Chemistry Reference
In-Depth Information
Figure 7.7.
(
Continued
)
suspension, which decreases over time as amorphous material dissolves; crystalline
content, which increases over time as the dissolved API nucleates and recrystallizes; the
total amount dissolved, which peaks in the interval between amorphous dissolution and
crystalline nucleation and then decreases with recrystallization; and heat, which
increases in the example shown monotonically over time and
finally plateaus.
In addition to a continuous readout of heat output, this ITC approach provides a
derived measurement of concentration over time. Concentration as a function of time can
be modeled with the data collected during the experiment. The total enthalpy, which is
measured directly, actually represents the sum of two processes, that is, the two halves of
a solvent-mediated phase transition: dissolution of the amorphous material, and its
recrystallization and precipitation as a less soluble crystalline solid. The one caveat of
ITC is that it is not always possible, in one experiment, to disaggregate these two
processes. Hence, we are unable to determine the rate-limiting step in a single run, and
assess whether a given SMPT is dissolution controlled or crystallization controlled. In
some cases, we can get a crystallization signature from a sample that has been stirred to
pseudo-equilibrium concentration, and then
filtered and run in the ITC. In this way, we
decouple the dissolution heat from the crystallization heat.In addition, we can use our
model to simulate the characteristic shapes of dissolution- versus crystallization-con-
trolled SMPTs.
With ITC, though, we can model the aqueous stability of a given SDD. Added to the
absorption model described above (in Section 7.2.1), these data may give us an
understanding of the parameters that are essential to choosing a suspension formulation
for preclinical and even early clinical use.
Developing a suspension formulation, no matter how successful, does not end the
formulation aspects of TDD, of course. Oral dosage forms are rarely commercialized as
solutions or suspensions; the desired embodiment is typically a solid form, be it a capsule
or a tablet. Hence, development scientists at this stage are already beginning to consider
how the SDD formulation used for preclinical (and possibly FIH) studies can be
translated into a solid dosage form. These considerations form the subject of the
next section.
