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In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [Carbohydr. Res.2011, 346, 1061−106421492830] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

Herein, broadband dielectric (BDS) and Fourier transform infrared spectroscopy (FTIR), together with differential scanning calorimetry (DSC) and X-ray diffraction (XRD), were applied to study the molecular dynamics, molecular interactions as well as physical stability of an amorphous Active Pharmaceutical Ingredient (API)-probucol (PRO)-infiltrated into anodic aluminum oxide (AAO) membranes of pore size, d ~ 10-160 nm. Interestingly, the behavior of examined substance strongly depends on the applied thermal protocol. Remarkably, for the first time, we observed that the structural dynamics of the slowly cooled PRO under confinement is significantly enhanced when compared to thatofthe quenched material. This unusual behavior was interpreted as a result of surface-induced effects (including the formation of well-resolved interfacial H-bonded layer and adsorption-desorption processes near the interface) that are magnified by the extremely high sensitivity to density fluctuation of studied PRO, reflected in the enormous pressure coefficient of the glass transition temperature dTg/dp = 427 K/GPa. In fact, FTIR investigations revealed that PRO tends to self-associate under confinement and forms a strongly bonded interfacial layer, which controls the variation in the structural dynamics of core molecules. Finally, we observed that the tendency to crystallize of confined API is reduced with respect to the bulk, even though the critical size of PRO nuclei (rc ~ 3 nm) is significantly lower than the smallest examined pore size. Nevertheless, after few weeks of storage, the investigated substance crystallized in larger pores, while it remained stable in the nanochannels of d = 10 nm. A combination of XRD and DSC measurements indicated that the infiltrated PRO forms two polymorphs, the stable form I (dominating in bulk) and unstable form II (prevailing under confinement). That means that porous matrices might be used to obtain and maintain prolonged stability of unstable polymorphic forms of API.

The impact of the chain length or dispersity of polymers in controlling the crystallization of amorphous active pharmaceutical ingredients (APIs) has been discussed for a long time. However, because of the weak control of these parameters in the majority of macromolecules used in pharmaceutical formulations, the abovementioned topic is poorly understood. Herein, four acetylated oligosaccharides, maltose (acMAL), raffinose (acRAF), stachyose (acSTA), and α-cyclodextrin (ac-α-CD) of growing chain lengths and different topologies (linear vs cyclic), mimicking the growing backbone of the polymer, were selected to probe the influence of these structural factors on the crystallization of naproxen (NAP)an API that does not vitrify regardless of the cooling rate applied in our experiment. It was found that in equimolar systems composed of NAP and linear acetylated oligosaccharides, the progress and activation barrier for crystallization are dependent on the molecular weight of the excipient despite the fact that results of Fourier transform infrared studies indicated that there is no difference in the interaction pattern between measured samples. On the other hand, complementary dielectric, calorimetric, and X-ray diffraction data clearly demonstrated that NAP mixed with ac-α-CD (cyclic saccharide) does not tend to crystallize even in the system with a much higher content of APIs. To explain this interesting finding, we have carried out further density functional theory computations, which revealed that incorporation of NAP into the cavity of ac- α-CD is hardly possible because this state is of much higher energy (up to 80 kJ/mol) with respect to the one where the API is located outside of the saccharide torus. Hence, although at the moment, it is very difficult to explain the much stronger impact of the cyclic saccharide on the suppression of crystallization and enhanced stability of NAP with respect to the linear carbohydrates, our studies clearly showed that the chain length and the topology of the excipient play a significant role in controlling the crystallization of this API.

In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature (Tg), reveal the presence of two secondary relaxations (β, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (β) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, Tc), as well as annealing at two temperatures in the vicinity of Tg and further heating up to Tc, showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δe) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (Tominaka, S.; Kawakami, K.; Fukushima, M.; Miyazaki, A.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-Tg Temperature Mol. Pharm. 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.), who demonstrated that the sub-Tg annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.

In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature (Tg), reveal the presence of two secondary relaxations (β, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (β) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, Tc), as well as annealing at two temperatures in the vicinity of Tg and further heating up to Tc, showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (TominakaS.; KawakamiK.; FukushimaM.; MiyazakiA.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-Tg TemperatureMol. Pharm.20171426427310.1021/acs.molpharmaceut.6b00866.28043129), who demonstrated that the sub-Tg annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.

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.

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, ΔSβ) 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 ΔSβ (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.

Broadband dielectric spectroscopy (BDS) has been used to study the molecular dynamics and aging process in neat probucol (PRO) as well as its binary mixtures with selected acetylated saccharides. In particular, we applied the Casalini and Roland approach to determine structural relaxation times in the glassy state of the examined systems (so-called isostructural times, τiso). Next, using the calculated τiso, primitive relaxation times of the coupling model were obtained and compared to the experimental secondary β (Johari-Goldstein (JG) type) relaxation times. Interestingly, it turned out that there is a correlation between the β-JG and the structural (α)-relaxation processes below the glass transition temperature (T < Tg) in each investigated sample. This is a new observation compared to previous studies demonstrating that such a relationship exists only in the supercooled liquid state of neat PRO. Moreover, it was revealed that the stretching parameters obtained from the aging procedure are very close to the ones determined by fitting the dielectric data above the Tg with the use of the Kohlrausch-Williams-Watts function, indicating that the aging process is governed by the α-relaxation. Complementary Fourier transform infrared and X-ray diffraction measurements allowed us to find a possible reason for these findings. It was demonstrated that although there are very weak intermolecular interactions between PRO and modified saccharides, the intra- and intermolecular structure of PRO is practically unaffected by the presence of modified saccharides.

Summary 8-Prenylnaryngenin (8-PN) is the strongest known phytoestrogen (PE). Its main source is the female inflorescences of hops (Humulus lupulus L.). 8-PN, which, in contrast to other PEs, is proven to have stronger activity and higher affinity for the α subtype of estrogen receptor (ER). Therefore, it may be an effective substitute for hormone replacement therapy (HRT). The studies in postmenopausal women have shown its particular effectiveness in reducing hot flashes. However, a strong stimulation of uterus by 8-PN may be associated with the occurrence of adverse effects (eg. bleeding) and increase the risk of carcinogenesis. The H. lupulus extracts preparations are currently supplements which makes control of the doses used and thus increases the occurrence of uncontrolled self-treatment difficult. This paper presents the current knowledge on 8-PN and discusses the potential risks associated with use of hops to alleviate the symptoms of menopause.

Poly(1-vinyl-2-pyrrolidone) (Povidone, PVP) is one of the most interesting and versatile synthetic polymers utilised in the pharmaceutical and cosmetic industries. Its large-scale commercial production offers an assortment of products in a wide range of molecular weights but poorly-controlled (macro)structural parameters (i.e., dispersity, functionality) limiting the efficiency of PVP-based drug delivery systems (DDS). In this work, synthesised linear and star-shaped PVPs with a strictly defined structure and functionality were compared with the linear, commercially-supplied product and explored as potential vehicles for physical entrapment of metronidazole (MTZ). Here, a question is addressed how differences in their macromolecular properties affect the amorphisation of MTZ, drug encapsulation, the stability of drug-loaded micellar structures and their in vitro release from the carrier. The X-ray diffraction studies and calorimetric measurements revealed that MTZ crystallises in all investigated herein systems reducing the glass transition temperature of the binary mixture significantly. Transmission electron microscopy and dynamic light scattering analysis revealed that MTZ-loaded DDS are able to form ultrasmall regular nanocarriers with an increasing effect of regularity and sphericity from star-shaped DDS to linear-based ones. We founded that synthesised linear-based DDS is the most effective for MTZ entrapment (PVP:MTZ = 1:1 weight ratio) due to their smallest hydrodynamic radius dh = 14.7 nm, the highest stability of micellar structures −2.37 mV, and the highest values of loaded drug 76.5%. Moreover, all applied PVP-based DDS revealed an initial burst release effect of MTZ (pH = 7.4) reaching up to 60% of drug released within the first 5 h (the first-order release model fits). The marked efficiency of MTZ-loaded DDS of strictly defined structural parameters indicates the great importance of polymer preparation strategy in the targeted therapy.

In this work, broadband dielectric spectroscopy (BDS) has been applied to investigate the aging kinetics in a low-molecular weight pharmaceutical - probucol (PRO) at various pressure (p) conditions. Unexpectedly, we found that isostructural relaxation times (τiso, i.e., τα in the glass), as well as the stretch exponent (βag) calculated using the Casalini and Roland (CR) approach at 115 and 160 MPa, vary from the respective τiso and βag determined at 0.1 MPa. These results were different in regard to the data reported earlier for polymethylmethacrylate (PMMA). Further Fourier transform infrared (FTIR) measurements on the glass recovered from high-p experiments (pressure densified glass, PDG) allowed us to certify that most likely the change in the specific intermolecular interactions, namely the formation of weak, rarely observed O H⋯S hydrogen bonds might be responsible for that. Moreover, taking into account the values of βag (free parameter) obtained from the analysis of aging data using the CR approach, we estimated primitive relaxation times (τ0) from the Coupling Model, which were close to experimental Johari-Goldstein (JG) β-relaxation times (τJG-β). Findings reported herein may contribute to a better understanding of the aging phenomenon occurring in the pressurized H-bonded systems.

In this paper, Broadband Dielectric Spectroscopy (BDS) has been applied to study the molecular dynamics of the two active pharmaceutical ingredients (APIs), probucol (PRO) and droperidol (DRO), above and below the glass transition temperature, at varying thermodynamic conditions. We found that the structural (α)-relaxation process in both compounds is sensitive to compression. It was reflected in the high pressure coefficients of the glass transition temperature, dTg/dp = 227 K/GPa and dTg/dp = 427 K/GPa for DRO and PRO, respectively. In this context, it is worthwhile to emphasize that dTg/dp calculated for the latter API is the highest reported to date for the low molecular weight glass formers. Furthermore, the data collected upon squeezing samples revealed that the pressure dependence of the relaxation times of the Johari Goldstein (JG) β-process in PRO is weaker with respect to that of structural relaxation. Thus, a breakdown of exact superposition of both modes has been noted. A slightly different scenario was observed in DRO, where relaxation times of the secondary non-JG γ-process, obtained at different T and p, plotted versus Tg/T, collapsed forming a single curve. A breakdown of exact isochronal superpositioning of α- and JG β-relaxation times at varying thermodynamic conditions in PRO, that is weakly H-bonded low molecular weight glass former, is in accordance with the data reported for the strongly associating compounds (e.g., sorbitol). Moreover, recently a similar scenario has been observed for some polymers, i.e., 1,4-polybutadiene (PBD) (Ransom et al., 2018), poly(methyl methacrylate) (PMMA) (Casalini and Roland, 2013) and polyisoprene (PI) (Kolodziej et al., 2018). This phenomenon, which is consistent with the approximate invariance of the ratio of these two relaxation times to change of thermodynamics conditions (as predicted by the Coupling Model), was assigned to the increasing torsional rigidity of the macromolecule backbone or alternatively to the non-uniform responses to variations of temperature and pressure of the distributed modes composing the JG β-process, resulting in changes of the spectral shape and different fβ(p,T) obtained from the fitting procedure. One can suppose that due to the variation in the population of weak H-bonds at elevated pressure in PRO, the latter effect might be enhanced, contributing to the observed experimental finding. Finally, the data reported herein emphasize the impact of molecular aspects related to specific interactions on the correlation between α- and JG β-relaxation at varying T and p conditions.

In this paper, we studied the impact of saccharides having a similar backbone but differing in the degree of freedom, local molecular mobility, flexibility of the ring and intermolecular interactions on the glass-forming ability (GFA) of naproxen (NAP) in binary mixtures. For this purpose, a series of methyl and acetyl derivatives of glucose (GLS) and anhydroglucose (anhGLS), as well as neat anhGLS have been used to produce homogeneous solid dispersions (SDs) of varying molar concentration of examined active pharmaceutical ingredient (API). Systematic measurements with the use of Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS) enabled us to determine the phase transitions, homogeneity and molecular mobility of the investigated binary mixtures as well as the impact of excipient on the crystallization tendency of NAP. It turned out that acetylated glucose (acGLS), one of the most mobile and flexible saccharides of all examined herein materials, is the best excipient enhancing the GFA of studied API. Although, it should be noted that upon storage at room temperature, we observed the recrystallization of NAP from binary mixtures. Interestingly, API always crystallized to the initial polymorphic form, as shown by X-ray diffraction (XRD) investigations. Finally, since additional measurements with the use of Fourier Transform Infrared (FTIR) Spectroscopy clearly indicated that there are no significant differences in the intermolecular interactions in the systems composed of NAP and all examined saccharides, one can postulate that the mobility and ring flexibility of the matrix have, , the most important impact on the crystallization tendency of NAP upon cooling. Consequently, it seems that in some cases, more mobile/flexible matrices can be a much better choice to enhance the glass-forming ability of studied pharmaceutical.