چکیده (انگلیسی):

The goal of this research was to assess the feasibility of
using lyophilization to stabilize an exploratory compound,
CNK-20402, with a minimal amount of impurity (CNK-
20193) formation. A mixed-level full factorial experimental
design was used to screen excipients of glycine, mannitol,
lactose monohydrate, and povidone K-12. Cryostage
microscopy, powder X-ray diffraction, Karl Fischer titration,
HPLC, and water vapor sorption were used to assess
the formulations
physicochemical properties and stability.
Initial physical characterization from powder X-ray diffraction
revealed that the mannitol- and glycine-containing
formulations were crystalline with the patterns of the pure
excipient, whereas the remaining formulations were amorphous
in structure. Chemically, the formulations stored at
50
C for 1 month had 2.36%, 1.05%, 0.81%, 0.79%, and
0.49% CNK-20193 for glycine, mannitol, drug alone, povidone
K-12, and lactose formulations, respectively. The formulations
containing drug-mannitol, drug alone, and druglactose
were selected for accelerated stability study based
on statistical analysis. Recovery of CNK-20193 in these
formulations was 1.22%, 1.00%, and 0.55%, respectively,
when stored at 40
C/75% relative humidity storage conditions
for 3 months. Water vapor sorption analysis revealed
weight gains of over 7%, 21%, and 24% for the mannitol,
lactose, and drug alone formulations, respectively. Testing
formulations with different concentrations of lactose by
water vapor sorption indicated that CNK-20402 concentrations
as low as 10% (wt/wt) could inhibit the recrystallization
of lactose. The lactose-containing formulation exhibited
the best stability among the formulations tested. The
protective mechanism of lactose on the CNK-20402, based
on water vapor sorption studies, is believed to be a result
of (1) the drug-lactose interaction, and (2) competition
between lactose and drug for the residual water in the
formulation.