L. Hawelek

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.

Dielectric Relaxation and Crystallization Kinetics of Ibuprofen at Ambient and Elevated Pressure

Dielectric spectroscopy (DS) was used to investigate the relaxation dynamics of supercooled and glassy ibuprofen at various isobaric and isothermal conditions (pressure up to 1750 MPa). The ambient pressure data are in good agreement with that reported previously in the literature. Our high pressure measurements revealed validity of temperature-pressure superpositioning (TPS) for the alpha-peak. We also found that the value of the fragility index decreases with compression from m = 87 +/- 2 at atmospheric pressure to m = 72.5 +/- 3.5 at high pressure (p = 920 MPa). The drop of fragility observed in our experiment was discussed in the framework of the two-order-parameter (TOP) model. In addition, we have also studied crystallization kinetics in a liquid state of examined drug at ambient and high pressure. We found out that, for the same structural relaxation time/same viscosities, the samples prepared by compression of liquid at high temperatures have significantly elongated induction times as well as overall crystallization times (sample 2: t(0) approximately = 4 h, t(1/2) approximately = 37.5 h; sample 3: t(0) approximately = 5.6 h, t(1/2) approximately = 49 h) compared to that held at lower temperature and ambient pressure (sample 1: t(0) approximately = 1.2 h, t(1/2) approximately = 12.2 h). A possible explanation of this finding is also given.

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.

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.

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27μg/ml) over 24h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low Tg (113°C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8MPa(0.5)) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.

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.

Physical Stability of the Amorphous Anticholesterol Agent (Ezetimibe): The Role of Molecular Mobility

The purpose of this paper is to examine the role of molecular mobility in the recrystallization process from the amorphous state of the anticholesterol drug ezetimibe. Both the molecular dynamics and crystallization kinetics have been studied using various experimental techniques, such as broadband dielectric spectroscopy (BDS), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Our investigations have shown that ezetimibe easily recrystallizes from the disordered state, both below and above its glass transition temperature (Tg = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > Tg. We predict that the structural relaxation time of amorphous ezetimibe at 293 K (storage temperature) and ambient pressure is only 22 days. This result corresponds to the characteristic time, determined from XRD measurements, for amorphous ezetimibe to recrystallize during storage at Troom = 298 K. It leads to the conclusion that the molecular mobility reflected in structural relaxation of ezetimibe is mainly responsible for devitrification of this drug. Finally, we determined a relatively easy way to improve the physical stability of the drug by preparing a binary amorphous ezetimibe-Soluplus mixture. Ezetimibe in an amorphous mixture with 20 wt % Soluplus has a much better (over six times) solubility than the pure crystalline material.

Molecular dynamics, physical stability and solubility advantage from amorphous indapamide drug.

This study for the first time investigates physicochemical properties of amorphous indapamide drug (IND), which is a known diuretic agent commonly used in the treatment of hypertension. The solid-state properties of the vitrified, cryomilled and ball-milled IND samples were analyzed using X-ray powder diffraction (XRD), mass spectrometry, nuclear magnetic resonance (NMR), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and broadband dielectric spectroscopy (BDS). These analytical techniques enabled us (i) to confirm the purity of obtained amorphous samples, (ii) to describe the molecular mobility of IND in the liquid and glassy state, (iii) to determine the parameters describing the liquid-glass transition i.e. Tg and dynamic fragility, (iv) to test the chemical stability of amorphous IND in various temperature conditions and finally (v) to confirm the long-term physical stability of the amorphous samples. These studies were supplemented by density functional theory (DFT) calculations and apparent solubility studies of the amorphous IND in 0.1 M HCl, phosphate buffer (pH=6.8), and water (25 and 37 °C).