Medicine raw material homology judgment method and device, computer equipment and medium

Abstract

The invention provides a medicine raw material homology judgment method and device, computer equipment and a medium, and belongs to the field of medicine identification, and the method comprises the following steps: obtaining a plurality of same sample medicines from different sources; determining the stable isotope abundance values of carbon, nitrogen, oxygen and hydrogen in the drug sample through a stable isotope ratio mass spectrometry and a chromium-assisted stable isotope ratio mass spectrometry; taking the stable isotope abundance value as a variable, and classifying sample drug sources by adopting a hierarchical clustering analysis and principal component analysis method to obtain a plurality of drug sources; obtaining stable isotope abundance values of to-be-classified target drugs, and respectively determining the stable isotope abundance values of the target drugs and Z values of the stable isotope abundance values of all classes based on a Z value analysis method; under the condition that the Z values of the stable isotope abundance values of all the elements are smaller than or equal to the preset threshold value, it is determined that the target drug and the sample drug of the corresponding category are homologous drugs, and therefore the accuracy of drug detection is improved.

Description

Technical Field

[0001] The present invention belongs to the field of drug identification, and specifically relates to a method, device, computer equipment and medium for determining the homology of drug raw materials. Background Art

[0002] Pharmaceutical chemicals (pharmaceuticals) are crucial to people's lives, crucial for their health and economic well-being, and crucial for pharmaceutical manufacturers. Various analytical techniques are used to detect counterfeit drugs, ranging from simple thin-layer chromatography to more advanced techniques such as near-infrared spectroscopy and liquid chromatography-mass spectrometry. However, counterfeiting techniques have become increasingly sophisticated, with counterfeit products containing identical compounds and possessing the same elemental composition as the original tablets. Chemical characterization of drug ingredients can only indirectly prove counterfeiting, failing to monitor patent infringement for generic drugs and failing to distinguish between synthetic and natural sources of materials. The World Health Organization (WHO) reports that 60% of counterfeit drug production involves the most popular therapeutic drug classes, such as antibiotics, hormones, analgesics, steroids, and antihistamines, resulting in economic losses for legitimate drug manufacturers.

[0003] In the pharmaceutical field, chemometrics is currently widely used to identify pharmaceutical raw materials. These methods primarily rely on quantitative comparisons of chemical composition (such as active ingredient content and impurity types), but cannot directly distinguish whether a material is synthetic or naturally derived. Furthermore, they typically rely on a single or limited number of chemical parameters (such as active ingredient content and spectral characteristics). This results in low data dimensionality, which can lead to insufficient evidence for identification and susceptibility to interference in complex matrices (such as pharmaceuticals containing multiple impurities). For example, near-infrared spectroscopy can cause signal drift due to differences in sample color and particle size, affecting identification results. Summary of the Invention

[0004] In order to solve the problem of low accuracy in identifying pharmaceutical raw materials using existing chemometric methods, the present invention provides a method, device, computer equipment and medium for determining the homology of pharmaceutical raw materials.

[0005] In order to achieve the above object, the present invention provides the following technical solutions: A method for determining the homology of pharmaceutical raw materials, comprising: Obtaining the same sample drug from multiple different sources; The stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen in pharmaceutical samples were determined by stable isotope ratio mass spectrometry (EA-IRMS) and chromium-assisted stable isotope ratio mass spectrometry (Cr-EA-IRMS); Taking the stable isotope abundance value as a variable, hierarchical cluster analysis and principal component analysis methods are used to classify the sources of sample drugs to obtain multiple drug sources; Obtain the stable isotope abundance value of the target drug to be determined, and determine the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each drug source based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, determine that the target drug and the sample drug of the corresponding drug source are homologous drugs.

[0006] Optionally, the determination of the stable isotope abundance value includes the following conditions: When determining the stable isotope abundance of carbon, the injection volume was 0.05-0.2 mg, the EA-IRMS method was used, the carrier gas flow rate was 100 mL / min, the oxygen flow rate was 200 mL / min, and the right furnace temperature was 960°C; When determining the stable isotope abundance of nitrogen, the injection volume was 0.2-0.8 mg, the EA-IRMS method was used, the carrier gas flow rate was 100 mL / min, and the oxygen flow rate was 200 mL / min; When determining the stable isotope abundance of oxygen, the injection volume was 0.2 mg, the EA-IRMS method was used, and the left furnace temperature was 1380 °C; When determining the stable isotope abundance value of hydrogen, the Cr-EA-IRMS method was adopted, chromium particles and corundum balls were used to fill the high-temperature cracking reaction tube, the carrier gas flow rate was 100 mL / min, and the left furnace temperature was 1380°C.

[0007] Optionally, the stable isotope abundance value is used as a variable, and hierarchical cluster analysis and principal component analysis methods are used to classify the sources of sample drugs, and multiple drug sources are obtained, including: Preprocess the stable isotope abundance values ​​corresponding to multiple sample drugs from different sources to eliminate dimensional differences; Calculating the Euclidean distance matrix between the stable isotope abundance values ​​corresponding to the sample drugs from different sources, and performing cluster analysis using the Ward minimum variance method in the hierarchical clustering method based on the Euclidean distance matrix to obtain cluster classification results of the sample drug sources; The principal component analysis is performed on the stable isotope abundance values ​​corresponding to the pretreated sample drugs. The final classification results of the source of the sample drugs are determined by comparing the sample distribution in the principal component space with the cluster classification results.

[0008] Optionally, the calculation formula of the Z value is: ; Where X is the stable isotope abundance value of the target drug, μ is the average stable isotope abundance value of the same sample drugs from each drug source, and σ is the standard deviation of the stable isotope abundance value of the same sample drugs from each drug source.

[0009] Optionally, when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, determining that the target drug and the sample drug of the corresponding category are homologous drugs includes: When the Z values ​​of the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen of the target drug and the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen corresponding to sample drugs of any category in multiple categories are all less than or equal to 2, the target drug is determined to be a homologous drug of the category.

[0010] A device for determining the homology of pharmaceutical raw materials, comprising: An acquisition module is used to obtain the same sample drug from multiple different sources; A determination module for determining the stable isotope abundance values ​​of carbon, nitrogen, oxygen, and hydrogen in pharmaceutical samples by stable isotope ratio mass spectrometry (EA-IRMS) and chromium-assisted stable isotope ratio mass spectrometry (Cr-EA-IRMS); A classification module is used to classify the sources of sample drugs using the stable isotope abundance value as a variable and adopt hierarchical cluster analysis and principal component analysis methods to obtain multiple drug sources; The determination module is used to obtain the stable isotope abundance value of the target drug to be determined, and determine the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each category based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, the target drug and the sample drugs of the corresponding category are determined to be homologous drugs.

[0011] A computer-readable storage medium stores a computer program, which, when executed by a processor, implements the above-mentioned method for determining the homology of pharmaceutical raw materials.

[0012] A computer device includes a memory, a processor, and a computer program stored in the memory and executable on the processor. When the processor executes the program, the method for determining the homology of pharmaceutical raw materials is implemented.

[0013] The method for determining the homology of pharmaceutical raw materials provided by the present invention has the following beneficial effects: The present invention is classified by measuring the stable isotope abundance of the medicine. The stable isotope abundance is directly related to the production process and geographical environment of the raw materials, and can directly trace the synthesis or natural properties of the raw materials. The stable isotope abundance is measured by EA-IRMS and Cr-EA-IRMS technology, which significantly reduces the interference of by-products. The isotope abundance values ​​of carbon, nitrogen, hydrogen and oxygen are also measured simultaneously to construct a high-dimensional data set. By hierarchical clustering and principal component analysis, the same medicines from multiple different sources are classified by source, so as to clarify the mean difference of the isotopes of each source, and then the rationality of the source classification is further verified by principal component analysis, ensuring that the key discriminant information is still retained after dimensionality reduction. Finally, the discrimination based on the Z value method has an accuracy rate far exceeding the possible overlap or misjudgment risk of traditional methods. In addition, the method can be directly used to track illegal production chains, such as quickly identifying unregistered raw material sources through isotope databases, and making up for the shortcomings of chemometrics in traceability. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] To more clearly illustrate the embodiments of the present invention and its design, the following briefly introduces the drawings required for this embodiment. The drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be derived from these drawings without inventive effort.

[0015] Figure 1 The present invention provides a flow chart of a method for determining the homology of pharmaceutical raw materials according to an exemplary embodiment.

[0016] Figure 2 The present invention is a flowchart of another method for determining the homology of pharmaceutical raw materials according to an exemplary embodiment of the present invention.

[0017] Figure 3 This is a block diagram of a device for determining the homology of pharmaceutical raw materials according to an exemplary embodiment of the present invention. DETAILED DESCRIPTION

[0018] In order to enable those skilled in the art to better understand the technical solution of the present invention and to be able to implement it, the present invention is described in detail below with reference to the accompanying drawings and specific embodiments. The following embodiments are only used to more clearly illustrate the technical solution of the present invention and are not intended to limit the scope of protection of the present invention.

[0019] The present invention takes amoxicillin antibiotic as an example. Amoxicillin is a commonly used antibiotic, mainly used to treat bacterial infections caused by Staphylococcus aureus, and is widely used in skin infections, intravenous infections, soil-borne diseases, etc. It is often provided as a basic medicine to help deal with bacterial infections. Amoxicillin belongs to the β-lactam antibiotics and works by inhibiting the synthesis process of bacterial cell walls. It has an inhibitory effect on β-lactamase, making it impossible for bacteria to break down the drug, thereby worsening the infection. The global annual production of amoxicillin is about 5,000 to 6,000 tons. The production of amoxicillin depends on key raw materials such as cysteine, zymolytic enzymes and ammonium chloride. Therefore, amoxicillin occupies an important position in public health, and understanding its production and use will help to better manage and use the drug. Such as Figure 1 As shown, the present invention uses an instrumental analysis method combining EA-IRMS and Cr-EA-IRMS to determine the δ 13 C, δ 15 N, δ 18 O and δ 2 H, and drug source classification was performed using HCA and PCA. Multivariate statistical analysis and Z-score comparison were then used to construct an amoxicillin raw material database and homology discrimination method. The operability and effectiveness of the method were verified through blind sample analysis. The present invention uses the instrumental analysis method of Cr-EA-IRMS to avoid the influence of byproducts on the hydrogen stable isotope ratio, thereby achieving the purpose of ensuring the accuracy of hydrogen stable isotope ratio determination.

[0020] The technical solutions provided by various embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0021] First, the present invention provides a method for determining the homology of pharmaceutical raw materials, specifically Figure 2 As shown, the following steps are included: S201. Obtain sample drugs of the same kind from multiple different sources.

[0022] Taking amoxicillin capsules as an example, the present invention purchased 34 brands of amoxicillin capsules, covering major amoxicillin manufacturers; at the same time, the present invention paid special attention to the sample injection volume and instrument parameter selection during sample preparation and instrument analysis and determination. The determination of the injection volume should consider the proximity of the sample peak to the reference peak, and the principle that the injection volume does not affect the measured value; the selection of instrument parameters is based on the principle of avoiding interference from by-product impurities and ensuring the accuracy of the measured value.

[0023] S202. Determine the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen in pharmaceutical samples by stable isotope ratio mass spectrometry EA-IRMS and chromium-assisted stable isotope ratio mass spectrometry Cr-EA-IRMS.

[0024] In one embodiment, the sample preparation is mainly used to detect the abundance values ​​of stable isotopes of four elements including carbon, nitrogen, oxygen and hydrogen.

[0025] Determine the stable isotope abundance value δ of carbon in the sample 13 When measuring C, the sample injection volume should consider whether the sample peak is close to the reference peak and whether the injection volume does not affect the measured value. Taking the amoxicillin capsule sample as an example, the injection volume is 0.05-0.2mg. For a capsule with a specification of 0.125g, 0.2mg of the powder in the capsule is taken and packed into a tin cup; for a capsule with a specification of 0.25g, 0.1mg of the powder in the capsule is taken and packed into a tin cup; for a capsule with a specification of 0.5g, 0.05mg of the powder in the capsule is taken and packed into a tin cup. Three samples of each sample are packaged as a quality sample, and the average value is used as the measured value. 13 C, it is necessary to generate a standard curve using the measured values ​​of at least three standards to convert the sample test results and obtain an accurate value for the sample. For the amoxicillin capsule test, three standards, B2157, B2205, and IA-R004, were selected.

[0026] Determine the stable isotope abundance of nitrogen in the sample δ 15 When N is used, the sample injection volume should be considered to ensure that the sample peak is close to the reference peak and that the injection volume does not affect the measured value. Taking amoxicillin capsule sample as an example, the injection volume is 0.2-0.8mg. For capsules with a specification of 0.125g, 0.8mg of powder from the capsule is packed into a tin cup; for capsules with a specification of 0.25g, 0.4mg of powder from the capsule is packed into a tin cup; for capsules with a specification of 0.5g, 0.2mg of powder from the capsule is packed into a tin cup. Three samples of each sample are packaged as a quality sample, and the average value is used as the measured value. 15 When N is used, it is necessary to generate a standard curve using the measured values ​​of at least three standards to convert the sample test results and obtain an accurate value for the sample. For the amoxicillin capsule test, three standards, B2157, B2205, and USG89, were selected.

[0027] Determine the stable isotope abundance of oxygen in the sample δ 18 When the sample injection volume is 0, the sample peak should be close to the reference peak, and the injection volume should not affect the measured value. Taking the amoxicillin capsule sample as an example, the specifications are 0.125g, 0.25g, and 0.5g capsules. 0.2mg of the powder in the capsule is taken and placed in a silver cup. Three samples of each sample are packaged as a quality sample, and the average value is used as the measured value. 18 When the concentration of amoxicillin is too low, a standard curve must be generated using the values ​​of at least three standards to convert the sample test results and obtain an accurate value for the sample. For the amoxicillin capsule test, three standards, B2203, B2213, and CBS, were selected.

[0028] Determine the stable isotope abundance value δ of hydrogen in the sample 2 When H is used, the sample injection volume should be considered to ensure that the sample peak is close to the reference peak and that the injection volume does not affect the measured value. Taking the amoxicillin capsule sample as an example, the capsules with specifications of 0.125g, 0.25g, and 0.5g were all filled with 0.4mg of powder from the capsules and placed in a silver cup. Three samples of each type of sample were packaged as a quality sample, and the average value was used as the measured value. 2 When H is used, it is necessary to generate a standard curve using the measured values ​​of at least three standards to convert the sample test results and obtain an accurate value for the sample. For the amoxicillin capsule test, four standards were selected: B2203, B2205, CBS, and USG63.

[0029] Specifically, the present invention 13 Carbon was determined using the EA-IRMS method using a ThermoFisher Delta V Advantage / Flash 2000 instrument. The carbon in the sample was converted to CO2 gas in the elemental analyzer unit and then introduced into a DELTA V Advangtage stable isotope ratio mass spectrometer for detection via a ConFlo IV continuous flow interface. Elemental analyzer parameters included: carrier gas flow rate: 100 mL / min, oxygen flow rate: 200 mL / min, reference gas flow rate: 200 mL / min, right furnace temperature: 960°C, furnace temperature (chromatographic column): 50°C, run time: 100 seconds, sample delay time: 12 seconds, oxygen flow time: 2 seconds, run mode: solid carbon, dilution ratio: CO20%. Isotope ratio mass spectrometer parameters included: ionization mode: EI ion source, ion source voltage: 3.03 kV, vacuum: 1.2 × 10 -6 mBar, current: 1.5Ma. 13 The continuous determination of C was <0.06‰ (n=10).

[0030] The present invention 15Nitrogen was determined using the EA-IRMS method using a ThermoFisher Delta VAdvantage / Flash 2000 instrument. Nitrogen in the sample was converted to N2 gas in the elemental analyzer unit and then introduced into a DELTA V Advangtage stable isotope ratio mass spectrometer via a ConFlo IV continuous flow interface for detection. Elemental analyzer parameters included: carrier gas flow rate: 100 mL / min, oxygen flow rate: 200 mL / min, reference gas flow rate: 200 mL / min, right furnace temperature: 960°C, furnace temperature (chromatographic column): 50°C, run time: 100 s, sample delay time: 12 s, oxygen flow time: 2 s, run mode: solid N / C, dilution ratio: N20% CO2100%. Isotope ratio mass spectrometer parameters included: ionization mode: EI ion source, ion source voltage: 3.03 kV, vacuum: 1.2 × 10 -6 mBar, current: 1.5Ma. 15 Continuous determination of N was <0.06‰ (n=10).

[0031] The present invention 18 O was determined using the EA-IRMS method using a ThermoFisher Delta VAdvantage / Flash 2000 instrument. Oxygen in the sample was converted to CO gas in the elemental analyzer unit and then introduced into a DELTA V Advangtage stable isotope ratio mass spectrometer for detection via a ConFlo IV continuous flow interface. Elemental analyzer parameters included: carrier gas flow rate: 100 mL / min, oxygen flow rate: 0 mL / min, reference gas flow rate: 150 mL / min, left furnace temperature: 1380°C, furnace temperature (chromatographic column): 80°C, run time: 50 seconds, sample delay time: 23 seconds, oxygen flow time: 3 seconds, run mode: solid O, dilution ratio: CO 0%. Isotope ratio mass spectrometer parameters included: ionization mode: EI ion source, ion source voltage: 3.03 kV, vacuum: 1.2 × 10 -6 mBar, current: 1.5Ma. 18 Continuous determination of O<0.06‰ (n=10).

[0032] The present invention 2 H was determined using δ 2H was analyzed using the Cr-EA-IRMS method, using a ThermoFisher Delta V Advantage / Flash 2000 instrument. When using the Cr-EA-IRMS method, the present invention fills a high-temperature cracking reaction tube with chromium particles and corundum balls. After the hydrogen element in the sample is converted into H2 gas in the elemental analyzer unit, it is introduced into a DELTA V Advangtage stable isotope ratio mass spectrometer for detection via a ConFlo IV continuous flow interface. The main parameters of the elemental analyzer are: carrier gas flow rate: 100 mL / min, oxygen flow rate: 0 mL / min, reference gas flow rate: 150 mL / min, left furnace temperature: 1380°C, furnace temperature (chromatographic column): 80°C, run time: 50 seconds, sample delay time: 23 seconds, oxygen flow time: 3 seconds, operating mode: solid H / O, dilution ratio: H2 0% CO 100%. Isotope ratio mass spectrometer parameters are: ionization mode: EI ion source, ion source voltage: 3.03 kV, vacuum: 1.2×10 -6 mBar, current: 1.5Ma. 2 The continuous determination of H was <0.4‰ (n=10).

[0033] S203. Using the stable isotope abundance value as a variable, hierarchical cluster analysis and principal component analysis are used to classify the sources of the sample drugs to obtain multiple drug sources.

[0034] The present invention uses the abundance of stable isotopes δ13C, δ15N, δ2H, and δ18O of different brands of medicines as variables, adopts the cluster package of R language to perform hierarchical cluster analysis and principal component analysis, and groups them according to the analysis results; the cluster package method of R language has strong operability and scientificity.

[0035] In this step, the stable isotope abundance values ​​corresponding to multiple sample drugs from different sources are first preprocessed to eliminate dimensional differences; then, the Euclidean distance matrix between the stable isotope abundance values ​​corresponding to the sample drugs from different sources is calculated. Based on the Euclidean distance matrix, the Ward minimum variance method in the hierarchical clustering method is used to perform cluster analysis to obtain the cluster classification results of the sample drug sources; finally, the stable isotope abundance values ​​corresponding to the preprocessed sample drugs are subjected to principal component analysis. By comparing the sample distribution in the principal component space with the cluster classification results, the final classification results of the sample drug sources are determined.

[0036] For example, the stable isotope δ 13 C, δ 15 N, δ 2 H and δ 18O abundance was used as a variable, and hierarchical cluster analysis and principal component analysis were performed using the cluster package of R language. Grouping was performed based on the analysis results. The specific process is as follows: (1) Hierarchical cluster analysis Hierarchical clustering is an unsupervised clustering method that can group data points into several hierarchical clusters. The following are the steps to perform hierarchical cluster analysis using the cluster package:

[0037] (1) Data preparation First, a data set is loaded. The present invention uses four stable isotope data sets of different brands of amoxicillin.

[0038] (2) Data preprocessing Hierarchical clustering is very sensitive to the scale of the data, so the data needs to be standardized, including calculating the distance matrix, standardizing the data, and finally determining the stable isotope abundance value.

[0039] (3) Hierarchical clustering Hierarchical clustering is performed using the hclust() function. Here, Ward's method (ward.D2) is used to calculate the clusters.

[0040] First, perform hierarchical clustering, and then determine the visual clustering results.

[0041] (4) Cutting the cluster tree The number of clusters is selected based on the height of the cluster tree. Four clusters are selected, which includes cutting the cluster tree, adding cluster labels to the data frame, and finally determining the stable isotope abundance values.

[0042] (5) Clustering results analysis You can use the aggregate() function to calculate the mean or other statistics for each cluster. For example, you can calculate the mean of each cluster.

[0043] 2. Principal Component Analysis (PCA) Principal component analysis is a dimensionality reduction technique that transforms high-dimensional data into a low-dimensional principal component space. Here are the steps to perform PCA using the cluster package:

[0044] (1) Data preparation To perform PCA on a dataset of four stable isotope abundances of different brands of amoxicillin, first load the necessary packages and then load the data.

[0045] (2) Calculate the principal components Use the princomp() function to perform PCA.

[0046] First, calculate the principal components, and then check the variance contribution of the principal components.

[0047] (3) Visualization of principal components Specifically, you can use the screeplot() and biplot() functions for visualization, and finally generate an image based on the visualization results.

[0048] (4) Select the number of principal components Select the number of principal components based on the inflection point of the scree plot and select the first two principal components.

[0049] (5) Explain the principal components The principal components can be expressed as linear combinations of the original variables. The coefficients of the principal components can be viewed using the loadings() function.

[0050] S204. Obtain the stable isotope abundance value of the target drug to be determined, determine the Z value of the stable isotope abundance value of the target drug and the Z value of the stable isotope abundance value of each category based on the Z value analysis method, and then determine the source of the target drug according to the Z value.

[0051] Specifically, the stable isotope abundance value of the target drug to be determined is obtained, and the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each category are determined respectively based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to the preset threshold value, the target drug and the sample drugs of the corresponding category are determined to be homologous drugs.

[0052] When the Z values ​​of the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen of the target drug and the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen corresponding to sample drugs of any category in multiple categories are all less than or equal to 2, the target drug is determined to be a homologous drug of the category.

[0053] For example, as shown in Table 1, the carbon of Group A ( δ 13 C / 12 C ),nitrogen( δ 15 N / 14 N ),hydrogen( δ 2 H / 1 H ) and oxygen ( δ 18 O / 16 O ) isotope abundances are high; while the four stable isotope abundances of group B are low; nitrogen ( δ 15 N / 14 N ) is more abundant than the other three groups, while oxygen ( δ 18O / 16 O ) is less abundant; the D group contains Chili, whose oxygen ( δ 18 O / 16 O ),carbon( δ 13 C / 12 C ) and hydrogen ( δ 2 H / 1 H ) were significantly higher than those in the other three groups. δ 13 C / 12 C ) and nitrogen ( δ 15 N / 14 N ) were used to analyze the isotope abundance distribution. Except for the 20% overlap between groups A and B, the carbon and nitrogen stable isotope abundance distribution thresholds of each group were relatively obvious. The specific maximum and minimum values ​​are shown in Table 2.

[0054] Table 1 Comparison of stable isotopes of carbon, nitrogen, oxygen and hydrogen in different groups of amoxicillin Table 2 Stable isotope carbon, nitrogen, oxygen, and hydrogen abundance thresholds for different groups of amoxicillin brands This method uses the Z-score method to determine whether the test data of the blind sample significantly deviates from the overall average value of the stable isotope abundance of different brands of amoxicillin groupings. The specific formula is: ; Where X is the stable isotope abundance value of the target drug, μ is the average stable isotope abundance value of the same sample drugs from each drug source, and σ is the standard deviation of the stable isotope abundance value of the same sample drugs from each drug source.

[0055] In the present invention, a Z value exceeding 2 is considered an outlier, that is, it is significantly different from the overall average of the stable isotope abundance values ​​of different groups and cannot be considered to belong to that group.

[0056] For example, the present invention measured the abundances of the four stable isotopes in blind samples Y5 and Y25, and calculated Z values ​​based on the abundance measurements of the blind samples. The four stable isotope abundances of blind sample Y5 were all less than 2 compared with the Z value of Group A, while the Z values ​​of the other groups all had isotope species with a value greater than 2. The four stable isotope abundances of blind sample Y25 were all less than 2 compared with the Z value of Group B, while the Z values ​​of the other groups all had isotope species with a value greater than 2. Therefore, it can be inferred that Y5 belongs to Group A and Y25 belongs to Group B.

[0057] Using the above method, the present invention is classified by measuring the stable isotope abundance of the medicine. Stable isotope abundance is directly related to the production process and geographical environment of the raw materials, and can directly trace the synthesis or natural properties of the raw materials. EA-IRMS and Cr-EA-IRMS techniques are used to measure stable isotope abundance, significantly reducing by-product interference, and simultaneously measuring the isotope abundance values ​​of carbon, nitrogen, hydrogen and oxygen to construct a high-dimensional data set. By hierarchical clustering and principal component analysis, the same medicines from multiple different sources are classified by source, so as to clarify the mean difference of the isotopes of each source, and then the rationality of the source classification is further verified by principal component analysis, ensuring that key discriminant information is still retained after dimensionality reduction. Finally, based on the discrimination of the Z value method, its accuracy far exceeds the possible overlap or misjudgment risk of traditional methods. In addition, the method can be directly used to track illegal production chains, such as quickly identifying unregistered raw material sources through isotope databases, making up for the shortcomings of chemometrics in traceability.

[0058] Secondly, the present invention also provides a device for determining the homology of pharmaceutical raw materials, such as Figure 3 As shown, including: The acquisition module 301 is used to acquire multiple sample drugs of the same type from different sources.

[0059] The determination module 302 is used to determine the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen in the drug sample by using stable isotope ratio mass spectrometry EA-IRMS and chromium-assisted stable isotope ratio mass spectrometry Cr-EA-IRMS.

[0060] The classification module 303 is used to classify the sources of the sample drugs using the stable isotope abundance value as a variable, using hierarchical cluster analysis and principal component analysis methods to obtain multiple drug sources.

[0061] Determination module 304 is used to obtain the stable isotope abundance value of the target drug to be determined, and determine the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each category based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to the preset threshold value, the target drug and the sample drugs of the corresponding category are determined to be homologous drugs.

[0062] Using the above-mentioned device, the present invention classifies drugs by measuring the stable isotope abundance. Stable isotope abundance is directly related to the production process and geographical environment of raw materials, and can directly trace the synthesis or natural properties of raw materials. EA-IRMS and Cr-EA-IRMS techniques are used to measure stable isotope abundance, significantly reducing by-product interference, and simultaneously measuring the four isotope abundance values ​​of carbon, nitrogen, hydrogen, and oxygen to construct a high-dimensional data set. Through hierarchical clustering and principal component analysis, the same drugs from multiple different sources are classified by source to clarify the mean difference in isotope values ​​of each source. The rationality of the source classification is then further verified by principal component analysis to ensure that key discriminant information is retained after dimensionality reduction. Finally, the discrimination based on the Z-value method has an accuracy rate far exceeding the possible overlap or misjudgment risk of traditional methods. In addition, this method can be directly used to track illegal production chains, such as quickly identifying unregistered raw material sources through isotope databases, making up for the shortcomings of chemometrics in traceability.

[0063] The present invention also provides a computer-readable storage medium, which stores a computer program, which can be used to execute the above Figure 2 The steps of the method for determining the homology of pharmaceutical raw materials are provided.

[0064] The present invention also provides a computer device. At the hardware level, the computer device includes a processor, an internal bus, a network interface, a memory, and a non-volatile memory. Of course, it may also include hardware required for other services. The processor reads the corresponding computer program from the non-volatile memory into the memory and then runs it to achieve the above Figure 2 The steps of the method for determining the homology of pharmaceutical raw materials are provided.

[0065] Those skilled in the art will appreciate that embodiments of the present invention may be provided as methods, systems, or computer program products. Thus, the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment, or an embodiment combining software and hardware aspects. Furthermore, the present invention may take the form of a computer program product implemented on one or more computer-usable storage media (including but not limited to magnetic disk storage, CD-ROM, optical storage, etc.) containing computer-usable program code.

[0066] The present invention is described with reference to flowcharts and / or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the present invention. It should be understood that each process and / or block in the flowcharts and / or block diagrams, as well as combinations of processes and / or blocks in the flowcharts and / or block diagrams, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general-purpose computer, a special-purpose computer, an embedded processor or other programmable data processing device to produce a machine, so that the instructions executed by the processor of the computer or other programmable data processing device generate instructions for implementing the processes in the flowcharts and / or block diagrams. Figure 1 a process or multiple processes and / or boxes Figure 1 A device that provides the functions specified in a block or multiple blocks.

[0067] These computer program instructions may also be stored in a computer readable memory that can direct a computer or other programmable data processing device to work in a specific manner, so that the instructions stored in the computer readable memory produce an article of manufacture comprising an instruction device, which implements the process Figure 1 a process or multiple processes and / or boxes Figure 1 The function specified in one or more boxes.

[0068] These computer program instructions can also be loaded onto a computer or other programmable data processing device so that a series of operational steps are executed on the computer or other programmable device to produce a computer-implemented process, thereby providing the instructions executed on the computer or other programmable device for implementing the process. Figure 1 a process or multiple processes and / or boxes Figure 1 A step that specifies a function in one or more boxes.

[0069] It should be noted that the above specific embodiments can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. Therefore, although this specification has described the present invention in detail, those skilled in the art should understand that the present invention can still be modified or replaced with equivalents; and all technical solutions and improvements that do not depart from the spirit and scope of the present invention are included in the scope of protection of the patent for the present invention. Any reference signs in the claims should not be construed as limiting the claims involved.

Claims

1. A method for determining the homology of pharmaceutical raw materials, characterized in that: The method comprises: Obtaining the same sample drug from multiple different sources; The stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen in pharmaceutical samples were determined by stable isotope ratio mass spectrometry (EA-IRMS) and chromium-assisted stable isotope ratio mass spectrometry (Cr-EA-IRMS); Taking the stable isotope abundance value as a variable, hierarchical cluster analysis and principal component analysis methods are used to classify the sources of sample drugs to obtain multiple drug sources; Obtain the stable isotope abundance value of the target drug to be determined, and determine the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each drug source based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, determine that the target drug and the sample drug of the corresponding drug source are homologous drugs.

2. A method for determining the homology of pharmaceutical raw materials according to claim 1, characterized in that: The determination of the stable isotope abundance value includes the following conditions: When determining the stable isotope abundance of carbon, the injection volume was 0.05-0.2 mg, the EA-IRMS method was used, the carrier gas flow rate was 100 mL / min, the oxygen flow rate was 200 mL / min, and the right furnace temperature was 960°C; When determining the stable isotope abundance of nitrogen, the injection volume was 0.2-0.8 mg, the EA-IRMS method was used, the carrier gas flow rate was 100 mL / min, and the oxygen flow rate was 200 mL / min; When determining the stable isotope abundance of oxygen, the injection volume was 0.2 mg, the EA-IRMS method was used, and the left furnace temperature was 1380°C; When determining the stable isotope abundance of hydrogen, the Cr-EA-IRMS method was used, using chromium particles and corundum balls to fill a high-temperature cracking reaction tube, with a carrier gas flow rate of 100 mL / min and a left furnace temperature of 1380°C.

3. The method for determining the homology of pharmaceutical raw materials according to claim 1, characterized in that: Taking the stable isotope abundance value as a variable, hierarchical cluster analysis and principal component analysis were used to classify the sources of sample drugs, and multiple drug sources were obtained, including: Preprocess the stable isotope abundance values ​​corresponding to multiple sample drugs from different sources to eliminate dimensional differences; Calculating the Euclidean distance matrix between the stable isotope abundance values ​​corresponding to the sample drugs from different sources, and performing cluster analysis using the Ward minimum variance method in the hierarchical clustering method based on the Euclidean distance matrix to obtain cluster classification results of the sample drug sources; The principal component analysis is performed on the stable isotope abundance values ​​corresponding to the pretreated sample drugs. The final classification results of the source of the sample drugs are determined by comparing the sample distribution in the principal component space with the cluster classification results.

4. A method for determining the homology of pharmaceutical raw materials according to claim 1, characterized in that: The calculation formula of the Z value is: ； Where X is the stable isotope abundance value of the target drug, μ is the average stable isotope abundance value of the same sample drugs from each drug source, and σ is the standard deviation of the stable isotope abundance value of the same sample drugs from each drug source.

5. The method for determining the homology of pharmaceutical raw materials according to claim 1, characterized in that: When the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, determining that the target drug and the sample drug of the corresponding category are homologous drugs includes: When the Z values ​​of the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen of the target drug and the stable isotope abundance values ​​of carbon, nitrogen, oxygen and hydrogen corresponding to sample drugs of any category in multiple categories are all less than or equal to 2, the target drug is determined to be a homologous drug of the category.

6. A device for determining the homology of pharmaceutical raw materials, characterized in that: The device comprises: An acquisition module is used to obtain the same sample drug from multiple different sources; A determination module for determining the stable isotope abundance values ​​of carbon, nitrogen, oxygen, and hydrogen in pharmaceutical samples by stable isotope ratio mass spectrometry (EA-IRMS) and chromium-assisted stable isotope ratio mass spectrometry (Cr-EA-IRMS); A classification module is used to classify the sources of sample drugs using the stable isotope abundance value as a variable and adopt hierarchical cluster analysis and principal component analysis methods to obtain multiple drug sources; The determination module is used to obtain the stable isotope abundance value of the target drug to be determined, and determine the Z value of the stable isotope abundance value of the target drug and the stable isotope abundance value of each category based on the Z value analysis method; when the Z values ​​of the stable isotope abundance values ​​of all elements are less than or equal to a preset threshold, the target drug and the sample drugs of the corresponding category are determined to be homologous drugs.

7. A computer-readable storage medium, characterized in that The storage medium stores a computer program, and when the computer program is executed by a processor, the method according to any one of claims 1 to 5 is implemented.

8. A computer device, characterized in that: The method comprises a memory, a processor and a computer program stored in the memory and executable on the processor, wherein the processor implements the method according to any one of claims 1 to 5 when executing the program.

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