Using thermally stimulated current (TSC) to investigate disorder in micronized drug substance produced at different milling energies.
OBJECTIVE
To investigate the use of thermally stimulated current (TSC) to characterize disorder resulting from micronization of a crystalline drug substance. Samples processed at different milling energies are characterized, and annealing studied.


METHODS
Molecular mobility in micronized drug substance was studied using TSC and compared to results from differential scanning calorimetry (DSC). The micronized drug substance TSC spectra are compared to crystalline and amorphous references.


RESULTS
TSC shows distinct relaxation modes for micronized material in comparison to a single weak exotherm observed with DSC. Molecular mobility modes are unique for micronized material compared to the amorphous reference indicating physically distinct disorder compared to phase-separated amorphous material. Signals are ascribed as arising from crystal defects. TSC differentiates material processed at different milling energies showing reasonable correlation between the AUC of the α-relaxation and micronization energy. The annealing process of crystal defects in micronized drug appears to proceed differently for α and β relaxations.


CONCLUSIONS
TSC proves sensitive to the crystal defects in the micronized drug substance studied here. The technique is able to differentiate distinct types of disorder and can be used to characterize noncrystalline regions arising from milling processes which are physically distinct from amorphous material.
Forcino
Rachel
R
Physical Properties Analytical Sciences, Pharmaceutical Development, GlaxoSmithKline Pharmaceuticals, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, USA.
Brum
Jeffrey
J
Galop
Marc
M
Sun
Yan
Y
D002152:Calorimetry, Differential Scanning / Q000379:methods; D003460:Crystallization; D006358:Hot Temperature; D006851:Hydrochloric Acid / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000592:standards*; D013678:Technology, Pharmaceutical / Q000379:methods*; D014835:Volatilization; D014961:X-Ray Diffraction
D004364:Pharmaceutical Preparations; D006851:Hydrochloric Acid