1 research outputs found
Quantifying Disproportionation in Pharmaceutical Formulations with <sup>35</sup>Cl Solid-State NMR
Reliable
methods for the characterization of drug substances are
critical for evaluating stability and bioavailability, especially
in dosage formulations under varying storage conditions and usage.
Such methods must also give information on the molecular identities
and structures of drug substances and any potential byproducts of
the formulation process, as well as providing a means of quantifying
the relative amounts of these substances. For example, active pharmaceutical
ingredients (APIs) are often formulated as ionic salts to improve
the pharmaceutical properties of dosage forms; however, exposure of
such formulations to elevated temperature and/or humidity can trigger
the conversion of an ionic salt of an API to a neutral form with different
properties, through a process known as disproportionation. It is particularly
challenging to identify changes of pharmaceutical components in solid
dosage formulations, which are complex heterogeneous mixtures of the
API and excipient components (e.g., binders, disintegrants, and lubricants).
In this study, we illustrate that ultra-wideline (UW) <sup>35</sup>Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation
reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate
excipients. <sup>35</sup>Cl SSNMR can quantitatively detect the amount
of PiogHCl in mixed samples within ±1 wt % and measure the degree
of PiogHCl disproportionation in formulation samples stressed at high
relative humidity and temperature. Unlike other methods used for characterizing
disproportionation, our experiments directly probe the Cl<sup>–</sup> anions in both the intact salt and disproportionation products,
revealing all of the chlorine-containing products in the solid-state
chemical reaction without interfering signals from the formulation
excipients