Broadband-dielectric-spectroscopy study of molecular dynamics in a mixture of itraconazole and glycerol in glassy, smectic-A, and isotropic phases.

Itraconazole (ITZ) is a thermotropic liquid crystal that exhibits isotropic, nematic, and smectic phases on cooling towards the glass transition upon melting. Over the years, new aspects regarding the liquid-crystalline ordering of this antifungal drug were systematically revealed. It has been shown recently that the temperature range of individual mesophases in ITZ can be modified by adding a small amount of glycerol (GLY). Moreover, above the critical concentration of 5% w/w, a smectic to nematic transition can be avoided. Here we go one step further, and we used broadband dielectric spectroscopy to investigate the new phase behavior of the ITZ-GLY mixture (5% w/w). To confirm the phase transformations of the ITZ-GLY mixture, differential scanning calorimetry was also employed. The analysis of molecular dynamics of the ITZ-GLY mixture in the glassy and isotropic phases revealed features similar to those observed for neat ITZ. Two relaxation processes were identified in the smectic-A phase, with similar temperature dependence, most likely related to the fast rotations around the long axis of a molecule. Additionally, the derivative analysis revealed another low-frequency process hidden under DC conductivity ascribed to the slow rotations about a short axis. We will show that the differences in the molecular organization in the smectic-A and isotropic phases leave a clear fingerprint on the temperature behavior of relaxation times and other dielectric parameters, such as DC conductivity and dielectric strength, for which a pretransition effect has been detected.

How does the high pressure affects the solubility of the drug within the polymer matrix in solid dispersion systems.

In this paper, we employed Broadband Dielectric Spectroscopy (BDS) in order to determine the effect of the high pressure on the solubility limits of the amorphous flutamide within Kollidon VA64 matrix. In order to achieve this goal, drug-polymer systems have been examined: (i) at ambient pressure and both isothermal and nonisothermal conditions by means of BDS as well as Differential Scanning Calorimetry (DSC), to validate proposed method; (ii) at high pressure conditions (20 and 50 MPa) and elevated temperatures (343 K, 353 K and 363 K) by means of dielectric spectroscopy. Our studies revealed that regardless of applied pressure the solubility of the flutamide within the co-polymer matrix increases with increasing temperature at isobar conditions. Moreover, our results clearly indicate that with increasing pressure the solubility of the drug within the polymer matrix is decreasing at isothermal conditions. Therefore, during the solubility limit studies one should consider the situation in which by increasing the pressure (at constant temperature) would achieve an effect similar to the lowering of the temperature (at constant pressure).

Effect of electrostatic interactions on the relaxation dynamics of pharmaceutical eutectics.

In this paper, we investigate the temperature-dependent relaxation dynamics in the glassy and supercooled liquid state of dipolar and ionic eutectic mixtures made of two anesthetic agents (lidocaine and prilocaine) and their hydrochloride salts, respectively. In addition to eutectic phases containing 1:1 and 4:1 mol/mol of LD/PRL and LD-HCl/PRL-HCl, respectively, the relaxation properties of non-eutectic compositions and parent compounds are also studied. We found that electrostatic long-range forces determine strongly the dielectric and mechanical response of eutectic material. As a result of Coulomb interactions between ion pairs, an additional ß-relaxation mode was found in the dielectric spectra of glassy LD-HCl/PRL-HCl mixtures. On the other hand, the studies of relaxation dynamics of ionic and non-ionic mixtures at T > Tg revealed a continuous decrease of both fragility mP and the length scale of dynamic heterogeneity NαB(Tg), with simultaneous growth of Tg, when the electrostatics forces appear. At the same time, we found the charge transport being decoupled from structural dynamics in all studied ionic binary mixtures that is due to the fast proton hopping. However, the efficiency of proton transport is dropping down with an increase of Tg.

Broadband dielectric spectroscopy as an experimental alternative to calorimetric determination of the solubility of drugs into polymer matrix: Case of flutamide and various polymeric matrixes.

In this paper we determined the solubility limits of the amorphous flutamide within the two different polymeric matrixes - poly vinylpyrrolidone and poly vinylacetate. In order to achieve this goal, series of broadband dielectric spectroscopy measurements were performed. As a result we found that the maximal amount of the drug that can be successfully dissolved within the PVAc (maintaining the non-supersaturated conditions) is equal to 35 wt% of the amorphous solid dispersion system. Interestingly enough similar results, in terms of solubility limits, were achieved utilizing significantly higher amount of the pharmaceutical - 71 wt% - in the PVP matrix. Accordingly, we established the following relationship in the solubility limits of the amorphous flutamide dispersed within examined polymer matrixes: PVP > PVAc. It is worth highlighting that in order to preserve the thermodynamic stability - one of the two contributors to the physical stability - drug loading in the amorphous solid dispersion system should not exceed its solubility limits. Hence, choosing appropriate amount of the polymer addition will determine if obtained system remains physically stable. Subsequently, we presented the "stability maps" for all investigated FL-based ASD systems from which one might predict the stabilization effect exerted by certain amount of polymer.

The effect of electrostatic interactions on the formation of pharmaceutical eutectics.

Over the past decade, the formation of pharmaceutical eutectics has become a very attractive strategy to increase the bioavailability of active pharmaceutical ingredients (APIs). A great advantage of a eutectic phase, which can be obtained by simple physical mixing of solid materials, is the possibility to obtain a material with desired physicochemical properties only by varying the molar ratio of the parent components. In this work, we have investigated the ability of two protic ionic liquids (PILs), which are hydrochloride salts of lidocaine and prilocaine, as well as their non-ionic counterparts, to form eutectic mixtures. To gain an insight into the calorimetric properties of the formed dipolar and ionic mixtures, differential scanning calorimetry was employed. The mechanism of formation of deep eutectic mixtures on the molecular level was investigated by ab initio quantum mechanics calculations. The effect of electrostatic interactions on the eutectic transition, glass forming ability and the physical stability of pharmaceutical eutectics was also revealed.

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.

Experimental evidence of high pressure decoupling between charge transport and structural dynamics in a protic ionic glass-former.

In this paper the relaxation dynamics of ionic glass-former acebutolol hydrochloride (ACB-HCl) is studied as a function of temperature and pressure by using dynamic light scattering and broadband dielectric spectroscopy. These unique experimental data provide the first direct evidence that the decoupling between the charge transport and structural relaxation exists in proton conductors over a wide T-P thermodynamic space, with the time scale of structural relaxation being constant at the liquid-glass transition (τα = 1000 s). We demonstrate that the enhanced proton transport, being a combination of intermolecular H+ hopping between cation and anion as well as tautomerization process within amide moiety of ACB molecule, results in a breakdown of the Stokes-Einstein relation at ambient and elevated pressure with the fractional exponent k being pressure dependent. The dT g /dP coefficient, stretching exponent ßKWW and dynamic modulus E a /ΔV # were found to be the same regardless of the relaxation processes studied. This is in contrast to the apparent activation volume parameter that is different when charge transport and structural dynamics are considered. These experimental results together with theoretical considerations create new ideas to design efficient proton conductors for potential electrochemical applications.

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.

How is charge transport different in ionic liquids? The effect of high pressure.

Modern ionic liquids (ILs) are considered green solvents for the future applications due to their inherited advantages and remarkable transport properties. One of the ubiquitous properties of ILs is their intrinsic ionic conductivity. However, understanding of the super-Arrhenius behavior of the ionic conductivity process at elevated pressure still remains elusive and crucial in glass science. In this work, we investigate the ion transport properties of 1-butyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide: [C4mim][NTf2], 1-butylimidazolium bis[(trifluoromethyl)-sulfonyl]imide: [C4Him][NTf2] and 1-butylimidazolium hydrogen sulfate: [C4Him][HSO4] ILs in the supercooled liquid state using dielectric spectroscopy at ambient and high pressure. We present the experimental data in the dynamic window of the conductivity formalism to examine the charge transport properties. The frequency-dependent ionic conductivity data have been analyzed using the time-temperature superposition principle. In the Arrhenius diagram, the thermal evolution of the dc-conductivity reveals similar temperature dependence for both protic and aprotic ILs thus making it difficult to distinguish the ion dynamics. However, our results demonstrate the key role of high pressure that unambiguously separates the charge transport properties of protic ILs from aprotic ones through the apparent activation volume parameter. We also highlight that the activation volume can be employed to assess the information connecting the ability of ionic systems to form H-bond networks and the impact of proton transfer involved in the conduction process.

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.