Chemistry Reference
In-Depth Information
Figure 7.6.
Concentration of suspensions of amorphous SDDs in simulated
fluids show
maintenance of supersaturation (
(filled squares) or not (open circles) according to the SDD
physical stability under the conditions tested.
simulated gastric
fluid (SGF) and simulated intestinal
fluid (SIF). Figure 7.6 shows the
differing behavior in simulated
fluids of two hypothetical compounds; while one (solid
squares) remains in suspension over a signi
cant timescale, the other (open circles)
precipitates in its crystalline form after less than 5 h. In general, given the residence time
in the stomach of typical laboratory animals (rats, mice, and dogs), a suspension is at
unacceptably high risk of recrystallizing if it nucleates in under 3 h. The exception could
be rapid nucleation combined with slow growth of the resultant crystals; while risky, this
situation could be manageable. The rate of crystal growth, given nucleation, can be
evaluated with
experiments, in which amorphous dispersions are contami-
nated with small amounts of crystalline drug. In practice, this seeding simulates the
possibility of small-scale crystalline regions occurring in the dispersion when it is
produced at scale, and helps determine speci
“
seeding
”
cations for acceptable levels of residual
crystallinity during manufacture. Frequently, a higher risk than a quick nucleation, slow
growth SDD would be an SDD in which crystalline material nucleates slowly but then
grows rapidly. Because nucleation is stochastic, results could be uneven.
The danger of solvent-mediated phase transitions was borne out in our own
experience. During a Phase I clinical study of telaprevir, lower than expected exposures
were obtained in one arm of the study. Amorphous suspensions crystallized and gave
lower exposure [16].
In response, we developed an alternative, more robust suspension with a different
polymer. We were able to arrive at a different choice of polymer without disrupting the
timeline of telaprevir
s Phase I trial by devising a novel assay to study the underlying
process, a solvent-mediated phase transition. (An SMPT is a two-step process in which a
metastable suspended solid such as an amorphous dispersion dissolves in the medium
and then crystallizes to a stable solid form.) Previously, we had investigated the physical
form of suspensions by pulling samples at discrete time points. To measure crystallinity,
the samples were
'
filtered and the solid subjected to X-ray powder diffraction (XRPD),
which was able to detect a crystallinity level of about 5%. For dissolution, the samples
were run on an HPLC to measure the level of dissolved solid. This approach was able to
