Screening of 12 elemental impurities in pharmaceutical excipient grades of titanium dioxide from various sources and their correlations with whiteness
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摘要:
在推动国际人用药品注册技术协调会（ICH）Q3D指导原则在我国的实施与转化过程中，天然来源药用辅料的元素杂质风险评估常面临元素杂质种类多、检测方法不足等挑战。本研究以常用天然来源药用辅料二氧化钛为例，采用优化后的酸提取前处理法，建立了筛查二氧化钛中12种元素杂质的电感耦合等离子体质谱（ICP-MS）方法。该分析方法在各元素测定范围内线性关系良好，精密度与重复性良好，镉、铅、汞、钴、镍、锂、钡、钼、铜、铬、铁的回收率为83.6%~101.6%，锑元素的回收率为54.1%，RSD为1.1%~10.2%（n=6）。元素杂质评估结果显示本品镉、汞、钴、镍、锂、钡、钼、铜、铬、锑元素风险较低，铅元素风险较高，建议在本品药典标准中增设铅盐检查项。基于统计数据，对比分析了国内外10家生产企业29批二氧化钛样品的元素杂质和白度值控制水平的差异，并采用Pearson相关系数法对元素杂质残留量与白度进行相关性分析，以可视化热图对结果进行直观展示。结果显示白度与钡残留量、元素杂质残留量总和呈显著负相关，建议生产企业将白度纳入内控指标，进一步提升药用辅料二氧化钛的质量。
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关键词:
- 药用辅料 /
- 二氧化钛 /
- 电感耦合等离子体质谱(ICP-MS) /
- 元素杂质
Abstract:In the process of promoting the implementation and transformation of the Q3D guideline of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in China, the risk assessment of elemental impurities in naturally sourced excipients often faces challenges such as multiple types of elemental impurities and insufficient detection methods. In this paper, an inductively coupled plasma mass spectrometry (ICP-MS) method for screening 12 elemental impurities in titanium dioxide was established using the optimized acid extraction pre-treatment method. The accuracy and repeatability of the method were good. The recoveries of cadmium, lead, mercury, cobalt, nickel, lithium, barium, molybdenum, copper, chromium and iron were 83.6%−101.6%, the recovery of antimony was 54.1%, and the RSD was 1.1%−10.2% (n=6). The evaluation results of elemental impurities showed that the risk of cadmium, mercury, cobalt, nickel, lithium, barium, molybdenum, copper, chromium and antimony was low, while the risk of lead was high, and it is recommended that a lead salt test be added to the pharmacopoeia standard for this product. Based on the statistical data, the differences in the control levels of elemental impurities and whiteness of 29 batches of titanium dioxide samples from 10 domestic and foreign manufacturers were compared and analyzed. The Pearson correlation coefficient method was used to analyze the correlation between residual elemental impurities and whiteness, and a heat map was used to visualize the results. The results showed that whiteness was significantly negatively correlated with the amount of residual barium and the sum of residual elemental impurities. It is suggested that the manufactures should include whiteness as an internally controlled indicator to further improve the quality of titanium dioxide used as a pharmaceutical excipient.
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Figure 1. Box plots of residual elemental impurities in titanium dioxide samples used as pharmaceutical excipients from domestic and imported from Europe and the United States(Euro&US): (A) Pb, Ba, Fe; (B) Ni, Cu, Cr; (C) Cd,Co,Mo. (Note：A1−F3 are domestic samples，19 batches in total; H1−J1 are samples imported in Europe and the United States, 7 batches in total)
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Figure 2. Box plots of blue-ray whiteness in pharmaceutical excipient grades of titanium dioxide samples from domestic and imported in Europe and the United States (Euro&US). (Note: A1−F3 are domestic samples, 19 batches in total; H1−J1 are samples imported from Europe and the United States, 7 batches in total)
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Figure 3. Heat map for correlation analysis of blue-ray whiteness, individual elemental impurity residue values and total elemental impurity residue values of 29 batches of titanium dioxide samples
Table 1 Results of elemental impurities in 29 batches of titanium dioxide samples（μg/g, n=3）in comparison with element concentration control thresholds according to ICH Q3D guidelines
Manufacturer (Country) Lot No. Sample ID Cd Pb Hg Co Ni Li Sb Ba Mo Cu Cr Fe A(China) 107720211101 A1 ND 1.10 ND 0.010 0.37 ND ND 5.40 0.080 1.33 0.51 6.16 107720211201 A2 0.001 1.09 ND 0.009 0.35 ND ND 5.53 0.054 1.45 0.48 6.67 B(China) 20191101 B1 0.001 3.02 ND 0.003 0.06 ND ND 4.48 0.057 0.32 0.19 12.30 20200301 B2 0.001 1.61 ND 0.004 0.01 ND ND 2.92 0.013 0.82 0.07 1.93 20201201 B3 ND 0.36 ND 0.003 ND ND ND 2.80 0.005 0.64 0.02 2.45 20220101 B4 ND 1.70 ND 0.003 0.03 ND ND 3.22 0.014 0.86 0.10 2.23 C(China) 202112120 C1 0.001 3.91 ND 0.017 1.02 ND ND 5.19 0.010 0.75 1.52 10.26 202112240 C2 ND 3.38 ND 0.019 1.07 ND 0.047 5.36 0.027 1.15 1.75 12.10 202201150 C3 0.001 3.34 ND 0.020 1.12 ND 0.055 5.82 0.032 1.30 1.81 12.40 D(China) 2110101 D1 ND 1.05 ND 0.004 0.04 ND ND 3.44 0.005 0.32 0.07 5.24 2112102 D2 ND 0.69 ND 0.006 0.01 ND 0.070 3.58 0.013 0.56 0.07 3.38 1903102 D3 0.003 0.71 ND 0.004 0.02 ND ND 3.70 0.025 0.31 0.07 3.00 1805101 D4 0.001 1.10 ND 0.005 0.08 ND ND 3.48 0.048 0.36 0.14 21.30 E(China) TF24211001 E1 ND 2.05 ND 0.005 ND ND ND 3.22 0.107 0.44 0.01 3.24 TF24211002 E2 ND 2.04 ND 0.006 ND ND ND 3.06 0.072 0.51 0.14 4.11 TF24220101 E3 0.004 2.09 ND 0.007 ND ND ND 3.06 0.071 0.54 0.04 3.04 F(China) 20210507 F1 0.004 2.23 ND 0.002 0.02 ND ND 3.55 0.002 0.71 0.04 5.47 20211105 F2 0.006 2.39 ND 0.003 0.03 ND 0.299 3.53 0.021 0.76 0.11 7.32 20211025 F3 0.003 2.45 ND 0.003 0.03 ND 0.026 3.53 0.016 0.73 0.09 8.45 G(India) PM220111 G1 ND 0.64 ND 0.003 0.02 ND ND 387.21 0.004 0.47 0.06 2.25 PM210911 G2 ND 0.70 ND 0.004 0.03 ND ND 389.31 0.119 0.40 0.09 2.60 PM210757 G3 ND 0.70 ND 0.004 0.03 ND ND 381.38 0.118 0.41 0.09 2.66 H
(United States)DOXR070042 H1 ND 0.29 ND 0.049 0.12 ND ND 0.33 0.037 0.20 0.75 4.39 D1AR170019 H2 0.001 0.29 ND 0.005 0.20 ND ND 0.34 0.075 0.20 0.65 3.18 D1BR090019 H3 0.001 0.20 ND 0.005 0.15 ND 0.046 0.30 0.076 0.17 0.88 3.83 I(Germany) 0037854 I1 ND 0.38 ND 0.002 0.10 ND ND 3.17 0.003 0.18 0.22 2.21 0031086 I2 ND 0.49 ND 0.010 0.10 ND ND 2.26 0.002 0.11 0.06 1.29 0038787 I3 0.002 0.69 ND 0.010 0.09 ND ND 2.70 0.008 0.16 0.11 ND J(Germany) K51900005 J1 ND 0.12 ND 0.003 0.05 ND ND 0.35 0.008 0.23 0.25 3.51 Oral element concentration control threshold according to ICH Q3D 0.15 0.15 0.9 1.5 6 16.5 36 42 90 90 330 ND indicates that the test result is below LOD. The oral element concentration control threshold values are calculated according to Option 1 in ICH Q3D guidelines (30% of oral permitted concentrations of elemental impurities), which is suitable for assessing the elemental impurity content in drug products with daily doses of not more than 10 g per day 
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