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Density fluctuations in amorphous pharmaceutical solids. Can SAXS help to predict stability?
1Research Center for Pharmaceutical Engineering (RCPE) GmbH, Graz, Austria; University of Technology, Graz, Austria.
Colloids and Surfaces. B, Biointerfaces
|May 13, 2018
Summary
X-ray scattering techniques reveal how amorphous pharmaceutical materials change at the nanoscale. Mean-square density fluctuation from SAXS quantifies nano-heterogeneity and predicts stability, crucial for amorphous drug formulation.
Area of Science:
- Materials Science
- Pharmaceutical Science
- Physical Chemistry
Background:
- Amorphous forms of active pharmaceutical ingredients (APIs) are crucial for drug delivery but can be unstable.
- Understanding the nanoscale structure and stability of amorphous APIs is essential for formulation development.
Purpose of the Study:
- To explore the analytical potential of X-ray small-angle scattering (SAXS) combined with wide-angle X-ray diffraction (WAXS).
- To identify quantitative SAXS parameters for describing amorphous API nanostructure and monitoring amorphization and aging.
- To correlate nanostructure with thermodynamic stability and recrystallization propensity.
Main Methods:
- Amorphization of desvenlafaxine, simvastatin, and sulfamerazine using cryo-milling, co-milling with polymer, melting, and melt-quenching.
- Simultaneous SAXS and WAXS measurements to analyze nanostructure and crystalline state.
- Calculation of SAXS invariant to determine mean-square density fluctuation.
Main Results:
- SAXS revealed significant nanostructure variations in amorphous samples produced by different methods.
- Mean-square density fluctuation, derived from the SAXS invariant, effectively characterized nano-heterogeneity and thermodynamic stability.
- Amorphous domain sizes were estimated from SAXS curves.
- Recrystallization propensity upon aging correlated with the presence of domains in the initial amorphous materials.
Conclusions:
- SAXS/WAXS is a powerful tool for characterizing amorphous API nanostructure and stability.
- Mean-square density fluctuation is a robust parameter for assessing nano-heterogeneity and predicting the stability of amorphous pharmaceuticals.
- Understanding nanoscale domain structure is key to controlling the aging behavior of amorphous drugs.
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