K. Grzybowska

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.

Molecular Dynamics and Physical Stability of Amorphous Anti-Inflammatory Drug: Celecoxib

By using dielectric spectroscopy we analyzed the relation between molecular mobility and tendency of the amorphous celecoxib to recrystallize. We found that celecoxib is kinetically a fragile glassformer, contrary to the conclusion reached by others from thermodynamic fragility. The possible correlation of the large tendency of celecoxib to crystallize with various molecular motions have been investigated. Our study shows that the structural relaxation seems to be responsible for devitrification of celecoxib if stored at room temperature ∼293 K. Notwithstanding, the crystallization can be considered to ultimately be affected by the β-process (JG-relaxation) because it is the precursor of the structural α-relaxation.

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...

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.

Molecular Dynamics Studies on the Water Mixtures of Pharmaceutically Important Ionic Liquid Lidocaine HCl

In this paper the molecular dynamics of a common local-anesthetic drug, lidocaine hydrochloride (LD-HCl), and its water mixtures were investigated. By means of broadband dielectric spectroscopy and calorimetric measurements it was shown that even a small addition of water causes a significant effect on the relaxation dynamics of analyzed protic ionic liquid. Apart from the two well-resolved relaxations (σ- and γ-processes) and the β-mode, identified as the JG-process, observed for anhydrous LD-HCl, a new relaxation peak (υ) is visible in the dielectric spectra of aqueous mixtures of this drug. Additionally, the significant effect of the water on the glass transition temperature of LD-HCl was found. The sample characterized with mole fraction of water X(w) = 0.44 reveals the glass transition temperature T(g), 42 K lower than that of anhydrous material (307 K). Finally, it was shown that by amorphization of the hydrochloride salt of lidocaine it is possible to obtain its room temperature ionic liquid form.

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.

Quantifying the Structural Dynamics of Pharmaceuticals in the Glassy State

Structural dynamics in the glassy state of two protic ionic liquids, carvedilol phosphate and procaine hydrochloride, were characterized from analysis of changes in the conductivity relaxation times during physical aging. The obtained relaxation times, having a magnitude exceeding feasible experimental time scales and thus not directly measurable, are consistent with published data from a method that relies on the presence of a secondary relaxation. We also observe a narrowing of the relaxation dispersion, specific to higher frequencies, that is a consequence of the heterogeneous dynamics of deeply supercooled materials.

Relaxation Dynamics and Crystallization Study of Sildenafil in the Liquid and Glassy States

In this paper, the physical stability and molecular dynamics of amorphous sildenafil are investigated in both the liquid and glassy states. We have established that the amorphous sildenafil is resistant to recrystallization at temperatures below the glass transition temperature Tg during the experimental period of its storage (i.e., above 6 months), however, it easily undergoes cold crystallization at T > Tg. To determine the crystallization mechanism, the isothermal and non-isothermal studies of the cold crystallization kinetics of the drug are performed by using the broadband dielectric spectroscopy (BDS) and the differential scanning calorimetry (DSC), respectively. The cold crystallization mechanism has been found to be similar in both the isothermal and non-isothermal cases. This mechanism has been analyzed from the point of view of the molecular mobility of sildenafil investigated in the supercooled liquid and glassy states by using the BDS measurements in the wide temperature range. This analysis has been enriched with a new approach based on a recently reported measure of dynamic heterogeneity given by a four-point dynamic susceptibility function. No tendency to recrystallization of glassy sildenafil at T < Tg is also discussed in relation to molecular dynamics of sildenafil in the glassy state. The relatively small molecular mobility reflected in one secondary relaxation as well as the predicted large time scale of structural relaxation of glassy sildenafil suggests that amorphous sildenafil should not recrystallize during its long-term storage at room temperature.

Decoupling of conductivity relaxation from structural relaxation in protic ionic liquids and general properties

The main focus of this work is the study of conductivity relaxation of amorphous lidocaine hemisuccinate near the glass transition at ambient pressure. Measurements have been made using broadband dielectric spectroscopy (BDS) and temperature-modulated differential scanning calorimetry. Our study shows that the ion conductivity relaxation becomes increasingly faster than the structural relaxation as the glass transition temperature Tg is approached. At Tg the structural relaxation time is longer than the conductivity relaxation times by three decades, i.e. the decoupling index Rτ is about 3. Decoupling is accompanied by the ion conductivity relaxation which narrows in its frequency dispersion with decreasing temperature. This abnormal behavior is identical to that found in two other protic ionic liquids (PILs), procaine HCl and procainamide HCl. Considering that the phenomenon has been found before in several inorganic ionic glass-formers and now in three protic ionic liquids, it could be a general property of ionically conducting glass-forming substances, although more cases have to be studied before a definitive conclusion can be made. We show that it can be rationalized within the framework of the Coupling Model.

The influence of amorphization methods on the apparent solubility and dissolution rate of tadalafil.

This study for the first time investigates the solubility and dissolution rate of amorphous tadalafil (Td)--a poorly water soluble chemical compound which is commonly used for treating the erectile dysfunction. To convert the crystalline form of Td drug to its amorphous counterpart we have employed most of the commercially available amorphization techniques i.e. vitrification, cryogenic grinding, ball milling, spray drying, freeze drying and antisolvent precipitation. Among the mentioned methods only quenched cooling of the molten sample was found to be an inappropriate method of Td amorphization. This is due to the thermal decomposition of Td above 200°C, as proved by the thermogravimetric analysis (TGA). Disordered character of all examined samples was confirmed using differential scanning calorimetry (DSC) and X-ray powder diffraction (PXRD). In the case of most amorphous powders, the largest 3-fold increase of apparent solubility was observed after 5 min, indicating their fast recrystallization in water. On the other hand, the partially amorphous precipitate of Td and hypromellose enhanced the solubility of Td approximately 14 times, as compared with a crystalline substance, which remained constant for half an hour. Finally, disk intrinsic dissolution rate (DIDR) of amorphous forms of Td was also examined.