Abstract
Compression effects on alpha and beta relaxation process of amorphous drugs are theoretically investigated by developing the elastically collective nonlinear Langevin equation theory. We describe the structural relaxation as a coupling between local and nonlocal activated process. Meanwhile, the secondary beta process is mainly governed by the nearest-neighbor interactions of a molecule. This assumption implies the beta relaxation acts as a precursor of the alpha relaxation. When external pressure is applied, a small displacement of a molecule is additionally exerted by a pressure-induced mechanical work in the dynamic free energy, which quantifies interactions between a molecule with its nearest neighbors. The local dynamics has more restriction and it induces stronger effects of collective motions on single-molecule dynamics. Thus, the alpha and beta relaxation times are significantly slowed down with increasing compression. We apply this approach to determine the temperature and pressure dependence of the alpha and beta relaxation time for curcumin, glibenclamide, and indomethacin, and compare numerical results with prior experimental studies. Both qualitative and quantitative agreement between theoretical calculations and experiments validate our assumptions and reveal their limitations. Our approach would pave the way for the development of the drug formulation process.
Highlights
Much attention has been devoted to understand molecular dynamics of amorphous drugs during vitrification due to the enhancement of solubility and bioavailability compared to their crystalline forms [1,2,3,4]
The parameters used in calculations are T0 = 518.6 K and ac = 1 for curcumin, and T0 = 525 K and ac = 0.9 for glibenclamide, and T0 = 476 K and ac = 1.5 for indomethacin
The agreement for curcumin is obtained without any adjustable parameter
Summary
Much attention has been devoted to understand molecular dynamics of amorphous drugs during vitrification due to the enhancement of solubility and bioavailability compared to their crystalline forms [1,2,3,4]. Molecules in amorphous materials undergo different relaxation processes including primary (structural/alpha) and secondary (beta) relaxation These relaxations are strongly temperature-dependent and external pressures [5,6,7,8]. To compare theoretical calculations with experimental data, Phan and his coworkers [14,15] used the thermal expansion process to propose a density-to-temperature conversion (a thermal mapping) from the averaged particle density to temperature. This predictive approach has successfully explained the temperature-dependent molecular dynamics in single- and multi-component amorphous drugs [14,15]. To validate the new developments more, we quantitatively compare theoretical calculations with experimental data of curcumin, glibenclamide, and indomethacin in previous studies [16,17,18]
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