Terahertz spectroscopy using an injection-seeded terahertz parametric generator for quantitative analysis and inspection of over-the-counter medicine tablets

Mohara, Mizuki; Shimura, Kei; Aiko, Kenji; Kawase, Kodo

doi:10.1117/12.2288029

Cited by 2 publications

(5 citation statements)

References 9 publications

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“…Figure 2 shows the developed frequency-domain THz (FD-THz) spectrometer with is-TPG. 19 Light emitted from a Q-switched Nd:YAG microchip laser (L11038-11, Hamamatsu Photonics) at a 15 Hz repetition rate (wavelength: 1064 nm) was amplified up to 26 mJ by double-pass Nd:YAG amplifiers (POD-CS3/300P-NY3, PHLUXi). This amplified high-peak-power light was focused on a MgO-doped LiNbO3 (LN) crystal and used as a pump light for generating is-TPG waves.…”

Section: Methodsmentioning

confidence: 99%

“…An injection-seeded THz parametric generation (is-TPG) technique has been developed for realizing a high-peak-power THz wave source, 16 and it has been used for THz frequency-domain spectroscopy (THz-FDS). 17 − 19 Although THz-TDS generally has a high dynamic range below 1 THz, an is-TPG source has the highest dynamic range between 1.5 and 2.0 THz, 17 where a number of characteristic absorption peaks exist. Its high-peak-power THz wave and large dynamic range over a wide frequency range make it applicable to inspecting crystal structures in a formulation tablet without sample damage.…”

Section: Introductionmentioning

confidence: 99%

“…Its high-peak-power THz wave and large dynamic range over a wide frequency range make it applicable to inspecting crystal structures in a formulation tablet without sample damage. The transmission THz spectrometer with an intense THz source such as this makes it possible to inspect a whole sample tablet, 19 not only the surface of the sample or a small portion of the sample like in other microscopic methods. Thus, it has another advantage, the ability to detect changes in crystalline forms directly in a formulation tablet.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Our FD THz spectrometer − that uses a tunable is-TPG THz source was used for obtaining the THz absorption spectra of the sample tablets through transmission measurements. The configuration of the optics is shown in Figure .…”

Section: Methodsmentioning

confidence: 99%

“…We have developed a new frequency-domain (FD) THz spectrometer that uses a high-peak-power tunable THz source called an injection-seeded THz parametric generator (is-TPG). − We demonstrated that clear absorption peaks can be obtained in the spectral range between 1.0 and 2.4 THz for thick ( t = 4.1 mm) nondiluted formulation tablets through transmission measurements, and the crystal forms of an API in low-dose (<5 wt %) formulation tablets can be identified with this spectrometer . We also showed that hydration and dehydration of an API in formulation tablets can be clearly observed with this spectrometer .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Terahertz spectroscopy using an injection-seeded terahertz parametric generator for quantitative analysis and inspection of over-the-counter medicine tablets

Cited by 2 publications

References 9 publications

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

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

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

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