiation
of crystallization. To a
first approximation, the
T
g
of the blended dispersion generally
follows linear mixing rules:
T
g
;
mix
Φ
1
T
g
;
1
Φ
2
T
g
;
2
:
However, other, harder to predict interactions between drug API and polymer may alter
the actual
T
g
. The Gordon
Taylor or Fox equation (see Section 7.2.2) can be used here to
more thoroughly describe the mixing of these components. Regardless, it is still the case
that the combined
T
g
of drug and polymer should ideally be 40
-
C above the expected
storage temperature. This is not a hard and fast rule, but simply a check based on the
behavior of amorphous materials that have been well investigated.
-
50
°
