Impact of chirality on the Glass Forming Ability and the crystallization from the amorphous state of 5-ethyl-5-methylhydantoin, a chiral poor glass former

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Abstract

Graphical abstract

The Glassy state of a chiral molecular poor glass former (5-ethyl-5-methylhydantoin) was achieved by FSC while crystallization occurs by DSC. The glass transition temperature of the system (independent from the composition) was determined for the first time. The pure enantiomer presented a higher crystallization propensity compared to other compositions: crystallization of amorphous enantiopure material occurred 36 °C below Tg. Possible metastable equilibria (previously unknown) between both enantiomers were evidenced.

The investigation of the glassy state of 5-ethyl-5-methylhydantoin (i.e. 12H, a chiral Active Pharmaceutical Ingredient) was attempted by Differential Scanning Calorimetry (DSC) and Fast Scanning Calorimetry (FSC). This compound exhibits a high crystallization propensity for every enantiomeric composition. Nevertheless, glassy states of pure enantiomer or mixtures between enantiomers were successfully reached by FSC at cooling rates of: 1000 °C/s and 300 °C/s respectively, even though limitations on the sampling reproducibility were evidenced due to FSC sample size. The Glass Forming Ability (GFA) was proven to increase with the counter-enantiomer content. From the glassy state, pure enantiomer displayed a more pronounced crystallogenic character (with a crystallization occurring 36 °C below Tg during ageing) than that of the mixture between enantiomers. Ageing of amorphous 12H promotes a strong nucleation behavior in both samples but enantiopure 12H crystallizes upon ageing while scalemic 12H evolves towards the metastable equilibrium. Finally, potential new phase equilibria (previously not reported) in the enantiomeric phase diagram could have been highlighted by FSC by recrystallization from the amorphous state.

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