title: Monitoring the Dissolution Mechanisms of Amorphous Bicalutamide Solid Dispersions via Real-Time Raman Mapping.
abstract: 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.
authors: †School of Pharmacy, University of Nottingham, Boots Science Building, Nottingham NG7 2RD, United Kingdom.
authors: Francesco
authors: F
authors: Tres
authors: †School of Pharmacy, University of Nottingham, Boots Science Building, Nottingham NG7 2RD, United Kingdom.
authors: Jamie D
authors: JD
authors: Patient
authors: †School of Pharmacy, University of Nottingham, Boots Science Building, Nottingham NG7 2RD, United Kingdom.
authors: Philip M
authors: PM
authors: Williams
authors: ‡Pharmaceutical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom.
authors: Kevin
authors: K
authors: Treacher
authors: ‡Pharmaceutical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom.
authors: Jonathan
authors: J
authors: Booth
authors: ‡Pharmaceutical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom.
authors: Leslie P
authors: LP
authors: Hughes
authors: ‡Pharmaceutical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom.
authors: Stephen A C
authors: SA
authors: Wren
authors: †School of Pharmacy, University of Nottingham, Boots Science Building, Nottingham NG7 2RD, United Kingdom.
authors: Jonathan W
authors: JW
authors: Aylott
authors: †School of Pharmacy, University of Nottingham, Boots Science Building, Nottingham NG7 2RD, United Kingdom.
authors: Jonathan C
authors: JC
authors: Burley
mesh_terms: D000813:Anilides / Q000737:chemistry*; D003460:Crystallization; D007700:Kinetics; D009570:Nitriles / Q000737:chemistry*; D033362:Powder Diffraction; D012995:Solubility; D013059:Spectrum Analysis, Raman; D014105:Tosyl Compounds / Q000737:chemistry*
chemical_list: D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide
keywords: Raman mapping; amorphous solid dispersions; bicalutamide; dissolution; kinetic modeling; multivariate curve resolution; polymorphic changes; poorly soluble drugs; solid-state transformations; spatial correlations