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.

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.

Glibenclamide (GCM) is an oral hypoglycemic agent of the sulfonylurea group used in the treatment of non-insulin-dependent diabetes. Crystalline GCM is characterized by low bioavailability, which is attributed to its poor dissolution properties. It prompted us to prepare this drug in its amorphous form as a means to enhance its dissolution characteristics. Two different methods were used to convert crystalline GCM into the glassy form: quench-cooling of the melt and cryogenic milling. To monitor solid-state properties of the amorphous samples, X-ray powder diffraction (XRD), infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), ultraperformance liquid chromatography (UPLC) and spectroscopy, and broadband dielectric spectroscopy (BDS) were applied. The results of UPLC separations along with associated infrared and NMR measurements unambiguously showed that the thermal degradation of the quenched GCM, as suggested in literature reports, does not occur. A similar analysis performed on the cryomilled material also did not indicate any chemical decomposition. On the other hand, both methods confirmed that the conversion to the amorphous form is connected with the amide-imidic acid tautomerism of the examined drug. Moreover it was shown that this transformation occurs regardless of the manner of amorphization. Finally, dielectric spectroscopy was employed to study the molecular dynamics of vitrified GCM. The analysis of the ε''(f) in terms of the KWW function from the dielectric measurements revealed the existence of an "excess wing" attributed to the true Johari-Goldstein process based on Ngai's coupling model. The dielectric properties of GCM obtained in the amorphous form both by rapid cooling of the melt and the cryogenic grinding of crystalline sample were also compared.

Purpose To investigate the effect of cryogrinding on chemical stability of the diuretic agent furosemide and its mixtures with selected excipients. Methods Furosemide was ground at liquid nitrogen temperature for 30, 60, 120 and 180 min. Mixtures of furosemide-PVP and furosemide-inulin (1:1) were milled under cryogenic conditions. Materials were analyzed by XRD, UPLC, MS and NMR.

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.

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).

The aim of this article is to examine the crystallization tendencies of three chemically related amorphous anti-inflammatory agents, etoricoxib, celecoxib, and rofecoxib. Since the molecular mobility is considered as one of the factors affecting the crystallization behavior of a given material, broadband dielectric spectroscopy was used to gain insight into the molecular dynamics of the selected active pharmaceutical ingredients. Interestingly, our experiments did not reveal any significant differences in their relaxation behavior either in the supercooled liquid or in the glassy state. Hence, as a possible explanation for the enhanced physical stability of etoricoxib, its ability to undergo a tautomerization reaction was recognized. The occurrence of intramolecular proton transfer in the disordered etoricoxib was proven experimentally by time-dependent dielectric and infrared (IR) measurements. Additionally, IR spectroscopy combined with density functional theory calculations pointed out that in the etoricoxib drug, being in fact a binary mixture of tautomers, the individual isomers may interact with each other through a hydrogen bonding network. A possible explanation of this issue was achieved by performing dielectric experiments at elevated pressure. Since compression results in etoricoxib recrystallization, the possible influence of pressure on the observed stabilization effect is also carefully discussed.

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.