Molecular dynamics simulations of amorphous siderol

Despite the several pharmacological uses of siderol (SRD) its successful formulation is limited by its extremely low aqueous solubility [1]. One way to overcome this, is to administrate the drug in a highly disordered – amorphous – state. However, in order to prepare a stable amorphous drug product, it is crucial to gain an insight into the several molecular phenomena occurring within this thermodynamically unstable state. Nowadays, this in-depth understanding can be expedited by the utilization of molecular simulations, and therefore, the aim of the present study was to apply molecular dynamics (MD) simulations in order to evaluate the several interactions occurring within the amorphous structure of the API. In this vein, SDRʼs initial molecular structure (obtained from cultivated Sideritis scardica [2]) was used (after energy minimization) to construct an amorphous cell consisting of 30 drug molecules. This drug amorphous assembly was validated by comparing the MD simulated glass transition temperature (Tg) with experimental results obtained from DSC. Results showed that the theoretical and the experimental Tgs were in good agreement, indicating that the prepared amorphous assembly can be considered reliable. Following this validation process, the amorphous SDR structure was subjected into a long MD simulation run for 10 ns. The analysis of the obtained trajectory revealed the formation of hydrogen bonds within the amorphous API structure. The nature and strength of these intermolecular H-bonds was analyzed from the obtained simulation results, and their interplay with APIʼs amorphous stability during storage was evaluated.

Publikationsverlauf

Artikel online veröffentlicht:
12. Dezember 2022

• References

• 1 Tomou E-M, Chatziathanasiadou MV, Chatzopoulou P. et al. NMR-Based Chemical Profiling, Isolation and Evaluation of the Cytotoxic Potential of the Diterpenoid Siderol from Cultivated Sideritis euboea Heldr. Molecules 2020; 25 (10) 2382
• 2 Koromili M. Formulation of insoluble diterpens of natural origin. Master Thesis. Thessaloniki: 2021