posted on 2022-01-21, 15:06authored byIsha Saraf, Robert Roskar, Dattatray Modhave, Michael Brunsteiner, Anjali Karn, Dmytro Neshchadin, Georg Gescheidt, Amrit Paudel
In the present study, the oxidative
degradation behavior of nifedipine
(NIF) in amorphous solid dispersions (ASDs) prepared with poly(vinyl
pyrrolidone) (PVP) with a short (K30) and a long (K90) chain length
was investigated. The ASDs were prepared via dry ball-milling and
analyzed using Fourier transform infrared (IR) spectroscopy, X-ray
scattering, and differential scanning calorimetry. The ASDs were exposed
to accelerated thermal-oxidative conditions using a pressurized oxygen
headspace (120 °C for 1 day) and high temperatures at atmospheric
pressure (60–120 °C for a period of 42 days). Additionally,
solution-state oxidative degradation studies showed that pure NIF
degrades to a greater extent than in the presence of PVP. Electronic
structure calculations were performed to understand the impact of
drug–polymer intermolecular interactions on the autoxidation
of drugs. While no drug degradation was observed in freshly prepared
ASD samples, alkyl free radicals were detected via electron paramagnetic
resonance (EPR) spectroscopy. The free radicals were found to be consumed
to a greater extent by PVP K30- than PVP K90-based ASDs upon exposure
to high oxygen pressures. This was consistent with the greater solid-state
oxidative degradation of NIF observed in ASDs with PVP K30 than with
PVP K90. As no drug recrystallization occurred during this study period,
the lower glass-transition temperature and presumed greater molecular
mobility of PVP K30 and its ASD as compared to the PVP K90 system
appear to contribute to the greater drug degradation in PVP-K30-based
ASDs. The extent and the rate of oxidative degradation were higher
in the case of PVP-K30-based ASD as compared to that in PVP-K90-based
ASD, and the overall degradation increased with an increase in temperature.
IR spectral analysis of drug–polymer interactions supports
the electronic calculations of the oxidation process. We infer that,
apart from the initial free radical content, the difference in the
extent of drug–polymer intermolecular interactions in ASDs
and amorphous stabilization during the forced oxidation experiments
contribute to the observed differences in the autoxidative reactivity
of the drug in ASDs with different PVP chain lengths. Overall, the
chemical degradation of NIF in ASDs with two PVP chain lengths obtained
from accelerated solid-state oxidation studies was in qualitative
agreement with that obtained from long-term (3 years) storage under
ambient conditions. The study highlights the ability of accelerated
processes to determine the oxidative degradation behavior of polymeric
ASDs and suggests that the polymer chain length could factor into
chemical as well as physical stability considerations.