The role of terahertz polariton absorption in the characterization of crystalline iron sulfate hydrates.

Iron sulfate compounds have been used extensively to produce iron gall ink, a widely used writing ink in the western world from the 12th-20th centuries. Iron gall ink is well known to corrode writing supports, so detection of iron species is important for the preservation of historical artwork and documents. Iron(ii) sulfate readily changes hydration states and oxidizes in ambient conditions, forming compounds that contribute to this deterioration. In this study, five forms of iron sulfate are characterized by terahertz spectroscopy and solid-state density functional theory (DFT). The results have revealed that the room temperature spectra of FeSO4·7H2O and FeSO4·4H2O are remarkably similar, differing by only a single absorption feature. The identifying terahertz spectra provide an unambiguous metric to determine the relative concentrations of the most common hydrates FeSO4·7H2O and FeSO4·4H2O in a mixed sample. Complete spectral assignments of these species were accomplished by quantum mechanical simulations, with the exception being a single anomalous feature at approximately 40 cm(-1) in the heptahydrate. This peak is believed to be due to polariton absorption, brought about by the particular coordination structure of FeSO4·7H2O that results in a greater charge separation relative to the other iron sulfate crystals.

Assignment of the terahertz spectra of crystalline copper sulfate and its hydrates via solid-state density functional theory.

Terahertz (THz) vibrational spectroscopy is a promising tool for the nondestructive and potentially noninvasive characterization of historical objects, which can provide information on the materials used for their production as well as identify and monitor their chemical degradation. Copper sulfate (CuSO4) has drawn interest due to its inclusion in the preparation of iron gall inks found in historical artwork and documents. Copper sulfate rapidly forms hydrates which contribute to the formulation of these ink species and may influence their corrosive nature. In this study, copper sulfate has been studied using a combination of THz time-domain spectroscopy, powder X-ray diffraction (PXRD), and solid-state density functional theory (DFT) in order to better understand the spectral absorbances in the THz region. The results have revealed that the THz spectrum of commercially available "anhydrous" copper sulfate results from the presence of not only the anhydrous form but also the monohydrate (CuSO4·H2O) and trihydrate (CuSO4·3H2O) forms. Complete assignment of the experimental spectrum was achieved through a comparison of density functionals and extensive investigation of the influence of basis set polarization functions on the bonding interactions, lattice parameters, and low-frequency motions in these crystalline solids.

Exploring in-vivo infrared spectroscopy for nail-based diabetes screening.

Diabetes screening is traditionally complex, inefficient, and reliant on invasive sampling. This study evaluates near-infrared spectroscopy for non-invasive detection of glycated keratin in nails in vivo. Glycation of keratin, prevalent in tissues like nails and skin, is a key indicator of T2DM risk. In this study involving 200 participants (100 with diabetes, 100 without), NIR's efficacy was compared against a point-of-care HbA1c analyzer. Results showed a specificity of 92.9% in diabetes risk assessment. This study highlights the proposed NIR system potential as a simple, reliable tool for early diabetes screening and risk management in various healthcare settings.

Systematic study of terahertz time-domain spectra of historically informed black inks.

The potential of terahertz-time domain spectroscopy (THz-TDS) as a diagnostic tool for studies of inks in historical documents is investigated in this paper. Transmission mode THz-TDS was performed on historically informed model writing and drawing inks. Carbon black, bistre and sepia inks show featureless spectra between 5 and 75 cm(-1) (0.15-2.25 THz); however, their analysis still provided useful information on the interaction of terahertz radiation with amorphous materials. On the other hand, THz-TDS can be used to distinguish different iron gall inks with respect to the amount of iron(II) sulfate contained, as sharp spectral features are observed for inks containing different ratios of iron(II) sulfate to tannic or gallic acid. Additionally, copper sulfate was found to modify the structure of iron(II) precipitate. Furthermore, Principal Component Analysis (PCA) applied to THz-TDS spectra, highlights changes in iron gall inks during thermal degradation, during which a decrease in the sharp spectral bands associated with iron(II) sulfate is observed. ATR-FTIR spectroscopy combined with THz-TDS of dynamically heated ink samples indicate that this phenomenon is due to dehydration of iron(II) sulfate heptahydrate. While this research demonstrates the potential of THz-TDS to improve monitoring of the chemical state of historical documents, the outcomes go beyond the heritage field, as it also helps to develop the theoretical knowledge on interactions between terahertz radiation and matter, particularly in studies of long-range symmetry (polymorphism) in complex molecular structures and the role played by the surrounding matrix, and also indicates the potential of THz-TDS for the optimization of contrast in terahertz imaging.

Delayed release tablet dissolution related to coating thickness by terahertz pulsed image mapping.

Delayed release dosage forms such as Asacol employ coatings that are engineered to breakdown and release the drug topically at the nominal pH of the lower intestinal tract. Asacol tablets were found to dissolve in an erratic fashion when they are dissolved in buffers below pH 7 which can occur naturally. In this study Terahertz pulsed imaging (TPI) was used to accurately map the coating thickness of a group of Asacol tablets that were subsequently dissolved using the USP method at pH 6.8. The mean dissolution times were found to correlate with the average coating thickness measured over all surfaces. Thickness values for a single randomly selected face did not correlate well with the dissolution results. The speed and ease of TPI mapping may make it an attractive replacement for wet dissolution testing both in product development and eventually for process analysis.

Pulsed terahertz attenuated total reflection spectroscopy.

Pulsed terahertz attenuated total reflection (ATR) spectra of solid materials and liquids covering the 10 cm(-1) to 120 cm(-1) (0.3 THz to 3.6 THz) region of the electromagnetic spectrum are recorded using a terahertz pulsed spectrometer and silicon ATR modules. Pulsed terahertz ATR measurements are completed nondestructively using small amounts of sample (typically 1 mg for solids) and no sample preparation. Many terahertz analyses can be run in rapid sequence, minimizing the analysis time.

Density mapping and chemical component calibration development of four-component compacts via terahertz pulsed imaging.

The purpose of this research was to investigate suitable procedures for generating multivariate prediction vectors for quantitative composition and density analysis of intact solid oral dosage forms using terahertz pulsed imaging (TPI) spectroscopy. Both frequency- (absorbance and refractive index) and time-domain data are presented. A set of calibration and prediction samples were created according to a quaternary mixture design with five levels of compaction at each concentration design point. Calibration models were generated by partial least-squares, type II (PLS-2) regression of the TPI spectra against nominal composition and relative density reference measurements. Quantitative frequency-domain composition calibration models were created for all crystalline components (R(2)>0.90), but the calibration models for individual amorphous components (R(2)<0.76) did not perform as well in testing. Combining both amorphous components into a single component variable for regression resulted in lower error statistics and equally good predictions of crystalline components. A non-linear attenuation of time-domain spectra was observed as a function of compaction force, which corresponded to compact density predictions (R(2)=0.948). While refractive index spectra were sensitive to density (R(2)=0.937), the absorbance spectra were not. Surface density maps were prepared based on refractive index calibrations.

Relaxation and crystallization of amorphous carbamazepine studied by terahertz pulsed spectroscopy.

At the example of carbamazepine the crystallization of a small organic molecule from its amorphous phase was studied using in situ variable temperature terahertz pulsed spectroscopy (TPS). Even though terahertz spectra of disordered materials in the glassy state exhibit no distinct spectral features we demonstrate subtle changes in the spectra with increasing temperature and discuss the findings in respect to the density of vibrational states. The crystallization leads to distinct spectral features allowing the crystallization and subsequent polymorphic phase transition at higher temperatures to be studied in detail. It is possible to study both relaxation and crystallization processes by variable temperature TPS.

Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging.

Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered controlled release tablets, and soft gelatin capsules. It is possible to determine the spatial and statistical distribution of coating thickness in single and multiple coated products using 3D TPI. The measurements are nondestructive even for layers buried underneath other coating structures. The internal structure of coating materials can be analyzed. As the terahertz signal penetrates up to 3 mm into the dosage form interfaces between layers in multilayered tablets can be investigated. In soft gelatin capsules it is possible to measure the thickness of the gelatin layer and to characterize the seal between the gelatin layers for quality control. TPI is a unique approach for the nondestructive characterization and quality control of solid dosage forms. The measurements are fast and fully automated with the potential for much wider application of the technique in the process analytical technology scheme.

Investigating dehydration from compacts using terahertz pulsed, Raman, and near-infrared spectroscopy.

The purpose of this study was to investigate the dehydration of piroxicam monohydrate (PRXMH) in compacts using terahertz pulsed spectroscopy (TPS), Raman spectroscopy, and reflectance near-infrared (NIR) spectroscopy. Compacts were prepared by using PRXMH and poly(tetrafluoro)ethylene powders and combining them in three different manners before compression to produce compacts in which the PRXMH was dispersed throughout the compact, deposited on one face of the compact, or included as a layer within the compact. TPS was a suitable technique to assess the effect of sample preparation on dehydration, whereas Raman and NIR spectroscopy were limited by their sampling depth and the interference of the polymer matrix. TPS revealed that the dehydration behavior depended largely on the compact preparation method. Non-isothermal dehydration was investigated with all three spectroscopic techniques, combined with principal component analysis (PCA) on samples where the PRXMH was deposited on one face of the compact. In addition, variable temperature X-ray powder diffractometry (VT-XRPD) was used to verify the transformation from PRXMH to anhydrous PRX form I, while thermogravimetric analysis (TGA) was used to monitor the water loss. All three spectroscopic techniques allowed in situ monitoring of the dehydration from the surface layers of the compacts. TPS and Raman spectroscopy detected structural changes of the crystal, while NIR spectroscopy was more sensitive to water loss. PCA of the TPS, Raman spectroscopy, and XRPD data revealed similar dehydration profiles. In contrast, the NIR spectroscopy profile was more similar to the TGA results. The spectroscopic techniques were more suitable than slower techniques such as VT-XRPD for monitoring rapid structural changes that occurred during the dehydration.

Drug hydrate systems and dehydration processes studied by terahertz pulsed spectroscopy.

Terahertz pulsed spectroscopy was used to distinguish between different hydrate systems. In the example of four pharmaceutical materials lactose, carbamazepine, piroxicam and theophylline it was demonstrated that all different hydrate and anhydrate forms exhibit distinct spectra in the far infrared. Furthermore the dehydration of theophylline monohydrate was characterised in situ. Here, a phase transition from the monohydrate to the anhydrous form was observed, followed by evaporation of the hydrate water in a second step. The rotational spectrum of water vapour is very characteristic in the far infrared and can easily be discerned from the terahertz spectrum of the solid state form.

Terahertz pulsed spectroscopy and imaging in the pharmaceutical setting--a review.

Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are two novel techniques for the physical characterization of pharmaceutical drug materials and final solid dosage forms, utilizing spectral information in the far infrared region of the electromagnetic spectrum. This review focuses on the development and performance of pharmaceutical applications of terahertz technology compared with other tools for physical characterization. TPS can be used to characterize crystalline properties of drugs and excipients. Different polymorphic forms of a drug can be readily distinguished and quantified. Recent developments towards a better understanding of the fundamental theory behind spectroscopy in the far infrared have been discussed. Applications for TPI include the measurement of coating thickness and uniformity in coated pharmaceutical tablets, structural imaging and 3D chemical imaging of solid dosage forms.

Characterization of temperature-induced phase transitions in five polymorphic forms of sulfathiazole by terahertz pulsed spectroscopy and differential scanning calorimetry.

The far-infrared properties of all five known polymorphic forms of the drug sulfathiazole have been studied by terahertz pulsed spectroscopy and low-frequency Raman spectroscopy. The observed spectra of the different polymorphs are distinctly different. Terahertz pulsed spectroscopy proves to be a rapid and complementary alternative to other physical characterization techniques reported in the literature for distinguishing between the five forms. Variable-temperature measurements (293-473 K) of all polymorphic forms have been performed. The phase transitions observed have been related to thermal analysis data. Form I is the form stable at high temperature of sulfathiazole with a melting point of about 475 K. Form II melts at around 470 K and recrystallizes at higher temperatures to form I. Forms III, IV, and V all convert to form I via a solid-solid phase transition at temperatures below 450 K. The phase transitions can be monitored by terahertz pulsed spectroscopy. Polymorphic impurities of the samples can be detected in the room temperature spectra and their effect on the phase transition behavior can be studied.

Terahertz pulsed spectroscopy of human Basal cell carcinoma.

Good contrast is seen between normal tissue and regions of tumor in terahertz pulsed imaging of basal cell carcinoma (BCC). To date, the source of contrast at terahertz frequencies is not well understood. In this paper we present results of a spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal human skin and BCC. Both the absorption coefficient and refractive index were higher for skin that contained BCC. The difference was statistically significant over the range 0.2 to 2.0 THz (6.6 cm(-1) to 66.6 cm(-1)) for absorption coefficient and 0.25 to 0.90 THz (8.3 cm(-1) to 30 cm(-1)) for refractive index. The maximum difference for absorption was at 0.5 THz(16.7 cm(-1)). These changes are consistent with higher water content. These results account for the contrast seen in terahertz images of BCC and explain why parameters relating to the reflected terahertz pulse provide information about the lateral spread of the tumor. Knowing the properties of the tissue over the terahertz frequency range will enable the use of mathematical models to improve understanding of the terahertz response of normal and diseased tissue.

Simulating the response of terahertz radiation to basal cell carcinoma using ex vivo spectroscopy measurements.

Studies of basal cell carcinoma using terahertz pulsed imaging have revealed a significant difference between regions of tumor and healthy tissue. These differences are manifested in the reflected pulse due to what is thought to be changes in refractive index and absorption. We present measurements of the refractive index and absorption coefficient of excised normal tissue and basal cell carcinoma using terahertz (THz) transmission spectroscopy. We extract Debye parameters from these data and enter them into a finite difference time domain simulation to predict the shape of the waveforms reflected off the normal tissue and basal cell carcinoma and compare them with published in vivo data. Simulating the interaction of terahertz radiation with normal and cancerous tissue is a key step toward understanding the origin of contrast in terahertz images of skin cancer.

Nondestructive analysis of tablet coating thicknesses using terahertz pulsed imaging.

An understanding of the finished structure of complex pharmaceutical coating is becoming desirable, because tablet coatings are now one of the preferred routes to control the release of active pharmaceutical ingredients. There are few nondestructive techniques capable of examining the coatings of compressed tablets; for example laser induced breakdown spectroscopy has been used but this is a destructive method. Terahertz pulsed imaging offers a potential technique to examine coatings quickly and nondestructively. In the study reported herein, it was possible to distinguish between two brands of across-the-counter ibuprofen tablets. The terahertz maps obtained were compared with obtained photographs of cut-through sections; there was good agreement. The technique is fast: a waveform can be obtained in <20 ms allowing the technique to be considered as a candidate for on-line or at-line analysis in a process analytical environment. The lateral resolution of the technique is limited by diffraction of the terahertz focus to about 150 microm at 3 THz, whereas the axial resolution is limited by the terahertz pulse duration, which is <200 fs, to about 30 microm.

Using terahertz pulsed spectroscopy to quantify pharmaceutical polymorphism and crystallinity.

Terahertz pulsed spectroscopy (TPS) is a new technique that is capable of eliciting rich information when investigating pharmaceutical materials. In solids, it probes long-range crystalline lattice vibrations and low energy torsion and hydrogen bonding vibrations. These properties make TPS potentially an ideal tool to investigate crystallinity and polymorphism. In this study four drugs with different solid-state properties were analyzed using TPS and levels of polymorphism and crystallinity were quantified. Carbamazepine and enalapril maleate polymorphs, amorphous, and crystalline indomethacin, and thermotropic liquid crystalline and crystalline fenoprofen calcium mixtures were quantified using partial least-squares analysis. Root-mean-squared errors of cross validation as low as 0.349% and limits of detection as low as approximately 1% were obtained, demonstrating that TPS is an analytical technique of potential in quantifying solid-state properties of pharmaceutical compounds.

Evaluating the effect of coating equipment on tablet film quality using terahertz pulsed imaging.

In this study, terahertz pulsed imaging (TPI) was employed to investigate the effect of the coating equipment (fluid bed and drum coater) on the structure of the applied film coating and subsequent dissolution behaviour. Six tablets from every batch coated with the same delayed release coating formulation under recommended process conditions (provided by the coating polymer supplier) were mapped individually to evaluate the effect of coating device on critical coating characteristics (coating thickness, surface morphology and density). Although the traditional coating quality parameter (weight gain) indicated no differences between both batches, TPI analysis revealed a lower mean coating thickness (CT) for tablets coated in the drum coater compared to fluid bed coated tablets (p<0.05). Moreover, drum coated tablets showed a more pronounced CT variation between the two sides and the centre band of the biconvex tablets, with the CT around the centre band being 22.5% thinner than the top and bottom sides for the drum coated tablets and 12.5% thinner for fluid bed coated tablets. The TPI analysis suggested a denser coating for the drum coated tablets. Dissolution testing confirmed that the film coating density was the drug release governing factor, with faster drug release for tablets coated in the fluid bed coater (98 ± 4% after 6h) compared to drum coated tablets (72 ± 6% after 6h). Overall, TPI investigation revealed substantial differences in the applied film coating quality between tablets coated in the two coaters, which in turn correlated with the subsequent dissolution performance.

Coating and Density Distribution Analysis of Commercial Ciprofloxacin Hydrochloride Monohydrate Tablets by Terahertz Pulsed Spectroscopy and Imaging.

Terahertz pulsed spectroscopy was used to qualitatively detect ciprofloxacin hydrochloride monohydrate (CPFX·HCl·H(2)O) in tablets, and terahertz pulsed imaging (TPI) was used to scrutinize not only the coating state but also the density distribution of tablets produced by several manufacturers. TPI was also used to evaluate distinguishability among these tablets. The same waveform, which is a unique terahertz absorption spectrum derived from pure CPFX·HCl·H(2)O, was observed in all of the crushed tablets and in pure CPFX·HCl·H(2)O. TPI can provide information about the physical states of coated tablets. Information about the uniformity of parameters such as a coating thickness and density can be obtained. In this study, the authors investigated the coating thickness distributions of film-coated CPFX·HCl·H(2)O from four different manufacturers. Unique terahertz images of the density distributions in these commercial tablets were obtained. Moreover, B-scan (depth) images show the status of the coating layer in each tablet and the density map inside the tablets. These features would reflect differences resulting from different tablet-manufacturing processes.