Deep venous thrombosis (DVT) is an orthopedic complication with an incidence rate ranging from 66% to 84%. When a thrombus dislodges, it can circulate through the bloodstream and obstruct blood vessels. In severe cases, this can lead to disability or even death in patients. Consequently, preventing thrombosis is a critical aspect of orthopedic treatment and is essential for patient recovery after surgery. Xarelto is currently the most widely used new oral anticoagulant in clinical practice. It achieves anticoagulation by inhibiting factor Xa in a combined state, reducing the risk of thrombosis by 30%. However, due to varying physiological conditions among patients, quantitative testing is necessary for individualized medication in clinical treatment to realize optimal therapeutic effects. Current quantitative measurement methods can be classified into direct and indirect measurement techniques. However, these methods have certain limitations, including high cost, accuracy issues, and controversy to a certain extent. They are also influenced by patients’ physiological characteristics, instruments, and reagents. Consequently, researchers are seeking a novel testing method to enable rapid and quantitative analysis of Xarelto contents. Far-infrared radiation, with a wavelength of 25 μm to 1000 μm, is highly sensitive to related low-frequency vibrations or rotational information, such as changes in configuration, crystal structure, and molecular agglomeration. The far-infrared spectrum detection boasts low photon energy, high resolution, and broad spectral bandwidth, making it widely used in molecular qualitative identification and quantitative analysis. In this study, we examined the far-infrared spectral characteristics of Xarelto using theoretical simulation and experimental testing methods and performed quantitative analysis based on these characteristics. We analyzed the absorption frequency of Xarelto in the wavenumber range of 0-100 cm-1 and related molecular motion modes to predict its far-infrared absorption characteristics using density theory. By collecting Xarelto experimental absorption spectrum and employing Fourier far-infrared precision spectrometer, we compared the results with theoretical analyses. This revealed Xarelto characteristic peaks in the far-infrared band. By examining multiple characteristic peaks, we studied the absorption spectrum changes of Xarelto samples with different contents in the far-infrared band. We then analyzed the correlation between Xarelto content and peak intensity, ultimately achieving quantitative testing of Xarelto.
This study utilized the PubChem Structure database to construct a molecular simulation model for Xarelto. We employed quantum chemical software Gaussian 09 and density functional theory to calculate and simulate Xarelto theoretical far-infrared spectral characteristics. Specifically, we selected the DFT/B3LYP/3-21G basis set to optimize and calculate the Xarelto molecular model, predicting its properties in the 0-100 cm-1 range and applying the Gaussian broadening of Xarelto spectral lines (with a full width at half-maximum of 4 cm-1). We then used a far-infrared spectrometer to conduct qualitative experimental tests on pure polyethylene (PE) and 25 mg and 60 mg Xarelto samples. We also collected the far-infrared absorption maps of Xarelto/PE hybrid chips with Xarelto masses ranging from 2.5 mg to 25 mg for quantitative experiments.
In this study, we obtained Xarelto theoretical spectrum through the theoretical simulation method (Fig. 1), which identified the peaks of Xarelto theoretical characteristics at 24.00, 40.22, 72.63, 81.38, and 100.60 cm-1. Through qualitative experimental tests of pure PE and 25 mg and 60 mg Xarelto samples, we obtained the drug experimental far-infrared absorption diagram (Fig. 3), revealing absorption peaks at 49.03, 80.54, and 96.29 cm-1, as well as two weak absorption shoulder peaks at 38.87 cm-1 and 72.66 cm-1. The relative peaks are consistent, and peak deviation is minimal. Based on Xarelto far-infrared absorption characteristics, we selected 49.03, 80.54, and 96.29 cm-1 as quantitative indicators to examine the far infrared spectrum rules of different samples with different Xarelto masses (Fig. 5) and conducted a quantitative analysis. There is a linear relationship between Xarelto mass and the three feature absorption peak heights, which aligns with Beer-Lambert’s law (Fig. 6). The specific expressions of the linear fitting functions are y
Based on density functional theory, in this study, far-infrared detection technology was employed to analyze the novel oral anticoagulant Xarelto, examining its far-infrared spectral characteristics and conducting quantitative analysis using its characteristic absorption peaks. Through theoretical simulation, it was predicted that Xarelto exhibits five characteristic peaks within the wavenumber range below 100 cm-1. Subsequently, we used far-infrared detection technology to collect experimental spectra consistent with the theoretical prediction results, determining the drug characteristic frequencies at 38.87, 49.03, 72.66, 80.54, and 96.29 cm-1. Theoretical simulation results were combined to analyze the corresponding molecular vibration modes for these characteristic absorption peaks. Building on this foundation, different samples with different Xarelto masses were detected and analyzed. Furthermore, it was discovered that the characteristic absorption peak height increases linearly with the Xarelto mass (correlation coefficients are greater than 0.993, and standard deviations are less than 0.026). The correlation between multiple characteristic peaks and Xarelto masses enables rapid and quantitative testing of Xarelto contens. The findings of this study will contribute to the development of rapid detection methods for antithrombotic drugs like Xarelto in the future.
