Investigating the Interaction Pattern and Structural
Elements of a Drug–Polymer Complex at the Molecular Level
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Abstract
Strong associations between drug
and polymeric carriers are expected
to contribute to higher drug loading capacities and better physical
stability of amorphous solid dispersions. However, molecular details
of the interaction patterns and underlying mechanisms are still unclear.
In the present study, a series of amorphous solid dispersions of clofazimine
(CLF), an antileprosy drug, were prepared with different polymers
by applying the solvent evaporation method. When using hypromellose
phthalate (HPMCP) as the carrier, the amorphous solid dispersion system
exhibits not only superior drug loading capacity (63% w/w) but also
color change due to strong drug–polymer association. In order
to further explain these experimental observations, the interaction
between CLF and HPMCP was investigated in a nonpolar volatile solvent
system (chloroform) prior to forming the solid dispersion. We observed
significant UV/vis and <sup>1</sup>H NMR spectral changes suggesting
the protonation of CLF and formation of ion pairs between CLF and
HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy
(NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate
the strength of associations between drug and polymers, as well as
the molecular mobility of CLF. Finally, by correlating the experimental
values with quantum chemistry calculations, we demonstrate that the
protonated CLF is binding to the carboxylate group of HPMCP as an
ion pair and propose a possible structural model of the drug–polymer
complex. Understanding the drug and carrier interaction patterns from
a molecular perspective is critical for the rational design of new
amorphous solid dispersions