The significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation.

The fundamental origins surrounding the dynamics of disordered solids near their characteristic glass transitions continue to be fiercely debated, even though a vast number of materials can form amorphous solids, including small-molecule organic, inorganic, covalent, metallic, and even large biological systems. The glass-transition temperature, Tg, can be readily detected by a diverse set of techniques, but given that these measurement modalities probe vastly different processes, there has been significant debate regarding the question of why Tg can be detected across all of them. Here we show clear experimental and computational evidence in support of a theory that proposes that the shape and structure of the potential-energy surface (PES) is the fundamental factor underlying the glass-transition processes, regardless of the frequency that experimental methods probe. Whilst this has been proposed previously, we demonstrate, using ab initio molecular-dynamics (AIMD) simulations, that it is of critical importance to carefully consider the complete PES - both the intra-molecular and inter-molecular features - in order to fully understand the entire range of atomic-dynamical processes in disordered solids. Finally, we show that it is possible to utilise this dependence to directly manipulate and harness amorphous dynamics in order to control the behaviour of such solids by using high-powered terahertz pulses to induce crystallisation and preferential crystal-polymorph growth in glasses. Combined, these findings provide compelling evidence that the PES landscape, and the corresponding energy barriers, are the ultimate controlling feature behind the atomic and molecular dynamics of disordered solids, regardless of the frequency at which they occur.

Quantification of cation-anion interactions in crystalline monopotassium and monosodium glutamate salts.

Crystalline salt compounds composed of metal cations and organic anions are becoming increasingly popular in a number of fields, including the pharmaceutical and food industries, where such formulations can lead to increased product solubility. The origins of these effects are often in the interactions between the individual components in the crystals, and understanding these forces is paramount for the design and utilisation of such materials. Monosodium glutamate monohydrate and monopotassium glutamate monohydrate are two solids that form significantly different structures with correspondingly dissimilar dynamics, while their chemistry only differs in cation identity. Crystals of each were characterised experimentally with single-crystal X-ray diffraction and terahertz time-domain spectroscopy and theoretically using solid-state density functional theory simulations, in order to explain the observed differences in their bulk properties. Specifically, crystal orbital overlap and Hamiltonian population analyses were performed to examine the role that the individual interactions between the cation and anion played in the solid-state structures and the overall energetic profiles of these materials.

A comprehensive spectroscopic study of the polymorphs of diflunisal and their phase transformations.

Understanding phase transitions in pharmaceutical materials is of vital importance for drug manufacturing, processing and storage. In this paper we have carried out comprehensive high-resolution spectroscopic studies on the polymorphs of the non-steroidal anti-inflammatory drug diflunisal that has four known polymorphs, forms I-IV (FI-FIV), three of which have known crystal structures. Phase transformations during milling, heating, melt-quenching and exposure to high relative humidity were investigated using Raman and terahertz spectroscopy in combination with differential scanning calorimetry and X-ray powder diffraction. The observed phase transformations indicate the stability order FIII>FI>FII, FIV. Furthermore, crystallization experiments from the gas phase and from solution by fast evaporation of different solvents were carried out. Fast evaporation of an ethanolic solution below 70°C was identified as a reliable and convenient method to obtain the somewhat elusive FII in bulk quantities.

Examination of l-Glutamic Acid Polymorphs by Solid-State Density Functional Theory and Terahertz Spectroscopy.

The ability of l-glutamic acid to crystallize in two different forms has long been the subject of study due to its commercial importance. While a solvent-mediated phase transformation between the α and ß polymorphs is the prevailing theory, recent reports indicate a thermal solid-solid transformation between the two may be possible. However, determining accurate thermodynamic stabilities of these crystals has been challenging. Here new low-temperature single-crystal X-ray diffraction data coupled to solid-state density functional theory simulations have enabled a detailed description to be achieved for the energetic parameters governing the stabilization of the two l-glutamic acid solids. The temperature-dependent Gibbs free-energy curves show that α-glutamic acid is the preferred form at low temperatures (<222 K) and the ß form is most stable at ambient temperatures. Terahertz time-domain spectroscopy was utilized to evaluate the quality of the intermolecular force modeling as well as to provide characteristic low-frequency spectral data that can be used for quantification of polymorph mixtures or crystal growth monitoring.

(19) F†NMR Spectroscopy as a Highly Sensitive Method for the Direct Monitoring of Confined Crystallization within Nanoporous Materials.

The introduction of fluorine into the structure of pharmaceuticals has been an effective strategy for tuning their pharmacodynamic properties, with more than 40 new drugs entering the market in the last 15 years. In this context, (19) F NMR spectroscopy can be viewed as a useful method for investigating the host-guest chemistry of pharmaceuticals in nanosized drug-delivery systems. Although the interest in confined crystallization, nanosized devices, and porous catalysts is gradually increasing, understanding of the complex phase behavior of organic molecules confined within nanochambers or nanoreactors is still lacking. Using (19) F magic-angle-spinning NMR spectroscopy, we obtained detailed mechanistic insight into the crystallization of flufenamic acid (FFA) in a confined environment of mesoporous silica materials with different pore diameters (3.2-29 nm), providing direct experimental evidence for the formation of a molecular-liquid-like layer besides crystalline confined FFA form I.

Measuring the Elasticity of Poly-l-Proline Helices with Terahertz Spectroscopy.

The rigidity of poly-l-proline is an important contributor to the stability of many protein secondary structures, where it has been shown to strongly influence bulk flexibility. The experimental Young's moduli of two known poly-l-proline helical forms, right-handed all-cis (Form I) and left-handed all-trans (Form II), were determined in the crystalline state by using an approach that combines terahertz time-domain spectroscopy, X-ray diffraction, and solid-state density functional theory. Contrary to expectations, the helices were found to be considerably less rigid than many other natural and synthetic polymers, as well as differing greatly from each other, with Young's moduli of 4.9 and 9.6 GPa for Forms I and II, respectively.

Direct measurement of molecular mobility and crystallisation of amorphous pharmaceuticals using terahertz spectroscopy.

Despite much effort in the area, no comprehensive understanding of the formation and behaviour of amorphous solids has yet been achieved. This severely limits the industrial application of such materials, including drug delivery where, in principle, amorphous solids have demonstrated their great usefulness in increasing the bioavailability of poorly aqueous soluble active pharmaceutical ingredients. Terahertz time-domain spectroscopy is a relatively novel analytical technique that can be used to measure the fast molecular dynamics of molecules with high accuracy in a non-contact and non-destructive fashion. Over the past decade a number of applications for the characterisation of amorphous drug molecules and formulations have been developed and it has been demonstrated how this technique can be used to determine the onset and strength in molecular mobility that underpins the crystallisation of amorphous drugs. In this review we provide an overview of the history, fundamentals and future perspective of pharmaceutical applications related to the terahertz dynamics of amorphous systems.

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallization of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. In the present study we provide terahertz spectroscopy evidence on the crystallization of amorphous naproxen well below its glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallization. We determine the onset temperature Tß above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallization in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.

The Disintegration Process in Microcrystalline Cellulose Based Tablets, Part 1: Influence of Temperature, Porosity and Superdisintegrants.

Disintegration performance was measured by analysing both water ingress and tablet swelling of pure microcrystalline cellulose (MCC) and in mixture with croscarmellose sodium using terahertz pulsed imaging (TPI). Tablets made from pure MCC with porosities of 10% and 15% showed similar swelling and transport kinetics: within the first 15 s, tablets had swollen by up to 33% of their original thickness and water had fully penetrated the tablet following Darcy flow kinetics. In contrast, MCC tablets with a porosity of 5% exhibited much slower transport kinetics, with swelling to only 17% of their original thickness and full water penetration reached after 100 s, dominated by case II transport kinetics. The effect of adding superdisintegrant to the formulation and varying the temperature of the dissolution medium between 20°C and 37°C on the swelling and transport process was quantified. We have demonstrated that TPI can be used to non-invasively analyse the complex disintegration kinetics of formulations that take place on timescales of seconds and is a promising tool to better understand the effect of dosage form microstructure on its performance. By relating immediate-release formulations to mathematical models used to describe controlled release formulations, it becomes possible to use this data for formulation design. © 2015 The Authors. Journal of Pharmaceutical Sciences published by Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3440-3450, 2015.

The Disintegration Process in Microcrystalline Cellulose Based Tablets, Part 1: Influence of Temperature, Porosity and Superdisintegrants.

Disintegration performance was measured by analysing both water ingress and tablet swelling of pure microcrystalline cellulose (MCC) and in mixture with croscarmellose sodium using terahertz pulsed imaging (TPI). Tablets made from pure MCC with porosities of 10% and 15% showed similar swelling and transport kinetics: within the first 15s, tablets had swollen by up to 33% of their original thickness and water had fully penetrated the tablet following Darcy flow kinetics. In contrast, MCC tablets with a porosity of 5% exhibited much slower transport kinetics, with swelling to only 17% of their original thickness and full water penetration reached after 100s, dominated by case II transport kinetics. The effect of adding superdisintegrant to the formulation and varying the temperature of the dissolution medium between 20°C and 37°C on the swelling and transport process was quantified. We have demonstrated that TPI can be used to non-invasively analyse the complex disintegration kinetics of formulations that take place on timescales of seconds and is a promising tool to better understand the effect of dosage form microstructure on its performance. By relating immediate-release formulations to mathematical models used to describe controlled release formulations, it becomes possible to use this data for formulation design. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3440-3450, 2015.

Crystallization and phase changes in paracetamol from the amorphous solid to the liquid phase.

For the case of paracetamol, we show how terahertz time-domain spectroscopy can be used to characterize the solid and liquid phase dynamics. Heating of supercooled amorphous paracetamol from 295 K in a covered sample under vacuum leads to its crystallization at 330 K. First, form III is formed followed by the transformation of form III to form II at 375 K, to form I at 405 K, and finally melting is observed around 455 K. We discuss the difference between the featureless spectra of the supercooled liquid and its liquid melt. Lastly, we studied the onset of crystallization from the supercooled liquid in detail and quantified its kinetics based on the Avrami-Erofeev model. We determined an effective rate constant of k = 0.056 min(-1) with a corresponding onset of crystallization at T = 329.5 K for a heating rate of 0.4 K min(-1).

Low-bias terahertz amplitude modulator based on split-ring resonators and graphene.

Split-ring resonators represent the ideal route to achieve optical control of the incident light at THz frequencies. These subwavelength metamaterial elements exhibit broad resonances that can be easily tuned lithographically. We have realized a design based on the interplay between the resonances of metallic split rings and the electronic properties of monolayer graphene integrated in a single device. By varying the major carrier concentration of graphene, an active modulation of the optical intensity was achieved in the frequency range between 2.2 and 3.1 THz, achieving a maximum modulation depth of 18%, with a bias as low as 0.5 V.

Thermal Decoupling of Molecular-Relaxation Processes from the Vibrational Density of States at Terahertz Frequencies in Supercooled Hydrogen-Bonded Liquids.

At terahertz frequencies, the libration-vibration motions couple to the dielectric relaxations in disordered hydrogen-bonded solids. The interplay between these processes is still poorly understood, in particular at temperatures below the glass transition temperature, Tg, yet this behavior is of vital importance for the molecular mobility of such materials to remain in the amorphous phase. A series of polyhydric alcohols were studied at temperatures between 80 and 310 K in the frequency range of 0.2-3 THz using terahertz time-domain spectroscopy. Three universal features were observed in the dielectric losses, ϵ″(ν): (a) At temperatures well below the glass transition, ϵ″(ν) comprises a temperature-independent microscopic peak, which persists into the liquid phase and which is identified as being due to librational/torsional modes. For 0.65 Tg < T < Tg, additional thermally dependent contributions are observed, and we found strong evidence for its relation to the Johari-Goldstein secondary ß-relaxation process. (b) Clear spectroscopic evidence is found for a secondary ß glass transition at 0.65 Tg, which is not related to the fragility of the glasses. (c) At temperatures above Tg, the losses become dominated by primary α-relaxation processes. Our results show that the thermal changes in the losses seem to be underpinned by a universal change in the hydrogen bonding structure of the samples.

Glassy dynamics of sorbitol solutions at terahertz frequencies.

The absorption spectra of D-sorbitol and a range of its concentrated aqueous solutions were studied by terahertz spectroscopy over the temperature interval of 80 K < T < 310 K. It is shown that the slow-down of molecules at around the glass transition temperature, Tg, dramatically influences the thermal dependence of the absorption at terahertz frequencies. Furthermore, two different absorption regimes are revealed below Tg: at temperatures well below Tg, the absorption resembles the coupling of terahertz radiation to the vibrational density of states (VDOS); above these temperatures, between 160 K and Tg, in the sample of pure sorbitol and the sample of a solution of 70 wt% sorbitol in water, another type of absorption is observed at terahertz frequencies. Several possibilities of the physical origin of this absorption are discussed and based on the experimental data this process is tentatively assigned to the Johari-Goldstein ß-relaxation processes shifting to lower frequencies at temperatures below Tg leaving behind a spectrum largely dominated by losses into the VDOS.