The Role of Molecular Mobility in Governing the Physical Stability of Amorphous Pharmaceuticals

The amorphous state is probably one of the most interesting and curious state of matter. This confirms large number of futuristic and next-generation materials that turned out to be partially or completely amorphous. However, physical properties of amorphous solids are incomprehensible in many aspects. Even the glassy formation is considered as one of the most important unsolved problems of solid state physics. Understanding what drives supercooled liquids and glasses towards crystallization is fundamental not only in the context of unexplained issues of condensed matter physics, but also many practical applications. In this Ph. D. dissertation I have made an attempt to answer the most important in recent days questions that relate to molecular dynamics of amorphous materials. The robustness of the ‘universal’ relationships between dynamics and crystallization tendencies of glass-formers was also uncovered. The first raised issue concerned dynamical properties of amorphous materials depending on the preparation method. Collected results for compounds of great pharmaceutical interest, Telmisartan and antibiotics, remarkably showed that dynamical properties of amorphous substances prepared using two different amorphization routes (vitrification and cryomilling) might differ. However, observed discrepancies in molecular dynamics results only from the fact that during manufacturing they uptake different amount of water from the surroundings, and this absorbed water has critical influence on their dynamical properties. Particularly interesting here are results for antibiotics. The presence of y-relaxation, of most probably the same molecular origin, was reported in anhydrous glassy state of Clarithromycin and Roxithromycin. In the anhydrous vitrified Azithromycin the lack of y-relaxation was reported, while in cryomilled amorphous sample this process became suddenly activated due to the presence of water

Testing density scaling in nanopore-confinement for hydrogen-bonded liquid dipropylene glycol

Recently, it has been demonstrated that the glassy dynamics of the molecular liquids and polymers confined at the nanoscale level might satisfy the density scaling law (rg/T) with the same value of the scaling exponent, g, as that determined from the high-pressure studies of the bulk material. In this work, we have tested the validity of this interesting experimental finding for strongly hydrogen-bonded molecular liquid, dipropylene glycol (DPG), which is known to violate the rg/T scaling rule in the supercooled liquid bulk state. The results of the independent dielectric relaxation studies carried out on increased pressure and in nanopores, have led to an important finding that when the density change induced by geometrical confinement is not very large, DPG can still obey the density scaling law with the same value of the scaling exponent as that found for the bulk sample. In this way, we confirm that the information obtained from the universal density scaling approach applied to nanoscale confined systems is somehow consistent with the macroscopic ones and that in both cases the same fundamental rules governs the glass-transition dynamics

The impact of the molecular weight on the nonequilibrium glass transition dynamics of poly(phenylmethyl siloxane) in cylindrical nanopores

Changes in the glass transition dynamics caused by nanoconfinement reveal pronounced out-of-equilibrium features. Therefore, the confinement effects weaken with time. Using dielectric spectroscopy, we have investigated the impact of molecular weight on the equilibration kinetics of the studied polymer embedded within anodic aluminum oxide nanoporous templates. For our research, we have used poly(phenylmethyl siloxane) (PMPS) with low (Mw = 2530 g/mol) and high (Mw = 27,800 g/mol) molecular weight. We have found that the observed faster dynamics of the nanopore-confined systems weakens with time, and ultimately it is possible to regain the bulk-like mobility. The equilibration time increases by reducing the pore size and lowering the annealing temperature much below the glass transition temperature of the interfacial layer, Tg_interface. The experimental data analysis has also revealed that the molecular weight of the nanopore-confined polymer influences the recovery of the bulk segmental relaxation time, τα. Low-molecular-weight PMPS rearrange and reach denser packing of the polymer chains with greater ease than the high-molecular-weight one. Finally, we have also demonstrated that the molecular weight affects the relationship between the time constant characterizing the equilibration kinetics and the characteristic time of viscous flow in cylindrical channels of nanometer size

Bimodal crystallization rate curves of a molecular liquid with fieldinduced polymorphism

In this study, we use dielectric spectroscopy to explore how frequency and amplitude of an applied strong electric field affect the overall crystallization kinetics over a range of temperatures, focusing on a molecular system with field-induced polymorphism: vinyl ethylene carbonate (VEC). The volume fraction of the field-induced polymorph can be controlled by the parameters of the high-electric field, i.e., frequency and amplitude. We find that the crystallization rate maximum of the field induced polymorph is located at lower temperatures relative to the that of the regular polymorph. The temperature of the highest crystallization rate for the regular polymorph was found to be unaffected by the electric field, but the overall rates increase with increasing field amplitude. The dimensionality of crystal growth is also analyzed via the Avrami parameter and is frequency invariant but affected by the field amplitude. Our results demonstrate that a detailed knowledge of the influence of high fields on crystallization facilitates control over the crystallization behavior and the final product outcome of molecular systems, providing new opportunities for material engineering and improving pharmaceuticals

The role of the dipole moment orientations in the crystallization tendency of the van der Waals liquids - molecular dynamics simulations

Computer simulations of model systems play a remarkable role in the contemporary studies of structural, dynamic and thermodynamic properties of supercooled liquids. However, the commonly employed model systems, i.e., simple-liquids, do not reflect the internal features of the real molecules, e.g., structural anisotropy and spatial distribution of charges, which might be crucial for the behavior of real materials. In this paper, we use the new model molecules of simple but anisotropic structure, to studies the effect of dipole moment orientation on the crystallization tendency. Our results indicate that proper orientation of the dipole moment could totally change the stability behavior of the system. Consequently, the exchange of a single atom within the molecule causing the change of dipole moment orientation might be crucial for controlling the crystallization tendency. Moreover, employing the classical nucleation theory, we explain the reason for this behavior

Stereoregulation, molecular weight, and dispersity control of PMMA synthesized via free-radical polymerization supported by the external high electric field

We show the remarkable effect of using static (DC) and alternating (AC) electric fields to control the free-radical polymerization of methyl methacrylate (MMA). The magnitude and/or frequency of the applied electric field (up to 154 kV cm−1) were found to control the molecular weight, dispersity, and stereochemistry of the produced polymers

Glass-forming tendency of molecular liquids and the strength of the intermolecular attractions

When we cool down a liquid below the melting temperature, it can either crystallize or become supercooled, and then form a disordered solid called glass. Understanding what makes a liquid to crystallize readily in one case and form a stable glass in another is a fundamental problem in science and technology. Here we show that the crystallization/glass-forming tendencies of the molecular liquids might be correlated with the strength of the intermolecular attractions, as determined from the combined experimental and computer simulation studies. We use van der Waals bonded propylene carbonate and its less polar structural analog 3-methyl-cyclopentanone to show that the enhancement of the dipole-dipole forces brings about the better glass-forming ability of the sample when cooling from the melt. Our finding was rationalized by the mismatch between the optimal temperature range for the nucleation and crystal growth, as obtained for a modeled Lennard-Jones system with explicitly enhanced or weakened attractive part of the intermolecular 6-12 potential

Molecular dynamics and cold crystallization process in a liquid-crystalline substance with para-, ferro- and antiferro-electric phases as studied by dielectric spectroscopy and scanning calorimetry

In this article, molecular dynamics and the cold crystallization kinetics of 4-(6-heptafluorobutanoiloxyhexyloxy) biphenyl-4′-carboxylan(S)-4-(1-methyloheptyloxycarbonyl) phenyl (abbreviated as 3F6Bi and/or 4H6) are presented. Rich polymorphismof the liquid-crystalline (SmA*, SmC*, SmC*A and SmI*A) phases and partially disordered crystal CrI and glassy GCrI were observed upon cooling. Both, molecular and collective relaxation processes were observed in the para-, ferro- and antiferro-electric liquid-crystalline phases over the frequency range of 3 × 10−2 to 3 × 106 Hz. An additional bias field in the dielectric experiments was used to identify individual processes. The high heating rates (5–10 K/min) phase sequence is the same as in case of the cooling experiment. On slow heating (0.5–2 K/min), cold crystallization of SmI*A to the more stable crystal CrII phase was observed in the dielectric and calorimetric experiments. The crystallization kinetics was analyzed using the Mo equation, which is a combination of the Avrami and Ozawa models. The activation energy of crystallization was calculated to be 138 and 99 kJ/mol using the Kissinger and Augis-Bennett models, respectively

Effect of the surface polarity, through employing nonpolar spacer groups, on the glass-transition dynamics of poly(phenyl methylsiloxane) confined in alumina nanopores

Broadband dielectric spectroscopy and differential scanning calorimetry were used to study the effect of changes in the surface conditions on the segmental dynamics of poly(phenylmethylsiloxane) confined in alumina nanopores. Functionalization was done using highly polar propyl phosphoric units separated by the assumed concentration of triethoxysilane groups (from N = 0 to N = 24). By adjusting the proportion between polar units and nonpolar spacers, it was possible to control the surface polarity. Modification of the surface conditions does not inhibit the formation of the adsorbed layer, as revealed by the presence of two Tg’s in calorimetric results. However, changes in the surface polarity will prevent the growth of the additional interlayer in between the core volume and the interfacial layer. Finally, we also found that the changes in the surface polarity affect the equilibration kinetics and can be used to control the time scale of the structural recovery toward the equilibrium state