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In this paper, the molecular dynamics at different thermodynamic conditions of hydrogen-bonded (H-bonded) active pharmaceutical ingredient—ticagrelor (TICA) have been investigated. Extensive high-pressure (HP) dielectric studies revealed surprising high sensitivity of the structural (α)-relaxation to compression. They also showed that unexpectedly the shape of the α-peak remains invariable at various temperature (T) and pressure (p) conditions at constant α-relaxation time. Further infrared measurements on the ordinary and pressure densified glasses of the examined compound indicated that the hydrogen-bonding pattern in TICA is unchanged by the applied experimental conditions. Such behavior was in contrast to that observed recently for ritonavir (where the organization of hydrogen bonds varied at high p) and explained the lack of changes in the width of α-dispersion with compression. Moreover, HP dielectric measurements performed in the glassy state of TICA revealed the high sensitivity of the slow secondary (β)-relaxation (Johari–Goldstein type) to pressure and fulfillment of the isochronal superpositioning of α- and JG-β-relaxation times. Additionally, it was found that the activation entropy for the β-process, estimated from the Eyring equation (a high positive value at 0.1 MPa) slightly increases with compression. We suggested that the reason for that are probably small conformational variations of TICA molecules at elevated p. [ABSTRACT FROM AUTHOR]

In this study, several experimental techniques were applied to probe thermal properties, molecular dynamics, crystallization kinetics and intermolecular interactions in binary mixtures (BMs) composed of flutamide (FL) and various poly(N-vinylpyrrolidone) (PVP) polymers, including a commercial product and, importantly, samples obtained from high-pressure syntheses, which differ in microstructure (defined by the tacticity of the macromolecule) from the commercial PVP. Differential Scanning Calorimetry (DSC) studies revealed a particularly large difference between the glass transition temperature (Tg) of FL+PVPsynth. mixtures with 10 and 30 wt% of the excipient. In the case of the FL+PVPcomm. system, this effect was significantly lower. Such unexpected findings for the former mixtures were strictly connected to the variation of the microstructure of the polymer. Moreover, combined DSC and dielectric measurements showed that the onset of FL crystallization is significantly suppressed in the BM composed of the synthesized polymers. Further non-isothermal DSC investigations carried out on various FL+10 wt% PVP mixtures revealed a slowing down of FL crystallization in all FL-based systems (the best inhibitor of this process was PVP Mn = 190 kg/mol). Our research indicated a significant contribution of the microstructure of the polymer on the physical stability of the pharmaceutical—an issue completely overlooked in the literature. [ABSTRACT FROM AUTHOR]

In this paper, the molecular dynamics as well as inter- and intramolecular interactions in the homogenous solid dispersions (SDs) of active pharmaceutical ingredient - probucol (PRO) with acetylated glucose (acGLU), acetylated sucrose (acSUC), and sucrose acetoisobutyrate (aibSUC), prepared in 5:1 molar ratio, have been investigated using broadband dielectric (BD) and Fourier transform infrared (FTIR) spectroscopy. Importantly, high pressure dielectric measurements revealed that as for neat PRO, a breakdown of the isochronal structural (α) and JG- β exact superpositioning, due to increasing separation between both processes under compression, can also be detected in its mixtures with acetylated saccharides (acSACCHs). Furthermore, the analysis of temperature dependences of JG- β -relaxation times for PRO and PRO-acSACCH SDs at selected isobaric conditions indicated the increase in the cooperativity of the secondary process (reflected in the value of the activation entropy, Δ S β) at elevated pressure in all systems. The mere addition of the small amount of excipient to neat PRO (p = 0.1 MPa) resulted in a greater value of Δ S β (it was the most noticeable in the case of aibSUC). Further FTIR studies carried out on the pressure densified glasses of PRO, and binary mixtures suggested that the observed changes in the cooperativity of the JG- β -process, as well as the failure of the exact isochronal superpositioning of α - and JG- β relaxation times, are due to varying H-bond pattern in the examined single- and two-component systems at high compression/in the presence of saccharide. [Display omitted] [ABSTRACT FROM AUTHOR]

Different experimental techniques were applied to study thermal and structural properties, strength of H-bonds, possible keto - enol tautomerism and molecular dynamics at various thermodynamic conditions in the H-bonded active substance, curcumin (CRM). Dielectric measurements revealed dynamical features of examined compound that are uncharacteristic for the associated systems. This includes enormously large pressure coefficient of the glass transition temperature and prominent drop of the fragility with compression. Simultaneously, the shape of α -process slightly broadened at elevated pressures. Infrared investigations demonstrated that this effect is related to the variation in the population of H-bonds. Moreover, we studied the changes in the structural and dynamical properties of the glasses prepared upon cooling of the melt (ordinary glass, OG) and the one obtained after compression of CRM in the liquid phase and decompression at T = 293 K (dense glass, DG). Interestingly, during the aging of the latter sample, a clear shift of the β -relaxation towards higher frequencies was noted. This unexpected result indicated that the density of DG is probably getting smaller with time. Complementary X-ray diffraction experiments confirmed this supposition. Additionally, they showed that in DG there are traces of polymorph II of CRM that has a higher density than initial crystals (polymorph I). Finally, infrared studies demonstrated that H-bond pattern in DG is slightly different with respect to OG. Furthermore, Raman investigations suggested that probably keto - enol tautomerism might be shifted towards diketo form in the glass obtained at high compression. Our investigations are very interesting in the context of better understanding of the behavior of associated systems at high compression as well as provide a better insight into dynamics of higher density glasses produced at elevated pressures. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] • H-bond strength influences the nature of phase transitions in 1-NH 2 -OH and 1-OH-ADM. • There are three transitions between various plastic crystal (PC) phases in 1-NH 2 -OH. • Only one transition between PC and ordinary crystal phases occurs in 1-OH-ADM. • Compression has a strong impact on phase transitions in both examined compounds. In this paper, several experimental techniques, i.e., differential scanning calorimetry, X-ray diffraction, Fourier transform infrared, Raman, and broadband dielectric spectroscopy were applied to study the nature of the phase transitions in 1-adamantylamine (1-NH 2 -ADM, C 10 H 17 N) and 1-adamantanol (1-OH-ADM, C 10 H 16 O). Calorimetric measurements showed one and three endothermic peaks in thermograms for the latter and the former substance, respectively. Indeed, results of spectroscopic investigations indicated that the observed thermal events in 1-NH 2 -ADM correspond to transitions between various plastic crystal (PC) phases (I, II, III, IV), while the endothermic process in 1-OH-ADM can be assigned to a phase transition between the PC and the ordinary crystal (OC). Especially interesting were the outcomes of dielectric studies carried out both at ambient and high-pressure conditions, during heating and cooling cycles. They showed: i) noticeable changes in the frequency dependencies of the imaginary ( ε ' ' ) and real ( ε ') parts of the complex dielectric permittivity that occurred around temperatures of the characteristic endothermic events detected by the calorimetry, and ii) significant fluctuations of ε ' ' and ε ' at pressures attributed to the respective phase transitions. Moreover, the pressure coefficients of the phase transition temperatures were estimated to be approximately equal to 0.2 K/MPa for both compounds. In turn, volume variation (Δ V) at the PC (II)-PC (III) and PC (III)-PC (IV) transition temperatures for 1-NH 2 -ADM was essentially different than Δ V for the PC-OC transition in 1-OH-ADM. [ABSTRACT FROM AUTHOR]

In this paper, thermal and structural properties, as well as molecular dynamics of co-amorphous binary mixtures composed of itraconazole (ITZ) and four other active pharmaceutical ingredients (APIs) with antifungal activity (posaconazole (POS), ketoconazole (KET), fluconazole (FLU), and voriconazole (VOR)), have been investigated. Calorimetric measurements indicated that with increasing concentration of each excipient (EXC), the glass transition temperature and phase transition temperatures, related to the formation of nematic and smectic order, are affected in the binary systems. Comprehensive analysis of the enthalpy of isotropic-nematic transition and the temperature dependence of the order parameter, calculated from infrared data for selected mixtures, supported by the results of X-ray diffraction , enabled us to confirm the suppression of liquid crystalline (LC) ordering in ITZ by KET, FLU, and VOR. On the other hand, ITZ enforced the nematic-like molecular arrangement of POS. Further dielectric measurements revealed that the type of EXC and its content in the mixture have no impact on the ratio of α - and δ -relaxation times (τ α and τ δ , respectively) in ITZ. Moreover, it was shown that δ -process is more sensitive to the isotropic-nematic phase transition than the α -one, and the formation of the nematic phase in this API occurs at different τ α and τ δ , dependently on the type of EXC and its concentration in the mixture. Summarizing, the results of our studies are much different with respect to those reported previously by Kozyra et al. [Mol. Pharm. 15 (2018) 5192–5206] and by some of us [Kaminska et al. Eur. J. Pharm. Biopharm. 88 (2014) 1094–1104] for ITZ mixed with various polymers and acetylated maltose, respectively. This finding clearly indicates that there is a different impact of the low and high molecular weight excipients on the ability in the formation of LC phases in ITZ, which may have important implications for the further development of the formulations of this pharmaceutical. Unlabelled Image • The degree of spatial arrangement of ITZ molecules is affected in binary systems. • The smectic ordering in ITZ is being suppressed by POS, KET, FLU and VOR. • In the ITZ-POS binary mixture, ITZ enforces the molecular (nematic) order of POS. • Results of our studies are in contrast to those reported for ITZ-polymer systems. [ABSTRACT FROM AUTHOR]