Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores.

In the present study, the behavior of the calcium channel blocker cilnidipine (CLN) infiltrated into silica (SiO2) and anodic aluminum oxide (AAO) porous membranes characterized by a similar pore size (d = 8 nm and d = 10 nm, respectively) as well as the bulk sample has been investigated using differential scanning calorimetry, broadband dielectric spectroscopy (BDS), and Fourier-transform infrared spectroscopy (FTIR) techniques. The obtained data suggested the existence of two sets of CLN molecules in both confined systems (core and interfacial). They also revealed the lack of substantial differences in inter- and intramolecular dynamics of nanospatially restricted samples independently of the applied porous membranes. Moreover, the annealing experiments (isothermal time-dependent measurements) performed on the confined CLN clearly indicated that the whole equilibration process under confinement is governed by structural relaxation. It was also found that the ßanneal parameters obtained from BDS and FTIR data upon equilibration of both confined samples are comparable (within 10%) to each other, while the equilibration constants are significantly different. This finding strongly emphasizes that there is a close connection between the inter- and intramolecular dynamics under nanospatial restriction.

On the relationship between the Debye process in dielectric response and a dissociation-association phenomenon in phenyl alcohols.

In this paper, we have examined a series of phenyl-substituted primary monohydroxy alcohols (phenyl alcohols, PhAs), from ethanol to hexanol by means of dielectric and Fourier transform infrared (FTIR) spectroscopies supported by the mechanical investigations. The combination of both dielectric and mechanical data allows calculation of the energy barrier, Ea, for dissociation by the Rubinstein approach developed to describe the dynamical properties of self-assembling macromolecules. It was observed that the determined activation energy remains constant, |Ea,RM| ∼ 12.9-14.2 kJ mol-1, regardless of the molecular weight of the examined material. Surprisingly, the obtained values agree very well with Ea of the dissociation process determined from the FTIR data analysed within the van't Hoff relationship, where Ea,vH ∼ 9.13-13.64 kJ mol-1. Thus, the observed agreement between Ea determined by both applied approaches clearly implies that in the case of the examined series of PhAs, the dielectric Debye-like process is governed by the association-dissociation phenomenon as proposed by the transient chain model.

Studies on the Vitrified and Cryomilled Bosentan.

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, 1061-1064] 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.

Impact of the Chain Length and Topology of the Acetylated Oligosaccharide on the Crystallization Tendency of Naproxen from Amorphous Binary Mixtures.

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.

Unique Behavior of Poly(propylene glycols) Confined within Alumina Templates Having a Nanostructured Interface.

Herein we show that the nanostructured interface obtained via modulation of the pore size has a strong impact on the segmental and chain dynamics of two poly(propylene glycol) (PPG) derivatives with various molecular weights (Mn = 4000 g/mol and Mn = 2000 g/mol). In fact, a significant acceleration of the dynamics was observed for PPG infiltrated into ordinary alumina templates (Dp = 36 nm), while bulklike behavior was found for samples incorporated into membranes of modulated diameter (19 nm < Dp < 28 nm). We demostrated that the modulation-induced roughness reduces surface interactions of polymer chains near the interface with respect to the ones adsorbed to the ordinary nanochannels. Interestingly, this effect is noted despite the enhanced wettability of PPG in the latter system. Consequently, as a result of weaker H-bonding surface interactions, the conformation of segments seems to locally mimic the bulk arrangement, leading to bulklike dynamics, highlighting the crucial impact of the interface on the overall behavior of confined materials.

Influence of Annealing in the Close Vicinity of Tg on the Reorganization within Dimers and Its Impact on the Crystallization Kinetics of Gemfibrozil.

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 (ß, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (ß) 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. (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.

Studies on the internal medium-range ordering and high pressure dynamics in modified ibuprofens.

Broadband dielectric spectroscopy (BDS), combined with the X-ray diffraction (XRD) and Fourier transform infrared (FTIR) techniques, was used to study the dynamics of the primary (α) relaxation process and slow mode (SM), as well as structural properties and intermolecular interactions, in the methyl-, isopropyl-, hexyl-, and benzyl derivative of a well-known pharmaceutical, ibuprofen (IBU). Unexpectedly, the XRD and FTIR methods revealed the formation of medium-range ordering together with some molecular organization, which probably leads to the creation of small aggregates at the scale of several microns at lower temperatures. Moreover, high pressure dielectric experiments revealed that the SM (observed in the ambient pressure data) is not detected in the loss spectra of compressed IBU esters, which is consistent with the results reported previously for propylene carbonate and dioxolane derivatives. This finding can be interpreted as connected to either the comparable time scale of the structural dynamics and slow mode or suppression of the motions responsible for the latter process at elevated pressure. Additionally, it was found that the pressure coefficient of the glass transition temperature (dTg/dp) and activation volume (ΔV) change with molecular weight (Mw) in a non-monotonic way. It might be related to various chemical structures, conformations, and intermolecular interactions, as well as different architecture of supramolecular aggregates in the investigated compounds.

Derivatives of Graphene Oxide as Potential Drug Carriers.

Chemically functionalized graphene oxides could be used as novel drug carriers. Covalent alterations of graphene oxides lead to surface changes via formation of chemical bonding while non-covalent ones involve van der Waals forces, hydrogen bonding, and π-π stacking interactions. Covalent modifications appear to be superior as they can yield compounds with desired properties and carriers prepared by other methods are less stable. Synthesis of graphene oxide-iminodiacetic acid and graphene oxide-glycine involves nucleophilic substitution of graphene oxide nanoparticles with iminodiacetic acid or glycine. As the first step, iminodiacetic acid or glycine were transformed into iminodiacetic acid or glycine methyl ester hydrochlorides, respectively, for C-terminus protection. The obtained product, activated in situ, was then used to form amide bonds between graphene oxide and iminodiacetic acid or glycine.

Variation of Activation Volume as an Indicator of the Difference in Clusterization Phenomenon Induced by H-Bonding and F-Π Stacking Interactions in Enantiomers and a Racemate of Flurbiprofen.

In this paper, X-ray diffraction (XRD), differential scanning calorimetry (DSC), broadband dielectric (BDS), and Fourier transform infrared (FTIR) spectroscopy supported by molecular dynamics (MD) simulations and quantum chemical computations were applied to investigate the structural and thermal properties, molecular dynamics, and H-bonding pattern of R-, S-, and RS-flurbiprofen (FLP). Experimental data indicated various spatial molecular arrangements in crystalline forms of examined systems, which seemed to disappear in the liquid state. Surprisingly, deeper analysis of high-pressure dielectric data revealed unexpected variation in the activation volume of pure enantiomers and a racemate. MD simulations showed that it is an effect of the clusterization phenomenon and a higher population of small associates in the former samples. Moreover, theoretical consideration exposed the particular role of unspecific F-Π interactions as a driving force underlying local molecular arrangements of molecules in the liquid and the crystal lattice of R-, S-, and RS-FLP.

The existence of a strongly bonded layer in associating liquids within silica pores - a spectral and molecular dynamics study.

The properties of confined materials are assumed to be governed by the phenomena occurring at the interface, especially the formation of an irreversible adsorption layer (IAL), which has been widely discussed and detected in the case of thin polymer films and silica nanoparticles. In this paper, we present a novel experimental approach allowing us to reveal the formation of an IAL in two phenyl alcohols infiltrated into various mesoporous silica templates. The proposed methodology (based on evaporation) allowed us to detect the alterations in the OH and aromatic CH stretching vibration bands in infrared spectra, which were considered as evidence of the existence of IAL in constrained systems. Such interpretation was also confirmed by complementary molecular dynamics (MD) simulations that indicated the creation of much stronger hydrogen bonds between alcohols and silanol units than between alcohols themselves. Moreover, computation allowed us to identify additional enormously strong π-stacking interactions between phenyl rings stabilizing the interfacial layer. MD simulations also shed new light on the clustering process of both alcohols under confinement. Simulation and experimental data presented in this paper allowed a much deeper understanding of the processes occurring at the interface-formation of IAL and the association phenomenon at the nanoscale level.

The Impact of Various Poly(vinylpyrrolidone) Polymers on the Crystallization Process of Metronidazole.

In this paper, we propose one-step synthetic strategies for obtaining well-defined linear and star-shaped polyvinylpyrrolidone (linPVP and starPVP). The produced macromolecules and a commercial PVP K30 with linear topology were investigated as potential matrices for suppressing metronidazole (MTZ) crystallization. Interestingly, during the formation of binary mixtures (BMs) containing different polymers and MTZ, we found that linear PVPs exhibit maximum miscibility with the drug at a 50:50 weight ratio (w/w), while the star-shaped polymer mixes with MTZ even at a 30:70 w/w. To explain these observations, comprehensive studies of MTZ-PVP formulations with various contents of both components were performed using Fourier-transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results clearly showed that the polymer's topology plays a significant role in the type of interactions occurring between the matrix and MTZ. Additionally, we established that for MTZ-PVP 50:50 and 75:25 w/w BMs, linear polymers have the most substantial impact on inhibiting the crystallization of API. The star-shaped macromolecule turned out to be the least effective in stabilizing amorphous MTZ at these polymer concentrations. Nevertheless, long-term structural investigations of the MTZ-starPVP 30:70 w/w system (which is not achievable for linear PVPs) demonstrated its complete amorphousness for over one month.

Pressure-Induced Aggregation of Associating Liquids as a Driving Force Enhancing Hydrogen Bond Cooperativity.

The behavior of hydrogen bonds under extreme pressure is still not well understood. Until now, the shift of the stretching vibration band of the X-H group (X = the donor atom) in infrared spectra has been attributed to the variation in the length of the covalent X-H bond. Herein, we combined infrared spectroscopy and X-ray diffraction experimental studies of two H-bonded liquid hexane derivatives, i.e., 2-ethyl-1-hexanol and 2-ethyl-1-hexylamine, in diamond anvil cells at pressures up to the GPa level, with molecular dynamics simulations covering similar thermodynamic conditions. Our findings revealed that the observed changes in the X-H stretching vibration bands under compression are not primarily due to H-bond shortening resulting from increased density but mainly due to cooperative enhancement of H-bonds caused by intensified molecular clustering. This sheds new light on the nature of H-bond interactions and the structure of liquid molecular systems under compression.

anti-Ethyl aceto-hydroximate.

In the crystal structure of the title compound, C4H9NO2, the O-H⋯N hydrogen bonds link the mol-ecules into supra-molecular chains extending along the b-axis direction. The conformation of the NOH group in the nearly planar (r.m.s. deviation = 0.0546 Å) ethyl aceto-hydroximate mol-ecule is trans to N=C.

Levulinic Acid.

THE TITLE COMPOUND (SYSTEMATIC NAME: 4-oxo-penta-noic acid), C5H8O3, is close to planar (r.m.s. deviation = 0.0762 Å). In the crystal, the mol-ecules inter-act via O-H⋯O hydrogen bonds in which the hy-droxy O atoms act as donors and the ketone O atoms in adjacent mol-ecules as acceptors, forming C(7) chains along [20-1].

High-pressure studies in the supercooled and glassy state of the strongly associated active pharmaceutical ingredient-ticagrelor.

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 (ß)-relaxation (Johari-Goldstein type) to pressure and fulfillment of the isochronal superpositioning of α- and JG-ß-relaxation times. Additionally, it was found that the activation entropy for the ß-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.

Studies on the nature and pressure evolution of phase transitions in 1-adamantylamine and 1-adamantanol.

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-NH2-ADM, C10H17N) and 1-adamantanol (1-OH-ADM, C10H16O). 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-NH2-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 (ΔV) at the PC (II)-PC (III) and PC (III)-PC (IV) transition temperatures for 1-NH2-ADM was essentially different than ΔV for the PC-OC transition in 1-OH-ADM.

Experimental and Computational Approach to Studying Supramolecular Structures in Propanol and Its Halogen Derivatives.

A series of four alcohols, n-propanol and its halogen (Cl, Br, and I) derivatives, were selected to study the effects of variation in polarity and halogen-driven interactions on the hydrogen bonding pattern and supramolecular structure by means of experimental and theoretical methods. It was demonstrated on both grounds that the average strength of H-bonds remains the same but dissociation enthalpy, the size of molecular nanoassemblies, as well as long-range correlations between dipoles vary with the molecular weight of halogen atom. Further molecular dynamics simulations indicated that it is connected to the variation in the molecular order introduced by specific halogen-based hydrogen bonds and halogen-halogen interactions. Our results also provided important experimental evidence supporting the assumption of the transient chain model on the molecular origin of the structural process in self-assembling alcohols.

Temperature and H/D isotopic "self-organization" effects in the IR spectra of the hydrogen bond tetramer systems in 3,5-diphenylpyrazole and 4-methyl-1,2,4-triazolethione crystals.

Polarized IR spectra of hydrogen-bonded 3,5-diphenylpyrazole and of 4-methyl-1,2,4-triazolethione crystals were measured at 293 and 77 K in the νN-H and νN-D band frequency ranges. These crystals contain molecular tetramers in their lattices. The individual crystal spectral properties remain in close relation with the electronic structure of the two different molecular systems. We show that a vibronic coupling mechanism involving the hydrogen bond protons and the electrons on the π-electronic systems in the molecules determines the way in which the vibrational exciton coupling between the hydrogen bonds in the tetramers occurs. A strong coupling in 3,5-diphenylpyrazole tetramers prefers a "tail-to-head"-type Davydov coupling widespread via the π-electrons. A weak through-space exciton coupling in 4-methyl-1,2,4-triazolethione tetramers involves two opposite hydrogen bonds in the cycles. The relative contributions of each exciton coupling mechanism in the tetramer spectra generation are temperature and the molecular electronic structure dependence. This explains the observed difference in the temperature-induced evolution of the compared spectra. The mechanism of the H/D isotopic ''self-organization'' processes in the crystal hydrogen bonds was also analyzed. The two types of hydrogen bond tetramers differ by the way in which the processes occur. In 3,5-diphenylpyrazole tetramers, identical hydrogen isotope atoms exist in the entire hydrogen bond system, whereas in the case of 4-methyl-1,2,4-triazolethione crystals, the H/D isotopic self-organization mechanism involves the opposite hydrogen bonds in a tetramer.

H/D isotopic and temperature effects in the polarized IR spectra of hydrogen-bond cyclic trimers in the crystal lattices of acetone oxime and 3,5-dimethylpyrazole.

Polarized IR spectra of hydrogen-bonded acetone oxime and 3,5-dimethylpyrazole crystals were measured at 293 and 77 K in the ν(X-H) and ν(X-D) band frequency ranges. These crystals contain molecular trimers in their lattices. The individual crystal spectral properties remain in a close relation with the electronic structure of the two different molecular systems. We show that a vibronic coupling mechanism involving the hydrogen-bond protons and the electrons on the π-electronic systems in the molecules determines the way in which the vibrational exciton coupling between the hydrogen bonds in the trimers occurs. A strong coupling in 3,5-dimethylpyrazole trimers prefers a "tail-to-head"-type Davydov coupling widespread via the π-electrons. A weak through-space exciton coupling in acetone oxime trimers involves three adjacent hydrogen bonds in each cycle. The relative contribution of each exciton coupling mechanism in the trimer spectra generation is temperature and the molecular electronic structure-dependent. This explains the observed difference in the temperature-induced evolution of the compared spectra. The mechanism of the H/D isotopic "self-organization" processes in the crystal hydrogen bonds was also analyzed. The two types of the hydrogen-bond trimers exhibit the same way, in which the H/D isotopic recognition mechanism occurs. In acetone oxime and 3,5-dimethylpyrazole trimers, identical hydrogen isotope atoms exist in these entire hydrogen-bond systems.

The impact of the size of acetylated cyclodextrin on the stability of amorphous metronidazole.

Modified oligosaccharides with cyclic topology seem to be promising excipients for the preparation of Amorphous Solid Dispersions (ASDs), especially with those Active Pharmaceutical Ingredients (APIs), which have a strong crystallization tendency from the amorphous/glassy state. Herein, the usefulness of two acetylated cyclodextrins (ac-α-CD and ac-ß-CD) with various molecular weights (Mw) as stabilizers for the supercooled metronidazole (Met) has been discussed. X-ray diffraction (XRD) studies carried out on Met-acCDs mixtures (prepared in molar ratios from 1:2 to 5:1) showed that the system with ac-α-CD containing the highest amount of API (5:1 m/m) crystallizes immediately after preparation, whereas all Met-ac-ß-CD ASDs remain stable. What is more, long-term XRD measurements confirmed that the Met-ac-α-CD 2:1 m/m system crystallizes after 100 days of storage in contrast to the same system containing ac-ß-CD. The non-isothermal calorimetric data revealed that the activation barrier for crystallization (Ecr) in ASDs with the oligosaccharide having a greater Mw (i.e., composed of seven acGLU molecules) is slightly higher. Finally, to explain the differences in behavior between the mixtures with both acCDs, infrared studies, DFT calculations and Molecular Dynamics simulations were performed. All methods excluded the scenario of API incorporation inside the acCDs' core. On the other hand, obtained results suggested that in comparison to ac-α-CD, the greater amount of Met molecules might be bounded on the outside surface of ac-ß-CD. Therefore, this modified saccharide is a better stabilizer of the examined API.