Chemistry Reference
In-Depth Information
While the mechanism of drying, and the observed second
T
g
, may be unusual,
measuring the plasticized
T
g
gave us actionable information. SDDs that had been
thoroughly dried (per GC) had a
T
g
of 105
C. When the same material
rst came
°
off the spray dryer, its
T
g
was about 60
C. While the common rule of thumb would not
recommend long-term room-temperature storage of fully plasticized telaprevir SDD
°
—
since its
T
g
is not quite 40
°
C above the storage temperature
—
this result also gave
con
dence that the drying temperature of 50
C would not cause the material to suddenly
°
crystallize on drying.
As noted above, an SDD is a thermodynamically higher energy state that would,
given suf
cient time, be expected to revert to its crystalline form. Our experience has
been that some degree of more sophisticated formulation development is required, even
at this early stage. Measuring, modeling, and predicting the kinetics of recrystallization
during distribution and shelf storage are described in Section 7.3. The next section
describes the development and characterization of the
first formulation required from an
SDD
a suspension for use in preclinical studies, including pharmacology and toxicol-
ogy, and possibly even for FIH.
—
7.2.3 Preparation and Characterization of SDD Suspension
Formulations: Vehicle and Aqueous Stability
The
first suspension formulation is meant to be a rough-and-ready way to get the API into
the systemic circulation and, ideally, to its target. Among the key parameters to measure
for a given formulation is its maximal exposure
in vivo
; stability of the suspension and
solubility and dissolution rate in simulated biological media are also key parameters to
evaluate
in vivo
in attempts to maximize exposure and formulation robustness.
To determine the optimal vehicle, several are typically tested, drawing on experience
to select excipients to test. These suspension formulations can include surfactants, as they
tend to increase the solubility of the SDD. The drawback to any suspension formulation,
however, is the possibility of disappointment later in development: it may produce such
excellent exposure that no solid form is ever able to equal it.
In addition to the surfactant TPGS, a large majority of the vehicles we screen also
include polymers. These are included to improve the physical stability of the SDD in
suspension and prevent an overly rapid solvent-mediated phase transition (SMPT)
a
process in which the SDD solubilizes, and then recrystallizes in its lower energy, lower
solubility crystalline state and precipitates out. While stability is, again, secondary to
solubility and dissolution rate, a certain stability in the vehicle is required to ensure
consistent exposure from the suspension formulations. If the API precipitates incon-
sistently from suspensions before or during dosing, the resultant exposures will be too
variable to be of any scienti
—
c use. It is worth noting that a suspension formulation is, by
de
nition, supersaturated with respect to the crystalline form; thus, the SDD needs to
resist recrystallizing not only in the vehicle, but speci
cally when supersaturated in the
vehicle. For a description of howwe determine more detailed and rigorous parameters for
acceptable stability, please see Section 7.3.4.
Since the suspension will be dosed orally, the SDD also needs to remain in
suspension at physiological temperature (i.e., 37
C) in simulated
uids
—
speci
cally,
°
