Terahertz frequency-domain sensing combined with quantitative multivariate analysis for pharmaceutical tablet inspection.

Near infrared (NIR) and Raman spectroscopy combined with multivariate analysis are established techniques for the identification and quantification of chemical properties of pharmaceutical tablets like the concentration of active pharmaceutical ingredients (API). However, these techniques suffer from a high sensitivity to particle size variations and are not ideal for the characterization of physical properties of tablets such as tablet density. In this work, we have explored the feasibility of terahertz frequency-domain spectroscopy, with the advantage of low scattering effects, combined with multivariate analysis to quantify API concentration and tablet density. We studied 33 tablets, consisting of Ibuprofen, Mannitol, and a lubricant with API concentration and filler particle size as the design factors. The terahertz signal was measured in transmission mode across the frequency range 750 GHz to 1.5 THz using a vector network analyzer, frequency extenders, horn antennas, and four off-axis parabolic mirrors. The attenuation spectral data were pre-processed and orthogonal partial least square (OPLS) regression was applied to the spectral data to obtain quantitative prediction models for API concentration and tablet density. The performance of the models was assessed using test sets. While a fair model was obtained for API concentration, a high-quality model was demonstrated for tablet density. The coefficient of determination (R2) for the calibration set was 0.97 for tablet density and 0.98 for API concentration, while the relative prediction errors for the test set were 0.7% and 6% for tablet density and API concentration models, respectively. In conclusion, terahertz spectroscopy demonstrated to be a complementary technique to Raman and NIR spectroscopy, which enables the characterization of physical properties of tablets like tablet density, and the characterization of API concentration with the advantage of low scattering effects.

Terahertz frequency domain sensing for fast porosity measurement of pharmaceutical tablets.

Porosity is an important property of pharmaceutical tablets since it may affect tablet disintegration, dissolution, and bio-availability. It is, therefore, essential to establish non-destructive, fast, and compact techniques to assess porosity, in situ, during the manufacturing process. In this paper, the terahertz frequency-domain (THz-FD) technique was explored as a fast, non-destructive, and sensitive technique for porosity measurement of pharmaceutical tablets. We studied a sample set of 69 tablets with different design factors, such as particle size of the active pharmaceutical ingredient (API), Ibuprofen, particle size of the filler, Mannitol, API concentration, and compaction force. The signal transmitted through each tablet was measured across the frequency range 500-750 GHz using a vector network analyzer combined with a quasi-optical set-up consisting of four off-axis parabolic mirrors to guide and focus the beam. We first extracted the effective refractive index of each tablet from the measured complex transmission coefficients and then translated it to porosity, using an empirical linear relation between effective refractive index and tablet density. The results show that the THz-FD technique was highly sensitive to the variations of the design factors, showing that filler particle size and compaction force had a significant impact on the effective refractive index of the tablets and, consequently, porosity. Moreover, the fragmentation behaviour of particles was observed by THz porosity measurements and was verified with scanning electron microscopy of the cross-section of tablets. In conclusion, the THz-FD technique, based on electronic solutions, allows for fast, sensitive, and non-destructive porosity measurement that opens for compact instrument systems capable of in situ sensing in tablet manufacturing.

High-resolution macromolecular crystallography at the FemtoMAX beamline with time-over-threshold photon detection.

Protein dynamics contribute to protein function on different time scales. Ultrafast X-ray diffraction snapshots can visualize the location and amplitude of atom displacements after perturbation. Since amplitudes of ultrafast motions are small, high-quality X-ray diffraction data is necessary for detection. Diffraction from bovine trypsin crystals using single femtosecond X-ray pulses was recorded at FemtoMAX, which is a versatile beamline of the MAX IV synchrotron. The time-over-threshold detection made it possible that single photons are distinguishable even under short-pulse low-repetition-rate conditions. The diffraction data quality from FemtoMAX beamline enables atomic resolution investigation of protein structures. This evaluation is based on the shape of the Wilson plot, cumulative intensity distribution compared with theoretical distribution, I/σ, Rmerge/Rmeas and CC1/2 statistics versus resolution. The FemtoMAX beamline provides an interesting alternative to X-ray free-electron lasers when studying reversible processes in protein crystals.

Direct nanoscopic observation of plasma waves in the channel of a graphene field-effect transistor.

Plasma waves play an important role in many solid-state phenomena and devices. They also become significant in electronic device structures as the operation frequencies of these devices increase. A prominent example is field-effect transistors (FETs), that witness increased attention for application as rectifying detectors and mixers of electromagnetic waves at gigahertz and terahertz frequencies, where they exhibit very good sensitivity even high above the cut-off frequency defined by the carrier transit time. Transport theory predicts that the coupling of radiation at THz frequencies into the channel of an antenna-coupled FET leads to the development of a gated plasma wave, collectively involving the charge carriers of both the two-dimensional electron gas and the gate electrode. In this paper, we present the first direct visualization of these waves. Employing graphene FETs containing a buried gate electrode, we utilize near-field THz nanoscopy at room temperature to directly probe the envelope function of the electric field amplitude on the exposed graphene sheet and the neighboring antenna regions. Mapping of the field distribution documents that wave injection is unidirectional from the source side since the oscillating electrical potentials on the gate and drain are equalized by capacitive shunting. The plasma waves, excited at 2 THz, are overdamped, and their decay time lies in the range of 25-70 fs. Despite this short decay time, the decay length is rather long, i.e., 0.3-0.5 µm, because of the rather large propagation speed of the plasma waves, which is found to lie in the range of 3.5-7 × 106 m/s, in good agreement with theory. The propagation speed depends only weakly on the gate voltage swing and is consistent with the theoretically predicted 1 4 power law.

Does carrier velocity saturation help to enhance f max in graphene field-effect transistors?

It has been argued that current saturation in graphene field-effect transistors (GFETs) is needed to get optimal maximum oscillation frequency (f max). This paper investigates whether velocity saturation can help to get better current saturation and if that correlates with enhanced f max. We have fabricated 500 nm GFETs with high extrinsic f max (37 GHz), and later simulated with a drift-diffusion model augmented with the relevant factors that influence carrier velocity, namely: short-channel electrostatics, saturation velocity effect, graphene/dielectric interface traps, and self-heating effects. Crucially, the model provides microscopic details of channel parameters such as carrier concentration, drift and saturation velocities, allowing us to correlate the observed macroscopic behavior with the local magnitudes. When biasing the GFET so all carriers in the channel are of the same sign resulting in highly concentrated unipolar channel, we find that the larger the drain bias is, both closer the carrier velocity to its saturation value and the higher the f max are. However, the highest f max can be achieved at biases where there exists a depletion of carriers near source or drain. In such a situation, the highest f max is not found in the velocity saturation regime, but where carrier velocity is far below its saturated value and the contribution of the diffusion mechanism to the current is comparable to the drift mechanism. The position and magnitude of the highest f max depend on the carrier concentration and total velocity, which are interdependent and are also affected by the self-heating. Importantly, this effect was found to severely limit radio-frequency performance, reducing the highest f max from ∼60 to ∼40 GHz.

Clustering of atomic displacement parameters in bovine trypsin reveals a distributed lattice of atoms with shared chemical properties.

Low-frequency vibrations are crucial for protein structure and function, but only a few experimental techniques can shine light on them. The main challenge when addressing protein dynamics in the terahertz domain is the ubiquitous water that exhibit strong absorption. In this paper, we observe the protein atoms directly using X-ray crystallography in bovine trypsin at 100 K while irradiating the crystals with 0.5 THz radiation alternating on and off states. We observed that the anisotropy of atomic displacements increased upon terahertz irradiation. Atomic displacement similarities developed between chemically related atoms and between atoms of the catalytic machinery. This pattern likely arises from delocalized polar vibrational modes rather than delocalized elastic deformations or rigid-body displacements. The displacement correlation between these atoms were detected by a hierarchical clustering method, which can assist the analysis of other ultra-high resolution crystal structures. These experimental and analytical tools provide a detailed description of protein dynamics to complement the structural information from static diffraction experiments.

Wide-field off-axis telescope for the Mesospheric Airglow/Aerosol Tomography Spectroscopy satellite.

We present the development of a compact f/7.3 (D=35 mm) three-mirror reflective telescope for the atmospheric-research microsatellite Mesospheric Airglow/Aerosol Tomography Spectroscopy (MATS). The telescope design was driven by the end users' need for a reflective wide-field (5.67°×0.91°) optic with high stray light rejection and six detection channels with separate image sensors, operating at wavelengths 270-772 nm. For the first time, a design method for wide-field off-axis telescopes-in which linear astigmatism is eliminated-was applied and tested in practice. Single-point diamond turning was used to produce two sets of 37-110 mm large free-form aluminum mirrors with surface figure errors and roughness values of 34-62 nm (RMS)/193-497 nm (PV) and 2.8-3.5 nm (RMS), respectively. A method that combines precise machining and geometry measurements (using a coordinate measuring machine) was employed to fabricate an aluminum structure to accurately position the mirrors without the need for manual alignment. The telescope was tested with a network of plate beamsplitters and filters, which define the spectral selection for the six detection channels. Imaging performance measurements were carried out using a reflective off-axis collimator, which projects imaging targets at infinite focus. A modulation transfer function (MTF) value of 0.45 at 20 lp/mm was measured at ∼760 nm (diffraction limit: 0.85) using a slanted edge target. By modeling the measured mirror surfaces in optical design software, a reoptimization of the mirror positions could be performed and an improved MTF of ∼0.75 at 20 lp/mm was predicted. The results demonstrate design- and building methods that can be utilized to make off-axis telescopes for a vast range of applications.

Terahertz radiation induces non-thermal structural changes associated with Fröhlich condensation in a protein crystal.

Whether long-range quantum coherent states could exist in biological systems, and beyond low-temperature regimes where quantum physics is known to be applicable, has been the subject to debate for decades. It was proposed by Fröhlich that vibrational modes within protein molecules can order and condense into a lowest-frequency vibrational mode in a process similar to Bose-Einstein condensation, and thus that macroscopic coherence could potentially be observed in biological systems. Despite the prediction of these so-called Fröhlich condensates almost five decades ago, experimental evidence thereof has been lacking. Here, we present the first experimental observation of Fröhlich condensation in a protein structure. To that end, and to overcome the challenges associated with probing low-frequency molecular vibrations in proteins (which has hampered understanding of their role in proteins' function), we combined terahertz techniques with a highly sensitive X-ray crystallographic method to visualize low-frequency vibrational modes in the protein structure of hen-egg white lysozyme. We found that 0.4 THz electromagnetic radiation induces non-thermal changes in electron density. In particular, we observed a local increase of electron density in a long α-helix motif consistent with a subtle longitudinal compression of the helix. These observed electron density changes occur at a low absorption rate indicating that thermalization of terahertz photons happens on a micro- to milli-second time scale, which is much slower than the expected nanosecond time scale due to damping of delocalized low frequency vibrations. Our analyses show that the micro- to milli-second lifetime of the vibration can only be explained by Fröhlich condensation, a phenomenon predicted almost half a century ago, yet never experimentally confirmed.

Antenna-integrated 0.6 THz FET direct detectors based on CVD graphene.

We present terahertz (THz) detectors based on top-gated graphene field effect transistors (GFETs) with integrated split bow-tie antennas. The GFETs were fabricated using graphene grown by chemical vapor deposition (CVD). The THz detectors are capable of room-temperature rectification of a 0.6 THz signal and achieve a maximum optical responsivity better than 14 V/W and minimum optical noise-equivalent power (NEP) of 515 pW/Hz(0.5). Our results are a significant improvement over previous work on graphene direct detectors and are comparable to other established direct detector technologies. This is the first time room-temperature direct detection has been demonstrated using CVD graphene, which introduces the potential for scalable, wafer-level production of graphene detectors.