Low physical stability is the main reason limiting the widespread use of amorphous pharmaceuticals. One approach to overcome this problem is to mix these drugs with various excipients. In this study ...coamorphous drug–drug compositions of different molar ratios of ezetimib and indapamid (i.e., EZB 10:1 IDP, EZB 5:1 IDP, EZB 2:1 IDP, EZB 1:1 IDP and EZB 1:2 IDP) were prepared and investigated using differential scanning calorimetry (DSC), broadband dielectric spectroscopy (BDS), and X-ray diffraction (XRD). Our studies have shown that the easily recrystallizing ezetimib drug can be significantly stabilized in its amorphous form by using even a small amount of indapamid (8.8 wt %). DSC experiments indicate that the glass transition temperature (T g) of the tested mixtures changes with the drug concentration in accordance with the Gordon–Taylor equation. We also investigated the effect of indapamid on the molecular dynamics of the ezetimib. As a result it was found that, with increasing indapamid content, the molecular mobility of the binary drug–drug system is slowed down. Finally, using the XRD technique we examined the long-term physical stability of the investigated binary systems stored at room temperature. These measurements prove that low-molecular-weight compounds are able to significantly improve the physical stability of amorphous APIs.
In this Letter we report the relation between ionic conductivity and structural relaxation in supercooled protic ionic liquids (PILs) under high pressure. The results of high-pressure dielectric and ...volumetric measurements, combined with rheological and temperature-modulated differential scanning calorimetry experiments, have revealed a fundamental difference between the conducting properties under isothermal and isobaric conditions for three PILs with different charge transport mechanisms (Grotthuss vs vehicle). Our findings indicate a breakdown of the fractional Stokes-Einstein relation and Walden rule when the ionic transport is controlled by fast proton hopping. Consequently, we demonstrate that the studied PILs exhibit significantly higher conductivity than one would expect taking into account that they are in fact a mixture of ionic and neutral species. Thus, the examined herein samples represent a new class of "superionic" materials desired for many advanced applications.
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.
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 γ) 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 (β), 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 ≥ 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 α-relaxation loss peak is the same when comparing dielectric spectra with the same τα 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.
Using broadband dielectric spectroscopy, we investigated the effect of hydrostatic pressure on the conductivity relaxation time τ{σ} of the supercooled protic ionic liquid, procainamide ...hydrochloride, a common pharmaceutical. The pressure dependence of τ{σ} exhibited anomalous behavior in the vicinity of the glass transition T{g}, manifested by abrupt changes in activation volume. This peculiar behavior, paralleling the change in temperature dependence of τ{σ} near T{g}, is a manifestation of the decoupling between electrical conductivity and structural relaxation. Although the latter effectively ceases in the glassy state, free ions retain their mobility but with a reduced sensitivity to thermodynamic changes. This is the first observation of decoupling of ion migration from structural relaxation in a glassy conductor by isothermal densification.
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 (T g = 336 K). Moreover, we found that an only slightly elevated pressure (5 MPa) significantly accelerates the recrystallization process at T > T g. 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 T room = 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.
The purpose of this paper is to investigate the influence of nanoconfinement on the molecular mobility, as well as on the physical stability, of amorphous ezetimibe drug. Two guest/host systems, ...ezetimibe–Aeroperl 300 and ezetimibe–Neusilin US2, were prepared and studied using various experimental techniques, such as X-ray diffraction (XRD), differential scanning calorimetry (DSC), and broadband dielectric spectroscopy (BDS). Our investigation has shown that the molecular mobility of the examined anticholesterol agent incorporated into nanopore matrices strongly depends on the pore size of the host system. Moreover, it was found that the amorphous ezetimibe confined in 30 nm pores of Aeroperl 300 has a tendency to recrystallize, while the drug incorporated into the smaller5 nmpores of Neusilin US2 is not able to crystallize. It has been shown that this significant stabilization of ezetimibe drug can be achieved by an interplay of three factors: changes in molecular dynamics of the confined amorphous drug, the immobilization effect of pore walls on a part of ezetimibe molecules, and the use of host materials with pores that are smaller than the critical size of the drug crystal nuclei.
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 polymerpolyvinylpyrrolidone (PVP K30)and the small molecular weight excipientoctaacetylmaltose (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 < T g). In contrast, PVP K30 is a better crystallization inhibitor of CEL than acMAL in the supercooled liquid state (at T > T g). We discuss molecular factors governing the recrystallization of amorphous CEL in examined solid dispersions.
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 T g during the experimental period of its storage (i.e., above 6 months), however, it easily undergoes cold crystallization at T > T g. 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 < T g 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.
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•A comprehensive study on self-aggregation of monohydroxy alcohols (MAs).•Impact of phenyl and cyclohexyl ring on the aggregation of MAs.•Aromaticity affects the self-assembling of ...MAs.•Phenyl ring introduces more heterogeneity in the organization of molecules than the cyclic one.
In this paper, the steric hindrance effect related to the presence of either a cyclic or aromatic ring on the self-association process in the series of monohydroxy alcohols (MAs), from cyclohexanemethanol to 4-cyclohexyl-1-butanol and from benzyl alcohol to 4-phenyl-1-butanol, was studied using X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Broadband Dielectric Spectroscopy (BDS) and the Pendant Drop (PD) methods. Based on FTIR results, it was shown that phenyl alcohol (PhA) and cyclohexyl alcohol (CA) derivatives reveal substantial differences in the association degree, the activation energy of dissociation, and the homogeneity of supramolecular nanoassociates suggesting that the phenyl ring exerts a stronger steric impact on the self-assembling of molecules than cyclohexyl one. Additionally, XRD data revealed that phenyl moiety introduces more heterogeneity in the organization of molecules compared to the cyclic one. The changes in the self-association process of alcohols were also reflected in differences in the molecular dynamics of the H-bonded aggregates, as well as in the Kirkwood factor, defining the long-range correlation between dipoles, which were slightly higher for CAs with respect to those determined for PhAs. Unexpectedly it was also found that the surface layers of PhAs were more organized than those formed by CAs. Thus, these findings provided insight into the impact of aromaticity on the self–assembly process, H-bonding pattern, supramolecular structure, and intermolecular dynamics of the studied alcohols.
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