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.We would like to acknowledge the U.K. Engineering and Physical Sciences Research Council (EP/J007803/1) as well as MedImmune for funding.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.addr.2015.12.02

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 Tβ 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.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

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 β-relaxation process. (b) Clear spectroscopic evidence is found for a secondary β 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.J.S. would like to thank the U. K. Engineering and Physical Sciences Research Council for financial support.This is the final published version, which can also be viewed on the publisher's website at: http://pubs.acs.org/doi/pdf/10.1021/jz500730

High-birefringence nematic liquid crystal for broadband THz applications

Liquid crystals (LCs) have been studied extensively in the visible range for their dielectric tunability, and the characterisation in the terahertz (THz) range has gained increasing interest due to the need for active THz modulation and switching devices. In this paper, we use THz time-domain spectroscopy to measure the frequency-dependent birefringence and the absorption coefficient of a number of commercial and non-commercial nematic LCs, including E7, BL037, MDA-98-1602, LCMS-107, GT3-23001 and 1825, over a range of bias voltages at room temperature. Furthermore, several basic components of LC mixture are analysed to establish their contributions to birefringence and theoretical model is used to fit the absorption spectra. The large tunability and low loss measured for a range of samples show that the LCs are useful tunable dielectrics for compact, efficient and broadband THz devices.The authors would like to thank the UK Engineering and Physical Sciences Research Council (EPSRC) for the support through the Platform Grant for Liquid Crystal Photonics (EP/F00897X/1).This is the final version of the article. It first appeared from Taylor & Francis via https://doi.org/10.1080/02678292.2016.115373

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

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.S.Y. would like to thank the U. K. Engineering and Physical Sciences Research Council (EPSRC) for a studentship. J.S. and J.A.Z. would like to acknowledge the EPSRC for funding (EP/J007803/1).This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.1002/jps.24544/abstract

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.M.T.R. and T.M.K acknowledge the support of a grant from the National Science Foundation (CHE-1301068). T.M.K. would like to acknowledge the Royal Society International Exchanges Scheme as well as the Royal Society of Chemistry JWT Jones Travelling Fellowship for support. J.S. and J.A.Z. would like to acknowledge the U.K. Engineering and Physical Sciences Research Council (EP/J007803/1) for funding

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 Tβ 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.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

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

The 2017 Terahertz Science and Technology Roadmap

Science and technologies based on terahertz frequency electromagnetic radiation (100GHz-30THz) have developed rapidly over the last 30 years. For most of the 20th century, terahertz radiation, then referred to as sub-millimeter wave or far-infrared radiation, was mainly utilized by astronomers and some spectroscopists. Following the development of laser based terahertz time-domain spectroscopy in the 1980s and 1990s the field of THz science and technology expanded rapidly, to the extent that it now touches many areas from fundamental science to “real world” applications. For example THz radiation is being used to optimize materials for new solar cells, and may also be a key technology for the next generation of airport security scanners. While the field was emerging it was possible to keep track of all new developments, however now the field has grown so much that it is increasingly difficult to follow the diverse range of new discoveries and applications that are appearing. At this point in time, when the field of THz science and technology is moving from an emerging to a more established and interdisciplinary field, it is apt to present a roadmap to help identify the breadth and future directions of the field. The aim of this roadmap is to present a snapshot of the present state of THz science and technology in 2016, and provide an opinion on the challenges and opportunities that the future holds. To be able to achieve this aim, we have invited a group of international experts to write 17 sections that cover most of the key areas of THz Science and Technology. We hope that The 2016 Roadmap on THz Science and Technology will prove to be a useful resource by providing a wide ranging introduction to the capabilities of THz radiation for those outside or just entering the field as well as providing perspective and breadth for those who are well established. We also feel that this review should serve as a useful guide for government and funding agencies