Colossal Reversible Barocaloric Effects in a Plastic Crystal Mediated by Lattice Vibrations and Ion Diffusion.

Solid-state methods for cooling and heating promise a sustainable alternative to current compression cycles of greenhouse gases and inefficient fuel-burning heaters. Barocaloric effects (BCE) driven by hydrostatic pressure (p) are especially encouraging in terms of large adiabatic temperature changes (|ΔT| ≈ 10 K) and isothermal entropy changes (|ΔS| ≈ 100 J K-1 kg-1). However, BCE typically require large pressure shifts due to irreversibility issues, and sizeable |ΔT| and |ΔS| seldom are realized in a same material. Here, the existence of colossal and reversible BCE in LiCB11H12 is demonstrated near its order-disorder phase transition at ≈380 K. Specifically, for Δp ≈ 0.23 (0.10) GPa, |ΔSrev| = 280 (200) J K-1 kg-1 and |ΔTrev| = 32 (10) K are measured, which individually rival with state-of-the-art BCE figures. Furthermore, pressure shifts of the order of 0.1 GPa yield huge reversible barocaloric strengths of ≈2 J K-1 kg-1 MPa-1. Molecular dynamics simulations are performed to quantify the role of lattice vibrations, molecular reorientations, and ion diffusion on the disclosed BCE. Interestingly, lattice vibrations are found to contribute the most to |ΔS| while the diffusion of lithium ions, despite adding up only slightly to the entropy change, is crucial in enabling the molecular order-disorder phase transition.

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.

Dynamics and local ordering of pentachloronitrobenzene: a molecular-dynamics investigation.

Plastic phases are constituted by molecules whose centers of mass form a long range ordered crystalline lattice, but rotate in a more or less constrained way. Pentachloronitrobenzene (PCNB) is a quasi-planar hexa-substituted benzene formed by a benzene ring decorated with a -NO2 group and five chlorine atoms that displays below the melting point a layered structure of rhombohedral (R3̄) planes in which the molecules can rotate around a six-fold-like axis. Dielectric spectroscopy [Romanini et al., The Journal of Physical Chemistry C, 2016, 120, 10614] of this highly anisotropic phase revealed a complex relaxation dynamics with two coupled primary α processes, initially ascribed to the in-plane and out-of-plane components of the molecular dipole. In this work, we perform a series of molecular dynamics simulations together with single crystal X-ray synchrotron diffraction experiments to investigate the puzzling dynamics of PCNB. We conclude that the molecule undergoes very fast movements due to the high flexibility of the -NO2 group, and two slower movements in which only the in-plane rotation of the whole ring is involved. These two movements are related to fast attempts to perform a 60° in-plane rotation, and a diffusive motion that involves the rotation of the molecule completely decorrelating the dipole orientation. We have also investigated whether a homogeneous or a heterogeneous scenario is better suited to describe the restricted orientational disorder of this anisotropic phase both from a structural and dynamical point of view.

SbSeI and SbSeBr micro-columnar solar cells by a novel high pressure-based synthesis process.

Van der Waals chalcogenides and chalcohalides have the potential to become the next thin film PV breakthrough, owing to the earth-abundancy and non-toxicity of their components, and their stability, high absorption coefficient and quasi-1D structure, which leads to enhanced electrical anisotropic properties when the material is oriented in a specific crystalline direction. However, quasi-1D semiconductors beyond Sb2(S,Se)3, such as SbSeX chalcohalides, have been scarcely investigated for energy generation applications, and rarely synthesised by physical vapor deposition methodologies, despite holding the promise of widening the bandgap range (opening the door to tandem or semi-transparent devices), and showing enticing new properties such as ferroelectric behaviour and defect-tolerant nature. In this work, SbSeI and SbSeBr micro-columnar solar cells have been obtained for the first time by an innovative methodology based on the selective halogenation of Sb2Se3 thin films at pressure above 1 atm. It is shown that by increasing the annealing temperature and pressure, the height and density of the micro-columnar structures grows monotonically, resulting in SbSeI single-crystal columns up to 30 µm, and tuneable morphology. In addition, solar cell prototypes with substrate configuration have shown remarkable Voc values above 550 mV and 1.8 eV bandgap.

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.

The Phase Diagram of the API Benzocaine and Its Highly Persistent, Metastable Crystalline Polymorphs.

The availability of sufficient amounts of form I of benzocaine has led to the investigation of its phase relationships with the other two existing forms, II and III, using adiabatic calorimetry, powder X-ray diffraction, and high-pressure differential thermal analysis. The latter two forms were known to have an enantiotropic phase relationship in which form III is stable at low-temperatures and high-pressures, while form II is stable at room temperature with respect to form III. Using adiabatic calorimetry data, it can be concluded, that form I is the stable low-temperature, high-pressure form, which also happens to be the most stable form at room temperature; however, due to its persistence at room temperature, form II is still the most convenient polymorph to use in formulations. Form III presents a case of overall monotropy and does not possess any stability domain in the pressure-temperature phase diagram. Heat capacity data for benzocaine have been obtained by adiabatic calorimetry from 11 K to 369 K above its melting point, which can be used to compare to results from in silico crystal structure prediction.

Immediate-sustained lactate release using alginate hydrogel assembled to proteinase K/polymer electrospun fibers.

This work proposes a microfibers-hydrogel assembled composite as delivery vehicle able to combine into a single system both burst and prolonged release of lactate. The prolonged release of lactate has been achieved by electrospinning a mixture of polylactic acid and proteinase K (26.0 mg of proteinase K and 0.99 g of PLA dissolved in 6 mL of 2:1 chloroform:acetone in the optimal case), which is a protease that catalyzes the degradation of polylactic acid into lactate. The degradation of microfibers into lactate reflects that proteinase K preserves its enzymatic activity even after the electrospinning process because of the mild operational conditions used. Besides, burst release is obtained from the lactate-loaded alginate hydrogel. The successful assembly between the lactate-loaded hydrogel and the polylactic acid/proteinase K fibers has been favored by applying a low-pressure (0.3 mbar at 300 W) oxygen plasma treatment, which transforms hydrophobic fibers into hydrophilic while the enzymatic activity is still maintained. The composite displays both fast (< 24 h) and sustained (> 10 days) lactate release, and allows the modulation of the release by adjusting either the amount of loaded lactate or the amount of active enzyme.

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.

Inter-enantiomer conversion dynamics and Johari-Goldstein relaxation of benzophenones.

We employ temperature- and pressure-dependent dielectric spectroscopy, as well as differential scanning calorimetry, to characterize benzophenone and the singly-substituted ortho-bromobenzophenone derivative in the liquid and glass states, and analyze the results in terms of the molecular conformations reported for these molecules. Despite the significantly higher mass of the brominated derivative, its dynamic and calorimetric glass transition temperatures are only ten degrees higher than those of benzophenone. The kinetic fragility index of the halogenated molecule is lower than that of the parent compound, and is found to decrease with increasing pressure. By a detailed analysis of the dielectric loss spectra, we provide evidence for the existence of a Johari-Goldstein (JG) relaxation in both compounds, thus settling the controversy concerning the possible lack of a JG process in benzophenone and confirming the universality of this dielectric loss feature in molecular glass-formers. Both compounds also display an intramolecular relaxation, whose characteristic timescale appears to be correlated with that of the cooperative structural relaxation associated with the glass transition. The limited molecular flexibility of ortho-bromobenzophenone allows identifying the intramolecular relaxation as the inter-enantiomeric conversion between two isoenergetic conformers of opposite chirality, which only differ in the sign of the angle between the brominated aryl ring and the coplanar phenyl-ketone subunit. The observation by dielectric spectroscopy of a similar relaxation also in liquid benzophenone indicates that the inter-enantiomer conversion between the two isoenergetic helicoidal ground-state conformers of opposite chirality occurs via a transition state characterized by a coplanar phenyl-ketone moiety.

The solid state of anti-inflammatory morniflumate diniflumate: A cocrystalline salt.

Morniflumate diniflumate, a molecular compound involving niflumic acid and its ß-morpholino ethyl ester (morniflumate) in the mole ratio 2:1, is found to crystallize in a triclinic P - 1 space group with a unit-cell volume of 2203.4(5) Å3. It is a cocrystal between a morniflumate+ niflumate- salt and a neutral niflumic acid molecule. The co-crystalline salt forms endothermically with a positive excess volume and it melts incongruently at 382.3(8) K. Differential scanning calorimetry executed at heating rates above 20 K⋅min-1, leads to congruent melting at 387.8(9)K with an enthalpy change of ΔfusH = 80(2) J g-1. The rare occurrence that incongruent and congruent melting can be observed for the same cocrystal may be due to the conformational versatility of the niflumic acid molecule and its slow conversion between the different conformations due to weak intramolecular hydrogen bonding.

Heat capacity anomalies of the molecular crystal 1-fluoro-adamantane at low temperatures.

Disorder-disorder phase transitions are rare in nature. Here, we present a comprehensive low-temperature experimental and theoretical study of the heat capacity and vibrational density of states of 1-fluoro-adamantane (C10H15F), an intriguing molecular crystal that presents a continuous disorder-disorder phase transition at T = 180 K and a low-temperature tetragonal phase that exhibits fractional fluorine occupancy. It is shown that fluorine occupancy disorder in the low-T phase of 1-fluoro-adamantane gives rise to the appearance of low-temperature glassy features in the corresponding specific heat (i.e., "boson peak" -BP-) and vibrational density of states. We identify the inflation of low-energy optical modes as the main responsible for the appearance of such glassy heat-capacity features and propose a straightforward correlation between the first localized optical mode and maximum BP temperature for disordered molecular crystals (either occupational or orientational). Thus, the present study provides new physical insights into the possible origins of the BP appearing in disordered materials and expands the set of molecular crystals in which "glassy-like" heat-capacity features have been observed.

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.

Polymorphism of benzylthiouracil, an active pharmaceutical ingredient against hyperthyroidism.

The crystal structures of dimorphic benzylthiouracil, a drug against hyperthyroidism, have been redetermined and the atom coordinates of the two independent molecules of form I have been obtained for the first time. The dimorphism convincingly demonstrates the conformational versatility of the benzylthiouracil molecule. It has been established through calorimetric studies that the low-temperature form II transforms endothermically (ΔII→IH = 5.6(1.5) J g-1) into form I at 405.4(1.0) K. The high-temperature form I melts at 496.8(1.0) K (ΔI→LH = 152.6(4.0) J g-1). Crystallographic and thermal expansion studies show that form II is denser than form I, leading to the conclusion that the slope of the II-I equilibrium curve in the pressure-temperature phase diagram is positive. It follows that this dimorphism corresponds to a case of overall enantiotropic behaviour, which implies that both solid phases possess their own stable phase region irrespective of the pressure. Moreover, form II is clearly the stable polymorph under ambient conditions.

Crystalline tetrazepam as a case study on the volume change on melting of molecular organic compounds.

The volume change on melting is a rarely studied quantity and it is not well understood even if it must reflect the changes in interaction between the solid and the liquid state. It is part of the solid-state information for materials and pharmaceuticals and it is important for the reliability of polymorph stability study results. Using the crystal structure of monoclinic tetrazepam at 150 K and at room temperature, in addition to powder X-ray diffraction as a function of the temperature, the specific volume of tetrazepam has been determined over a large temperature domain. In combination with a pressure-temperature curve for the melting of tetrazepam, its volume change on melting could be determined. With this information and previous data from the literature, the assumption that the volume of the solid increases on average with 11% on melting has been investigated. It can be concluded that this value is not constant; however so far, no simple relationship has been found to relate the solid state to its volume change on melting and using 11% remains best practice. A comparison of the tetrazepam crystal structure with diazepam and nordiazepam has been provided too.

Does the trihydrate of atorvastatin calcium possess a melting point?

To decide whether an active pharmaceutical ingredient can be used in its amorphous form in drug formulations, often the glass transition is studied in relation to the melting point of the pharmaceutical. If the glass transition temperature is high enough and found relatively close to the melting point, the pharmaceutical is considered to be a good glass former. However, it is obviously important that the observed melting point and glass transition involve exactly the same system, otherwise the two temperatures cannot be compared. Although this may seem trivial, in the case of hydrates, where water may leave the system on heating, the composition of the system may not be evident. Atorvastatin calcium is a case in point, where confusing terminology, absence of a proper anhydrate form, and loss of water on heating lead to several doubtful conclusions in the literature. However, considering that no anhydrate crystal has ever been observed and that the glass transition of the anhydrous system is found at 144 °C, it can be concluded that if the system is kept isolated from water, the chances that atorvastatin calcium crystallises at room temperature is negligible. The paper discusses the various thermal effects of atorvastatin calcium on heating and proposes a tentative binary phase diagram with water.

The phase relationship between the pyrazinamide polymorphs α and γ.

Pyrazinamide is an active pharmaceutical compound for the treatment of tuberculosis. It possesses at least four crystalline polymorphs. Polymorphism may cause solubility problems as the case of ritonavir has clearly demonstrated; however, polymorphs also provide opportunities to improve pharmaceutical formulations, in particular if the stable form is not very soluble. The four polymorphs of pyrazinamide constitute a rich system to investigate the usefulness of metastable forms and their stabilization. However, despite the existence of a number of papers on the polymorphism of pyrazinamide, well-defined equilibrium conditions between the polymorphs appear to be lacking. The main objectives of this paper are to establish the temperature and pressure equilibrium conditions between the so-called α and γ polymorphs of pyrazinamide, its liquid phase, and vapor phase and to determine the phase-change inequalities, such as enthalpies, entropies, and volume differences. The equilibrium temperature between α and γ was experimentally found at 392(1) K. Moreover, vapor pressures and solubilities of both phases have been determined, clearly indicating that form α is the more stable form at room temperature. High-pressure thermal analysis and the topological pressure-temperature phase diagram demonstrate that the γ form is stabilized by pressure and becomes stable at room temperature under a pressure of 260 MPa.

Giant and Reversible Inverse Barocaloric Effects near Room Temperature in Ferromagnetic MnCoGeB0.03.

Hydrostatic pressure represents an inexpensive and practical method of driving caloric effects in brittle magnetocaloric materials, which display first-order magnetostructural phase transitions whose large latent heats are traditionally accessed using applied magnetic fields. Here, moderate changes of hydrostatic pressure are used to drive giant and reversible inverse barocaloric effects near room temperature in the notoriously brittle magnetocaloric material MnCoGeB0.03 . The barocaloric effects compare favorably with those observed in barocaloric materials that are magnetic. The inevitable fragmentation provides a large surface for heat exchange with pressure-transmitting media, permitting good access to barocaloric effects in cooling devices.

[60]Fullerene for Medicinal Purposes, A Purity Criterion towards Regulatory Considerations.

Since the early nineties countless publications have reported promising medicinal applications for [60]fullerene (C60) related to its unparalleled affinity towards free radicals. Yet, until now no officially approved C60-based drug has reached the market, notably because of the alleged dangers of C60. Nevertheless, since the publication of the effects of C60 on the lifespan of rodents, a myriad of companies started selling C60 worldwide for human consumption without any approved clinical trial. Nowadays, several independent teams have confirmed the safety of pure C60 while demonstrating that previously observed toxicity was due to impurities present in the used samples. However, a purity criterion for C60 samples is still lacking and there are no regulatory recommendations on this subject. In order to avoid a public health issue and for regulatory considerations, a quality-testing strategy is urgently needed. Here we have evaluated several analytical tools to verify the purity of commercially available C60 samples. Our data clearly show that differential scanning calorimetry is the best candidate to establish a purity criterion based on the sc-fcc transition of a C60 sample (Tonset ≥ 258 K, ∆sc-fccH ≥ 8 J g-1).