Determination method of flunarizine hydrochloride bulk drug element impurities
Through inductively coupled plasma mass spectrometry (ICP-MS) combined with digestion solution, the accuracy and sensitivity of elemental impurities detection in flucinarizine hydrochloride raw materials was solved, and efficient and accurate quantitative analysis of multi-element impurities was achieved, which was suitable for drug quality control.
Patent Information
- Application Number
- CN202510738957.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-04
- Publication Date
- 2025-08-19
AI Technical Summary
The existing impurity detection methods for flucinarizine hydrochloride raw material drug element have problems with low detection accuracy and sensitivity, especially the limited ability to quantify trace elements, and the organic components in the drug matrix are prone to interfere with the detection results.
Inductively coupled plasma mass spectrometry (ICP-MS) was used to combine a specific proportion of nitric acid, hydrochloric acid and hydrogen peroxide digestion for sample pretreatment to digest the drug matrix, and then detect the ion signal of a specific mass number through a mass spectrometer to achieve high sensitivity and high accuracy quantitative analysis of multi-element impurities, and use internal standard solution to correct signal drift.
It has achieved high sensitivity and simultaneous detection of multi-element impurities in flucinarizine hydrochloride raw materials, with excellent anti-interference performance, improved the detection accuracy and stability of trace elements, and met the high-throughput needs of modern drug quality control.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of analysis and detection, and in particular to a method for determining elemental impurities in a flunarizine hydrochloride raw material drug. Background Art
[0002] Flunarizine hydrochloride is a commonly used calcium channel blocker used to treat various cerebrovascular diseases. Elemental impurities in the API may affect the safety and efficacy of the drug, so an accurate and sensitive method is needed to measure these impurities.
[0003] Traditional elemental impurity detection methods (such as atomic absorption spectrometry (AAS) and atomic fluorescence spectrometry (AFS)) often suffer from limitations such as insufficient sensitivity, low efficiency in multi-element detection, and weak anti-interference capabilities. For example, AAS can only detect a single element at a time and has limited quantification capabilities for trace elements (ppb level), making it difficult to meet the high-throughput and high-sensitivity requirements of modern pharmaceutical quality control. Furthermore, organic components in complex drug matrices may interfere with test results, leading to the risk of false positives or false negatives.
[0004] Therefore, developing a method for determining elemental impurities in flunarizine hydrochloride raw materials not only conforms to the international trend of drug quality control, but also provides key technical support for companies to efficiently monitor production processes and reduce drug risks for patients. Summary of the Invention
[0005] The present invention provides a method for determining elemental impurities in a flunarizine hydrochloride raw material drug, which solves the problem of low detection accuracy and sensitivity when detecting elemental impurities in the flunarizine hydrochloride raw material drug in the related art.
[0006] The technical solutions of the present invention are as follows: The present invention provides a method for determining elemental impurities in flunarizine hydrochloride raw material medicine, which adopts inductively coupled plasma mass spectrometry to detect elemental impurities in flunarizine hydrochloride raw material medicine; When the inductively coupled plasma mass spectrometry method is used for detection, the preparation method of the test solution includes the following steps: taking a flunarizine hydrochloride test sample and a digestion solution, mixing them and digesting them to obtain a test solution; The digestion solution includes nitric acid, hydrochloric acid and hydrogen peroxide in a volume ratio of 10:1:0.5-2.
[0007] As a further technical solution, the digestion solution includes nitric acid, hydrochloric acid and hydrogen peroxide in a volume ratio of 10:1:1.
[0008] As a further technical solution, the mass fraction of the nitric acid is 65% to 68%; The mass fraction of the hydrochloric acid is 36% to 38%; The mass fraction of the hydrogen peroxide is 20% to 40%.
[0009] As a further technical solution, a diluent is added after the digestion.
[0010] As a further technical solution, the mass volume ratio of the flunarizine hydrochloride test sample and the digestion solution is 0.1g:11.5~13mL.
[0011] As a further technical solution, the elemental impurities include cadmium, lead, arsenic, cobalt, vanadium, nickel and mercury.
[0012] As a further technical solution, the following steps are included: S1. Prepare the test solution; S2. Preparation of reference solution: using a mixed standard solution of cadmium, lead, arsenic, cobalt, vanadium, nickel and mercury as a reference substance, adding a diluent to obtain a reference solution; S3. Preparation of internal standard solution: taking an internal standard multi-element standard solution, a scandium single element standard solution, and a gold single element standard solution and mixing them with a diluent to obtain an internal standard solution; S4. Perform inductively coupled plasma mass spectrometry on the test solution, reference solution, and internal standard solution.
[0013] As a further technical solution, the diluent in the test solution, the diluent in the reference solution, and the diluent in the internal standard solution independently include nitric acid with a mass fraction of 1% to 3% and hydrochloric acid with a mass fraction of 1% to 3%.
[0014] As a further technical solution, in the diluent, the volume ratio of nitric acid to hydrochloric acid is 1:0.5~2.
[0015] As a further technical solution, the elements in the internal standard multi-element standard solution include bismuth, germanium and indium.
[0016] The working principle and beneficial effects of the present invention are: In the present invention, when detecting elemental impurities in the flunarizine hydrochloride raw material, the test sample is first pre-treated with a digestion solution of nitric acid, hydrochloric acid and hydrogen peroxide in a volume ratio of 10:1:0.5-2 to ensure complete digestion of the drug matrix and avoid interference of residual organic matter with ionization efficiency. Then, inductively coupled plasma mass spectrometry (ICP-MS) is used to ionize elements in the sample through high-temperature plasma, and ion signals of specific mass numbers are detected by a mass spectrometer. This achieves high-sensitivity and high-accuracy rapid quantitative analysis of multi-element impurities in the flunarizine hydrochloride raw material. The method also eliminates interference of the main components and excipients of the drug on the target element signal, has the characteristics of strong specificity, and controls the stability of trace elements. For example, mercury is easily volatile, and its recovery rate is improved by the detection method of the present application.
[0017] In the present invention, inductively coupled plasma mass spectrometry has ultra-high sensitivity (up to ppt level), multi-element simultaneous detection capability and excellent anti-interference performance, and is particularly suitable for the screening and quantitative analysis of multi-element impurities in raw materials. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.
[0019] Figure 1 This is a standard curve diagram of vanadium (V) element of the present invention; Figure 2 This is the standard curve of cobalt (Co) element of the present invention; Figure 3 This is the standard curve of nickel (Ni) element of the present invention; Figure 4 This is the standard curve of arsenic (As) element of the present invention; Figure 5 This is the standard curve diagram of cadmium (Cd) element of the present invention; Figure 6 This is the standard curve of mercury (Hg) element of the present invention; Figure 7 This is the standard curve of lead (Pb) element of the present invention. DETAILED DESCRIPTION
[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.
[0021] Example 1 1. Experimental instruments: Inductively coupled plasma mass spectrometer (ICP-MS, equipped with collision / reaction cell technology); Microwave digestion instrument (for sample pretreatment); Ultrapure water system (18.2 MΩ·cm); Precision electronic balance (accuracy 0.0001g).
[0022] 2. Experimental reagents: Flunarizine hydrochloride API (Batch No. 174230512); Nitric acid (HNO3, ultrapure grade); Hydrochloric acid (HCl, ultrapure grade); Hydrogen peroxide (H2O2, ultrapure grade); Single element standard solution (lead, cadmium, arsenic, mercury, copper, etc., concentration 1000 mg / L); Internal standard solution (indium, bismuth, etc., used to correct signal drift); Tuning solution (containing elements such as Li, Co, Y, Ce, Ti, etc., used for instrument performance optimization); Scandium single element standard solution (concentration 1000 mg / L); Gold single element standard solution (concentration 1000 mg / L); The diluent is 2% by mass nitric acid and 2% by mass hydrochloric acid (the mass ratio of nitric acid to hydrochloric acid is 1:1).
[0023] 3. The method for determining elemental impurities in flunarizine hydrochloride raw material comprises the following steps: S1. Preparation of test solution: Take the flunarizine hydrochloride raw material, accurately weigh 0.1g of fine powder and place it in a digestion tube, add 10mL of nitric acid, 1mL of hydrochloric acid and 1mL of 30% hydrogen peroxide, and microwave digest it. After removing the acid at 140℃ for 1h, cool it to room temperature, and quantitatively transfer it to a 50mL volumetric flask with diluent and dilute to the scale. Shake well and use it for the determination of cadmium, lead, arsenic, cobalt, vanadium, nickel and mercury.
[0024] S2. Preparation of reference solution: Mixed reference solution of 7 elements including cadmium: Accurately measure 1 mL of ICH Q3D element mixed standard solution, place it in a 100 mL volumetric flask, dilute to the mark with diluent, and shake well to prepare the mixed element linear stock solution; accurately measure 0.05 mL, 0.2 mL, 0.4 mL, 0.5 mL, 0.6 mL, and 1 mL of the mixed element linear stock solution, place them in 50 mL volumetric flasks, respectively, and dilute to the mark with diluent. The concentrations from small to large are linear solution 1 to linear solution 6.
[0025] S3. Preparation of internal standard element solution: Internal standard element reference solution: Take appropriate amounts of internal standard multi-element standard solution, scandium single element standard solution, and gold single element standard solution, and dilute them with diluent to a solution containing approximately 0.125 mg / L each of bismuth, indium, germanium, scandium, and gold as a mixed internal standard solution. The role of gold is to suppress mercury residue. The corresponding relationship between elemental impurities and internal standard elements is shown in Table 1.
[0026] Table 1 Correspondence between elemental impurities and internal standard elements
[0027] According to the impurity analysis method, the corresponding test sample diluent was used as a blank. Testing was performed in ascending linear concentration order. A linear regression equation was constructed with the reference sample concentration C (μg / L) as the horizontal axis and the ratio (Ratio) of the internal standard element response value to the response value of the analyte in the reference sample as the vertical axis (Y). The test sample solution was then analyzed by inductively coupled plasma mass spectrometry, and the metal element concentrations in the test sample were calculated based on the linear equation. The elemental impurity contents of cadmium, lead, arsenic, cobalt, vanadium, nickel, and mercury were 0.005 μg / g, not detected, not detected, not detected, not detected, 0.1844 μg / g, and 0.0033 μg / g, respectively.
[0028] Methodological validation 1. Exclusivity Every element found in nature has one or more isotopes. During ICP-MS testing, elemental impurities in the sample are completely evaporated, dissociated, atomized, and ultimately ionized in the high-temperature ICP atmosphere. These isotopic ions can then be separated according to their specific mass-to-charge ratios. The working principle of ICP-MS ensures that this method can accurately identify and detect each elemental impurity.
[0029] 2. Linearity and range The preparation of linear solutions for each element is as described in Example 1 for the preparation of reference solution. Take the linear solutions for each element and, according to the analytical method, use the reference concentration C (μg / L) as the horizontal axis and the ratio (Ratio) of the response value of the internal standard element to the response value of the element to be measured in the reference as the vertical axis (Y) to make a linear regression equation. The linear equations and regression coefficients for each element are shown in Table 2, and the standard curves are shown in Figures 1 to 7 As shown, Figure 1 This is a standard curve diagram of vanadium (V) element of the present invention; Figure 2 This is the standard curve of cobalt (Co) element of the present invention; Figure 3 This is the standard curve of nickel (Ni) element of the present invention; Figure 4 This is the standard curve of arsenic (As) element of the present invention; Figure 5 This is the standard curve diagram of cadmium (Cd) element of the present invention; Figure 6 This is the standard curve of mercury (Hg) element of the present invention; Figure 7This is the standard curve of lead (Pb) element of the present invention.
[0030] Table 2 Linear equations and correlation coefficients of each element
[0031] It can be seen from Table 2 that within a certain concentration range, the concentration of each impurity element has a good linear relationship with the Ratio value.
[0032] 3. Limit of detection and limit of quantification According to the method for determining the limit of detection and limit of quantification in Pharmacopoeia 0412 (2020 edition), based on the standard deviation of the ratio value and the slope of the standard curve, the limits of detection and quantification are calculated according to the formulas LOD = 3δ / S; LOQ = 10δ / S. Where LOD is the limit of detection; LOQ is the limit of quantification; δ is the deviation of the ratio value; and S is the slope of the standard curve. δ can be replaced by the standard deviation of seven blank values.
[0033] The sample was injected 11 times continuously. According to the analytical method of Example 1, the standard deviation of the blank ratio value was obtained. The slope of the standard curve was obtained according to the results under the linear item. The test results are shown in Table 3.
[0034] Table 3 Results of detection limit and quantification limit
[0035] 4. Accuracy Accurately weigh 0.1 g of sample into a digestion tube. Nine replicates were weighed and added to the reference solution to prepare 0.4 mL, 0.5 mL, and 0.6 mL of the lower element linear stock solutions, respectively. The samples were processed according to the sample preparation method. Test solutions were prepared at low, medium, and high concentrations, with triplicates prepared for each concentration and tested. The recovery of each element was calculated. The results are shown in Table 4.
[0036] Table 4 Comparison of element impurity recovery test results
[0037] Conclusion: The average recoveries of each element ranged from 86.73% to 98.57%, and the RSDs of the nine determination results were all less than 10%. This method has good accuracy in detecting elemental impurities.
[0038] 5. Precision Instrument precision: Accurately measure 0.5 mL of the mixed element linear mother solution, place it in a 50 mL volumetric flask, dilute it to the scale with diluent, shake well, and use it as the linear midpoint reference solution. Measure it six times continuously and detect it according to the analytical method of Example 1 to examine the instrument precision. The results are shown in Table 5.
[0039] Table 5 Instrument precision
[0040] Intermediate precision: Accurately measure 0.5 mL of the mixed element linear mother solution, place it in a 50 mL volumetric flask, dilute it to the scale with diluent, shake well, and use it as the linear intermediate point reference solution. The intermediate precision was examined by six consecutive measurements, performed by different experimenters at different times, according to the analytical method of Example 1. The results are shown in Table 6.
[0041] Table 6 Intermediate precision
[0042] Conclusion: After 6 consecutive determinations, the RSDs of the detected amounts of various impurity elements were in the range of 0.46% to 6.86%. This method has good precision in detecting elemental impurities.
[0043] 6. Repeatability According to the method of Example 1, 6 parallel portions of the test solution were prepared and tested. The results are shown in Table 7.
[0044] Table 7 Repeatability test results
[0045] Conclusion: The determination was repeated 6 times, and the detection amounts of each element were basically consistent. This method has good repeatability in detecting elemental impurities.
[0046] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.
Claims
1. A method for determining elemental impurities in flunarizine hydrochloride raw material, characterized in that: Inductively coupled plasma mass spectrometry was used to determine the elemental impurities in flunarizine hydrochloride API; When the inductively coupled plasma mass spectrometry method is used for detection, the preparation method of the test solution includes the following steps: taking a flunarizine hydrochloride test sample and a digestion solution, mixing them and digesting them to obtain a test solution; The digestion solution includes nitric acid, hydrochloric acid and hydrogen peroxide in a volume ratio of 10:1:0.5-2.
2. The method for determining elemental impurities in a flunarizine hydrochloride bulk drug according to claim 1, wherein: The digestion solution includes nitric acid, hydrochloric acid and hydrogen peroxide in a volume ratio of 10:1:
1.
3. The method for determining elemental impurities in a flunarizine hydrochloride bulk drug according to claim 1, wherein: The mass fraction of the nitric acid is 65% to 68%; The mass fraction of the hydrochloric acid is 36% to 38%; The mass fraction of the hydrogen peroxide is 20% to 40%.
4. The method for determining elemental impurities in a flunarizine hydrochloride bulk drug according to claim 1, wherein: A diluent is also added after the digestion.
5. The method for determining elemental impurities in a flunarizine hydrochloride bulk drug according to claim 1, wherein: The mass volume ratio of the flunarizine hydrochloride test sample and the digestion solution is 0.1 g:11.5~13 mL.
6. The method for determining elemental impurities in flunarizine hydrochloride bulk drug according to claim 1, wherein: The elemental impurities include cadmium, lead, arsenic, cobalt, vanadium, nickel and mercury.
7. The method for determining elemental impurities in flunarizine hydrochloride bulk drug according to claim 1, wherein: The following steps are involved: S1. Prepare the test solution; S2. Preparation of reference solution: using a mixed standard solution of cadmium, lead, arsenic, cobalt, vanadium, nickel and mercury as a reference substance, adding a diluent to obtain a reference solution; S3. Preparation of internal standard solution: taking an internal standard multi-element standard solution, a scandium single element standard solution, and a gold single element standard solution and mixing them with a diluent to obtain an internal standard solution; S4. Perform inductively coupled plasma mass spectrometry on the test solution, reference solution, and internal standard solution.
8. The method for determining elemental impurities in the flunarizine hydrochloride bulk drug according to claim 7, wherein: The diluent in the test solution, the diluent in the reference solution, and the diluent in the internal standard solution independently include nitric acid with a mass fraction of 1% to 3% and hydrochloric acid with a mass fraction of 1% to 3%.
9. The method for determining elemental impurities in the flunarizine hydrochloride bulk drug according to claim 8, wherein: In the diluent, the volume ratio of nitric acid to hydrochloric acid is 1:0.5-2.
10. The method for determining elemental impurities in flunarizine hydrochloride bulk drug according to claim 7, wherein: The elements in the internal standard multi-element standard solution include bismuth, germanium and indium.