Metody poprawy fizycznej stabilności amorficznej formy ezetimibu

This dissertation is concerned with the physical stability of the amorphous form of the drug, ezetimibe. Experiments performed by means of Differential Scanning Calorimetry (DSC), Broadband Dielectric Spectroscopy (BDS) as well as X-Ray Diffraction (XRD) show that the disordered form of ezetimib stored at room temperature starts reverting to its crystalline form just after two weeks of amorphization. This of course also results in a loss of its superior properties e.g. higher water solubility as well as better bioavailability. In order to inhibit the ezetimib’s re-crystallization three different methods have been applied. The drug was mixed with a polymer named Soluplus, with a small molecular weight excipient – indapamid drug, as well as it being incorporated inside the nonometric scale pores present in silica materials: Aeroperl 300 and Neusilin US2. Results based on a series of experiments show us that besides Aeroperl 300, all used methods can effectively stabilize the amorphous form of the ezetimibe drug

Ionic liquids and their bases : striking differences in the dynamic heterogeneity near the glass transition

Ionic liquids (ILs) constitute an active field of research due to their important applications. A challenge for these investigations is to explore properties of ILs near the glass transition temperature Tg, which still require our better understanding. To shed a new light on the issues, we measured ILs and their base counterparts using the temperature modulated calorimetry. We performed a comparative analysis of the dynamic heterogeneity at Tg for bases and their salts with a simple monoatomic anion (Cl-). Each pair of ionic and non-ionic liquids is characterized by nearly the same chemical structure but their intermolecular interactions are completely different. We found that the size of the dynamic heterogeneity of ILs near Tg is considerably smaller than that established for their dipolar counterparts. Further results obtained for several other ILs near Tg additionally strengthen the conclusion about the relatively small size of the dynamic heterogeneity of molecular systems dominated by electrostatic interactions. Our finding opens up new perspectives on designing different material properties depending on intermolecular interaction type

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

Isochronal conditions - the key to maintain the given solubility limit, of a small molecule within the polymer matrix, at elevated pressure

In this work, we proposed the method to maintain the desired level of drug’s solubility within the polymer matrix by adjusting conditions to uphold the same molecular dynamics of the system (e.g., temperature for set elevated pressure or vice versa). Namely, we observed, that recrystallization of the drug from the supersaturated drug−polymer system, initiated for the same structural relaxation time of the sample (τα‑1) ceases when certain, different than the initial, molecular mobility of the systems is reached (τα‑2)regardless of a given combination of temperature and pressure conditions. Based on the presented results, one can conclude that the molecular dynamics seem to control the process of recrystallization of the excess amount of solute from the supersaturated solution (e.g., small molecules dissolved within the polymer). Therefore, it appears that the elevated pressure compensates the effect of solubility enhancement caused by the elevated temperature. Such information not only is of fundamental relevance in science but also, from a much broader perspective, could be potentially very useful considering extrusion-based manufacturing methods

New limits of secondary β-relaxation

Glass is an ultraviscous liquid that ceases to flow on a laboratory timescale but continues to relax on a geological timescale. Quintessentially, it has become hopeless for humans to explore the equilibrium behavior of glass, although the technology of glass making witness a remarkable advance. In this work, we propose a novel thermodynamic path to prepare a high density amorphous state of matter (carvedilol dihydrogen phosphate) using high pressure. In addition, we provide the impeccable experimental evidence of heterogeneous nature of secondary β-relaxation and probe its properties to understand the various aspects of pressure densified glass, such as dynamics, packing and disorder. These features are expected to provide new horizons to glass preparation and functional response to pharmaceutical applications

Physical Stability and Viscoelastic Properties of Co-Amorphous Ezetimibe/Simvastatin System

The purpose of this paper is to examine the physical stability as well as viscoelastic properties of the binary amorphous ezetimibe–simvastatin system. According to our knowledge, this is the first time that such an amorphous composition is prepared and investigated. The tendency toward re-crystallization of the amorphous ezetimibe–simvastatin system, at both standard storage and elevated temperature conditions, have been studied by means of X-ray diffraction (XRD). Our investigations have revealed that simvastatin remarkably improves the physical stability of ezetimibe, despite the fact that it works as a plasticizer. Pure amorphous ezetimibe, when stored at room temperature, begins to re-crystallize after 14 days after amorphization. On the other hand, the ezetimibe-simvastatin binary mixture (at the same storage conditions) is physically stable for at least 1 year. However, the devitrification of the binary amorphous composition was observed at elevated temperature conditions (T = 373 K). Therefore, we used a third compound to hinder the re-crystallization. Finally, both the physical stability as well as viscoelastic properties of the ternary systems containing different concentrations of the latter component have been thoroughly investigated

Ternary eutectic ezetimibe-simvastatin-fenofibrate system and the physical stability of Its amorphous form

In this study, the phase diagram of the ternary system of ezetimibe−simvastatin−fenofibrate was established. It has been proven that the ternary composition recommended for the treatment of mixed hyperlipidemia forms a eutectic system. Since eutectic mixtures are characterized by greater solubility and dissolution rate, the obtained result can explain the marvelous medical effectiveness of combined therapy. Considering that another well-known method for improving the aqueous solubility is amorphization, the ternary system with eutectic concentration was converted into an amorphous form. Thermal properties, molecular dynamics, and physical stability of the obtained amorphous system were thoroughly investigated through various experimental techniques compared to both: neat amorphous active pharmaceutical ingredients (considered separately) and other representative concentrations of ternary mixture. The obtained results open up a new way of selecting the therapeutic concentrations for combined therapies, a path that considers one additional variable: eutecticity

Molecular relaxations in supercooled liquid and glassy states of amorphous gambogic acid: Dielectric spectroscopy, calorimetry, and theoretical approach

The relaxation dynamics and thermodynamic properties of supercooled and glassy gambogic acid are investigated using both theory and experiment. We measure the temperature dependence of the relaxation times in three polymorphs (α-, β-, and γ-form). To gain insight into the relaxation processes, we propose a theoretical approach to quantitatively understand the nature of these three relaxations. The α-relaxation captures cooperative motions of molecules, while the β-process is mainly governed by the local dynamics of a single molecule within the cage formed by its nearest neighbors. Based on quantitative agreement between theory and experimental data, our calculations clearly indicate that the β-process is a precursor of the structural relaxation and intramolecular motions are responsible for the γ-relaxation. Moreover, the approach is exploited to study the effects of the heating process on alpha relaxation. We find that the heating rate varies logarithmically with Tg and 1000/Tg . These variations are qualitatively consistent with many prior studies

High-Pressure Dielectric Studies—a Way to Experimentally Determine the Solubility of a Drug in the Polymer Matrix at Low Temperatures

In this work, we employed broad-band dielectric spectroscopy to determine the solubility limits of nimesulide in the Kollidon VA64 matrix at ambient and elevated pressure conditions. Our studies confirmed that the solubility of the drug in the polymer matrix decreases with increasing pressure, and molecular dynamics controls the process of recrystallization of the excess of amorphous nimesulide from the supersaturated drug−polymer solution. More precisely, recrystallization initiated at a certain structural relaxation time of the sample stops when a molecular mobility different from the initial one is reached, regardless of the temperature and pressure conditions. Finally, based on the presented results, one can conclude that by transposing vertically the results obtained at elevated pressures, one can obtain the solubility limit values corresponding to low temperatures. This approach was validated by the comparison of the experimentally determined points with the theoretically obtained values based on the Flory−Huggins theory