Detection system for valproic acid drug concentration and detection method based on detection system

Abstract

The invention relates to a valproic acid drug concentration detection system and a detection method based on the same, and belongs to the technical field of medical detection. The invention provides a detection system for quantifying the drug concentration of valproic acid in a sample to be detected, the detection system comprises a detection kit and a mass spectrum analyzer, the detection kit takes a valproic acid isotope solution as an internal standard working solution, and the invention correspondingly provides a valproic acid concentration detection method based on the system. The method comprises the following steps: mixing a to-be-detected sample with an internal standard working solution, dropwise adding the mixture into an ionization kit, carrying out electrospray on the solution, feeding the solution into a mass spectrum analyzer, and optimizing and adjusting parameters in a series of steps such as mass spectrum analysis, data collection and working curve establishment. The valproic acid concentration data can be quickly obtained without pre-processing the sample, the time of the whole detection process is shortened to about 5 minutes, and a brand new tool is provided for clinically and instantly feeding back the blood concentration in the body of a patient.

Description

Technical Field

[0001] The present invention relates to the technical field of medical detection, and in particular to a detection system for valproic acid drug concentration and a detection method based thereon. Background Art

[0002] Valproate-type drugs are a class of anti-epileptic drugs widely used in clinical practice. Their main ingredient, sodium valproate, has broad-spectrum anti-epileptic effects and can effectively prevent and control various types of epileptic seizures, including generalized and partial epilepsy. Valproate-type drugs are also used to treat psychiatric disorders such as bipolar disorder and to prevent neurological conditions such as migraine. Their mechanism of action is primarily through inhibiting neuronal hyperexcitability and regulating the release and metabolism of neurotransmitters, thereby exerting anti-epileptic and neuroprotective effects. Due to their excellent efficacy and relatively low toxicity, valproate-type drugs have been widely used in clinical treatment.

[0003] Monitoring drug concentrations of valproic acid-based drugs is crucial for assessing their clinical efficacy and safety. Accurately monitoring drug concentrations in the body ensures optimal therapeutic efficacy while effectively reducing the risk of side effects caused by overdose or underdose. Real-time monitoring of drug concentrations allows for precise dosing based on individual patient constitutions and metabolic characteristics, thereby better preventing epileptic seizures. Furthermore, rapid drug concentration testing allows for timely dosage adjustments in postoperative brain surgery patients, optimizing anti-epileptic efficacy and ensuring their postoperative recovery and safety.

[0004] Currently, the mainstream method for detecting valproic acid is liquid chromatography-mass spectrometry (LC-MS). Although this method has the advantages of high sensitivity and high specificity, its operation is relatively complex and requires specialized technicians. Specifically, the blood sample must first be centrifuged to obtain plasma, followed by the addition of an organic reagent and an internal standard reagent to precipitate proteins. After further centrifugation, the supernatant is obtained for testing. Before testing, a standard curve must be established and calibrated with actual samples. For valproic acid, due to its relatively stable molecular structure and low tendency to endogenous fragmentation during mass spectrometry analysis, derivatization is often required, further increasing the complexity and time-consuming nature of the test, making it difficult to meet the needs of timely on-site testing. In addition to LC-MS, other detection methods such as immunoassays and chemiluminescence, while relatively simple to operate, are susceptible to interference from analogs, leading to false-positive results and poor accuracy. Therefore, the development of a rapid, accurate, and on-site valproic acid concentration monitoring method is of great practical significance for improving clinical treatment efficacy and patient safety. Summary of the Invention

[0005] To solve the above technical problems, the present invention provides a detection system for valproic acid drugs and a detection method based thereon, wherein the detection system includes a detection kit and a mass spectrometer, the detection kit includes an ionization kit and an internal standard working solution, and provides a valproic acid drug concentration detection method based on the detection system. The mass spectrometry analysis conditions are adjusted and screened, and the stored waveform inverse Fourier transform technology is combined with the adjustment of the working curve slope and intercept to further improve the sensitivity and accuracy of valproic acid detection.

[0006] The first object of the present invention is to provide a method for detecting valproic acid drugs, the method comprising the following specific steps: mixing a sample to be tested with an internal standard working solution, dropwise adding the mixed solution to an ionization kit, inserting the ionization kit into a mass spectrometer for detection, using a stored waveform inverse Fourier transform technique to acquire data in the mass spectrometer, obtaining a working curve based on the signal peak area ratio of valproic acid and the internal standard, and calculating the concentration of valproic acid in the sample to be tested;

[0007] The ionization kit comprises a shell, a sample-loading substrate, a capillary and a conductive metal, and the internal standard working solution is a valproic acid isotope solution.

[0008] Furthermore, the sample to be tested is a whole blood sample, a plasma sample or a serum sample.

[0009] Furthermore, the sample to be tested is dropped onto the sample loading base, and the sample to be tested enters the capillary, undergoes voltage conduction through the conductive metal, forms an electrospray under the drive of high voltage, and enters the mass spectrometer.

[0010] The stored waveform inverse Fourier transform technology uses the inverse Fourier transform algorithm to generate a mixed waveform in the frequency domain in which there is a frequency range with zero intensity components and other frequency ranges with intensity components. This waveform is loaded into the ion trap to achieve ion isolation within a certain range, which can effectively reduce interference from other substances and improve the specificity and accuracy of the detection method.

[0011] In one embodiment of the present invention, the mass spectrometer is a CELL small portable mass spectrometer.

[0012] Furthermore, the valproic acid isotope solution is a valproic acid-D6 solution.

[0013] Furthermore, the concentration of the valproic acid-D6 solution is 0.05-50 μg / mL.

[0014] Preferably, the concentration of the valproic acid-D6 solution is 0.1-50 μg / mL.

[0015] Furthermore, the volume ratio of the sample to be tested to the internal standard working solution is 1:(1-10)

[0016] In one embodiment of the present invention, the volume ratio of the sample to be tested to the internal standard working solution is 1:4.

[0017] Furthermore, the sample to be tested is mixed with the internal standard working solution and then allowed to stand for 5-30 seconds.

[0018] Furthermore, the mass spectrometry detection mode of the valproic acid is set to: negative mode, ion isolation mode, the precursor ion m / z is 143, the quantitative ion is m / z 143, the ion selection energy is 0.5-5V, and the collision induced dissociation energy is 0-5V.

[0019] Furthermore, the mass spectrometry detection mode of the internal standard working solution is set to: negative mode, ion isolation mode, precursor ion is m / z 149, quantitative ion is m / z 149, ion selection energy is 0.5-5V, and collision induced dissociation energy is 0-5V.

[0020] Furthermore, the method further includes the step of correcting the slope and intercept of the working curve.

[0021] Furthermore, the method specifically includes the following steps:

[0022] Step S1, mixing a valproic acid standard and an internal standard working solution of the same concentration at a volume ratio of 1:1 and performing detection to obtain a peak area ratio of the valproic acid standard to the internal standard, which is recorded as a relative correction factor;

[0023] Step S2, keeping the absolute amount of the internal standard substance constant, convert the volume ratio of the sample to be tested to the internal standard working solution at 1: (1-10) to obtain the concentration of the internal standard working solution, which is recorded as the internal standard concentration;

[0024] Step S3, obtaining the ratio of the internal standard concentration to the relative correction factor, taking the integer as the calibration internal standard concentration, i.e., the slope correction factor;

[0025] Step S4: Mix the blank sample with the internal standard working solution and then test to obtain the peak area ratio of the blank sample to the internal standard, multiply it by the ratio of the internal standard concentration obtained in step S2 to the relative correction factor, and take the inverse of the ratio to obtain the intercept correction factor.

[0026] Furthermore, the calculation formula of the intercept correction factor is as follows:

[0027]

[0028] Where Cistd is the internal standard concentration and RCF is the relative correction factor.

[0029] A second object of the present invention is to provide a detection system for valproic acid drugs, the detection system comprising a detection kit and a mass spectrometer, the detection kit comprising an ionization kit, a quantitative liquid dispenser, and an internal standard working solution;

[0030] The ionization kit comprises a shell, a sample-loading substrate, a capillary and a conductive metal, and the internal standard working solution is a valproic acid isotope solution.

[0031] Furthermore, the sample-carrying substrate may be paper, cotton, linen or other cellulose materials that can effectively absorb proteins.

[0032] Furthermore, the inner diameter of the capillary is 70-80 μm.

[0033] Furthermore, the conductive metal may be steel, gold, silver, copper, aluminum, etc.

[0034] Furthermore, the internal standard working solution is valproic acid-D6 solution.

[0035] Furthermore, the concentration of the internal standard working solution is 0.05-50 μg / mL.

[0036] Preferably, the concentration of the internal standard working solution is 0.1-50 μg / mL.

[0037] Beneficial effects of the present invention:

[0038] (1) The present invention provides a detection system for detecting the concentration of valproic acid drugs, which uses an in situ ionization kit combined with a small portable mass spectrometry system. It does not require pretreatment of the test sample, is simple to operate, and can obtain test results within 5 minutes. It can provide instant feedback on the patient's blood drug concentration, which is conducive to the rapid designation of individualized dosing regimens and pharmacokinetic studies in the clinic. It has broad application prospects and is of great significance for the clinical application of valproic acid drugs;

[0039] (2) The method for detecting the concentration of valproic acid drugs provided by the present invention creatively uses the stored waveform inverse Fourier transform technology in a mass spectrometer for data acquisition, and optimizes and adjusts the parameters of different processes such as mass spectrometry analysis and data processing, thereby improving the accuracy and precision of the detection method. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below based on specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0041] Figure 1 The in situ ionization kit in Example 1 of the present invention;

[0042] Figure 2Schematic diagram of the detection process of valproic acid in Example 2 of the present invention;

[0043] Figure 3 The detection results of valproic acid in different modes in Example 2 of the present invention are shown, where A is the ion intensity result in full scan mode, B is the ion intensity result in ion isolation mode, C is the comparison of blank limits in the two modes, D is the comparison of detection limits in the two modes, and E is the ratio of the signal intensity of valproic acid and internal standard in the two modes;

[0044] Figure 4 Schematic diagram of the inverse Fourier transform technology for storing waveforms in Example 2 of the present invention;

[0045] Figure 5 Schematic diagram of the potential well in Example 2 of the present invention;

[0046] Figure 6 Schematic diagram of the LC-MS detection process of valproic acid in Example 3 of the present invention;

[0047] Figure 7 This is a fitting curve of the LC-MS test results in Example 3 of the present invention and the test results obtained by the method provided by the present invention. DETAILED DESCRIPTION

[0048] The present invention will be further described below with reference to the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. However, the embodiments are not intended to limit the present invention.

[0049] Example 1: Establishment of a valproic acid concentration detection system

[0050] The detection system for valproic acid drugs provided by the present invention comprises a detection kit and a mass spectrometer, wherein the detection kit comprises an ionization kit, a quantitative liquid dispenser and an internal standard working solution.

[0051] The ionization kit is an in situ ionization kit, such as Figure 1 As shown (refer to Chinese patent CN113725063A for internal structure), it includes a shell, a sample-carrying base, a capillary tube, and a conductive metal, wherein:

[0052] The sample-carrying substrate includes, but is not limited to, paper, cotton, linen and other cellulose materials that can effectively absorb proteins. In this embodiment, the sample-carrying substrate is a paper substrate.

[0053] The inner diameter of the capillary is 70-80 μm.

[0054] Conductive metals include steel, gold, silver, copper, aluminum and other metals with good conductivity.

[0055] The internal standard working solution is valproic acid-D6 (CAS#: 87745-18-4), which is thoroughly mixed with a fixed volume of the sample to be tested and then added dropwise to the ionization kit. The ionization kit integrates pretreatment and chromatographic separation functions. The liquid is added dropwise to the sample-carrying substrate, and the liquid solvent enters the capillary. Voltage is conducted through the conductive metal, and driven by a high voltage, an electrospray is formed. The spray then enters the detector of the mass spectrometer for analysis. The signal peak area ratio of valproic acid to valproic acid-D6 is obtained. Combined with the actual concentration of valproic acid-D6, the concentration of sodium valproate in the sample is calculated through data calculation.

[0056] The mass spectrometer used in the embodiment is a CELL small portable mass spectrometer, which is from Beijing Qingpu Technology Co., Ltd., with a length × width × height = 35 cm × 25 cm × 15 cm, a weight of 8.5 kg, and a power of ≤100 W. It mainly consists of a discontinuous atmospheric pressure interface, a small vacuum pump, a linear ion trap mass analyzer, and an ion detector.

[0057] Example 2: Establishment of a method for detecting valproic acid concentration

[0058] Schematic diagram of the valproic acid detection process Figure 2 shown.

[0059] The sample to be tested is placed in the isotope internal standard working solution and vortexed to mix thoroughly. The mixed liquid is dropped onto the ionization kit and allowed to stand for 5-30 seconds. The sample is then inserted into the CELL small portable mass spectrometer for electrospray ionization. The sample is analyzed by the mass spectrometry system to obtain the signal peak area ratio of valproic acid and the isotope, and the content of the fatty acid drug in the sample to be tested is calculated.

[0060] Adjust and optimize the mass spectrometry analysis conditions. The specific ideas are as follows:

[0061] (1) Valproic acid has strong structural stability. Due to its relatively stable molecular structure and low endogenous fragmentation tendency in mass spectrometry analysis, no product ions can be used for quantification. Therefore, the precursor ion m / z: 143 ([MH]-) was selected for quantification of valproic acid, and the precursor ion m / z 149 was selected for quantification of valproic acid-D6;

[0062] (2) The CELL small portable mass spectrometer has two modes for detecting the precursor ion m / z 143: full scan mode and ion isolation mode. The ion intensity scan results of the full scan mode and ion isolation mode are as follows: Figure 3 As shown in A and B, it can be seen that the influence of impurity interference in ion isolation mode is smaller; the blank limit comparison between full scan mode and ion isolation mode is as follows: Figure 3 As shown in C, the detection limit comparison is Figure 3As shown in D, it can be seen that the detection sensitivity in the ion isolation mode is higher. The ratio of the signal intensity of valproic acid and internal standard in the full scan mode and the ion isolation mode is as follows Figure 3 As shown in E, it can be seen that the detection stability in the ion isolation mode is higher, so the ion isolation mode is selected for detection;

[0063] (3) Considering that the larger the ion selection energy, the better the removal effect of non-target ions, but too large will reduce the target ion signal intensity, according to the results of the number of spectral interference peaks and the target peak signal intensity, the ion selection energy is optimal when the number of spectral interference peaks is the least and the target peak signal intensity is the highest, so the optimal ion selection energy is selected to be 0.5-5V;

[0064] (4) Since valproic acid is an acidic compound, it is easy to lose protons to form negatively charged ions in the negative mode, which has a higher signal intensity, so the negative mode was selected;

[0065] (5) The collision-induced dissociation energy is used to break up the precursor ions. Since valproic acid has no product ions, the collision-induced dissociation energy is set to 0.

[0066] Based on the above results, the mass spectrometer analysis conditions are as follows:

[0067] Valproic acid detection mode: negative mode, ion isolation mode, precursor ion m / z 143, quantification ion m / z 143, ion selection energy 0.5-5V, collision-induced dissociation energy 0-5V;

[0068] Detection mode of valproic acid-d6: negative mode, ion isolation mode, precursor ion m / z 149, quantitative ion m / z 149, ion selection energy 0.5-5V, collision-induced dissociation energy 0-5V.

[0069] This detection method uses stored waveform inverse Fourier transform (SWIFT) technology to implement segmented analysis data acquisition technology in a small mass spectrometry system using hydrazine as the mass analyzer. Figure 4 As shown, SWIFT technology first uses an inverse Fourier transform algorithm to generate a mixed waveform in the frequency domain, where the intensity component is zero in a certain frequency range and intensity components are present in other frequency ranges. This waveform is then loaded into the ion trap to isolate ions within a certain range. The theoretical basis for SWIFT is that ions of different mass-to-charge ratios have different ion resonance frequencies. The upper and lower cutoff frequencies v for SWIFT can be calculated based on the ion trap instrument parameters and the mass-to-charge ratios of the starting and ending ions to be scanned. The SWIFT time-domain waveform is then generated using the inverse Fourier transform equation and loaded into the ion trap.

[0070] SWIFT occurs after ion injection. By adjusting the RF voltage, the q value of the central ion of the mass segment to be isolated is between 0.6 and 0.8, ensuring that the ions within the range are in a stable region. In a quadrupole field, the rapidly changing electric field is similar to a resonator potential well, and there is a local low point on the potential energy surface. When the ion is at the low point of the potential energy surface, it requires a large amount of energy to leave the point of low potential energy, so it is called a potential well. The depth of the potential well determines the minimum kinetic energy required for the ion to be resonantly ejected, and the maximum kinetic energy that cannot be exceeded by the fragments formed during the excitation dissociation process. For a linear ion trap, at low q, the depth of the potential well is approximately Dx,y=qV / 4, and the potential well is positively correlated with q. For example Figure 5 As shown, the well depth reaches its maximum at q = 0.72. When capturing and storing ions, a deeper potential well facilitates stable ion storage. Furthermore, when perturbing ions (such as ion screening and dissociation), it is desirable to keep the target ions in a deeper well depth. Therefore, when screening ions, the target ion q value is set within the range of 0.6-0.8.

[0071] When the ion trap is loaded with the SWIFT signal, all ions except the ions with mass-to-charge ratio corresponding to the resonance frequency range with zero intensity component will be cleared out of the ion trap to achieve ion isolation within a specific range. Figure 3 As shown in Figure B, the signals loaded into the ion trap are ions with upper and lower cutoff frequencies corresponding to m / z 142.5 and m / z 143.5, respectively, and ions with upper and lower cutoff frequencies corresponding to m / z 148.5 and m / z 149.5, respectively. This effectively isolates ions between m / z 142.5 and m / z 143.5, and between m / z 148.5 and m / z 149.5, while eliminating other ions. This effectively reduces interference from other substances and improves the specificity and accuracy of the detection method.

[0072] In the monoisotopic internal standard quantification method, the concentration of the isotopic internal standard is known. Based on the identical properties of valproic acid and valproic acid-D6, including ionization efficiency, fragmentation efficiency, and matrix effects, the method proposes quantification using the peak area ratio of the fragments of the analyte and the isotopic internal standard. Due to the difference in mass spectrometric response signal intensity between valproic acid and valproic acid-D6, a slope correction factor k is proposed. Because blank interference occurs during valproic acid quantification, an intercept correction factor b is proposed to mitigate the interference and improve the accuracy of the results (if the intercept correction is not performed, the relative deviation between the test result and the theoretical value is between 9-155%). The slope correction factor k and intercept correction factor b are calculated as follows:

[0073] (1) Confirm the relative correction factor (RCF) and internal standard concentration (C istd): The valproic acid standard and the internal standard working solution were mixed at a volume ratio of 1:1 and then injected into the CELL small portable mass spectrometer. The peak area ratio of the analyte to the internal standard (Area analyte / Area internal standard) was measured and recorded as RCF;

[0074] (2) Keeping the absolute amount of the internal standard substance constant, convert the volume ratio of the sample to be tested to the internal standard working solution at 1:(1-10) to obtain the concentration of the internal standard working solution, which is recorded as the internal standard concentration C istd ;

[0075] (3) According to C istd The value of / RCF is selected as an integer as close as possible as the equivalent internal standard concentration C after calibration. 内标 , that is, the slope correction factor k;

[0076] (4) Calculate the intercept correction factor as follows, where the blank sample is a serum or whole blood sample without the analyte:

[0077]

[0078] (3) According to the working curve Output the actual concentration of valproic acid in the sample to be tested.

[0079] Example 3: Detection of valproic acid

[0080] Fifty actual patient serum samples containing valproic acid standards (with concentrations ranging from 12.6 to 129 μg / mL) were collected to validate the detection systems and methods established in Examples 1 and 2. A valproic acid-D6 acetonitrile solution (internal standard working solution, 40 μg / mL) of a predetermined concentration was prepared, and 400 μL was added to an ampoule. A 100 μL spiked blood sample was then taken using a quantitative liquid dispenser and added to the ampoule. A dripper was installed, and the sample was vortexed for 15 seconds or stirred with a binaural tube for 15 seconds. The mixed solution was then added dropwise to the ionization kit described in Example 1, with the binaural tube inverted. The kit was then inserted into a small mass spectrometer for detection. The accuracy and precision were within 15%. The test results are shown in Table 1, where replicates represent multiple tests on the same sample.

[0081] The working curve was calculated according to the detection method described in Example 2 to obtain the concentration of valproic acid in the serum sample to be tested. The LC-MS detection was used as a control. The LC-MS determination process is as follows: Figure 6 As shown, the small mass spectrum was fitted with the LC-MS measurement results to draw a curve, R 2 =0.9803>0.95, the fitting curve is as follows Figure 7 shown.

[0082] The valproic acid detection system and method provided by the present invention greatly shorten the detection process and simplify the detection method while ensuring detection accuracy and sensitivity. No sample pretreatment is required, and the corresponding test results can be obtained within 5 minutes. The LC-MS detection method in the prior art takes more than 1.5 hours.

[0083] Table 1 Valproic acid concentration test results

[0084] Solution concentration (μg / mL) 38 80 150 Repeated measurement results 1 41.32 74.11 130.62 Repeated measurement results 2 34.46 74.37 146.87 Repeated measurement results 3 37.33 74.94 151.55 Repeated measurement results 4 35.71 74.47 153.44 Repeated measurement results 5 40.37 78.85 150.13 Mean±SD (μg / mL) 37.84±2.95 75.35±1.98 146.52±9.21 RSD 7.8％ 2.6％ 6.3％ Relative deviation -0.4％ -5.8％ -2.3％

[0085] Obviously, the above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will appreciate that other variations or modifications can be made based on the above description. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for detecting the concentration of valproic acid drugs, characterized in that: The detection method specifically comprises the following steps: mixing a sample to be tested with an internal standard working solution, dripping the mixed solution into an ionization kit, inserting the ionization kit into a mass spectrometer for detection, acquiring data in the mass spectrometer using a stored waveform inverse Fourier transform technique, obtaining a working curve based on the signal peak area ratio of valproic acid and the internal standard, and calculating the concentration of valproic acid in the sample to be tested; The ionization kit comprises a shell, a sample-loading substrate, a capillary and a conductive metal, and the internal standard working solution is a valproic acid isotope solution.

2. The detection method according to claim 1, wherein: The volume ratio of the sample to be tested to the internal standard working solution is 1:(1-10).

3. The detection method according to claim 1, wherein: The sample to be tested is mixed with the internal standard working solution and allowed to stand for 5-30 seconds.

4. The detection method according to claim 1, wherein The mass spectrometry detection mode of the valproic acid was set to: negative mode, ion isolation mode, the m / z of the precursor ion was 143, the m / z of the quantitative ion was 143, the ion selection energy was 0.5-5V, and the collision induced dissociation energy was 0-5V.

5. The detection method according to claim 1, wherein The mass spectrometry detection mode of the internal standard working solution was set to: negative mode, ion isolation mode, precursor ion m / z 149, quantitative ion m / z 149, ion selection energy 0.5-5V, collision induced dissociation energy 0-5V.

6. The detection method according to claim 1, wherein: The method also includes the steps of correcting the slope and intercept of the working curve.

7. The detection method according to claim 6, characterized in that The specific steps include: Step S1, mixing a valproic acid standard and an internal standard working solution of the same concentration at a volume ratio of 1:1 and performing detection to obtain a peak area ratio of the valproic acid standard to the internal standard, which is recorded as a relative correction factor; Step S2, keeping the absolute amount of the internal standard substance constant, convert the volume ratio of the sample to be tested to the internal standard working solution at 1: (1-10) to obtain the concentration of the internal standard working solution, which is recorded as the internal standard concentration; Step S3, obtaining the ratio of the internal standard concentration to the relative correction factor, taking the integer as the calibration internal standard concentration, i.e., the slope correction factor; Step S4: Mix the blank sample with the internal standard working solution and then test to obtain the peak area ratio of the blank sample to the internal standard, multiply it by the ratio of the internal standard concentration obtained in step S2 to the relative correction factor, and take the inverse of the ratio to obtain the intercept correction factor.

8. A system for detecting the concentration of valproic acid drugs, characterized in that: The detection system includes a detection kit and a mass spectrometer, wherein the detection kit includes an ionization kit, a quantitative liquid dispenser and an internal standard working solution; The ionization kit comprises a shell, a sample-loading substrate, a capillary and a conductive metal, and the internal standard working solution is a valproic acid isotope solution.

9. The detection system according to claim 8, characterized in that: The internal standard working solution is valproic acid-D6 solution.

10. The detection system according to claim 9, characterized in that: The concentration of the internal standard working solution is 0.05-50 μg / mL.

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