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Preparation of Rimantadine Hydrochloride Purity Certified Reference Material
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摘要: 采用“质量平衡法”和“定量核磁法”两种独立方法研制了盐酸金刚乙胺纯度标准物质（GBW10262）。对标准物质研制过程中的关键因素，如均匀性、稳定性、定值和不确定度等进行了系统研究。两种方法测得的盐酸金刚乙胺纯度值为99.7%±0.3%（k=2）。所研制的盐酸金刚乙胺标准物质均匀性良好，长期稳定性可保持20个月，并且在7天内保持稳定（50 °C）。同时，对定值、稳定性、均匀性等不确定度来源进行了评估。所研制的盐酸金刚乙胺有证标准物质将为仪器检定、方法验证、质量安全风险监测等实施提供支撑。Abstract: The development of a rimantadine hydrochloride purity certified reference material (CRM) (GBW 10262) was carried out using two independent methods: the mass balance (MB) method and quantitative nuclear magnetic resonance (qNMR) spectroscopy. Critical aspects of the CRM development process, including homogeneity, stability, calibration, and uncertainty, were systematically investigated. The purity of rimantadine hydrochloride CRM, as determined by both methods, was found to be 99.7%±0.3% (k=2). The CRM demonstrated excellent homogeneity, maintaining long-term stability for 20 months, and short-term stability for seven days at 50°C. The study also involved a thorough assessment of uncertainty sources, including characterization, stability, and homogeneity. The rimantadine hydrochloride CRM will support activities such as instrument calibration, method validation, and quality and safety risk monitoring.
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Key words:
- metrology /
- rimantadine /
- homogeneity /
- purity /
- certified reference material /
- uncertainty evaluation /
- MB /
- qNMR
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图 1 盐酸金刚乙胺红外光谱
Figure 1. Fourier-transform infrared (FTIR) spectra of rimantadine hydrochloride
图 2 盐酸金刚乙胺UPLC-QE高分辨质谱
Figure 2. Ultra-performance liquid chromatography (UPLC) Q-Exactive Orbitrap mass spectrometry (MS) spectra of rimantadine hydrochloride
图 5 盐酸金刚乙胺中主要杂质碎片谱图
Figure 5. Spectra of major impurity fragments in rimantadine hydrochloride
图 6 替硝唑核磁谱图
Figure 6. Proton quantitative nuclear magnetic resonance (1H qNMR) spectrum of tinidazole
图 7 盐酸金刚乙胺核磁谱图
Figure 7. Proton quantitative nuclear magnetic resonance (1H qNMR) spectrum of rimantadine hydrochloride CRM
图 8 替硝唑和盐酸金刚乙胺混合核磁谱图
Figure 8. Proton quantitative nuclear magnetic resonance (1H qNMR) spectrum of a mixture of tinidazole and rimantadine hydrochloride CRM
图 9 盐酸金刚乙胺均匀性检验纯度
Figure 9. Results from the homogeneity testing of rimantadine hydrochloride CRM
图 12 盐酸金刚乙胺有证标准物质不确定度来源示意图
Figure 12. Cause-and-effect diagram for uncertainty sources in rimantadine hydrochloride CRM
表 1 盐酸金刚乙胺中水分含量（%）
Table 1. Percentage of moisture content in rimantadine hydrochloride
样品 水分含量 平均值 标准偏差 1 0.11 0.13 0.022 2 0.17 3 0.13 4 0.15 5 0.12 6 0.16 7 0.11 
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表 2 盐酸金刚乙胺中氯离子摩尔含量（mmol）
Table 2. Molar content of chloride ions in rimantadine hydrochloride
样品 氯离子摩尔含量 平均值 标准偏差 1 0.004802 0.004611 0.000214 2 0.004385 3 0.004723 4 0.004743 5 0.004858 6 0.004520 7 0.004246
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表 3 盐酸金刚乙胺的质量平衡法定值结果（%）
Table 3. Purity determination of rimantadine hydrochloride CRM using the mass balance method
样品 有机纯度 水分含量 挥发性组分 不挥发性组分 定值结果 1 99.96 0.11 0.0146 0.0148 99.82 2 99.92 0.17 99.72 3 99.97 0.13 99.81 4 99.90 0.15 99.72 5 99.97 0.12 99.82 6 99.89 0.16 99.70 7 99.85 0.11 99.71 平均值 99.92 0.13 0.0146 0.0148 99.76 标准偏差 0.043 0.022 - - 0.0520
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表 4 盐酸金刚乙胺的定量核磁法定值结果（%）
Table 4. Purity determination of rimantadine hydrochloride CRM using the qNMR method
样品 $ \dfrac{{I}_{\mathrm{x}}}{{I}_{\mathrm{s}\mathrm{t}\mathrm{d}}} $ $ \dfrac{{N}_{\mathrm{s}\mathrm{t}\mathrm{d}}}{{N}_{\mathrm{x}}} $ $ \dfrac{{M}_{\mathrm{x}}}{{M}_{\mathrm{s}\mathrm{t}\mathrm{d}}} $ $ \dfrac{{m}_{\mathrm{s}\mathrm{t}\mathrm{d}}}{{m}_{\mathrm{x}}} $ $ P_{\mathrm{q}\mathrm{N}\mathrm{M}\mathrm{R}\mathrm{ }} $ 1 0.5652 2 0.8726 1.0121 99.82 2 0.5883 2 0.8726 0.9726 99.84 3 0.5866 2 0.8726 0.9747 99.78 4 0.5699 2 0.8726 1.0015 99.59 5 0.5652 2 0.8726 1.0102 99.64 6 0.5758 2 0.8726 0.9926 99.74 7 0.5765 2 0.8726 0.9906 99.65 平均值 99.72% 标准偏差 0.10%
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表 5 盐酸金刚乙胺不确定度评估（%）
Table 5. Uncertainty evaluation for rimantadine hydrochloride CRM
不确定度来源 计算公式 不确定度 均匀性 $ \dfrac{\sqrt{\dfrac{{{s}_{2}}^{2}}{n}}*\sqrt[4]{\dfrac{2}{{v}_{2}}}}{\stackrel{-}{X}} $ 0.0107 长期稳定性 $ \dfrac{\mathrm{s}\left({\beta }_{1}\right)\times t}{\stackrel{-}{X}} $ 0.021 短期稳定性 $ \dfrac{\mathrm{s}\left({\beta }_{1}\right)\times t}{\stackrel{-}{X}} $ 0.011 质量平衡法 $ \dfrac{{P}_{{\mathrm{HPLC-AN}}}.\sqrt{{\left(\dfrac{u\left({P}_{0}\right)}{{P}_{0}}\right)}^{2}+\dfrac{{u}^{2}\left({X}_{w}\right)+{u}^{2}\left({X}_{n}\right)+{u}^{2}\left({X}_{v}\right)}{{（1-{X}_{w}-{X}_{n}-{X}_{v}）}^{2}}}}{\stackrel{-}{X}} $ 0.138 定量核磁法 $ \sqrt{{\left(\dfrac{u\left({I}_{\mathrm{x}}/{I}_{\mathrm{s}\mathrm{t}\mathrm{d}}\right)}{{I}_{\mathrm{x}}/{I}_{\mathrm{s}\mathrm{t}\mathrm{d}}}\right)}^{2}+{\left(\dfrac{u\left({M}_{\mathrm{x}}\right)}{{M}_{\mathrm{x}}}\right)}^{2}+{\left(\dfrac{u\left({M}_{\mathrm{s}\mathrm{t}\mathrm{d}}\right)}{{M}_{\mathrm{s}\mathrm{t}\mathrm{d}}}\right)}^{2}+{\left(\dfrac{u\left({m}_{\mathrm{x}}\right)}{{m}_{\mathrm{x}}}\right)}^{2}+{\left(\dfrac{u\left({m}_{\mathrm{s}\mathrm{t}\mathrm{d}}\right)}{{m}_{\mathrm{s}\mathrm{t}\mathrm{d}}}\right)}^{2}+{\left(\dfrac{u\left({p}_{\mathrm{s}\mathrm{t}\mathrm{d}}\right)}{{p}_{\mathrm{s}\mathrm{t}\mathrm{d}}}\right)}^{2}} $ 0.151 定值 $ \sqrt{\left[\dfrac{u_{\mathrm{r}\mathrm{e}\mathrm{l}}\left(P_{\mathrm{M}\mathrm{B}}\right)}{2}\right]^2+\left[\dfrac{u_{\mathrm{r}\mathrm{e}\mathrm{l}}\left(P_{\mathrm{q}\mathrm{N}\mathrm{M}\mathrm{R}}\right)}{2}\right]^2} $ 0.102 相对不确定度 $ \sqrt{u_{\mathrm{char}，\mathrm{r}\mathrm{e}\mathrm{l}}^2+u_{\mathrm{bb}，\mathrm{r}\mathrm{e}\mathrm{l}}^2+u_{\mathrm{lts}，\mathrm{r}\mathrm{e}\mathrm{l}}^2+u_{\mathrm{sts}，\mathrm{r}\mathrm{e}\mathrm{l}}^2} $ 0.106 包含因子 k 2 扩展不确定度 $ k\times u\mathrm{_{CRM}} $ 0.3
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