Capturing the Freeze-Drying Dynamics of NaCl Nanoparticles Using THz Spectroscopy.

Sodium chloride (NaCl) aqueous solution becomes NaCl hydrate, NaCl·2H2O, at low temperature, which is different from potassium chloride and is a typical complex model for studying the freeze-drying process in foods and pharmaceuticals. Here, we detected unit-cell-sized NaCl particles in ice as precursor substances of NaCl·2H2O during freezing of NaCl solution by using terahertz (THz) spectroscopy. In the freezing process, Na+ and Cl- ions form two types of metastable unit-cell-sized NaCl particles on the pathway to the well-known NaCl·2H2O crystal production, which are not listed in the phase diagram of freezing of NaCl solution but have absorption peaks in THz spectra. This finding of single unit-cell-sized particles signifies the importance of studying the freeze-drying process in-depth and offers a new possibility for the development of freeze-drying technology for the manufacture of nanometer-sized particles such as ultrafine pharmaceutical powders, which more readily dissolve in water.

Coexistence of Kosmotropic and Chaotropic Impacts of Urea on Water As Revealed by Terahertz Spectroscopy.

Whether urea can serve as a kosmotrope or chaotrope has long been a topic of debate. In this study, broad-band THz spectroscopy (0.2-12 THz) of aqueous solutions of urea was used to characterize the hydration state and the hydrogen bond structure of water around urea. Three low-frequency vibration modes of urea were found around 2, 4, and above 12 THz. After eliminating the contribution of these modes, the "urea-vibration-free" complex dielectric constant was decomposed into the relaxation modes of bulk water and the oscillation modes of water. When hydration water is defined to be reorientationally retarded relative to bulk, our analysis revealed that the hydration number is 1.9 independent of urea concentrations up to 5 M, and this number is in close agreement with that of water constrained by strong acceptor hydrogen bonds of urea oxygen. Regarding the hydrogen bond structure, it was found that the tetrahedral-like water structure is mostly preserved (though the hydrogen bond lifetime is significantly shortened) but the population of non-hydrogen-bonded water molecules fragmented from the network is markedly increased, presumably due to urea's NH2 inversion. These experimental results point to the coexistence of apparently two contradictory aspects of urea: dynamical retardation (the kosmotropic aspect) by the -CO group and slight structural disturbance (the chaotropic aspect) by the -NH2 group.

Characterization of the hydrogen-bond network of water around sucrose and trehalose: Microwave and terahertz spectroscopic study.

Modification of the water hydrogen bond network imposed by disaccharides is known to serve as a bioprotective agent in living organisms, though its comprehensive understanding is still yet to be reached. In this study, aiming to characterize the dynamical slowing down and destructuring effect of disaccharides, we performed broadband dielectric spectroscopy, ranging from 0.5 GHz to 12 THz, of sucrose and trehalose aqueous solutions. The destructuring effect was examined in two ways (the hydrogen bond fragmentation and disordering) and our result showed that both sucrose and trehalose exhibit an obvious destructuring effect with a similar strength, by fragmenting hydrogen bonds and distorting the tetrahedral-like structure of water. This observation strongly supports a chaotropic (structure-breaking) aspect of disaccharides on the water structure. At the same time, hydration water was found to exhibit slower dynamics and a greater reorientational cooperativity than bulk water because of the strengthened hydrogen bonds. These results lead to the conclusion that strong disaccharide-water hydrogen bonds structurally incompatible with native water-water bonds lead to the rigid but destructured hydrogen bond network around disaccharides. Another important finding in this study is that the greater dynamical slowing down of trehalose was found compared with that of sucrose, at variance with the destructuring effect where no solute dependent difference was observed. This discovery suggests that the exceptionally greater bioprotective impact especially of trehalose among disaccharides is mainly associated with the dynamical slowing down (rather than the destructuring effect).

Raman Spectroscopy of Pharmaceutical Cocrystals in Nanosized Pores of Mesoporous Silica.

The Raman spectroscopy of pharmaceutical cocrystals based on caffeine and oxalic acid in nanosized pores of mesoporous silica has been demonstrated at various molar amounts. The Raman peak shifts of caffeine molecules express the existence of pharmaceutical cocrystals in mesoporous silica. The molar amount dependence of the peak shifts describes that caffeine and oxalic acid cocrystallized on the surface of the nanosized pores and piled up layer by layer. This is the first report that shows the Raman spectroscopy is a powerful tool to observe the synthesis of pharmaceutical cocrystals incorporated in the nanosized pores of mesoporous silica. The results indicate a way to control the size of cocrystals on a nanometer scale, which will provide higher bioavailability of pharmaceuticals.

Broadband dielectric spectroscopy of glucose aqueous solution: Analysis of the hydration state and the hydrogen bond network.

Recent studies of saccharides' peculiar anti-freezing and anti-dehydration properties point to a close association with their strong hydration capability and destructuring effect on the hydrogen bond (HB) network of bulk water. The underlying mechanisms are, however, not well understood. In this respect, examination of the complex dielectric constants of saccharide aqueous solutions, especially over a broadband frequency region, should provide interesting insights into these properties, since the dielectric responses reflect corresponding dynamics over the time scales measured. In order to do this, the complex dielectric constants of glucose solutions between 0.5 GHz and 12 THz (from the microwave to the far-infrared region) were measured. We then performed analysis procedures on this broadband spectrum by decomposing it into four Debye and two Lorentz functions, with particular attention being paid to the ß relaxation (glucose tumbling), δ relaxation (rotational polarization of the hydrated water), slow relaxation (reorientation of the HB network water), fast relaxation (rotation of the non-HB water), and intermolecular stretching vibration (hindered translation of water). On the basis of this analysis, we revealed that the hydrated water surrounding the glucose molecules exhibits a mono-modal relaxational dispersion with 2-3 times slower relaxation times than unperturbed bulk water and with a hydration number of around 20. Furthermore, other species of water with distorted tetrahedral HB water structures, as well as increases in the relative proportion of non-HB water molecules which have a faster relaxation time and are not a part of the surrounding bulk water HB network, was found in the vicinity of the glucose molecules. These clearly point to the HB destructuring effect of saccharide solutes in aqueous solution. The results, as a whole, provide a detailed picture of glucose-water and water-water interactions in the vicinity of the glucose molecules at various time scales from sub-picosecond to hundreds of picoseconds.

Compact and stable THz vector spectroscopy using silicon photonics technology.

We present a compact and stable terahertz (THz) vector spectroscopy system using silicon photonics technology. A silicon-based integrated phase control circuit greatly reduces the physical size of the continuous-wave THz spectroscopy system and enhances environmental phase stability. Differential lightwave phase control using two carrier-injection electro-optic modulators enables fast and linear phase sweeps of THz-waves. Using the silicon-photonic circuit, we demonstrate a THz vector spectrometer; the dynamic ranges are 65 and 35 dB at 300 GHz and 1 THz with 1-ms integration time and phase variation is less than ± 10° without thermal packaging.

CW-THz vector spectroscopy and imaging system based on 1.55-µm fiber-optics.

We present a continuous-wave terahertz (THz) vector spectroscopy and imaging system based on a 1.5-µm fiber optic uni-traveling-carrier photodiode and InGaAs photo-conductive receiver. Using electro-optic (EO) phase modulators for THz phase control with shortened optical paths, the system achieves fast vector measurement with effective phase stabilization. Dynamic ranges of 100 dB · Hz and 75 dB · Hz at 300 GHz and 1 THz, and phase stability of 1.5° per minute are obtained. With the simultaneous measurement of absorbance and relative permittivity, we demonstrate non-destructive analyses of pharmaceutical cocrystals inside tablets within a few minutes.

Chemical mapping of pharmaceutical cocrystals using terahertz spectroscopic imaging.

Terahertz (THz) spectroscopic imaging is a promising technique for distinguishing pharmaceuticals of similar molecular composition but differing crystal structures. Physicochemical properties, for instance bioavailability, are manipulated by altering a drug's crystal structure through methods such as cocrystallization. Cocrystals are molecular complexes having crystal structures different from those of their pure components. A technique for identifying the two-dimensional distribution of these alternate forms is required. Here we present the first demonstration of THz spectroscopic imaging of cocrystals. THz spectra of caffeine-oxalic acid cocrystal measured at low temperature exhibit sharp peaks, enabling us to visualize the cocrystal distribution in nonuniform tablets. The cocrystal distribution was clearly identified using THz spectroscopic data, and the cocrystal concentration was calculated with 0.3-1.3% w/w error from the known total concentration. From this result, THz spectroscopy allows quantitative chemical mapping of cocrystals and offers researchers and drug developers a new analytical tool.

Quantitative analysis of amino acids in dietary supplements using terahertz time-domain spectroscopy.

We successfully analyzed the concentrations of five amino acids in commercially available dietary amino acid supplements by using terahertz time-domain spectroscopy (THz-TDS) with an error of ± 12% for the best reproduced components. We also succeeded in analyzing tablets of the supplements wrapped in paper, and thus showed the merit of using THz waves for the nondestructive quantitative analysis of packaged samples by employing the fact that THz waves are capable of passing through several types of packaging material. The ability of THz waves to pass through the paper made it possible to perform a quantitative analysis using the same standard spectra as those used for an unwrapped sample, and the accuracy of a direct quantitative analysis of a packaged sample was almost the same as that of an unwrapped sample.

Analytical terahertz spectroscopy.

Recent progress in analytical terahertz (THz) spectroscopy is reviewed with illustrative examples showing that it is an effective method for detecting and identifying intermolecular interactions in chemical compounds, such as hydrogen bonds. The unique and characteristic properties of THz waves, their significance to both science and industry, and the bases of one of the successful fields of analytical THz spectroscopy, namely THz time-domain spectroscopy and THz imaging for chemical analysis, are described. Preliminary quantitative studies are presented to show the potential of THz spectroscopy for the detection and identification of intermolecular hydrogen bonds in unknown mixture samples. The selective detection of intramolecular hydrogen bonds and the detection of intramolecular interactions in ice are also introduced. Some brief remarks are provided on future developments, the main issues, and the prospects for analytical THz spectroscopy.

Terahertz time-domain spectra of aromatic carboxylic acids incorporated in nano-sized pores of mesoporous silicate.

Terahertz time-domain spectroscopy (THz-TDS) is used to study the intra- and intermolecular vibrational modes of aromatic carboxylic acids, for example, o-phthalic acid, benzoic acid, and salicylic acid, which form either intra- or intermolecular hydrogen bond(s) in different ways. Incorporating the target molecules in nano-sized spaces in mesoporous silicate (SBA-16) is found to be effective for the separate detection of intramolecular hydrogen bonding modes and intermolecular modes. The results are supported by an analysis of the differences in the peak shifts, which depend on temperature, caused by the different nature of the THz absorption. Raman spectra revealed that incorporating the molecules in the nano-sized pores of SBA-16 slightly changes the molecular structures. In the future, THz-TDS using nanoporous materials will be used to analyze the intra- and intermolecular vibrational modes of molecules with larger hydrogen bonding networks such as proteins or DNA.

Detecting a sodium chloride ion pair in ice using terahertz time-domain spectroscopy.

The hydrogen bond resonance of a sodium chloride (NaCl) ion pair trapped in aqueous ice has been observed by transmission terahertz time-domain spectroscopy. The absorption peak of a sodium chloride ion pair in ice is 1.65 THz at 83 K. By investigating the interaction of the cation and anion with other chemical compounds, we deduce that the absorption peak originates from the hydrogen bond resonance of sodium chloride and water molecules. The charge redistribution that occurs when other ion pairs are added to aqueous salt solution changes the absorption spectrum. Furthermore, the results also indicate that simple molecules such as sodium halides have fingerprints in the terahertz region when the ions are trapped in ice. NaCl ion pairs in seawater and in Ringer's solution were examined.

Observation of a small number of molecules at a metal nanogap arrayed on a solid surface using surface-enhanced Raman scattering.

In situ Raman spectroscopic measurements with 785 nm excitation were carried out in aqueous solutions containing bipyridine derivatives. Intense Raman signals were observed when the Ag dimer structure was optimized. The SERS activity was dependent upon on the structure of the Ag dimer with a distinct gap distance, suggesting that the intense SERS originates from the gap part of the dimer. Characteristic time-dependent spectral changes were observed. Not only a spectrum which was the superposition of two bipyridine spectra but also spectra which can be assigned to one of the bipyridine derivatives were frequently observed. Observation using solutions with different concentrations proved that the spectra originated from very small numbers of molecules at the active SERS site of the dimer.

Angle-dependent terahertz time-domain spectroscopy of amino acid single crystals.

The measurement of absorption spectra using angle-dependent terahertz (THz) time-domain spectroscopy for amino acid single crystals of l-cysteine and l-histidine is reported for the first time. Linearly polarized THz radiation enables us to observe angle-dependent far-infrared absorption spectra of amino acid single crystals and determine the direction of the oscillating dipole of the molecules in the 20-100 cm(-1) range. By comparing the THz spectra of a single crystal and powder, we found that there was a clear hydrogen-bond peak in the crystal spectrum as a result of the larger hydrogen-bond network. The low-temperature THz spectra of amino acid microcrystals showed more intermolecular vibrational modes than those measured at room temperature. An ab initio frequency calculation of a single amino acid molecule was used to predict the intramolecular vibrational modes. The validity of the calculation models was confirmed by comparing the results with experimentally obtained data in the Raman spectral region.

Quantitative measurements of amino acids by terahertz time-domain transmission spectroscopy.

The quantitative analysis of amino acids by terahertz (THz) time-domain absorption spectroscopy is demonstrated. The optical densities of the amino acids were found to be linearly proportional to the concentration. The molar absorption coefficients of L-glutamic acid (L-Glu), L-glutamic acid sodium salt (Na-L-Glu), L-glutamic acid hydrochloric salt (HCl-L-Glu), L-cysteine (L-Cys), and L-histidine (L-His) were calculated by averaging the THz spectra of the amino acids at several different concentrations in approximately the 0.2-1.0 mol L(-1) range. The concentrations of L-Glu, L-Cys, and L-His mixed samples were successfully calculated with errors of less than 11% and 20% when their concentrations were higher than 0.45 and 0.22 mol L(-1), respectively, by using the obtained molar absorption coefficient.

Control of near-infrared optical response of metal nano-structured film on glass substrate for intense Raman scattering.

Near-infrared SERS activity of the Ag film under electric polarization was evaluated in aqueous solution containing 1 mM glutamic acid. Spectra were obtained in situ from the near infrared laser Raman microscope system with an excitation wavelength of 785 nm. Intensity of the SERS increased significantly upon application of an external electric field to the film. Empirical signal enhancement factor, which was determined from the peak integration ratio of the SERS vibration to the unenhanced signal from the solution of a defined sample concentration, was estimated to be in the range between 10(5) and 10(9). The evolution of the scattering signal was not observed in the absence of an applied external field. Under the present conditions, the SERS intensity was fully controlled by the applied field and the time. Relatively strong enhancement observed at the present system could be attributable to closed-packed particulate structure characterized by the diameters of approximately 20-90 nm on the Ag film. Raman images prove that the scattering signals are highly localized at the specific sites on the films showing possible achievement of relatively larger enhancement more than 10(12). Importance of the control of the size and inter-particle distance for intense Raman scattering was proved by the preparation of the well-ordered chained Ag dot array showing stronger SERS signals than those at the Ag films.

Terahertz notch filter using intermolecular hydrogen bonds in a sucrose crystal.

We propose a THz notch filter that uses the absorption of the intermolecular hydrogen bonds in a molecular crystal such as sucrose. Terahertz (THz) time-domain spectroscopy was used to investigate the absorption characteristics of a rotationally oriented sucrose single crystal in the 0.3 - 3.0 THz frequency range. The crystal was set so that the (100) face (cleavage) was normal to the THz propagation direction. The two lowest frequency intermolecular hydrogen bonding bands clearly exist at room temperature and at 1.45 and 1.64 THz when the b-axis of the crystal is parallel and perpendicular to the THz polarization, respectively. In contrast, they disappear when the b-axis is reversed. This absorption feature means that it would be possible to utilize a sucrose crystal as a notch filter with a 1.45-THz band center for the 0.1-1.7 THz range and with a 1.64-THz band center for the 0.1-1.9 THz range. When the crystal is rotated, the transmitted intensities of the frequency components near the absorption bands alternate as a sine function against angle. The spectroscopic properties of the sucrose filter were confirmed by continuous THz wave imaging.

A self-assembled nano optical switch and transistor based on a rigid conjugated polymer, thioacetyl-end-functionalized poly(para-phenylene ethynylene).

A nanometer-scale optical switch and transistor were fabricated with thioacetyl-end-functionalized poly(para-phenylene ethynylene)s and Au nanogap electrodes by self-assembly. With photoirradiation, the switch can be switched on/off quickly with a switching ratio as high as 1000. Moreover, the device works well as a p-type transistor. With an increase in gate bias, strong conductance oscillation was observed in this self-assembled transistor (under low temperature 147 K), which is very likely due to single-electron charging oscillations arising from electron tunneling through the nanometer-scale transistor.

Selective chemisorption of end-functionalized conjugated polymer on macro- and nanoscale surfaces.

Linear and conjugated poly(p-phenylene ethynylene)s (PPEs) with three different types of functionalized end groups (thiolacetate, isocyanide, and carboxylic acid groups) were synthesized, and their selective chemisorption behavior on various substrate surfaces were investigated using UV/vis transmission absorption spectroscopy. The UV/vis spectra of the PPEs were clearly dependent on the chemical affinity between the PPE end group and the solid surfaces. Furthermore, regarding the chemisorption of thiolacetate modified polymer on a nanoscopic gold particle surface, we visualized novel polymer-colloid nanoarchitectures such as a barbell-type nanohybrid and interconnected polymer nanowire structures that are successively linked through gold nanoparticles.

Detection of glutamate in optically trapped single nerve terminals by Raman spectroscopy.

Glutamate is the major excitatory neurotransmitter and is of particular interest in light of current models of memory and learning. The paper describes the first in situ detection of glutamate in single nerve terminals (synaptosomes), which is achieved by using laser trapping Raman spectroscopy. The near-infrared laser light captures a single synaptosome obtained from a Wister rat brain. The release of glutamate in a single laser-trapped synaptosome was detected by subtracting the Raman spectrum before depolarization from that after depolarization with the addition of the K(+)-channel blocker, 4-aminopyridine. The result indicated that the single synaptosome released approximately 3 amol of glutamate and that the release rate depended on the 4-aminopyridine concentration.