Monitoring the Dissolution Mechanisms of Amorphous Bicalutamide Solid Dispersions via Real-Time Raman Mapping

Real-time in situ Raman mapping has been employed
to monitor, during dissolution, the crystallization transitions of
amorphous bicalut­amide formulated as a molecular dispersion
in a copovidone VA64 matrix. The dissolution performance was also
investigated using the rotating disc dissolution rate methodology,
which allows simultaneous determination of the dissolution rate of
both active ingredient and polymer. The dissolution behavior of two
bicalut­amide:​copovidone VA64 dispersion formulations,
containing 5% (w/w) and 50% (w/w) bicalut­amide, respectively,
was investigated, with the aim of exploring the effect of increasing
the bicalut­amide loading on the dissolution performance. Spatially
time-resolved Raman maps generated using multivariate curve resolution
indicated the simultaneous transformation of amorphous bicalut­amide
present in the 50% drug-loaded extrudate into metastable polymorphic
form II and low-energy polymorphic form I. Fitting a kinetic model
and spatially correlating the data extracted from the Raman maps also
allowed us to understand the re-crystallization mechanisms by which
the low-energy form I appears. Form I was shown to crystallize mainly
directly from the amorphous solid dispersion, with crystallization
from the metastable form II being a minor contribution.