Aromaticity effect on supramolecular aggregation. Aromatic vs. cyclic monohydroxy alcohols.

In this paper, the steric hindrance effect related to the presence of either a cyclic or aromatic ring on the self-association process in the series of monohydroxy alcohols (MAs), from cyclohexanemethanol to 4-cyclohexyl-1-butanol and from benzyl alcohol to 4-phenyl-1-butanol, was studied using X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Broadband Dielectric Spectroscopy (BDS) and the Pendant Drop (PD) methods. Based on FTIR results, it was shown that phenyl alcohol (PhA) and cyclohexyl alcohol (CA) derivatives reveal substantial differences in the association degree, the activation energy of dissociation, and the homogeneity of supramolecular nanoassociates suggesting that the phenyl ring exerts a stronger steric impact on the self-assembling of molecules than cyclohexyl one. Additionally, XRD data revealed that phenyl moiety introduces more heterogeneity in the organization of molecules compared to the cyclic one. The changes in the self-association process of alcohols were also reflected in differences in the molecular dynamics of the H-bonded aggregates, as well as in the Kirkwood factor, defining the long-range correlation between dipoles, which were slightly higher for CAs with respect to those determined for PhAs. Unexpectedly it was also found that the surface layers of PhAs were more organized than those formed by CAs. Thus, these findings provided insight into the impact of aromaticity on the self-assembly process, H-bonding pattern, supramolecular structure, and intermolecular dynamics of the studied alcohols.

The impact of the length of alkyl chain on the behavior of benzyl alcohol homologues - the interplay between dispersive and hydrogen bond interactions.

In this work, we examined the effect of the length of alkyl chain attached to the benzene ring on the self-assembling phenomena for a series of phenyl alcohol (PhA) derivatives, from phenylmethanol (benzyl alcohol) to 7-phenyl-1-heptanol, by means of X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, and Broadband Dielectric Spectroscopy (BDS) methods. XRD data in the reciprocal and real spaces showed a gradual increase in the local order with the elongation of the alkyl chain. However, the position and full width at half maximum of the main diffraction peak exhibited a non-systematic behavior. To better understand this fact, PhAs were subjected to FTIR spectroscopic studies. These investigations revealed that the association degree and the activation energy of dissociation increase as the alkyl chain length grows. On the other hand, BDS data showed a non-monotonic variation in the Kirkwood correlation factor with increasing length of the alkyl chain, indicating a competition between interactions of the non-polar and polar parts of the molecules in the studied PhAs. Finally, it was also found that the molar surface entropy for PhAs increases with the number of methylene groups, approaching values reported for alkanes, which indicates suppression of the surface order for PhAs with a long alkyl chain. This variability of the various parameters as a function of the length of the side chain shows that the interplay between soft interactions has a strong impact on the local structure and intra and intermolecular dynamics of the studied PhAs.

The dielectric response of phenothiazine-based glass-formers with different molecular complexity.

We examined a series of structurally related glass-forming liquids in which a phenothiazine-based tricyclic core (PTZ) was modified by attaching n-alkyl chains of different lengths (n = 4, 8, 10). We systematically disentangled the impact of chemical structure modification on the intermolecular organization and molecular dynamics probed by broadband dielectric spectroscopy (BDS). X-ray diffraction (XRD) patterns evidenced that all PTZ-derivatives are not 'ordinary' liquids and form nanoscale clusters. The chain length has a decisive impact on properties, exerting a plasticizing effect on the dynamics. Its elongation decreases glass transition temperature with slight impact on fragility. The increase in the medium-range order was manifested as a broadening of the dielectric loss peak reflected in the lower value of stretching parameter ßKWW. A disagreement with the behavior observed for non-associating liquids was found as a deviation from the anti-correlation between the value of ßKWW and the relaxation strength of the α-process. Besides, to explain the broadening of loss peak in PTZ with the longest (decyl) chain a slow Debye process was postulated. In contrast, the sample with the shortest alkyl chain and a less complex structure with predominant supramolecular assembly through π-π stacking exhibits no clear Debye-mode fingerprints. The possible reasons are also discussed.

Broadband Dielectric Study of Sizable Molecular Glass Formers: Relationship Between Local Structure and Dynamics.

In this Letter we report significant differences in the dielectric behavior of four nonpolymeric and sizable glass-forming molecules with related chemical structures. They belong to the recently constituted class of sizable glass-formers [Jedrzejowska et al. Phys. Rev. E: Stat. Phys., Plasmas, Fluids, Relat. Interdiscip. Top. 2020, 101, 010603], for which the pattern of change in dielectric properties with structure has not yet been fully discovered. In the present study we tackle the fundamental problem of the structure-dynamics relationship. It was made possible by judicious choice of investigated systems with the values of dipole moments purposely kept at about the same level, and the only difference is the structure of the terminal substituents applied. The remarkable effect revealed by broadband dielectric spectroscopy is a large difference in the frequency dispersion of the α-relaxation for the systems studied. This interesting finding can be rationalized by the results of X-ray diffraction, clearly indicating the dissimilarities in the local intermolecular structure.

Influence of the Internal Structure and Intermolecular Interactions on the Correlation between Structural (α) and Secondary (ß-JG) Relaxation below the Glass Transition Temperature in Neat Probucol and Its Binary Mixtures with Modified Saccharides.

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 ß (Johari-Goldstein (JG) type) relaxation times. Interestingly, it turned out that there is a correlation between the ß-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.

New paradigm of dielectric relaxation of sizable and rigid molecular glass formers.

In this Rapid Communication we report the unusual dynamics of planar, rigid, and anisotropy glass-forming molecules of unusually large size by dielectric spectroscopy by using two examples. The size of the molecules is much larger than the dipolar moiety located at the end of the longer axis of each molecule. The observed dynamics deviates strongly from the anticorrelation between ß_{KWW} (fractional exponent of the Kohlrausch-Williams-Watts function) and dielectric strength, Δɛ(T_{g}), established generally for small van der Waals molecular glass formers. Moreover, the dynamics of the two large molecules differ greatly, albeit the difference is the dipole moment being orthogonal or parallel to the longer axis of the molecules. The drastic variation in dielectric response of the two materials coming from different portions of the structural α-relaxation spectrum is probed by the dipole. Thus, the new behavior opens up a new research area of the dynamics and thermodynamics of nonpolymeric sizable molecules, the dielectric response of which can be varied by the design of the dipole moiety.

Does the molecular mobility and flexibility of the saccharide ring affect the glass-forming ability of naproxen in binary mixtures?

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.

Dramatic slowing down of the conformational equilibrium in the silyl derivative of glucose in the vicinity of the glass transition temperature.

The vitrification process is usually preceded by a significant change (around 6-8 decades) in the viscosity, structural relaxation times, or diffusion that occurs in a relatively small range of temperatures in fragile liquids. Along with this phenomenon, conformations of the molecules vary as well. In fact, this process is studied in bulk polymers and high molecular weight materials deposited in the form of thin films. On the other hand, spatial rearrangement of small glass formers in the supercooled liquid state has not been intensively investigated, so far. Herein, data obtained from measurements carried out using various experimental techniques on supercooled 1,2,3,4,6-penta-O-(trimethylsilyl)-d-glucopyranose (S-GLU) have revealed that rotations of silyl moieties along with the deformation in the saccharide ring are significantly slowed down in the vicinity of the glass transition temperature (Tg). These intramolecular reorganizations affect the structural relaxation time, atomic pair distribution function, integrated intensity, as well as a number of bands and signals observed, respectively, in the Raman and NMR spectra. Data reported herein offer a better understanding of the conformational variation and time scale of this process in the complex and flexible molecules around the Tg.

A New Method To Identify Physically Stable Concentration of Amorphous Solid Dispersions (I): Case of Flutamide + Kollidon VA64.

In this paper, a novel approach to determine stable concentration in API-polymer systems is presented. As a model, binary amorphous mixtures flutamide (FL) drug with a copolymer Kollidon VA64 (PVP/VA) have been used. It is worthwhile to note that finding an effective method to achieve this goal is a matter of great importance because physical stability of the amorphous pharmaceuticals is the key issue that is investigated worldwide. Due to the fact that molecular dynamics was found to be the crucial factor affecting physical stability of disordered pharmaceuticals, we examined it for both neat FL and its PVP/VA mixtures by means of broadband dielectric spectroscopy (BDS). Thorough investigation of the impact of polymeric additive on the molecular mobility of disordered FL reveals unusual, previously unreported behavior. Namely, simultaneously with the beginning of the recrystallization process, we observe some transformation from unstable supersaturated concentration of investigated mixture to the different, unknown concentration of FL-PVP/VA. Observed, during BDS experiment, transformation enables us to determine the limiting, highly physically stable concentration of FL in PVP/VA polymer (saturated solution), which is equivalent to FL + 41% wt. of PVP/VA. The described high physical stability of this unveiled system has been confirmed by means of long-term XRD measurements. According to our knowledge, this is the first time when such a behavior has been observed by means of BDS.

Atorvastatin as a Promising Crystallization Inhibitor of Amorphous Probucol: Dielectric Studies at Ambient and Elevated Pressure.

The aim of this article was to check the physical stability of the amorphous form of probucol at both standard storage and manufacturing conditions. Our studies clearly show that disordered form of the examined, cholesterol lowering, agent stored at ambient pressure does not reveal any tendency toward recrystallization. The physical stability of neat probucol stored at ambient pressure has been investigated (i) at room temperature by means of X-ray diffraction technique (XRD) as well as (ii) at T = 333 K by means of broadband dielectric spectroscopy (BDS). Due to the fact that compression is an important stage of drugs manufacturing we additionally performed physical stability tests of amorphous probucol at elevated pressure. The recrystallization tendency of the examined pharmaceutical has been tracked online from the initial and further up to a few hours after compression by means of the high pressure BDS technique. These experiments indicate that even very small pressure applied during the sample compression immediately induce its recrystallization. Since, the sensitivity on pressure eliminates probucol from the group of physically stable amorphous APIs, its stabilization is required. Taking into account that there are many scientific reports describing the positive effect of coadministration of probucol with the drug atorvastatin, we used the latter as probucol's crystallization inhibitor.

Studying the Crystallization of Various Polymorphic Forms of Nifedipine from Binary Mixtures with the Use of Different Experimental Techniques.

In this paper the crystal growth of nifedipine from pure system and from binary mixtures composed of active substance (API) and two acetylated disaccharides, maltose and sucrose (NIF-acMAL, NIF-acSUC, 5:1 weight ratio), was investigated. Optical snapshots supported by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) measurements showed that mainly ß and α forms of nifedipine grow up in all investigated samples. They also revealed that the morphology of growing crystals strongly depends on the presence of modified carbohydrates and temperature conditions. Interestingly, it was found that the activation barrier for the crystal growth of the ß polymorph is not affected by acetylated saccharides while the one estimated for the α form changes significantly from 48.5 kJ/mol (pure API) up to 122 kJ/mol (NIF-acMAL system). Moreover, the relationship between the crystal growth rate and structural relaxation times for pure NIF and solid dispersions were analyzed. It turned out that there is a clear decoupling between the crystal growth rate and structural dynamics in both NIF-acMAL and NIF-acSUC binary mixtures. This is in line with recent reports indicating the decoupling phenomenon to be a universal feature of soft matter in the close vicinity of the glass transition temperature.

Interplay between the static ordering and dynamical heterogeneities determining the dynamics of rotation and ordinary liquid phases in 1,6-anhydro-ß-D-glucose.

In this letter, we reported thorough the structural and molecular dynamics studies on 1,6-anhydro-ß-D-glucose, the second compound reported so far that is capable to form rotator and supercooled liquid phases. In contrast to the data presented for ethanol, temperature dependences of structural dynamics in both phases are very comparable. On the other hand, X ray measurements revealed unusually long range ordering/correlations between molecules in the ODIC (d ≈ 95 Å) and supercooled phases (d ≈ 30-40 Å) of this carbohydrate. Our consideration clearly demonstrated that the interplay between length scales of static range ordering and dynamical heterogeneities as well as internal molecular arrangement seem to be the key to understanding the molecular dynamics of different materials characterized by varying degree of disorder in the vicinity of the glass transition temperature.

Molecular Factors Governing the Liquid and Glassy States Recrystallization of Celecoxib in Binary Mixtures with Excipients of Different Molecular Weights.

Transformation of poorly water-soluble crystalline pharmaceuticals to the amorphous form is one of the most promising strategies to improve their oral bioavailability. Unfortunately, the amorphous drugs are usually thermodynamically unstable and may quickly return to their crystalline form. A very promising way to enhance the physical stability of amorphous drugs is to prepare amorphous compositions of APIs with certain excipients which can be characterized by significantly different molecular weights, such as polymers, acetate saccharides, and other APIs. By using different experimental techniques (broadband dielectric spectroscopy, differential scanning calorimetry, X-ray diffraction) we compare the effect of adding the large molecular weight polymer-polyvinylpyrrolidone (PVP K30)-and the small molecular weight excipient-octaacetylmaltose (acMAL)-on molecular dynamics as well as the tendency to recrystallization of the amorphous celecoxib (CEL) in the amorphous solid dispersions: CEL-PVP and CEL-acMAL. The physical stability investigations of the binary systems were performed in both the supercooled liquid and glassy states. We found that acMAL is a better inhibitor of recrystallization of amorphous CEL than PVP K30 deep in the glassy state (T < Tg). In contrast, PVP K30 is a better crystallization inhibitor of CEL than acMAL in the supercooled liquid state (at T > Tg). We discuss molecular factors governing the recrystallization of amorphous CEL in examined solid dispersions.

Studying of crystal growth and overall crystallization of naproxen from binary mixtures.

Broadband dielectric spectroscopy (BDS) and differential scanning calorimetry (DSC) were applied to investigate the molecular dynamics and phase transitions in binary mixtures composed of naproxen (NAP) and acetylated saccharides: maltose (acMAL) and sucrose (acSUC). Moreover, the application of BDS method and optical microscopy enabled us to study both crystallization kinetics and crystal growth of naproxen from the solid dispersions with the highest content of modified carbohydrates (1:5wt ratio). It was found that the activation barriers of crystallization estimated from dielectric measurements are completely different for both studied herein mixtures. Much higher Ea (=205kJ/mol) was obtained for NAP-acMAL solid dispersion. It is probably due to simultaneous crystallization of both components of the mixture. On the other hand, lower value of Ea in the case of NAP-acSUC solid dispersion (81kJ/mol) indicated, that naproxen is the only crystallizing compound. This hypothesis was confirmed by X-ray diffraction studies. We also suggested that specific intermolecular dipole-dipole interactions between active substance and excipient may be an alternative explanation for the difference between activation barrier obtained for NAP-acMAL and NAP-acSUC binary mixtures. Furthermore, optical measurements showed that the activation energy for crystal growth of naproxen increases in binary mixtures. They also revealed that both excipients: acMAL and acSUC move the temperature of the maximum of crystal growth towards lower temperatures. Interestingly, this maximum occurs for nearly the same structural relaxation time, which is a good approximation of viscosity, for all samples. Finally, it was also noticed that although naproxen crystallizes to the same polymorphic form in both systems, there are some differences in morphology of obtained crystals. Thus, the observed behavior may have a significant impact on the bioavailability and dissolution rate of API produced in that way.

Stabilization of the Amorphous Ezetimibe Drug by Confining Its Dimension.

The purpose of this paper is to investigate the influence of nanoconfinement on the molecular mobility, as well as on the physical stability, of amorphous ezetimibe drug. Two guest/host systems, ezetimibe-Aeroperl 300 and ezetimibe-Neusilin US2, were prepared and studied using various experimental techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielectric spectroscopy (BDS). Our investigation has shown that the molecular mobility of the examined anticholesterol agent incorporated into nanopore matrices strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller--5 nm--pores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in molecular dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe molecules, and the use of host materials with pores that are smaller than the critical size of the drug crystal nuclei.

High pressure dielectric studies on the structural and orientational glass.

High pressure dielectric studies on the H-bonded liquid D-glucose and Orientationally Disordered Crystal (ODIC) 1,6-anhydro-D-glucose (levoglucosan) were carried out. It was shown that in both compounds, the structural relaxation is weakly sensitive to compression. It is well reflected in the low pressure coefficient of the glass transition and orientational glass transition temperatures which is equal to 60 K/GPa for both D-glucose and 1,6-anhydro-D-glucose. Although it should be noted that ∂Tg(0)/∂p evaluated for the latter compound seems to be enormously high with respect to other systems forming ODIC phase. We also found that the shape of the α-loss peak stays constant for the given relaxation time independently on the thermodynamic condition. Consequently, the Time Temperature Pressure (TTP) rule is satisfied. This experimental finding seems to be quite intriguing since the TTP rule was shown to work well in the van der Waals liquids, while in the strongly associating compounds, it is very often violated. We have also demonstrated that the sensitivity of the structural relaxation process to the temperature change measured by the steepness index (mp) drops with pressure. Interestingly, this change is much more significant in the case of D-glucose with respect to levoglucosan, where the fragility changes only slightly with compression. Finally, kinetics of ODIC-crystal phase transition was studied at high compression. It is worth mentioning that in the recent paper, Tombari and Johari [J. Chem. Phys. 142, 104501 (2015)] have shown that ODIC phase in 1,6-anhydro-D-glucose is stable in the wide range of temperatures and there is no tendency to form more ordered phase at ambient pressure. On the other hand, our isochronal measurements performed at varying thermodynamic conditions indicated unquestionably that the application of pressure favors solid (ODIC)-solid (crystal) transition in 1,6-anhydro-D-glucose. This result mimics the impact of pressure on the crystallization of fully disordered supercooled van der Waals liquids.

Toward a Better Understanding of the Physical Stability of Amorphous Anti-Inflammatory Agents: The Roles of Molecular Mobility and Molecular Interaction Patterns.

The aim of this article is to examine the crystallization tendencies of three chemically related amorphous anti-inflammatory agents, etoricoxib, celecoxib, and rofecoxib. Since the molecular mobility is considered as one of the factors affecting the crystallization behavior of a given material, broadband dielectric spectroscopy was used to gain insight into the molecular dynamics of the selected active pharmaceutical ingredients. Interestingly, our experiments did not reveal any significant differences in their relaxation behavior either in the supercooled liquid or in the glassy state. Hence, as a possible explanation for the enhanced physical stability of etoricoxib, its ability to undergo a tautomerization reaction was recognized. The occurrence of intramolecular proton transfer in the disordered etoricoxib was proven experimentally by time-dependent dielectric and infrared (IR) measurements. Additionally, IR spectroscopy combined with density functional theory calculations pointed out that in the etoricoxib drug, being in fact a binary mixture of tautomers, the individual isomers may interact with each other through a hydrogen bonding network. A possible explanation of this issue was achieved by performing dielectric experiments at elevated pressure. Since compression results in etoricoxib recrystallization, the possible influence of pressure on the observed stabilization effect is also carefully discussed.

Molecular Dynamics and Physical Stability of Coamorphous Ezetimib and Indapamide Mixtures.

Low physical stability is the main reason limiting the widespread use of amorphous pharmaceuticals. One approach to overcome this problem is to mix these drugs with various excipients. In this study coamorphous drug-drug compositions of different molar ratios of ezetimib and indapamid (i.e., EZB 10:1 IDP, EZB 5:1 IDP, EZB 2:1 IDP, EZB 1:1 IDP and EZB 1:2 IDP) were prepared and investigated using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), and X-ray diffraction (XRD). Our studies have shown that the easily recrystallizing ezetimib drug can be significantly stabilized in its amorphous form by using even a small amount of indapamid (8.8 wt %). DSC experiments indicate that the glass transition temperature (Tg) of the tested mixtures changes with the drug concentration in accordance with the Gordon-Taylor equation. We also investigated the effect of indapamid on the molecular dynamics of the ezetimib. As a result it was found that, with increasing indapamid content, the molecular mobility of the binary drug-drug system is slowed down. Finally, using the XRD technique we examined the long-term physical stability of the investigated binary systems stored at room temperature. These measurements prove that low-molecular-weight compounds are able to significantly improve the physical stability of amorphous APIs.

Studying the Impact of Modified Saccharides on the Molecular Dynamics and Crystallization Tendencies of Model API Nifedipine.

Molecular dynamics of pure nifedipine and its solid dispersions with modified carbohydrates as well as the crystallization kinetics of active pharmaceutical ingredient (API) above and below the glass transition temperature were studied in detail by means of broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction method. It was found that the activation barrier of crystallization increases in molecular dispersions composed of acetylated disaccharides, whereas it slightly decreases in those consisting of modified monocarbohydrates for the experiments carried out above the glass transition temperature. As shown by molecular dynamics simulations it can be related to the strength, character, and structure of intermolecular interactions between API and saccharides, which vary dependently on the excipient. Long-term physical stability studies showed that, in solid dispersions consisting of acetylated maltose and acetylated sucrose, the crystallization of nifedipine is dramatically slowed down, although it is still observable for a low concentration of excipients. With increasing content of modified carbohydrates, the crystallization of API becomes completely suppressed. This is most likely due to additional barriers relating to the intermolecular interactions and diffusion of nifedipine that must be overcome to trigger the crystallization process.