Comparative Physical Study of Three Pharmaceutically Active Benzodiazepine Derivatives: Crystalline versus Amorphous State and Crystallization Tendency

Abstract

unidimensional growth with only sporadic nucleation, which allows a direct assessment of the crystal growth rate. Despite the very similar growth mode, the two derivatives exhibit very different kinetics for a fixed value of the reduced temperature and thus of the structural relaxation time, with Nordazepam displaying slower growth kinetics. Diazepam does not instead display any tendency towards recrystallization over short periods of time (even close to T m ). Both these observations in three very similar diazepine derivatives provide direct evidence that the kinetics of recrystallization of amorphous pharmaceuticals is not a universal function, at least in the supercooled liquid phase, of the structural or the conformational relaxation dynamics, and it is not simply correlated with related parameters such as the kinetic fragility or activation barrier of the structural relaxation. Only the crystal growth rate, and not the nucleation rate, shows a correlation with the presence or absence of hydrogen bonding.

Drug-Biopolymer Dispersions: Morphology- and Temperature- Dependent (Anti)Plasticizer Effect of the Drug and Component-Specific Johari–Goldstein Relaxations

“…The inset to Figure 9 a displays representative low-temperature spectra of pure NOR. As we reported already in an earlier study [ 17 ], a secondary relaxation, labelled here as β N , is observed on the high-frequency flank of the α relaxation. Like the α process, the β N relaxation shifted to higher frequency with increasing temperature.…”

“…As we discussed in a recent publication [ 17 ], in the pure drug, this relaxation corresponds to a non-diffusive relaxation of the whole molecule known as Johari–Goldstein (JG) β relaxation [ 36 , 37 ]. These secondary relaxations are observed in fully rigid molecules [ 38 , 39 , 40 ] and in polymers with monoatomic or methyl side groups such as polybutadiene and 1,4-polyisoprene [ 41 , 42 ] and correspond to rigid roto-translations of whole molecules or chain segments.…”

“…Nordazepam, besides being a commercial drug, is also the main metabolite of Diazepam and an active metabolite of several other benzodiazepine drugs [ 16 ] in the human body. Contrary to Diazepam, it possesses a secondary amine group, which allows it to act as a H-bond donor and increases self-interactions, which in turn enhance the T g of the demethylated derivative [ 17 ] (the T g of Diazepam is lower than that of polylactide).…”

Inter-enantiomer conversion dynamics and Johari–Goldstein relaxation of benzophenones

“…As mentioned in the introduction, a recent X-ray diffraction study of the two crystalline forms of BrBPh has shown that the molecular structure of the brominated derivative is not helicoidal as the ground-state structure of unsubstituted BPh, but rather displays a coplanar phenyl-ketone moiety, tilted with respect to the brominated ring 45 . This molecular geometry entails the existence of two possible enantiomers with same energy and opposite chirality, and both the stable and metastable crystal phases of BrBPh are in fact racemic mixtures with equal population of both enantiomers 40 . Since the metastable crystalline phase is formed by recrystallization from supercooled liquid BrBPh, it is likely that the inter-enantiomer conversion is active in the liquid state (we cannot exclude a priori the possibility that conformers with different internal torsion angles coexist in the liquid phase).…”

“…In order to investigate the origin of the secondary dielectric response of BPh and further analyze the effect of constrained internal rotation in molecules with germinal aromatic rings, in the present contribution we analyze the temperature- and pressure-dependent relaxation dynamics of a singly-substituted halogenated derivative of BPh, namely ortho-bromobenzophenone (hereafter, BrBPh), and compare the results with more detailed dielectric spectra of BPh that we have acquired near the glass transition of this compound. The comparative analysis of the molecular relaxations of closely-related molecular derivatives can indeed be a valuable tool for the identification of secondary processes 40 . We choose BrBPh because it only differs from the parent molecule by substitution of a single atom, and it has better glass-forming ability and kinetic stability of the supercooled liquid phase than pristine BPh.…”