P. Wlodarczyk

Broadband Dielectric Relaxation Study at Ambient and Elevated Pressure of Molecular Dynamics of Pharmaceutical: Indomethacin

Broadband dielectric measurements on the pharmaceutical indomethacin (IMC) were performed at ambient and elevated pressure. Data on molecular dynamics collected at ambient pressure are in good agreement with that published in the literature. In the glassy state, there is a well-resolved secondary relaxation with Arrhenius activation energy E(a) = 38 kJ/mol. This commonly observed relaxation process (labeled gamma) is of intramolecular origin because it is pressure-insensitive. Closer analysis of the ambient pressure dielectric spectra obtained in the vicinity of the T(g) indicated the presence of one more secondary relaxation (beta), which is slower than that commonly observed. Application of the CM predictions enabled us to classify it as a true JG relaxation. Pressure measurements confirmed our supposition concerning the origins of the two secondary relaxations in IMC. Moreover, we have found that IMC under pressure does not crystallize, even at very high temperatures of T > or = 372 K. This finding was discussed in the framework of the two-order parameter model proposed by Tanaka (Konishi, T.; Tanaka, H. Phys. Rev B 2007, 76, 220201), as well as the JG relaxation proposal by Oguni (Hikima T.; Hanaya M.; Oguni M. J. Mol Struct. 1999, 479, 245). We also showed that the shape of the alpha-relaxation loss peak is the same when comparing dielectric spectra with the same tau(alpha) but obtained at ambient and elevated pressure. Additionally, we found out that the fragility of IMC decreases with increasing pressure. In addition, the pressure coefficient of the glass transition temperature, dT(g)/dP, was determined, and it is 255 K/GPa. Finally, we discuss the possibility of preparation of the amorphous state with higher density than by cooling of the liquid.

Study of molecular dynamics of pharmaceutically important protic ionic liquid-verapamil hydrochloride. I. Test of thermodynamic scaling

Relaxation dynamics of verapamil hydrochloride (VH), which is a representative of ionic liquids, was studied under isobaric and isothermal conditions by using dielectric spectroscopy. In addition we also carried out pressure-temperature-volume (PVT) measurements. The obtained data enable us to examine the structural α-relaxation time τα as a function of temperature, pressure, and volume. Since the examined sample is a typical ionically conducting material, we employed the dielectric modulus formalism to gain information about α-relaxation process. It was found that application of pressure changes the shape of the modulus spectrum. The α-peak becomes narrower with compression. Consequently, it was also shown that the stretching parameter βKWW increases with pressure. Based on experimental data both the isobaric fragility (mp) at various pressures and isothermal fragility (mT) at various temperatures were calculated. Analyzing the effect of pressure on the dependences τα(T) as well as on the shape parameter...

Dielectric relaxation studies and dissolution behavior of amorphous verapamil hydrochloride

Verapamil hydrochloride (VH) is a very popular calcium channel blocker. Solubility of its crystalline form in the blood reaches only 10-20%. Thus, it seems to be very important to improve its bioavailability. In this article, we show that the preparation of the amorphous form of VH enhance its dissolution rate. In addition we performed dielectric measurements to describe molecular dynamics of this active pharmaceutical ingredient (API). Since examined sample is typical ionically conducting material, to gain information about structural relaxation we employed the dielectric modulus formalism. The temperature dependence of the structural relaxation time can be described over the entire measured range by a single Vogel-Fulcher-Tamman (VFT) equation. From the VFT fits the glass transition temperature was estimated as T(g) = 320.1 K. Below glass transition temperature one clearly visible secondary relaxation, with activation energy E(a) = 37.8 kJ/mol, was reported. Deviations of experimental data from KWW fits on high-frequency flank of alpha-peak indicate the presence of an excess wing in tested sample. Based on Kia Ngais coupling model we identified the excess wing as true Johari-Goldstein process.

Dielectric studies on mobility of the glycosidic linkage in seven disaccharides.

Isobaric dielectric relaxation measurements were performed on seven chosen disaccharides. For five of them, i.e., sucrose, maltose, trehalose, lactulose, and leucrose, we were able to observe the temperature evolution of the structural relaxation process. In the case of the other disaccharides studied (lactose and cellobiose), it was impossible to obtain such information because of the large contribution of the dc conductivity and polarization of the capacitor plates to the imaginary and real part of the complex permittivity, respectively. On the other hand, in the glassy state, two secondary relaxations have been identified in the dielectric spectra of all investigated carbohydrates. The faster one (gamma) is a common characteristic feature of the entire sugar family (mono-, di-, oligo-, and polysaccharide). The molecular origin of this process is still not unambiguously identified but is expected to involve intramolecular degrees of freedom as inferred from insensitivity of its relaxation time to pressure found in some monosaccharides (fructose and ribose). The slower one (labeled beta) was recently identified to be intermolecular in origin (i.e., a Johari-Goldstein (JG) beta-relaxation), involving twisting motion of the monosugar rings around the glycosidic bond. The activation energies and dielectric strengths for the beta-relaxation determined herein provide us valuable information about the flexibility of the glycosidic bond and the mobility of this particular linkage in the disaccharides studied. In turn, this information is essential for the control of the diffusivity of drugs or water entrapped in the sugar matrix.

Molecular mobility in liquid and glassy states of Telmisartan (TEL) studied by Broadband Dielectric Spectroscopy

The molecular relaxation in liquid and glassy states of Telmisartan (TEL) has been studied by Broadband Dielectric Spectroscopy (BDS) covering wide temperature and frequency range. Multiple relaxation processes were observed. Besides the primary alpha-relaxation, two secondary relaxations beta and gamma (labelled in order of decreasing time scale) have been reported. Well-separated beta-process observed above and below glass transition temperature T(g), has activation energy E(beta)=81.8 kJ/mol and was identified as intermolecular Johari-Goldstein (JG) process. The gamma-relaxation visible in dielectric loss spectra at very low temperatures is most likely non-JG relaxation. The temperature dependence of the relaxation times of alpha-process, measured over 11 orders of magnitude, cannot be described by a single Vogel-Fulcher-Tamman-Hesse (VFTH) equation. At temperature T(B)=475.8K the change in relaxation dynamics occurred, consequently a new set of VFTH parameters was required. From low temperature VFTH fits the glass transition temperature T(g) was estimated as T(g)=400.3 K and fragility index m=87 was calculated. Of particular interest was the time scale of molecular motion below the glass transition temperature. Our observation clearly indicates that the alpha-relaxation times at room temperature most probably would exceed 3 years and amorphous TEL should maintain physically and chemically stable over prolonged storage time.

Enhancement of amorphous celecoxib stability by mixing it with octaacetylmaltose: the molecular dynamics study.

In this paper, we present a novel way of stabilization of amorphous celecoxib (CEL) against recrystallization by preparing binary amorphous celecoxib-octaacetylmaltose (CEL-acMAL) systems by quench-cooling of the molten phase. As far as we know this is the first application of carbohydrate derivatives with acetate groups to enhance the stability of an amorphous drug. We found that CEL in the amorphous mixture with acMAL is characterized by a much better solubility than pure CEL. We report very promising results of the long-term measurements of stability of the CEL-acMAL binary amorphous system with small amount of stabilizer during its storage at room temperature. Moreover, we examined the effect of adding acMAL on molecular dynamics of CEL in the wide temperature range in both the supercooled liquid and glassy states. We found that the molecular mobility of the mixture of CEL with 10 wt % acMAL in the glassy state is much more limited than that in the case of pure CEL, which correlates with the better stability of the amorphous binary system. By dielectric measurements and theoretical calculations within the framework of density functional theory (DFT), we studied the role of acMAL in enhancing the stability of amorphous CEL in mixtures and postulated which interactions between CEL and acMAL molecules can be responsible for preventing devitrification.

On the kinetics of tautomerism in drugs: New application of broadband dielectric spectroscopy

There are a number of chemical compounds that readily convert to other isomers when their crystalline structure is lost (e.g., during melting or dissolution). This phenomenon, commonly known as tautomerism, is a subject of intense research. It is an important problem especially in pharmaceutical industry because various isomers of a drug may have different pharmacological activity. Therefore, it is important to find appropriate experimental technique which enables the determination of the isomerization ability of compounds. In this communication, we demonstrate that broadband dielectric spectroscopy (BDS) method has the potential of detection and monitoring of tautomerism of drugs. To investigate the tautomerism phenomenon we have chosen one of the hypoglycemic agents that belong to the class II of sulfonylurea drugs. Based on density functional theory (DFT) calculations we have analyzed two possible tautomerization pathways of glibenclamide. By using BDS as a tool, we show it can detect the conversion between the isomeric forms through time dependence in the dielectric properties. The activation energy (E(a)) of this process is in good agreement with that obtained from DFT analysis. Finally, we discuss the possible effects of tautomerism on basic pharmaceutical parameters such as biological activity or bioavailability in the case of the glibenclamide drug.

Identification of the Molecular Motions Responsible for the Slower Secondary (β) Relaxation in Sucrose

Broad-band isothermal dielectric relaxation measurements of anhydrous sucrose were made at ambient pressure in its liquid and glassy states. We found a new secondary relaxation that is slower than the one commonly observed in sugars. Additionally, we carried out the dielectric measurements of the equimolar mixture of D-glucose and D-fructose in wide ranges of temperature and frequency. Comparison of the behavior of these two systems allowed us to make suggestions on the origin of the slower beta-relaxation in sucrose. Computer simulations and coupling model calculations were performed to support our interpretation of the kind of molecular motions responsible for the slower secondary relaxation in the disaccharide considered.

Identifying the Origins of Two Secondary Relaxations in Polysaccharides

The main goal of this paper is to identify the molecular origins of two secondary relaxations observed in mechanical as well as in dielectric spectra in polysaccharides, including cellulose, and starches, such as pullulan and dextran. This issue has been actively pursued by many research groups, but consensus has not been reached. By comparing experimental data of monosaccharides, disaccharides, and polysaccharides, we are able to make conclusions on the origins of two secondary relaxations in polysaccharides. The faster secondary relaxations of polysaccharides are similar to the faster secondary relaxations of mono-, di-, and oligosaccharides. These include comparable relaxation times and activation energies in the glassy states, and also all the faster secondary relaxations have larger dielectric strengths than the slower secondary relaxation. The similarities indicate that the faster secondary relaxations in the polysaccharides have the same origin as that in mono-, di-, and oligosaccharides. Furthermore, since the relaxation time of the faster secondary relaxation in several mono- and disaccharides was found to be insensitive to applied pressure, the faster secondary relaxations of the polysaccharides are identified as internal motions within their monomeric units. The slower secondary relaxations in polysaccharides also have similar characteristics to those of the slower secondary relaxations of the disaccharides (maltose, cellobiose, sucrose, and trehalose), which indicates the analogous motions govern the slower process in these two groups of carbohydrates. Earlier we have shown in disaccharides that the rotation of the monomeric units around the glycosidic bond is responsible for this process. The same motion can occur in polysaccharides in the form of a local chain rotation. These motions involve the whole molecule in disaccharides and a local segment in polysaccharides. It is intermolecular in nature (with relaxation time pressure dependent, as found before in a disaccharide), and hence, it is the precursor of the structural alpha-relaxation. These results lead us to identify the slower secondary relaxation of the polysaccharides as the Johari-Goldstein beta-relaxation, which is supposedly a universal and fundamental process in all glass-forming substances.

Dielectric Relaxation Study on Tramadol Monohydrate and Its Hydrochloride Salt

Dielectric relaxation measurements as well as differential scanning calorimetry and X-ray diffraction investigations were performed on tramadol monohydrate and its hydrochloride salt. Examined samples do not crystallize during cooling and in consequence they reach the glassy state. In the case of the hydrochloride tramadol we are able to monitor alpha-relaxation process despite large contribution of dc conductivity to the loss spectra. It is the first such study on the salt of the drug. Up to now the dielectric spectroscopy has been regarded as useless in measuring such kind of API (active pharmaceutical ingredient). In this paper we also made some suggestions about the nature of the secondary relaxations in the amorphous tramadol monohydrate and its salt. The knowledge about the molecular mechanisms, which govern the observed secondary relaxations seems to be the key in predicting the stability of the amorphous form of the examined API. Finally additional dissolving measurements on the amorphous and crystal tramadol hydrochloride were performed. As a result we understood that dissolution properties of the amorphous form of the considered drug are comparable to those of crystalline one. However, we have found out that amorphous tramadol hydrochloride has greater ability to form tablets than its crystalline equivalent. This finding shows that amorphous drugs can be alternative even for the freely solved pharmaceuticals such as tramadol hydrochloride, because the former one has better ability to form tablets. It implies that during tabletting of the amorphous drugs there is no need to use any excipients and chemicals improving compaction properties of the API.