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

作者：Tres Francesco^*; Patient Jamie D; Williams Philip M; Treacher Kevin; Booth Jonathan; Hughes Leslie P; Wren Stephen A C; Aylott Jonathan W; Burley Jonathan C

来源：Molecular Pharmaceutics, 2015, 12(5): 1512-1522.

DOI：10.1021/mp500829v

• bicalutamide
• poorly soluble drugs
• amorphous solid dispersions
• dissolution
• solid-state transformations
• polymorphic changes
• Raman mapping
• multivariate curve resolution
• kinetic modeling
• spatial correlations

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.

• 出版日期2015-5