Dielectric Spectroscopy Studies of Conformational Relaxation Dynamics in Molecular Glass-Forming Liquids.

We review experimental results obtained with broadband dielectric spectroscopy concerning the relaxation times and activation energies of intramolecular conformational relaxation processes in small-molecule glass-formers. Such processes are due to the interconversion between different conformers of relatively flexible molecules, and generally involve conformational changes of flexible chain or ring moieties, or else the rigid rotation of planar groups, such as conjugated phenyl rings. Comparative analysis of molecules possessing the same (type of) functional group is carried out in order to test the possibility of assigning the dynamic conformational isomerism of given families of organic compounds to the motion of specific molecular subunits. These range from terminal halomethyl and acetyl/acetoxy groups to both rigid and flexible ring structures, such as the planar halobenzene cycles or the buckled saccharide and diazepine rings. A short section on polyesters provides a generalisation of these findings to synthetic macromolecules.

Amorphous solid dispersions of curcumin in a poly(ester amide): Antiplasticizing effect on the glass transition and macromolecular relaxation dynamics, and controlled release.

In order to exploit the pharmacological potential of natural bioactive molecules with low water solubility, such as curcumin, it is necessary to develop formulations, such as amorphous polymer dispersions, which allow a constant release rate and at the same time avoid possible toxicity effects of the crystalline form of the molecule under scrutiny. In this study, polymer dispersions of curcumin were obtained in PADAS, a biodegradable semicrystalline copolymer based on 1,12-dodecanediol, sebacic acid and alanine. The dispersions were fully characterized by means of differential scanning calorimetry and broadband dielectric spectroscopy, and the drug release profile was measured in a simulated body fluid. Amorphous homogeneous binary dispersions were obtained for curcumin mass fraction between 30 and 50%. Curcumin has significantly higher glass transition temperature Tg (≈ 347 K) than the polymer matrix (≈274-277 K depending on the molecular weight), and dispersions displayed Tg's intermediate between those of the pure amorphous components, implying that curcumin acts as an effective antiplasticizer for PADAS. Dielectric spectroscopy was employed to assess the relaxation dynamics of the binary dispersion with 30 wt% curcumin, as well as that of each (amorphous) component separately. The binary dispersion was characterized by a single structural relaxation, a single Johari-Goldstein process, and two local intramolecular processes, one for each component. Interestingly, the latter processes scaled with the Tg of the sample, indicating that they are viscosity-sensitive. In addition, both the pristine polymer and the dispersion exhibited an interfacial Maxwell-Wagner relaxation, likely due to spatial heterogeneities associated with phase disproportionation in this polymer. The release of curcumin from the dispersion in a simulated body fluid followed a Fickian diffusion profile, and 51% of the initial curcumin content was released in 48 h.

Eutectic Mixture Formation and Relaxation Dynamics of Coamorphous Mixtures of Two Benzodiazepine Drugs.

The formation of coamorphous mixtures of pharmaceuticals is an interesting strategy to improve the solubility and bioavailability of drugs, while at the same time enhancing the kinetic stability of the resulting binary glass and allowing the simultaneous administration of two active principles. In this contribution, we describe kinetically stable amorphous binary mixtures of two commercial active pharmaceutical ingredients, diazepam and nordazepam, of which the latter, besides being administered as a drug on its own, is also the main active metabolite of the other in the human body. We report the eutectic equilibrium-phase diagram of the binary mixture, which is found to be characterized by an experimental eutectic composition of 0.18 molar fraction of nordazepam, with a eutectic melting point of Te = 395.4 ± 1.2 K. The two compounds are barely miscible in the crystalline phase. The mechanically obtained mixtures were melted and supercooled to study the glass-transition and molecular-relaxation dynamics of amorphous mixtures at the corresponding concentration. The glass-transition temperature was always higher than room temperature and varied linearly with composition. The Te was lower than the onset of thermal decomposition of either compound (pure nordazepam decomposes upon melting and pure diazepam well above its melting point), thus implying that the eutectic liquid and glass can be obtained without any degradation of the drugs. The eutectic glass was kinetically stable against crystallization for at least a few months. The relaxation processes of the amorphous mixtures were studied by dielectric spectroscopy, which provided evidence for a single structural (α) relaxation, a single Johari-Goldstein (ß) relaxation, and a ring-inversion conformational relaxation of the diazepinic ring, occurring on the same timescale in both drugs. We further characterized both the binary mixtures and pure compounds by FTIR spectroscopy and first-principles density functional theory (DFT) simulations to analyze intermolecular interactions. The DFT calculations confirm the presence of strong attractive forces within the heteromolecular dimer, leading to large dimer interaction energies of the order of -0.1 eV.

Drug-Biopolymer Dispersions: Morphology- and Temperature- Dependent (Anti)Plasticizer Effect of the Drug and Component-Specific Johari-Goldstein Relaxations.

Amorphous molecule-macromolecule mixtures are ubiquitous in polymer technology and are one of the most studied routes for the development of amorphous drug formulations. For these applications it is crucial to understand how the preparation method affects the properties of the mixtures. Here, we employ differential scanning calorimetry and broadband dielectric spectroscopy to investigate dispersions of a small-molecule drug (the Nordazepam anxiolytic) in biodegradable polylactide, both in the form of solvent-cast films and electrospun microfibres. We show that the dispersion of the same small-molecule compound can have opposite (plasticizing or antiplasticizing) effects on the segmental mobility of a biopolymer depending on preparation method, temperature, and polymer enantiomerism. We compare two different chiral forms of the polymer, namely, the enantiomeric pure, semicrystalline L-polymer (PLLA), and a random, fully amorphous copolymer containing both L and D monomers (PDLLA), both of which have lower glass transition temperature (Tg) than the drug. While the drug has a weak antiplasticizing effect on the films, consistent with its higher Tg, we find that it actually acts as a plasticizer for the PLLA microfibres, reducing their Tg by as much as 14 K at 30%-weight drug loading, namely, to a value that is lower than the Tg of fully amorphous films. The structural relaxation time of the samples similarly depends on chemical composition and morphology. Most mixtures displayed a single structural relaxation, as expected for homogeneous samples. In the PLLA microfibres, the presence of crystalline domains increases the structural relaxation time of the amorphous fraction, while the presence of the drug lowers the structural relaxation time of the (partially stretched) chains in the microfibres, increasing chain mobility well above that of the fully amorphous polymer matrix. Even fully amorphous homogeneous mixtures exhibit two distinct Johari-Goldstein relaxation processes, one for each chemical component. Our findings have important implications for the interpretation of the Johari-Goldstein process as well as for the physical stability and mechanical properties of microfibres with small-molecule additives.

Chloramphenicol loaded polylactide melt electrospun scaffolds for biomedical applications.

Melt electrospinning of polylactide (PLA) loaded with chloramphenicol (CAM) has been performed and characteristics of fibers, physical properties of scaffolds, CAM release behavior, antibacterial properties and biocompatibility have been evaluated. The interest of CAM loaded samples is nowadays enhanced for biomedical applications since this antibiotic has been demonstrated to be efficient for the treatment of cancer. Melt electrospinning has been selected as an ideal preparation process because it avoids the use of toxic solvents which are harmful to the environment and could be problematic for biomedical applications. The electrospinning process rendered fibers with a relatively large diameter (between 20 µm and 40 µm depending on the load) and minimum polymer degradation. Characteristics of melt electrospun scaffolds were also compared with those prepared by solution electrospinning. Differences consisted in a more sustained release and a higher biocompatibility for the melt processed samples. Bactericide effect was evaluated as an evidence of the maintenance of the CAM bioactivity after melt processing at high temperature and the slower release caused by the relatively high diameter of the constitutive fibers. Since pure CAM showed thermal degradation at temperatures relatively close to the PLA melting temperature, a complete analysis of the degradation process of pure CAM as well as of PLA samples loaded with CAM was performed. The Invariant Kinetic Parameters method allowed determining an initial decomposition step that followed an autoaccelatory Avrami model, and then an autocatalytic decomposition reaction took place for conversions higher than 50%. Dispersion in the PLA matrix enhances the thermal stability of the antibiotic, with an onset temperature of degradation that was higher by 16 °C in the melt-electrospun fibers than in the liquid state of pure CAM.

Comparative Physical Study of Three Pharmaceutically Active Benzodiazepine Derivatives: Crystalline versus Amorphous State and Crystallization Tendency.

Chemical derivatization and amorphization are two possible strategies to improve the solubility and bioavailability of drugs, which is a key issue for the pharmaceutical industry. In this contribution, we explore whether both strategies can be combined by studying how small differences in the molecular structure of three related pharmaceutical compounds affect their crystalline structure and melting point (Tm), the relaxation dynamics in the amorphous phase, and the glass transition temperature (Tg), as well as the tendency toward recrystallization. Three benzodiazepine derivatives of almost same molecular mass and structure (Diazepam, Nordazepam and Tetrazepam) were chosen as model compounds. Nordazepam is the only one that displays N-H···O hydrogen bonds both in crystalline and amorphous phases, which leads to a significantly higher Tm (by 70-80 K) and Tg (by 30-40 K) compared to those of Tetrazepam and Diazepam (which display similar values of characteristic temperatures). The relaxation dynamics in the amorphous phase, as determined experimentally using broadband dielectric spectroscopy, is dominated by a structural relaxation and a Johari-Goldstein secondary relaxation, both of which scale with the reduced temperature T/Tg. The kinetic fragility index is very low and virtually the same (mp ≈ 32) in all three compounds. Two more secondary relaxations are observed in the glass state: the slower of the two has virtually the same relaxation time and activation energy in all three compounds, and is assigned to the inter-enantiomer conversion dynamics of the flexible diazepine heterocycle between isoenergetic P and M conformations. We tentatively assign the fastest secondary relaxation, present only in Diazepam and Tetrazepam, to the rigid rotation of the fused diazepine-benzene double ring relative to the six-membered carbon ring. Such motion appears to be largely hindered in glassy Nordazepam, possibly due to the presence of the hydrogen bonds. Supercooled liquid Tetrazepam and Nordazepam are observed to crystallize into their stable crystalline form with an Avrami exponent close to unity indicating unidimensional growth with only sporadic nucleation, which allows a direct assessment of the crystal growth rate. Despite the very similar growth mode, the two derivatives exhibit very different kinetics for a fixed value of the reduced temperature and thus of the structural relaxation time, with Nordazepam displaying slower growth kinetics. Diazepam does not instead display any tendency toward recrystallization over short periods of time (even close to Tm). Both these observations in three very similar diazepine derivatives provide direct evidence that the kinetics of recrystallization of amorphous pharmaceuticals is not a universal function, at least in the supercooled liquid phase, of the structural or the conformational relaxation dynamics, and it is not simply correlated with related parameters such as the kinetic fragility or activation barrier of the structural relaxation. Only the crystal growth rate, and not the nucleation rate, shows a correlation with the presence or absence of hydrogen bonding.

Nose Temperature and Anticorrelation between Recrystallization Kinetics and Molecular Relaxation Dynamics in Amorphous Morniflumate at High Pressure.

We probe the dielectric response of the supercooled liquid phase of Morniflumate, a drug with anti-inflammatory and antipyretic properties, studying in particular the pressure and temperature dependence of the relaxation dynamics, glass transition temperature Tg, and recrystallization kinetics. Tg increases by roughly 20 K every 100 MPa at low applied pressure, where the ratio Tg/Tm has a constant value of ∼0.8 (Tm = melting point). Liquid Morniflumate displays two dielectric relaxations: the structural α relaxation associated with the collective reorientational motions, which become arrested at Tg, and a secondary relaxation likely corresponding to an intramolecular dynamics. The relaxation times of both processes scale approximately with the inverse reduced temperature Tg/T. Near room temperature and under an applied pressure of 50 MPa, supercooled Morniflumate recrystallizes in a characteristic time of few hours, with an Avrami exponent of 1.15. Under these conditions, the recrystallization rate is a nonmonotonic function of temperature, displaying a maximum at around 298 K, which can be taken to be the optimum crystal growth temperature Tnose. The ß relaxation becomes kinetically frozen at ambient temperature under an applied hydrostatic pressure higher than 320 MPa, suggesting that the Morniflumate glass should be kinetically stable under these conditions.

Amorphous binary dispersions of chloramphenicol in enantiomeric pure and racemic poly-lactic acid: Morphology, molecular relaxations, and controlled drug release.

We characterize amorphous solid dispersions (ASDs) of the Chloramphenicol antibiotic in two biodegradable polylactic acid polymers, namely a commercial sample of enantiomeric pure PLLA and a home-synthesized PDLLA copolymer, investigating in particular the effect of polylactic acid in stabilizing the amorphous form of the drug and controlling its release (e.g. for antitumoral purposes). Broadband dielectric spectroscopy and differential scanning calorimetry are employed to study the homogeneity, glass transition temperature and relaxation dynamics of solvent-casted ASD membranes with different drug concentrations. We observe improved physical stability of the ASDs with respect to the pure drug, as well as a plasticizing effect of the antibiotic on the polymer, well described by the Gordon-Taylor equation. The release of the active pharmaceutical ingredient from the films in a simulated body fluid is studied by UV/vis spectroscopy at two different drug concentrations (5 and 20% in weight). The amount of released drug is found to be proportional to the square root of time, with proportionality constant that is almost the same in both dispersions, despite the fact that the relaxation time and thus the viscosity of the two samples differ by four orders of magnitude at body temperature. Since the drug release kinetics does not display a significant dependence on the drug content in the carrier, it may be expected to remain roughly constant during longer release times.

Tuning the Kinetic Stability of the Amorphous Phase of the Chloramphenicol Antibiotic.

We employ broadband dielectric spectroscopy to study the relaxation dynamics and crystallization kinetics of a broad-spectrum antibiotic, chloramphenicol, in its supercooled liquid form. Two dynamic processes are observed: the structural α relaxation, which becomes kinetically frozen at Tg = 302 ± 1 K, and an intramolecular secondary relaxation. Under isothermal conditions, the supercooled drug displays interconversion between different isomers, followed by recrystallization. Recrystallization follows the Avrami law with Avrami exponent n = 1.3 ± 0.1, consistent with a one-dimensional growth of crystalline platelets, as observed by electron microscopy. Exposure to humid atmosphere and subsequent heating to high temperature is found to degrade the compound. The partially degraded sample displays a much lower tendency to crystallize, likely because the presence of the degradation products results in spatial frustration. This sample exhibits enhanced conductivity and an additional relaxation, intermediate to the ones observed in the pure sample, which likely corresponds to the noncooperative dynamics of the main degradation product. We find that dispersing the antibiotic in polylactic acid results in an amorphous sample, which does not crystallize at room temperature for relatively long times.

Direct Evidence of Relaxation Anisotropy Resolved by High Pressure in a Rigid and Planar Glass Former.

Rigid molecular glass-formers with no internal degrees of freedom nonetheless have a single secondary ß-relaxation. For a rigid and planar molecule, 1-methylindole (1MID), although a secondary relaxation is resolved at ambient pressure, its properties do not conform to the rules established for rigid molecules reported in early studies. By applying pressure to the dielectric spectra of 1MID, we find the single secondary relaxation splits into two. The slower one is pressure sensitive showing connections to the α-relaxation as observed in other rigid molecules, while the faster one is almost pressure insensitive and dominate the loss at ambient pressure. The two secondary relaxations, identified to associate with the out-of-plane and in-plane rotations of the rigid and planar 1MID, are resolved and observed for the first time by increasing density via elevating pressure.