General detection method for 21 element impurities in injection
By combining inductively coupled plasma mass spectrometry and inductively coupled plasma atomic emission spectrometry, 21 elemental impurities in the injection solution were detected in groups, which solved the problems of inaccuracy and interference in the existing technology, and achieved efficient and accurate batch detection, meeting the ICH Q3D and packaging compatibility requirements.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-31
- Publication Date
- 2026-03-27
AI Technical Summary
Existing technologies are insufficient for efficient, universal, and accurate batch detection of 21 elemental impurities in injection solutions. In particular, ICP-MS is susceptible to interference from polyatomic ions for elements such as silicon, calcium, and iron, while ICP-OES lacks sufficient sensitivity for detecting trace toxic elements such as cadmium, mercury, and lead. There is also a lack of systematic group detection strategies and integrated calibration schemes.
The 21 analytes were divided into two groups for detection using a combination of inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES). The first group was detected using ICP-MS, and the second group was detected using ICP-AES. Mercury was stabilized by the addition of gold, and a quaternary internal standard solution was used for calibration to optimize the detection parameters and detection mode.
It achieves efficient and accurate detection of 21 elemental impurities in injection solutions, overcomes the limitations of single technologies, ensures the accuracy of trace element detection, meets ICH Q3D and packaging material compatibility requirements, and provides scientific, accurate and reliable quality control data.
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical analysis technology, and in particular to a general detection method for 21 elemental impurities in injection solutions. Background Technology
[0002] Elemental impurities in pharmaceuticals can originate from raw materials, excipients, production equipment, packaging materials, or the storage process. These impurities can not only affect the stability and efficacy of drugs, but some elements (such as lead, cadmium, mercury, and arsenic) also possess clear toxicity and may pose risks to patient health. Therefore, establishing accurate and reliable methods for monitoring elemental impurities in pharmaceuticals is a crucial step in ensuring drug quality and safety.
[0003] For injection administration, the ICH Q3D guideline and the Technical Guidelines for Compatibility Studies of Chemical Injectables and Pharmaceutical Glass Packaging Containers (Trial) jointly specify 21 elemental impurities that need to be studied and controlled, including cadmium, lead, arsenic, mercury, cobalt, vanadium, nickel, lithium, antimony, copper, aluminum, boron, silicon, calcium, titanium, chromium, iron, zinc, molybdenum, tin, and barium, and specify their permissible daily exposure (PDE).
[0004] Currently, commonly used techniques for elemental analysis include atomic absorption spectrometry (AAS), inductively coupled plasma atomic emission spectrometry (ICP-OES), and inductively coupled plasma mass spectrometry (ICP-MS). ICP-OES and ICP-MS are widely used due to their advantages such as simultaneous determination of multiple elements, wide linear range, and fast analysis speed. However, for the systematic detection of 21 elements in the complex matrix of injection solutions, single techniques face challenges: ICP-MS is susceptible to interference from polyatomic ions for elements such as silicon (Si), calcium (Ca), and iron (Fe), resulting in poor accuracy; while the sensitivity of ICP-OES for trace toxic elements such as cadmium (Cd), mercury (Hg), and lead (Pb) sometimes fails to meet stringent limits. Existing techniques have reported the use of ICP-MS coupled with ICP-OES, but these methods typically suffer from problems such as fragmented approaches, cumbersome procedures, and a lack of systematic grouping detection strategies and integrated calibration schemes for 21 elements, making it difficult to achieve efficient, universal, and accurate batch detection.
[0005] Based on this, the present invention aims to provide an improved universal detection method for 21 elemental impurities in injection solutions to overcome the shortcomings of the prior art. Summary of the Invention
[0006] The purpose of this invention is to provide an analytical method for 21 elemental impurities in injection solutions, thereby enabling the determination of 21 elemental impurities in injection solutions and achieving quality control of injection solutions.
[0007] To achieve the above objectives, the present invention adopts the following technical solution: This invention proposes a universal detection method for 21 elemental impurities in injection solutions. It employs a combined technique of inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES) to divide the 21 analytes into two groups for detection. The first group of elements includes lithium (Li), aluminum (Al), vanadium (V), cobalt (Co), nickel (Ni), copper (Cu), arsenic (As), cadmium (Cd), antimony (Sb), mercury (Hg), and lead (Pb), which are detected by inductively coupled plasma mass spectrometry. The second group of elements includes boron (B), silicon (Si), calcium (Ca), titanium (Ti), chromium (Cr), iron (Fe), zinc (Zn), molybdenum (Mo), tin (Sn), and barium (Ba), which were detected using inductively coupled plasma atomic emission spectrometry.
[0008] Preferably, the inductively coupled plasma mass spectrometry (ICP-MS) detection is performed using a helium collision mode; the inductively coupled plasma atomic emission spectrometry (ICP-AES) detection is performed using an axial observation mode.
[0009] Preferably, the instrument detection parameters for the inductively coupled plasma mass spectrometry are: plasma power 1400~1550 W, plasma gas flow rate 12~14 L / min, auxiliary gas flow rate 0.8~1.0 L / min, and nebulizing gas flow rate 0.8~1.0 L / min; and the instrument detection parameters for the inductively coupled plasma atomic emission spectrometry are: plasma power 1150~1350 W, plasma gas flow rate 12~13 L / min, auxiliary gas flow rate 0.4~0.6 L / min, and nebulizing gas flow rate 0.4~0.6 L / min.
[0010] Preferably, during the inductively coupled plasma mass spectrometry detection process, gold (Au) stock solution is added to the test sample solution, standard series solutions and reagent blank solutions to achieve a final concentration of 200 μg / L, serving as a stabilizer for mercury (Hg).
[0011] Preferably, during the inductively coupled plasma mass spectrometry detection process, a quaternary internal standard solution is used for calibration. The quaternary internal standard includes scandium (Sc), germanium (Ge), indium (In), and bismuth (Bi), and the final concentration of each is 20 μg / L.
[0012] Preferably, the correspondence between the quaternary internal standard and the element to be measured is as follows: scandium (Sc) is used as the internal standard for lithium (Li), aluminum (Al), and vanadium (V); germanium (Ge) is used as the internal standard for cobalt (Co), nickel (Ni), copper (Cu), and arsenic (As); indium (In) is used as the internal standard for cadmium (Cd) and antimony (Sb); and bismuth (Bi) is used as the internal standard for mercury (Hg) and lead (Pb).
[0013] Preferably, it includes the following steps: (1) Preparation of the test solution: (a) Test solution for inductively coupled plasma mass spectrometry: Accurately measure an appropriate amount of the injection sample, add gold stock solution and quaternary internal standard stock solution, dilute to volume with nitric acid solution, and shake well to obtain the solution; (b) Test solution for detection by inductively coupled plasma atomic emission spectrometry: Accurately measure an appropriate amount of the injection sample, dilute to volume with nitric acid solution, and shake well to obtain the solution; (2) Determination of the first group of elements by inductively coupled plasma mass spectrometry: Prepare a series of standard solutions containing the first group of elements, gold and quaternary internal standard, and establish a standard curve; set the instrument to helium collision mode and optimize the parameters; inject the test solution obtained in step (1)(a) into the instrument and calculate the content of each element in the first group according to the internal standard curve method; (3) Determination of the second group of elements by inductively coupled plasma atomic emission spectrometry: Prepare a series of standard solutions containing the second group of elements and establish a standard curve; set the instrument to axial observation mode and select the characteristic wavelength of each element; inject the test solution obtained in step (1) (b) into the instrument and calculate the content of each element in the second group according to the standard curve method.
[0014] Preferably, in step (2), the preparation method of the series of standard solutions is as follows: accurately measure different volumes of standard stock solutions containing the first group of elements and gold, mix them with a constant volume of gold stock solution and a constant volume of quaternary internal standard stock solution, and dilute them to the same volume with nitric acid solution to obtain at least 5 standard points with different concentrations.
[0015] Preferably, the inductively coupled plasma atomic emission spectrometry is used to detect silicon (Si) in a series of standard solutions, where the concentration of silicon ranges from 0 to 6 μg / mL.
[0016] The present invention has the following technical effects: 1. This invention is the first to propose a grouping principle based on instrument characteristics and elemental properties for 21 injectable liquid elemental impurities required by ICH Q3D and packaging compatibility guidelines, thereby optimizing the allocation of detection resources and effectively avoiding the limitations of a single technology.
[0017] 2. This invention establishes a composite anti-interference and correction scheme for ICP-MS detection groups. The addition of gold effectively stabilizes mercury, which is easily adsorbed and lost; based on the quaternary internal standards Sc, Ge, In, and Bi matched with the mass number and chemical properties of the analyte, fine-tuning is performed in groups, significantly overcoming signal suppression or enhancement caused by complex injection matrix, and ensuring the accuracy of trace element detection, including arsenic and mercury.
[0018] 3. The method described in this invention has undergone systematic and rigorous methodological verification, including specificity, system suitability, linearity, range, limit of detection, limit of quantitation, accuracy, precision, and repeatability. All verification results meet the requirements of relevant guidelines, proving the scientific validity, accuracy, and reliability of the method. Detailed Implementation
[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention. Unless otherwise specified, all reagents used in the following embodiments are of analytical or chromatographic purity.
[0020] Example: Detection of 21 elemental impurities in injection solutions 1. Instruments and Reagents: Inductively Coupled Plasma Mass Spectrometer (ICP-MS, equipped with a collision reaction cell); Inductively Coupled Plasma Atomic Emission Spectrometer (ICP-OES).
[0021] Reagents: Nitric acid (analytical grade, MOS grade); experimental water was ultrapure water (resistivity ≥18.2 MΩ·cm); single-element standard solutions of 21 elements including lithium (Li), aluminum (Al)...barium (Ba) (all concentrations 1000 mg / L); single-element standard solutions of gold (Au), scandium (Sc), germanium (Ge), indium (In), and bismuth (Bi) (all concentrations 1000 mg / L).
[0022] 2. Solution preparation and dilution solvent: 2% nitric acid solution (take 20 ml of nitric acid and dilute with water to 1000 ml).
[0023] Gold (Au) stock solution (20 µg / mL): Prepared by accurately measuring an appropriate amount of gold element standard solution and diluting it with 2% nitric acid solution.
[0024] Quaternary internal standard stock solution (1 µg / mL each): Accurately measure appropriate amounts of standard solutions of scandium (Sc), germanium (Ge), indium (In), and bismuth (Bi), and dilute with 2% nitric acid solution to prepare a mixed solution containing 1 µg of each internal standard element per 1 mL.
[0025] ICP-MS Standard Stock Solution (Multi-element Mixture): Accurately measure appropriate amounts of Li, Al, V, Co, Ni, Cu, As, Cd, Sb, Hg, Pb, and Au standard solutions, dilute with 2% nitric acid solution, and prepare mixed stock solutions with the concentrations shown in the table below.
[0026] ICP-OES Standard Stock Solution (Multi-element Mixture): Accurately measure appropriate amounts of B, Si, Ca, Ti, Cr, Fe, Zn, Mo, Sn, and Ba standard solutions, dilute with 2% nitric acid solution, and prepare a mixed stock solution with the concentrations shown in the table below. Table 1. Stock solution concentration
[0027]
[0028] 3. Preparation of the test solution for ICP-MS: Accurately measure 0.2 mL of the test injection solution and place it in a 50 mL plastic centrifuge tube. Accurately add 500 µL of gold stock solution (20 µg / mL) and 1.0 mL of quaternary internal standard stock solution (1 µg / mL each), dilute to the 50 mL mark with 2% nitric acid solution, and mix well. Prepare the reagent blank solution (without sample) using the same method.
[0029] ICP-OES test solution: Accurately measure 0.4 mL of the same batch of the test solution and place it in a 50 mL plastic centrifuge tube. Dilute to the 50 mL mark with 2% nitric acid solution and mix well. The reagent blank is 2% nitric acid solution. 4. ICP-MS determination of Group I elements 4.1 Preparation of Standard Solutions (STDs) Accurately measure 0 µL, 100 µL, 200 µL, 500 µL, 1000 µL, and 1500 µL of ICP-MS standard stock solution, and corresponding volumes of gold stock solution (500 µL, 480 µL, 460 µL, 400 µL, 300 µL, and 200 µL), and place them sequentially into six 50 mL centrifuge tubes. Then, accurately add 1.0 mL of quaternary internal standard stock solution to each tube. Finally, dilute to the 50 mL mark with 2% nitric acid solution and mix well to obtain the series of standard solutions STD0 (blank), STD1, STD2, STD3, STD4, and STD5. The concentrations of each element are shown in Table 2.
[0030] Table 2. Concentrations of ICP-MS Standard Solutions (µg / L)
[0031]
[0032] 4.2 Instrument conditions and analytical parameters: Detection mode: Helium collision cell kinetic energy discrimination mode (KED) Plasma power: 1450 W Plasma gas flow rate: 13 L / min Auxiliary gas flow rate: 0.9 L / min Atomizing gas flow rate: 0.9 L / min Helium collision flow rate: 4.5 mL / min Sampling depth: 8.0 mm Acquisition mode: Peak Hopping Integration time: 0.5 s / point Number of repetitions: 3 The isotopes to be tested and their corresponding internal standards are: ^7Li (internal standard ^45Sc), ^27Al (internal standard ^45Sc), ^51V (internal standard ^45Sc), ^59Co (internal standard ^72Ge), ^60Ni (internal standard ^72Ge), ^63Cu (internal standard ^72Ge), ^75As (internal standard ^72Ge), ^111Cd (internal standard ^115In), ^121Sb (internal standard ^115In), ^202Hg (internal standard ^209Bi), ^208Pb (internal standard ^209Bi).
[0033] 4.3 Determination Method After powering on and preheating, optimize the instrument with tuning fluid until sensitivity, oxide content, and double charge levels meet requirements. Sequentially measure reagent blanks and a series of standard solutions (STD0-STD5). The instrument software automatically plots a standard curve with the ratio of the response value of each analyte to its corresponding internal standard as the ordinate (Y) and concentration as the abscissa (X), and calculates the regression equation and correlation coefficient (r). System suitability requirements: standard curve r ≥ 0.995 for each element, and internal standard response value recovery rate between 70% and 130%. Then measure the test solution; the software automatically calculates the concentration of each element based on the standard curve.
[0034] 5. ICP-OES method for determining group II elements 5.1 Preparation of Standard Solutions (STDs) Accurately measure 0 µL, 100 µL, 200 µL, 500 µL, 1000 µL, and 1500 µL of ICP-OES standard stock solution into six 50 mL centrifuge tubes, respectively. Dilute to the mark with 2% nitric acid solution and mix well to obtain a series of standard solutions STD0 (blank), STD1, STD2, STD3, STD4, and STD5. The concentrations of each element are shown in Table 3.
[0035] Table 3. Concentrations of ICP-OES series standard solutions (µg / mL)
[0036] 5.2 Instrument conditions and analytical parameter observation method: Axial observation Plasma power: 1250 W Plasma gas flow rate: 12.5 L / min Auxiliary gas flow rate: 0.5 L / min Atomizing gas flow rate: 0.5 L / min Pump speed: 1.5 mL / min Analysis wavelengths (nm): B 249.773, Si 251.611, Ca 393.366, Ti 334.941, Cr 283.563, Fe 259.940, Zn 213.856, Mo 202.030, Sn 189.989, Ba 455.403.
[0037] 5.3 Determination Method Ignite and preheat the instrument to stabilize it. Sequentially determine the reagent blank and a series of standard solutions (STD0-STD5). The instrument software automatically generates standard curves for each element, requiring a correlation coefficient r ≥ 0.995. Then, analyze the ICP-OES test solution prepared in step 3 using the instrument; the software automatically calculates the content based on the standard curves.
[0038] 6. Result Calculation The concentrations of 11 elements (µg / L) measured by ICP-MS and the concentrations of 10 elements (µg / mL) measured by ICP-OES were converted into their contents in the original injection solution (µg / vial or µg / mL) based on their respective sample dilution factors (both 50mL fixed volume).
[0039] 7. Methodological Validation Results The method described in this invention was fully verified. Taking a glass ampoule-packaged injection solution as an example, the results are as follows: Specificity: In the standard blank and reagent blank, the response values (or ratios to internal standards) of all elements were much lower than the lowest concentration standard point (STD1), indicating that the method has good specificity.
[0040] System suitability: Six consecutive measurements of the system suitability solution (approximately STD3 concentration level) showed that the RSD of the 11 element concentrations in the ICP-MS group was 0.37%–1.6%, and the RSD of the 10 element concentrations in the ICP-OES group was 0.26%–0.98%, both far less than 20%, indicating that the instrument system is stable.
[0041] Linearity and range: All 21 elements showed good linearity within their respective concentration ranges, with correlation coefficients r greater than 0.999.
[0042] Limits of Detection (LOD) and Limits of Quantification (LOQ): For the ICP-MS method, the LOD for each element ranged from 0.0003 to 0.262 µg / L, and the LOQ ranged from 0.0009 to 0.873 µg / L; for the ICP-OES method, the LOD for each element ranged from 0.00007 to 0.003 µg / mL, and the LOQ ranged from 0.0002 to 0.011 µg / mL. The LOQs for all elements were significantly lower than their corresponding control limits, indicating that the method sensitivity meets the requirements.
[0043] Accuracy (spiking recovery): At low, medium, and high spiking concentration levels, the average recoveries of 11 elements in the ICP-MS group were 93.1%–107.9%, with RSDs of 0.83%–2.5%; the average recoveries of 10 elements in the ICP-OES group were 93.9%–101.8%, with RSDs of 1.2%–2.0%. All recovery results met the requirements.
[0044] Repeatability: In six parallel spiked samples, the RSD of the recoveries for each element in the ICP-MS group ranged from 0.32% to 1.4%; the RSD of the recoveries for each element in the ICP-OES group ranged from 0.63% to 0.96%. This indicates good repeatability of the method. Example Results: This method was successfully applied to detect 21 elemental impurities in multiple batches of injectable liquid samples with different packaging. The method successfully overcomes the interference problem of ICP-MS determination of elements such as silicon, calcium, and iron, and also ensures the accurate detection of trace elements such as cadmium, mercury, and lead. The entire process is efficient and stable, providing comprehensive and reliable data support for product quality control and packaging material compatibility studies.
[0045] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A universal detection method for 21 elemental impurities in an injection solution, characterized in that, Using a combined inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma atomic emission spectrometry (ICP-AES) technique, 21 analytes were divided into two groups for detection. The first group of elements includes lithium, aluminum, vanadium, cobalt, nickel, copper, arsenic, cadmium, antimony, mercury, and lead, which are detected by inductively coupled plasma mass spectrometry. The second group of elements includes boron, silicon, calcium, titanium, chromium, iron, zinc, molybdenum, tin, and barium, which were detected using inductively coupled plasma atomic emission spectrometry.
2. The universal detection method for 21 elemental impurities in injection solutions according to claim 1, characterized in that, The inductively coupled plasma mass spectrometry method uses helium collision mode for detection; the inductively coupled plasma atomic emission spectrometry method uses axial observation mode for detection.
3. The universal detection method for 21 elemental impurities in injection solutions according to claim 2, characterized in that, The instrument detection parameters for the inductively coupled plasma mass spectrometry are: plasma power 1400~1550 W, plasma gas flow rate 12~14 L / min, auxiliary gas flow rate 0.8~1.0 L / min, and nebulizing gas flow rate 0.8~1.0 L / min; the instrument detection parameters for the inductively coupled plasma atomic emission spectrometry are: plasma power 1150~1350 W, plasma gas flow rate 12~13 L / min, auxiliary gas flow rate 0.4~0.6 L / min, and nebulizing gas flow rate 0.4~0.6 L / min.
4. The universal detection method for 21 elemental impurities in injection solutions according to claim 1, characterized in that, During the inductively coupled plasma mass spectrometry (ICP-MS) detection process, gold stock solution is added to the test sample solution, standard series solutions, and reagent blank solutions to achieve a final concentration of 200 μg / L, serving as a mercury stabilizer.
5. The universal detection method for 21 elemental impurities in injection solutions according to claim 4, characterized in that, During the inductively coupled plasma mass spectrometry (ICP-MS) detection process, a quaternary internal standard solution is used for calibration. The quaternary internal standard includes scandium, germanium, indium, and bismuth, and the final concentration of each is 20 μg / L.
6. The universal detection method for 21 elemental impurities in injection solutions according to claim 5, characterized in that, The correspondence between the quaternary internal standards and the elements to be measured is as follows: scandium is used as the internal standard for lithium, aluminum, and vanadium; germanium is used as the internal standard for cobalt, nickel, copper, and arsenic; indium is used as the internal standard for cadmium and antimony; and bismuth is used as the internal standard for mercury and lead.
7. The universal detection method for 21 elemental impurities in injection solutions according to any one of claims 1-6, characterized in that, Specifically, the following steps are included: (1) Preparation of the test solution: (a) Test solution for inductively coupled plasma mass spectrometry: Accurately measure an appropriate amount of the injection sample, add gold stock solution and quaternary internal standard stock solution, dilute to volume with nitric acid solution, and shake well to obtain the solution; (b) Test solution for inductively coupled plasma atomic emission spectrometry: Accurately measure an appropriate amount of the injection sample, dilute it with nitric acid solution to make up to volume, and shake well to obtain the solution; (2) Determination of the first group of elements by inductively coupled plasma mass spectrometry: Prepare a series of standard solutions containing the first group of elements, gold and quaternary internal standard, and establish a standard curve; set the instrument to helium collision mode and optimize the parameters; inject the test solution obtained in step (1)(a) into the instrument and calculate the content of each element in the first group according to the internal standard curve method; (3) Determination of Group II elements by inductively coupled plasma atomic emission spectrometry: Prepare a series of standard solutions containing Group II elements and establish a standard curve; Set the instrument to axial observation mode and select the characteristic wavelengths of each element; Inject the test solution obtained in step (1) (b) into the instrument, and calculate the content of each element in the second group according to the standard curve method.
8. The universal detection method for 21 elemental impurities in injection solutions according to claim 7, characterized in that, In step (2), the preparation method of the series of standard solutions is as follows: accurately measure different volumes of standard stock solutions containing the first group of elements and gold, mix them with a constant volume of gold stock solution and a constant volume of quaternary internal standard stock solution, dilute them with nitric acid solution to the same volume, and obtain at least 5 standard points with different concentrations.
9. The universal detection method for 21 elemental impurities in injection solutions according to claim 7, characterized in that, The inductively coupled plasma atomic emission spectrometry method described herein is used to detect silicon in a series of standard solutions with a silicon concentration range of 0–6 μg / mL.