Study on Hydration and Dehydration of Ezetimibe by Terahertz Spectroscopy with Humidity-Controlled Measurements and Theoretical Analysis.

Understanding the solid-state transitions of active pharmaceutical ingredients (APIs) is essential for quality control since differences in their forms affect the bioavailability of APIs. Terahertz (THz) frequency-domain spectroscopy is suitable for such an application since it can sensitively probe the lattice phonon modes originating in the crystal structures. THz absorption spectra were obtained for ezetimibe (EZT) and ezetimibe monohydrate (EZT-MH), which have similar crystalline structures and belong to the same space group. The observed absorption spectrum of EZT matched well with the solid-state density functional theory (ss-DFT)-simulated spectrum for the structures at 0 K and room temperature (modeled using constrained unit cell volumes). However for EZT-MH, the ss-DFT spectrum of the room-temperature structure showed better correlation with the experimental THz spectrum than that of the simulated spectrum of the 0 K structures, suggesting that the EZT-MH crystal has greater anharmonic character. Gibbs free-energy curves were calculated, and EZT-MH was found to be more stable than pure EZT and water in a broad temperature range. The hydrate stability may be influenced by the existence of more hydrogen bonds in EZT-MH. The hydration and dehydration of EZT in a pure API tablet and formulation tablets were monitored using a THz spectrometer with a humidity-controlled sample chamber. The effect of the excipient in the formulation tablet on hydration was successfully confirmed by showing that the solid-state transition of the API with excipients is significantly slower than that without it. Under a relative humidity of 60%, hydration of EZT in a pure EZT tablet occurred in 200 min, while the hydration of EZT in a formulation tablet was 50 times slower.

Simulation and Assignment of the Terahertz Vibrational Spectra of Enalapril Maleate Cocrystal Polymorphs.

The identification of crystalline drug polymorphs using terahertz vibrational spectroscopy is a powerful approach for the nondestructive and noninvasive characterization of solid-state pharmaceuticals. However, a complete understanding of the terahertz spectra of molecular solids is challenging to obtain because of the complex nature of the low-frequency vibrational motions found in the sub-3 THz (sub-100 cm-1) range. Unambiguous assignments of the observed spectral features can be achieved through quantum mechanical solid-state simulations of crystal structures and lattice vibrations utilizing the periodic boundary condition approach. The terahertz spectra of two polymorphs of enalapril maleate are presented here to demonstrate that even large pharmaceuticals can be successfully modeled using solid-state density functional theory, including cocrystalline solids comprised of multiple distinct species. These simulations enable spectral assignments to be made, but also provide insights into the conformational and cohesion energies that contribute to the polymorph stabilities. The results reveal that the Form II polymorph of enalapril maleate is the more stable of the two under ambient conditions, and that this stability is driven by a greater intermolecular cohesion energy as compared to Form I.

Programmable deep-UV laser platform for inspection and metrology.

This Letter reports on a high-power, narrow-linewidth deep-UV laser platform built upon a frequency-quintupled, Yb-fiber master-oscillator and power-amplifier system. The source, emitting at a pulse repetition rate of 120 MHz with a linewidth of 90 GHz and beam quality of MX/Y2∼2.1/1.5, has been stably maintained over two weeks by successively changing positions and temperatures of nonlinear crystals in parallel, while outputting a 0.5-W average power at 213 nm.

Discrimination of Pharmaceutical Tablets Based on the Analysis of Solid-State Structures of Ingredients Using Terahertz Transmission Spectroscopy with the Injection-Seeded Parametric Generation Technique.

A frequency-domain terahertz (THz) spectrometer that uses a tunable source, called an injection-seeded THz parametric generator, was applied to the analysis of solid-state structures of ingredients in pharmaceutical tablets, and its performance on discriminating pharmaceutical products was evaluated. The spectrometer has a dynamic range of 70 dB at 2 THz and is suitable for analyzing materials such as pharmaceutical ingredients that often have characteristic absorption peaks between 0.5 and 2.5 THz. Nine ofloxacin (racemate) and four levofloxacin (levorotatory enantiomer) tablet products commercially available in Japan were used as samples. They contain 8-12 additives in addition to the API. The sample tablets were filed down to a thickness of 1.2 mm (ofloxacin tablets) and 1.6 mm (levofloxacin tablets) to obtain transmission spectra over the wide spectral range of 0.8-2.1 THz. The absorption spectra obtained from the spectrometer were preprocessed by the second derivative; then, principal component analysis (PCA) was conducted on the results. Next, quadratic discriminant analysis (DA) was conducted on the scores of the three PCA components. The accuracy of the DA for all 13 products was 96.1%. In addition to the difference in crystal forms of the active ingredient, the small differences in the formulation were clearly discriminated using the THz absorption spectra. The spectrometer combined with data analysis shows potential for applications such as identifying pharmaceutical tablets, monitoring the stability of production processes, evaluating the stability of formulations during storage, and detecting counterfeit drugs on the market.