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

Abstract

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.

Physical aging of selenium glass: Assessing the double mechanism of equilibration and the crystallization process

“…when the gap between T g and T a is more and more important. This behavior has been already observed in literature [27][28][29] . We may note that the rejuvenated curve is perfectly superimposed to the others in both glass and liquid states, which is the expected calorimetric response when only physical aging occurs.…”

Impact of chirality on the amorphous state of conglomerate forming systems: a case study of N-acetyl-α-methylbenzylamine

“…These results suggest that, higher cooling rate than 10 K/min are required in order to vitrify the samples with an ee > 0%, and the cooling rate needed to inhibit crystallization increases proportionally to the ee. As illustrated in figure 5 been mentioned by some of us in a previous work for the case of another conglomerate forming system: 5-ethyl-5-methylhydantoïn 30 . To our knowledge this is the second compound for which such behavior is revealed.…”

“…Systematic studies on the amorphous state of molecular compounds with a stereogenic chiral center are largely available in the literature [15][16][17][18][19][20][21][22][23][24][25] . A recent and increasing interest is paid to the investigation of chirality influence in molecular amorphous systems regarding their molecular mobility [26][27][28][29] , their glass forming ability 30 and their crystallization behavior 26,28,[31][32][33] as function of the initial enantiomeric composition. From these studies, it is clear that the glass transition temperature Tg appears to be independent of the enantiomeric excess (ee: the absolute difference between the mole fractions of each enantiomer (ee = 0% racemic composition, ee = 100% pure enantiomer) 7,[26][27][28]32,33 , same for the characteristic size of cooperative movements and relaxation landscape 28,33 .…”

“…When differences exist, they are mostly expressed in the glass forming ability 30 and the kinetic of crystallization 26,30,33 , structural effects due to specific interactions inducing changes in polarization and dielectric properties 28,34 . A brief picture of the state of the art related to the impact of chirality on the amorphous state is mentioned in one of our recent work 28 .…”

Chirality impact on physical ageing: An original case of a small organic molecule

“…Sample masses (few ten nanograms) were estimated by normalizing the heat capacity jump at T g with the value obtained from classical DSC measurements. As well explained in ref[17] it is not easy to perfectly master the ee value during sample preparation for FSC experiments. Ageing was performed 6 °C below T g for different ageing duration t a (0.01 s to 14400s) after a rejuvenation cycle (sample heated above T g and at 1000°C/s down to T a ).…”