CN111122285B - Method for detecting additive in amide local anesthetic - Google Patents
Method for detecting additive in amide local anesthetic Download PDFInfo
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- CN111122285B CN111122285B CN201910122177.1A CN201910122177A CN111122285B CN 111122285 B CN111122285 B CN 111122285B CN 201910122177 A CN201910122177 A CN 201910122177A CN 111122285 B CN111122285 B CN 111122285B
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- 238000000034 method Methods 0.000 title claims abstract description 70
- 239000000654 additive Substances 0.000 title claims abstract description 14
- 230000000996 additive effect Effects 0.000 title claims description 13
- 150000001408 amides Chemical class 0.000 title claims description 12
- 239000003589 local anesthetic agent Substances 0.000 title claims description 12
- 239000000243 solution Substances 0.000 claims abstract description 70
- 238000001514 detection method Methods 0.000 claims abstract description 47
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 claims abstract description 20
- 229910052785 arsenic Inorganic materials 0.000 claims abstract description 18
- 229910052720 vanadium Inorganic materials 0.000 claims abstract description 18
- 229960001813 ropivacaine hydrochloride Drugs 0.000 claims abstract description 16
- 238000001095 inductively coupled plasma mass spectrometry Methods 0.000 claims abstract description 15
- 229910052721 tungsten Inorganic materials 0.000 claims abstract description 15
- 239000012490 blank solution Substances 0.000 claims abstract description 14
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000012452 mother liquor Substances 0.000 claims description 108
- 239000000523 sample Substances 0.000 claims description 71
- 238000002360 preparation method Methods 0.000 claims description 47
- 239000003085 diluting agent Substances 0.000 claims description 38
- 239000012488 sample solution Substances 0.000 claims description 26
- 239000010413 mother solution Substances 0.000 claims description 25
- 239000007789 gas Substances 0.000 claims description 21
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- 239000012086 standard solution Substances 0.000 claims description 20
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 15
- 229910017604 nitric acid Inorganic materials 0.000 claims description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 238000007865 diluting Methods 0.000 claims description 10
- 238000012360 testing method Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 229910052786 argon Inorganic materials 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 238000012795 verification Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 229910052750 molybdenum Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 18
- 238000010998 test method Methods 0.000 abstract description 4
- 229940052294 amide local anesthetics Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract 1
- 238000002372 labelling Methods 0.000 description 18
- 238000004458 analytical method Methods 0.000 description 13
- 229910052742 iron Inorganic materials 0.000 description 12
- 238000002347 injection Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 230000003252 repetitive effect Effects 0.000 description 10
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000002184 metal Substances 0.000 description 4
- 150000002739 metals Chemical class 0.000 description 4
- 229960001549 ropivacaine Drugs 0.000 description 4
- 230000036592 analgesia Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 239000012776 electronic material Substances 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229910052706 scandium Inorganic materials 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 238000011895 specific detection Methods 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 229910052767 actinium Inorganic materials 0.000 description 1
- QQINRWTZWGJFDB-UHFFFAOYSA-N actinium atom Chemical compound [Ac] QQINRWTZWGJFDB-UHFFFAOYSA-N 0.000 description 1
- 229910052789 astatine Inorganic materials 0.000 description 1
- RYXHOMYVWAEKHL-UHFFFAOYSA-N astatine atom Chemical compound [At] RYXHOMYVWAEKHL-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010892 electric spark Methods 0.000 description 1
- 238000002692 epidural anesthesia Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052730 francium Inorganic materials 0.000 description 1
- KLMCZVJOEAUDNE-UHFFFAOYSA-N francium atom Chemical compound [Fr] KLMCZVJOEAUDNE-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- -1 protactinium Chemical compound 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N1/38—Diluting, dispersing or mixing samples
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
- G01N27/64—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode using wave or particle radiation to ionise a gas, e.g. in an ionisation chamber
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Electrochemistry (AREA)
- Toxicology (AREA)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
- Sampling And Sample Adjustment (AREA)
Abstract
The application provides a method for detecting additives in amide local anesthetics, which adopts an ICP-MS method to verify 20 elements (As, cd, B, al, si, cr, mn, fe, zn, ba, co, cu, hg, li, ni, pb, sb, V, mo, W) in ropivacaine hydrochloride process liquid, the correlation coefficient of an equation is greater than 0.995, the recovery rate of all accuracy solutions is between 70% and 150%, the RSD is not more than 20%, the recovery rate of LOQ solution is between 70% and 150%, the RSD is less than 20%, the detection value of a process blank solution is not more than LOQ, the concentration level recovery rate in accuracy solutions is between 70% and 150%, the RSD is not more than 20%, the RSD of the calculation result of 6 copies of repeatability solutions is less than 20%, and the method has good accuracy and can be used as a test method to measure 20 elements in ropivacaine hydrochloride process liquid in biological medicine department.
Description
Technical Field
The application relates to the field of analysis and test, in particular to a method for detecting an additive in amide local anesthetics.
Background
Ropivacaine (Ropivacaine) is a long-acting amide local anesthetic, and has the pharmacological characteristics of low cardiotoxicity, more obvious separation of sensory retardation and movement retardation, and vasoconstriction. Ropivacaine has dual effects of anesthesia and analgesia, is suitable for surgical anesthesia, epidural anesthesia, postoperative analgesia and local anesthesia of 72 hours in the delivery process, can effectively block sensory nerve transmission to generate analgesia, and has small influence on motor nerves. The product is first developed by the company astla, sweden in 1994 to obtain ropivacaine hydrochloride injection, which was approved to be marketed in the united states in 1995.
There are few studies on methods for controlling and analyzing various components such as metal elements in ropivacaine and its salts. Moreover, the method is also applicable to the field of the present application. Of 92 natural elements that are known to exist in nature, 81 other than inert gas elements and technetium, francium, actinium, protactinium, astatine, and the like are all present in organisms. At present, due to the limitations of sample processing methods and detection conditions, the sampling amount of a detected sample is usually smaller when element detection is carried out, which results in low detection value of the sample in the detection process, difficult detection of some components or large detection errors. It is therefore necessary to establish a more robust, more accurate, more reproducible, less limited detection, etc.
Disclosure of Invention
In order to solve the technical problems, the application provides a detection method of an additive in amide local anesthetics by adopting an ICP-MS method, which comprises the following steps:
(1) Preparing a solution;
(2) Detecting by an instrument;
(3) Verifying performance;
the solution preparation comprises diluent preparation, standard solution preparation, sample mother solution preparation, sample solution preparation, process blank solution preparation, accuracy solution preparation and repeatability solution preparation.
As a preferred embodiment, the diluent is formulated as a 2% strength by mass nitric acid solution and a 2% strength by mass hydrogen peroxide solution.
As a preferable technical scheme, the weight part ratio of the nitric acid solution with the mass concentration of 2% and the hydrogen peroxide with the mass concentration of 2% is (5-10): 2.
as a preferable technical scheme, the preparation of the standard solution comprises the preparation of Hg element standard mother liquor, 7 element mixed standard mother liquor, 3 element mixed standard mother liquor and 15 element mixed standard mother liquor; wherein 7 elements comprise As, cd, co, ni, pb, sb, V,3 elements comprise Mo, sn and W, and 15 elements comprise Al, B, li, mn, ba, cr, cu, ti, na, mg, K, ca, fe, zn, si.
As a preferable technical scheme, the sample mother solution is prepared by dissolving sodium chloride in water, adding ropivacaine hydrochloride in a stirring state, and stirring until the ropivacaine hydrochloride is completely dissolved; and continuing to add water and stirring to obtain a sample mother solution.
As a preferable technical scheme, the pH value of the sample mother solution is 4-6.
As a preferable technical scheme, a sample solution is prepared by diluting a sample mother solution in a volumetric flask to a scale with a diluent, and shaking uniformly to obtain 2 parts of sample mother solution in parallel by the same method.
As a preferred embodiment, the dilution factor of the diluent is (40-60).
As a preferred technical scheme, the instrument detection is carried out by ICP-MS, wherein the ratio of the flow rate of the atomizing gas to the flow rate of the auxiliary gas is (0.5-1): 1.2.
as a preferred technical scheme, the instrument detection is carried out by ICP-MS, wherein the plasma gas is argon, and the flow rate is 18L/min.
Compared with the prior art, the application has the beneficial effects that: the application provides a method for detecting an additive in an amide local anesthetic, which adopts an ICP-MS method to carry out methodological verification on 20 elements (As, cd, B, al, si, cr, mn, fe, zn, ba, co, cu, hg, li, ni, pb, sb, V, mo, W) in ropivacaine hydrochloride process liquid, wherein verification items comprise specificity, linearity, accuracy, quantitative limit and precision (repeatability). The correlation coefficient of the equation is greater than 0.995, the recovery rate of all accuracy solutions is between 70% and 150%, the recovery rate of the RSD is not more than 20%, the recovery rate of the LOQ solution is between 70% and 150%, the RSD is less than 20%, the detection value of the blank solution in the process is not more than LOQ, the recovery rate of the concentration level in the accuracy solutions is between 70% and 150%, the RSD is not more than 20%, and the RSD of the calculation result of 6 parts of repeatability solutions is less than 20%.
Detailed Description
The contents of the present application can be more easily understood by referring to the following detailed description of preferred embodiments of the present application and examples included. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In case of conflict, the present specification, definitions, will control.
For the purposes of the following detailed description, it is to be understood that the application may assume various alternative variations and step sequences, except where expressly specified to the contrary. Furthermore, except in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present application. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the application are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein. For example, a specified range from "1 to 10" should be considered to include any and all subranges between the minimum value of 1 and the maximum value of 10. Exemplary subranges from 1 to 10 include, but are not limited to, 1 to 6.1, 3.5 to 7.8, 5.5 to 10, and the like.
The application provides a method for detecting an additive in an amide local anesthetic, which comprises the following steps:
(1) Preparing a solution;
(2) Detecting by an instrument;
(3) Verifying performance;
the solution preparation comprises diluent preparation, standard solution preparation, sample mother solution preparation, sample solution preparation, process blank solution preparation, accuracy solution preparation and repeatability solution preparation.
In one embodiment, the configuration of the standard solution comprises the configuration of Hg element standard mother liquor, 7 element mixed standard mother liquor, 3 element mixed standard mother liquor and 15 element mixed standard mother liquor; wherein 7 elements comprise As, cd, co, ni, pb, sb, V,3 elements comprise Mo, sn and W,15 elements comprise Al, B, li, mn, ba, cr, cu, ti, na, mg, K, ca, fe, zn, si, corresponding standard mother solutions are selected for configuration, and the standard mother solutions can be purchased from the market and can be self-configured, such as standard mother solutions of national nonferrous metals and electronic material analysis and test centers.
In one embodiment, the configuration of the internal standard solution is a configuration of a 3 element internal standard solution; the 3 elements comprise Sc, Y and Bi, and the standard mother solutions can be purchased from the market and can also be self-configured, such as standard mother solutions of national nonferrous metals and electronic material analysis and test centers.
In one embodiment, the standard solution and the internal standard solution are formulated as described in table 1:
TABLE 1 Standard solution and internal Standard solution information
In one embodiment, the diluent is formulated as a 2% strength by mass nitric acid solution and a 2% strength by mass hydrogen peroxide solution; preferably, the weight part ratio of the nitric acid solution with the mass concentration of 2% and the hydrogen peroxide with the mass concentration of 2% is (5-10): 2, preferably 7:2.
the inventor finds that because the sensitivity of MS detection to As is lower, and As is easily interfered by environment or chlorine element in a system to cause the test accuracy to be reduced, and hydrogen peroxide and nitric acid are used As diluent to help interact with plasma gas (argon), so that the ionization speed of elements such As metal in the system under the action of electric sparks is accelerated, and the detection sensitivity and accuracy are improved. Meanwhile, nitric acid has stronger oxidative decomposition capability, is singly used and is not completely digested, so that the hydrogen peroxide and nitric acid are compounded to improve the oxidative capability of nitric acid, so that a sample is completely digested, and the dissolution effect of metal elements is further improved. And when the concentrated nitric acid is hydrogen peroxide=7:2, the interference of the concentrated nitric acid to the matrix is minimal, so that the test result is more accurate.
In one embodiment, the linear solution formulation process is: taking reference mother liquor, fixing volume with diluent, preparing linear solution according to table, and obtaining linear concentration of each element
Table 3.
Table 2 linear solution formulation
| Removing the solution | Remove volume (μL) | Constant volume (mL) |
| Hg element standard mother liquor | 50 | 50 |
| Hg element standard mother liquor | 250 | 50 |
| Hg element standard mother liquor | 500 | 50 |
| Hg element standard mother liquor | 750 | 50 |
| Hg element standard mother liquor | 1000 | 50 |
| 7 element/3 element/15 element | 50/50/50 | 50 |
| 7 element/3 element/15 element | 250/250/100 | 50 |
| 7 element/3 element/15 element | 500/500/250 | 50 |
| 7 element/3 element/15 element | 1000/1000/500 | 50 |
| 7 element/3 element/15 element | 2500/2500/1000 | 50 |
TABLE 3 Linear solution concentration
In one embodiment, the sample mother liquor is prepared by the following steps: firstly, dissolving sodium chloride in water, adding ropivacaine hydrochloride in a stirring state, and stirring until the ropivacaine hydrochloride is completely dissolved; continuously adding water and stirring to obtain a sample mother solution; preferably, the pH value of the sample mother liquor is 4-6.
In one embodiment, the sample mother liquor is prepared by the following steps: 13.4957g of sodium chloride is taken and dissolved in 1500ml of water, 19.0044g of ropivacaine hydrochloride is added, the mixture is stirred until the ropivacaine hydrochloride is completely dissolved, water is added to 1900ml, the mixture is stirred for 10min, and the pH value is measured to be 4.960, thus obtaining the sample mother liquor.
In one embodiment, the sample solution is prepared by: diluting the mother solution of the sample in a volumetric flask with a diluent to a scale, and shaking uniformly to obtain 2 parts of mother solution in parallel by the same method; preferably, the diluent is diluted by a factor of (40-60).
In one embodiment, the sample solution is prepared by: and (3) 1.0mL of the sample mother solution is placed in a 50mL volumetric flask, diluted to a scale by a diluent, and uniformly shaken to obtain the product. A total of 2 parts were prepared in parallel in the same manner.
In one embodiment, the process blank solution is prepared by: taking water into a volumetric flask, diluting to scale with a diluent, and shaking uniformly to obtain the final product; preferably, taking 1mL into a 50mL volumetric flask, diluting to a scale with a diluent, and shaking uniformly to obtain the product.
In one embodiment, the accuracy solution is prepared by:
low concentration level: 1mL of sample mother liquor is put into a 50mL volumetric flask, 50 mu L of Hg element mixed standard mother liquor, 50 mu L of 7 element mixed standard mother liquor, 50 mu L of 3 element mixed standard mother liquor and 50 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, and 3 parts of sample solutions are prepared in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 0.1 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn elements is 10 mug/L, and the standard concentration of Fe, zn and Si elements is 100 mug/L.
Medium concentration level: 1mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, and 3 parts of sample solutions are prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
High concentration level: and (3) adding 1mL of sample mother liquor into a 50mL volumetric flask, adding 750 mu L of Hg element mixed standard mother liquor, 1000 mu L of 7 element mixed standard mother liquor, 1000 mu L of 3 element mixed standard mother liquor and 500 mu L of 15 element mixed standard mother liquor, diluting to a scale by using a diluent, and shaking uniformly to obtain 3 parts of sample solutions in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V element is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn element is 100 mug/L, and the standard concentration of Fe, zn and Si elements is 1000 mug/L.
In one embodiment, the repetitive solution is prepared by the steps of:
1mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken to obtain 6 parts of repetitive solution which is prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, sb, pb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
In one embodiment, the instrument detection is performed using ICP-MS, wherein the ratio of the atomizing gas flow rate to the assist gas flow rate is (0.5-1): 1.2, preferably 0.8:1.2.
in one embodiment, the instrument detection is performed using ICP-MS, wherein the plasma gas is argon and the flow rate is 18L/min.
The inventor discovers that the ion state corresponding to the dissociation planning function of metal elements such as copper, molybdenum and the like can be facilitated by regulating parameters such as the ratio of the flow rate of the atomizing gas to the flow rate of the auxiliary gas, dilution factors and the like. Since only the element with the secondary ionization energy lower than the primary ionization energy (16 eV) of the plasma gas (argon) can form obvious double-charge ions, the yield of the double-charge ions is improved by controlling the size of the atomizing gas flow rate and the ratio between the atomizing gas flow rate and the auxiliary gas flow rate, so that the quantitative limit of detection is improved. The inventor also discovers that in the application, by adjusting the dilution factor, the detection resolution is improved as much as possible while the sensitivity of the equipment to the detection objects is ensured, so that the detection results of different detection objects are not overlapped and the like. Meanwhile, by ensuring the plasma gas with a specific speed, the tested sample is ionized with charges, so that the situation that the plasma gas flow rate is unsuitable, different metals form different ionization actions with different intensities, the response degree of some metals (such As As and the like) to the plasma gas is low, and the detection limit is influenced is avoided. Improves precision, repeatability and accuracy.
In one embodiment, the internal standard elements Sc, Y and Bi in the instrument detection process are obtained by a T-shaped sample injection valve at a ratio of 1:1 is introduced on-line.
Preferably, the program in the instrument detection process is as described in table 4:
TABLE 4ICP-MS detection procedure
In one embodiment, performance verification includes linearity, accuracy, specificity, quantification limit, precision-repeatability detection.
In one embodiment, the linear detection process is to take linear solution for sample injection analysis, and the instrument automatically calculates the correlation coefficient (r) of the linear equation to be not lower than 0.995 by taking the standard solution concentration as the abscissa and the intensity as the ordinate.
In one embodiment, the accuracy testing process is sample solution and accuracy solution sample injection analysis, and the recovery rate and relative error (RSD) are calculated, the recovery rate should be between 70% and 150%, and the recovery rate RSD should not exceed 20%.
In one embodiment, the specific detection process is to take a process blank solution, a sample solution and an accuracy solution with medium concentration level for sample injection analysis, wherein the detection value of the process blank solution is not more than a quantitative Limit (LOQ), and the recovery rate is 70% -150%.
In one embodiment, the quantitative limit detection process is to take quantitative limit solution (i.e. low concentration level accuracy solution) for sample injection analysis, and calculate the recovery rate, wherein the recovery rate is between 70 and 150%.
In one embodiment, the precision-repeatability test procedure is to take a sample of the repetitive solution for analysis, and calculate the RSD of the concentration of 6 parts of the repetitive solution, wherein the RSD should not exceed 20%.
Example 1
The embodiment 1 of the application provides a detection method for an additive in an amide local anesthetic by adopting ICP-MS, which comprises the following steps:
(1) Preparing a solution;
(2) Detecting by an instrument;
(3) Verifying performance;
the solution preparation comprises standard solution preparation, internal standard solution preparation, diluent preparation, linear solution preparation, sample mother solution preparation, sample solution preparation, process blank solution preparation, accuracy solution preparation and repeatability solution preparation.
The standard solution and internal standard solution were formulated as described in table 5:
TABLE 5 Standard solution and internal Standard solution information
The diluent is prepared from 2% nitric acid solution and 2% hydrogen peroxide in the weight ratio of 7:2.
the preparation process of the linear solution comprises the following steps: taking reference mother liquor, fixing volume with diluent, preparing linear solution according to table, and obtaining linear concentration of each element
| Removing the solution | Remove volume (μL) | Constant volume (mL) |
| Hg element standard mother liquor | 50 | 50 |
| Hg element standard mother liquor | 250 | 50 |
| Hg element standard mother liquor | 500 | 50 |
| Hg element standard mother liquor | 750 | 50 |
| Hg element standard mother liquor | 1000 | 50 |
| 7 element/3 element/15 element | 50/50/50 | 50 |
| 7 element/3 element/15 element | 250/250/100 | 50 |
| 7 element/3 element/15 element | 500/500/250 | 50 |
| 7 element/3 element/15 element | 1000/1000/500 | 50 |
| 7 element/3 element/15 element | 2500/2500/1000 | 50 |
Table 7.
Table 6 linear solution formulation
TABLE 7 Linear solution concentration
The preparation process of the sample mother solution comprises the following steps: 13.4957g of sodium chloride is taken and dissolved in 1500ml of water, 19.0044g of ropivacaine hydrochloride is added, the mixture is stirred until the ropivacaine hydrochloride is completely dissolved, water is added to 1900ml, the mixture is stirred for 10min, and the pH value is measured to be 4.960, thus obtaining the sample mother liquor.
The preparation process of the sample solution comprises the following steps: and (3) 1.0mL of the sample mother solution is placed in a 50mL volumetric flask, diluted to a scale by a diluent, and uniformly shaken to obtain the product. A total of 2 parts were prepared in parallel in the same manner.
The preparation process of the blank solution comprises the following steps: taking 1mL of water into a 50mL volumetric flask, diluting to a scale with a diluent, and shaking uniformly to obtain the product.
The preparation process of the accuracy solution comprises the following steps:
low concentration level: 1mL of sample mother liquor is put into a 50mL volumetric flask, 50 mu L of Hg element mixed standard mother liquor, 50 mu L of 7 element mixed standard mother liquor, 50 mu L of 3 element mixed standard mother liquor and 50 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, and 3 parts of sample solutions are prepared in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 0.1 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn elements is 10 mug/L, and the standard concentration of Fe, zn and Si elements is 100 mug/L.
Medium concentration level: 1mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, and 3 parts of sample solutions are prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
High concentration level: and (3) adding 1mL of sample mother liquor into a 50mL volumetric flask, adding 750 mu L of Hg element mixed standard mother liquor, 1000 mu L of 7 element mixed standard mother liquor, 1000 mu L of 3 element mixed standard mother liquor and 500 mu L of 15 element mixed standard mother liquor, diluting to a scale by using a diluent, and shaking uniformly to obtain 3 parts of sample solutions in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V element is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn element is 100 mug/L, and the standard concentration of Fe, zn and Si elements is 1000 mug/L.
The preparation process of the repetitive solution comprises the following steps: 1mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken to obtain 6 parts of repetitive solution which is prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, sb, pb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
The procedure in the instrument testing process is described in table 8:
TABLE 8ICP-MS detection procedure
The performance verification comprises linearity, accuracy, specificity, quantitative limit, precision and repeatability detection;
the linear detection process is to take linear solution sample injection analysis, and the instrument automatically calculates the correlation coefficient (r) of a linear equation to be not lower than 0.995 by taking the standard solution concentration as an abscissa and the intensity as an ordinate;
the accuracy detection process is sample solution and accuracy solution sample injection analysis, and recovery rate and relative error (RSD) are calculated;
the specific detection process is to take a process blank solution, a sample solution and an accuracy solution with medium concentration level for sample injection analysis respectively, wherein the detection value of the process blank solution does not exceed a quantitative Limit (LOQ);
the quantitative limit detection process is to take quantitative limit solution sample injection (namely low concentration level accuracy solution) for analysis, and calculate recovery rate;
in one embodiment, the precision-repeatability test procedure is to take a sample of the repetitive solution for analysis and calculate the RSD of the concentration of 6 parts of the repetitive solution.
Example 2
The embodiment 2 of the application provides a detection method for an additive in an amide local anesthetic by adopting ICP-MS, and the specific implementation mode is the same as the embodiment 1, wherein the diluent is prepared by taking 2mL of concentrated nitric acid, diluting to 100mL by using water, and shaking uniformly.
Example 3
The embodiment 3 of the present application provides a method for detecting an additive in an amide local anesthetic by ICP-MS, which is similar to the embodiment 1, and is characterized in that the diluent is prepared from a nitric acid solution with a mass concentration of 2% and hydrogen peroxide with a mass concentration of 2% in a weight ratio of 1:2.
example 4
Example 4 of the present application provides a method for detecting an additive in an amide local anesthetic by ICP-MS, and the specific embodiment is the same as example 1 in that:
the preparation process of the sample solution comprises the following steps: 2.5mL of the sample mother liquor is put in a 50mL volumetric flask, diluted to a scale by a diluent, and uniformly shaken to obtain the product. A total of 2 parts were prepared in parallel in the same manner.
The preparation process of the blank solution comprises the following steps: taking 2.5mL of water into a 50mL volumetric flask, diluting to a scale with a diluent, and shaking uniformly to obtain the product.
The preparation process of the accuracy solution comprises the following steps:
low concentration level: 2.5mL of sample mother liquor is put into a 50mL volumetric flask, 50 mu L of Hg element mixed standard mother liquor, 50 mu L of 7 element mixed standard mother liquor, 50 mu L of 3 element mixed standard mother liquor and 50 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, and 3 parts of sample solutions are prepared in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 0.1 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn elements is 10 mug/L, and the standard concentration of Fe, zn and Si elements is 100 mug/L.
Medium concentration level: 2.5mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample solution is prepared by shaking uniformly, and 3 parts of sample solutions are prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, pb, sb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
High concentration level: 2.5mL of sample mother liquor is put into a 50mL volumetric flask, 750 mu L of Hg element mixed standard mother liquor, 1000 mu L of 7 element mixed standard mother liquor, 1000 mu L of 3 element mixed standard mother liquor and 500 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample solution is prepared by shaking uniformly, and 3 parts of sample solutions are prepared in parallel by the same method. The standard concentration of As, cd, co, ni, pb, sb, V element is 2 mug/L, the standard concentration of Hg element is 1.5 mug/L, the standard concentration of Al, B, ba, cr, cu, li, mn element is 100 mug/L, and the standard concentration of Fe, zn and Si elements is 1000 mug/L.
The preparation process of the repetitive solution comprises the following steps: 2.5mL of sample mother liquor is put into a 50mL volumetric flask, 500 mu L of Hg element mixed standard mother liquor, 500 mu L of 7 element mixed standard mother liquor, 500 mu L of 3 element mixed standard mother liquor and 250 mu L of 15 element mixed standard mother liquor are added, the sample mother liquor is diluted to a scale by a diluent, and the sample mother liquor is uniformly shaken, thus obtaining 6 parts of repetitive solution which is prepared in parallel by the same method. The labeling concentration of As, cd, co, ni, sb, pb, V, hg, mo, W elements is 1 mug/L, the labeling concentration of Al, B, ba, cr, cu, li, mn elements is 50 mug/L, and the labeling concentration of Fe, zn and Si elements is 500 mug/L.
Example 5
The embodiment 5 of the application provides a method for detecting an additive in an amide local anesthetic by adopting ICP-MS, and the specific implementation mode is the same as the embodiment 1, wherein in the instrument detection process, the flow rate of auxiliary gas (argon) is 1.2L/min, and the flow rate of an atomizer is 1.5L/min.
Example 6
The embodiment 6 of the application provides a detection method for an additive in an amide local anesthetic by adopting ICP-MS, and the specific implementation mode is the same as the embodiment 1, wherein in the instrument detection process, the plasma gas is argon, and the flow rate is 25L/min.
Performance evaluation:
the linear results of example 1 are shown in table 9;
TABLE 9
The accuracy and quantitative limits of example 1 can be found in table 10;
table 10
The specificity of example 1 is shown in Table 11;
TABLE 11
| Element(s) | RB(ug/L) | LOQ(ug/L) | ACC2-1(％) | ACC2-2(％) | ACC2-3(％) | RSD％ |
| Li | -0.001 | 10 | 95 | 96 | 97 | 1 |
| B | -3.076 | 10 | 92 | 96 | 97 | 3 |
| Al | 0.192 | 10 | 99 | 103 | 103 | 2 |
| Si | 0.506 | 100 | 100 | 100 | 101 | 1 |
| V | 0.003 | 0.1 | 101 | 99 | 98 | 2 |
| Cr | 0.053 | 10 | 95 | 94 | 95 | 1 |
| Mn | 0.031 | 10 | 97 | 97 | 98 | 1 |
| Fe | 0.284 | 100 | 95 | 96 | 97 | 1 |
| Co | 0.001 | 0.1 | 95 | 96 | 97 | 1 |
| Ni | 0.003 | 0.1 | 91 | 94 | 94 | 2 |
| Cu | 0.037 | 10 | 93 | 93 | 92 | 1 |
| Zn | 0.079 | 100 | 96 | 97 | 96 | 1 |
| As | -0.006 | 0.1 | 103 | 103 | 100 | 2 |
| Mo | -0.001 | 0.1 | 97 | 97 | 95 | 1 |
| Cd | -0.006 | 0.1 | 93 | 101 | 95 | 4 |
| Sb | 0.005 | 0.1 | 96 | 96 | 97 | 1 |
| Ba | 0.011 | 10 | 97 | 97 | 95 | 1 |
| W | 0.002 | 0.1 | 105 | 108 | 107 | 1 |
| Hg | 0.001 | 0.1 | 103 | 105 | 107 | 2 |
| Pb | 0.004 | 0.1 | 102 | 105 | 104 | 1 |
The precision-repeatability of example 1 is shown in table 12;
table 12
The test result of the embodiment 1 shows that the correlation coefficient of the equation is greater than 0.995, the recovery rate of all accuracy solutions is between 70% and 150%, the RSD is not more than 20%, the recovery rate of LOQ solution is between 70% and 150%, the RSD is less than 20%, the detection value of a blank solution in the process is not more than LOQ, the recovery rate of concentration level in the accuracy solutions is between 70% and 150%, the RSD is not more than 20%, and the RSD of the calculation result of 6 parts of repeatability solutions is less than 20%, so that the method has good accuracy and can be used as a test method for measuring 20 elements in ropivacaine hydrochloride process liquid in the department of biomedical industry.
The average RSD for accuracy in the detection method of example 2 is shown in table 13:
TABLE 13
Example 3 average RSD for accuracy in the detection method is shown in table 14:
TABLE 14
The average RSD for accuracy in the detection method of example 4 is shown in table 15:
TABLE 15
The average RSD for accuracy in the detection method of example 5 is shown in table 16:
table 16
The average RSD for accuracy in the detection method of example 6 is shown in table 17:
TABLE 17
Claims (2)
1. The method for detecting the additive in the amide local anesthetic is characterized by adopting an ICP-MS method to carry out methodological verification on 20 elements As, cd, B, al, si, cr, mn, fe, zn, ba, co, cu, hg, li, ni, pb, sb, V, mo, W in ropivacaine hydrochloride process liquid, and comprises the following steps:
(1) Preparing a solution;
(2) Detecting by an instrument;
(3) Verifying performance;
the solution preparation comprises diluent preparation, standard solution preparation, sample mother solution preparation, sample solution preparation, process blank solution preparation, accuracy solution preparation and repeatability solution preparation;
the diluent is prepared by mixing a nitric acid solution with the mass concentration of 2% and hydrogen peroxide with the mass concentration of 2%;
the weight part ratio of the nitric acid solution with the mass concentration of 2% to the hydrogen peroxide with the mass concentration of 2% is 7:2;
the instrument test was performed using ICP-MS, wherein the ratio of the atomizing gas flow rate to the assist gas flow rate was 0.8:1.2; wherein the plasma gas is argon, and the flow rate is 18L/min;
preparing a sample solution, namely preparing a sample mother solution into 2 parts by parallel preparation in the same method in a volumetric flask, diluting the sample mother solution to a scale with a diluent, and shaking the sample solution uniformly;
the dilution factor of the diluent is (40-60);
the sample mother solution is prepared by dissolving sodium chloride in water, adding ropivacaine hydrochloride in a stirring state, and stirring until the ropivacaine hydrochloride is completely dissolved; continuously adding water and stirring to obtain a sample mother solution;
the pH value of the sample mother solution is 4-6.
2. The detection method according to claim 1, wherein the configuration of the standard solution includes configurations of Hg element standard mother liquor, 7 element mixed standard mother liquor, 3 element mixed standard mother liquor, and 15 element mixed standard mother liquor; wherein 7 elements comprise As, cd, co, ni, pb, sb, V,3 elements comprise Mo, sn and W, and 15 elements comprise Al, B, li, mn, ba, cr, cu, ti, na, mg, K, ca, fe, zn, si.
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| "电感耦合等离子体-质谱法测定生脉注射液中14种元素含量";黄小琴等;《中国药业》;20181220;第27卷(第24期);第19-21页 * |
| 《空气和废气监测分析方法指南》编委会编.第一节 电感耦合等离子体质谱法简述.《空气和废气监测分析方法指南 下》.2014,第378-383页. * |
| 质量技术监督行业职业技能鉴定指导中心组编."十三 总砷的测定".《食品检验 肉蛋及其制品 罐头 水产品》.2013,第187-193页. * |
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