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Communication Dans Un Congrès Année : 2022

Probing dynamics of an amorphous drug by Dielectric Relaxation Spectroscopy and MD simulations: effect of low concentration strongly hydrogen-bonded water

Résumé

Active Pharmaceutical Ingredients (API) are usually formulated in the crystalline state but, over the years, the interest for the amorphous state has strongly developed. Indeed, the better bioavailuability of the glassy state appears as a way to circumvent the solubility issue encountered by the API of increasing complexity in the pipeline. However, the instability of this physical state can lead to the recrystallisation of the API, which is an obvious hindrance to its use. In order to limit this hurdle, it is important to control all parameters favoring this recrystallisation. Water is an important one since it is well-known for fastening the main mobility of amorphous compounds by lowering the glass transition. It can also influence, in the glassy state, more localized mobilities (plasticization or anti-plasticization) from which effects on sub-Tg recrystallisation is still an issue. It is all the more important to understand the mechanisms of action of water since environmental moisture can hardly be avoided and because it can impact the dynamics even at low water content such 1%w. Moreover, even API that are poorly soluble in water in the crystalline state may be hygroscopic in the amorphous state and absorb water upon storage. In the presented work, we investigate by means of complementary Dynamic Relaxation Spectroscopy (DRS) and Molecular Dynamics simulations (MD), the impact of a low water concentration on the dynamics of an amorphous API (of poor solubility in the crystalline state) and we focus in particular on localised intramolecular mobilities, the microscopic origin of which often remains unclear. By DRS, we evidence that these residual water molecules give rise to a new secondary relaxation mode in the glassy state. It originates through the motion of water molecules hydrogen-bonded to API molecules and this dynamic is coupled the intramolecular motions of a flexible part of API molecules carrying functional groups. MD computations and analyses of the hydrogen bonding interaction (HB) allows to understand and rationalise these results. They establish that these water molecules can be divided in two categories: - a majority of weakly or moderately HB water molecules to API which are easily removed from the system by usual drying process, - a minority of much more highly HB water molecules strongly interacting with functional groups of the API molecules, creating some kind of bridges between drug molecules. These strongly HB water molecules localise themselves in small pockets in empty space existing between the API molecules due to the poor packing of the glassy state and are much more difficult to remove without a specific treatment. This project has received financial support from the European projects Interreg 2 Seas programme 2014-2020 and the European Regional Development Fund under subsidy contracts "IMODE 2S01-059" and “Site Drug 2S07-033”.
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Dates et versions

hal-04461406 , version 1 (16-02-2024)

Identifiants

  • HAL Id : hal-04461406 , version 1

Citer

Emeline Dudognon, Jeanne Annick Bama, Frédéric Affouard. Probing dynamics of an amorphous drug by Dielectric Relaxation Spectroscopy and MD simulations: effect of low concentration strongly hydrogen-bonded water. 11th Conference on Broadband Dielectric Spectroscopy and its Applications (BDS2022), Sep 2022, San Sebastian, Spain. ⟨hal-04461406⟩
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