(T1430-09-61) Identification of Levofloxacin Hydrates and Observation of Their Crystal-Form Transition in Drug Products by Terahertz Frequency-Domain Spectroscopy

Purpose: Demonstrating that the Terahertz (THz) frequency-domain spectrometer (FDS) which uses a high-peak-power THz source based on parametric generation is useful for inspecting difference in crystal structures of active pharmaceutical ingredients (APIs) in drug products and their stability. Terahertz spectroscopy has been an important tool used to identify, differentiate, and quantify polymorphs of various pharmaceutical materials. It is also shown that THz spectroscopy is useful for analyzing hydrates or hydration/dehydration of pure APIs. We have been developing the THz-FDS and showing that our technique is applicable to not only the analysis of pure materials but also the analysis of APIs in drug products. In this work, we evaluated its performance by measuring THz absorption spectra of commercial levofloxacin tablets.

Methods: Levofloxacin (LVFX) hemihydrate was purchased from Tokyo Chemical Industry Co., Ltd. and monohydrate was obtained by recrystallization from mixture of water and ethanol. The crystal structures of these hydrates were confirmed by powder X-ray diffraction (PXRD). Their THz spectra were measured as reference spectra. Four brands of levofloxacin tablets (Tablet A to D) commercially available in Japan were used as samples. Each formulation tablet contained 250 mg (75wt%) of levofloxacin. Eight additives were commonly used in those products, and the use of four additives depended on the product. Tablets A and D had all the same ingredients. These tablets were filed to obtain appropriate signal intensity over the spectral range necessary for the analysis. Their thickness after filing was about 1.6 mm. Terahertz absorption spectra were recorded using our THz FD spectrometer [1]. Tunable high-peak-power THz wave was generated with an injection-seeded terahertz parametric generation (is-TPG) technique. The generated THz wave was focused on a sample tablet in a chamber in which the relative humidity was controlled to less than 1%. The transmitted THz wave was upconverted to near infrared light using a nonlinear crystal and detected by a 2D-CMOS sensor at room temperature. The spectra were measured repeatedly for 31 hours.

Results: Figure 1 shows the absorption spectra of levofloxacin hemihydrate and monohydrate. Absorption peaks of hemihydrate appear clearly at 0.93, 1.35 and 1.50 THz. Those of monohydrate appear at 1.15, 1.35 and 1.60 THz. Therefore, we could identify those hydrates using those characteristic absorption peaks. Absorption spectra of the commercial pharmaceutical tablets measured repeatedly in dry condition (RH < 1%) are shown in Fig. 2. Figure 2(a) shows the spectra of Tablet A. Absorption peaks of hemihydrate form appear at 1.35 and 1.50 THz in the initial spectrum. Therefore, we could identify the API in this product is in hemihydrate form. Those peaks lowered gradually and the peak at around 1.0 THz appeared over time. This suggests that the hemihydrate form dehydrated in the dry condition. On the other hand, the initial spectrum in Fig.2(b), the spectra of Tablet D, is similar to that of monohydrate form. Therefore, we could expect the API in this product to be in monohydrate form. The PXRD analysis showed that this tablet contains both hemihydrate and monohydrate forms. The absorption peaks observed in the spectrum also lowered gradually but the change was faster than that observed in Fig.2(a). This suggests that the hydrate forms dehydrated in the dry condition, and this is much faster than dehydration of pure hemihydrate form. Figure 3 shows the change of extinction value at 1.37 THz for all four levofloxacin tablets. The extinction of Tablet A, B, and C shows linear decrease and Tablet C is the slowest among them. The extinction of Tablet D shows nonlinear behavior, and the change is much faster than the others. Those results indicate that the stability of hydrate forms in drug products depends on their formulations and, in addition, possibly their manufacturing processes.

Conclusion: The hydrate forms of levofloxacin in drug products were identified and their crystal-form transition in dry condition were observed using our THz FD spectrometer. Difference in the hydrate forms was identified by the initial spectra and difference in the stability was suggested by the difference in the change rate of the extinction value. The THz FD spectrometer could be applied to identification of drug products and inspection of their stability during manufacturing processes and in storages.

References: 1. M. Mohara et al., Proc. SPIE 10531, 1053121 (2018).

Fig. 1: THz absorption spectra of levofloxacin hemihydrate and monohydrate.

Fig. 2 THz absorption spectra of commercial levofloxacin tablets, (a) Product A and (b) Product D, measured repeatedly under dry condition (RH < 1%).

Fig.3　Time dependence of the extinction at 1.37 THz for four levofloxacin drug products