Method, apparatus, device and storage medium for determining correction factor

Abstract

Embodiments of the present disclosure relate to a method and device for determining a correction factor, an apparatus and a storage medium. The method comprises: obtaining, for each of a plurality of test solutions having different concentrations, a first UV peak area and a CAD peak area of each component in the test solution; obtaining, for each test solution, a second UV peak area of each component in the test solution; for each component, correcting the first UV peak area of the component in each test solution based on the second UV peak area of the component in the test solutions, to obtain a third UV peak area of the component in each test solution; and for each impurity, calculating a correction factor of the impurity relative to a main drug based on the third UV peak area and the CAD peak area of the impurity in the test solutions and the third UV peak area and the CAD peak area of the main drug in the test solutions. Embodiments of the present disclosure can accurately determine the correction factor of the impurity without relying on an impurity control.

Description

Technical Field

[0001] This disclosure relates to the field of drug analysis and quality control technology, and in particular to a method, apparatus, device and storage medium for determining a correction factor. Background Technology

[0002] The relative response factor (RRF) is a core concept in quantitative chromatographic analysis, used to correct for differences in detector responses caused by variations in the chemical structures of different compounds. Currently, the most common method for determining RRF is high-performance liquid chromatography-ultraviolet (HPLC-UV). However, this method typically requires impurity standards of high purity and known concentration. In practical applications, impurity standards are often difficult to obtain or their concentrations are difficult to accurately determine, thus limiting the applicability of RRF determination. Electrofoil detectors, as a mass-based detector, do not rely on ultraviolet absorption characteristics and can provide a supplementary means for RRF determination.

[0003] Therefore, it is necessary to provide a method that can still achieve accurate determination of the correction factor while reducing dependence on high-purity impurity reference standards. Summary of the Invention

[0004] To solve the above-mentioned technical problems, or at least partially solve them, embodiments of this disclosure provide a method, apparatus, device, and storage medium for determining a correction factor.

[0005] A first aspect of this disclosure provides a method for determining a correction factor, the method comprising: For each of the multiple test solutions with different concentrations, the first UV peak area and CAD peak area of ​​each component in the test solution are obtained, wherein the components in the test solution include the active ingredient and impurities, the first UV peak area is calculated based on the first UV detection signal, the CAD peak area is calculated based on the CAD detection signal, and the first UV detection signal and the CAD detection signal are obtained by analyzing the test solution using a liquid chromatography system equipped with a UV detector and an electrospray detector under the first mobile phase conditions; For each of the test solutions, the second UV peak area of ​​each component in the test solution is obtained, wherein the second UV peak area is calculated based on a second UV detection signal, which is obtained by analyzing the test solution using the UV detector under the second mobile phase condition, and the first mobile phase and the second mobile phase are different; For each component, the first UV peak area of ​​the component in each test solution is corrected based on the second UV peak area of ​​the component in each of the various test solutions to obtain the third UV peak area of ​​the component in each test solution. For each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and the CAD peak area of ​​the impurity in each of the various test solutions and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in each of the various test solutions.

[0006] A second aspect of this disclosure provides an apparatus for measuring a correction factor, the apparatus comprising: The first acquisition module is used to acquire the first UV peak area and CAD peak area of ​​each component in each of a variety of test solutions with different concentrations, wherein the components in the test solutions include the active ingredient and impurities, the first UV peak area is calculated based on a first UV detection signal, the CAD peak area is calculated based on a CAD detection signal, and the first UV detection signal and the CAD detection signal are obtained by analyzing the test solutions using a liquid chromatography system equipped with a UV detector and an electrospray detector under first mobile phase conditions; The second acquisition module is used to acquire the second UV peak area of ​​each component in each of the test solutions for each of the test solutions. The second UV peak area is calculated based on the second UV detection signal. The second UV detection signal is obtained by analyzing the test solution using the UV detector under the second mobile phase condition. The first mobile phase and the second mobile phase are different. The first correction module is used to correct the first UV peak area of ​​the component in each of the various test solutions based on the second UV peak area of ​​the component in each of the various test solutions, so as to obtain the third UV peak area of ​​the component in each of the test solutions. The first calculation module is used to calculate, for each impurity, a correction factor relative to the active pharmaceutical ingredient based on the third UV peak area and the CAD peak area of ​​the impurity in various test solutions and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in various test solutions.

[0007] A third aspect of this disclosure provides an electronic device comprising: a processor and a memory, wherein the memory stores a computer program, and when the computer program is executed by the processor, the processor performs the method described in the first aspect.

[0008] A fourth aspect of this disclosure provides a computer-readable storage medium storing a computer program that, when executed by a processor, can implement the method of the first aspect described above.

[0009] The technical solution provided in this disclosure has the following advantages compared with the prior art: In this embodiment, by combining an ultraviolet detector and an electro-fogging detector, the correction factor of the impurity relative to the active pharmaceutical ingredient is calculated. This allows for accurate determination of the impurity correction factor even in the absence or inability to obtain a high-purity impurity reference standard. Furthermore, considering the influence of the mobile phase on the ultraviolet response, corrections are made to the area of ​​the first UV peak to effectively compensate for the ultraviolet response shift caused by differences in mobile phase conditions. Consequently, the correction factor estimated based on UV-CAD is closer to the true value. Therefore, according to this embodiment, the correction factor of the impurity can be accurately determined without relying on an impurity reference standard. Attached Figure Description

[0010] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate embodiments consistent with this disclosure and, together with the description, serve to explain the principles of this disclosure.

[0011] To more clearly illustrate the technical solutions in the embodiments of this disclosure or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0012] Figure 1 This is a flowchart of a method for determining a correction factor provided in an embodiment of this disclosure; Figure 2 This is a schematic diagram of a first UV detection signal provided in an embodiment of this disclosure; Figure 3 This is a schematic diagram of a first CAD detection signal provided in an embodiment of this disclosure; Figure 4 This is a schematic diagram of the structure of a correction factor measuring device provided in an embodiment of this disclosure; Figure 5 This is a schematic diagram of the structure of an electronic device according to an embodiment of this disclosure. Detailed Implementation

[0013] To better understand the above-mentioned objectives, features, and advantages of this disclosure, the solutions disclosed herein will be further described below. It should be noted that, unless otherwise specified, the embodiments and features described herein can be combined with each other.

[0014] Numerous specific details are set forth in the following description in order to provide a full understanding of this disclosure, but this disclosure may also be implemented in other ways different from those described herein; obviously, the embodiments in the specification are only some, and not all, of the embodiments of this disclosure.

[0015] Among related technologies, high-performance liquid chromatography-ultraviolet (HPLC-UV) is the most widely used method in drug analysis and quality control, offering advantages such as high sensitivity and good repeatability. However, different compounds exhibit significant differences in their ultraviolet absorption capacity at the same wavelength. Direct quantification based on peak area often introduces substantial systematic errors. To correct for this difference, a correction factor (RRF) is typically established using high-purity impurity standards. However, in actual drug analysis and quality control, impurity standards are often difficult to obtain or their purity cannot be accurately confirmed, resulting in significant deviations in the calculated correction factor and affecting the accuracy of quantification.

[0016] In recent years, charged aerosol detectors (CAD) have been introduced as a supplement to ultraviolet (UV) detection due to their ability to approximate the mass response of most non-volatile compounds. The HPLC-UV-CAD coupling technique can simultaneously obtain UV and mass response signals in a single injection, providing a new approach for estimating correction factors. However, many related techniques do not fully consider the influence of factors such as mobile phase pH, detection wavelength, and instrument type differences on the UV response, resulting in significant differences in results under different experimental conditions. Furthermore, some methods still rely on linear regression of impurities, making operation complex and limiting their practical application. Therefore, these techniques still have the following shortcomings: 1) Strong dependence on reference standards, making it difficult to meet the actual needs of impurity reference standards shortages; 2) The UV response is significantly affected by differences in mobile phase pH and structure, resulting in insufficient stability of quantitative results; 3) The UV-CAD coupling method lacks a unified correction strategy, leading to poor comparability of results between different instruments. In view of this, there is an urgent need for a correction factor determination method that does not require high-purity impurity reference standards, can simultaneously correct for differences in UV response, and has good instrument applicability, in order to improve the accuracy and reliability of quantitative analysis of drug impurities.

[0017] Based on this, the present disclosure provides a method, apparatus, device, and storage medium for determining a correction factor. The method for determining the correction factor will be described in detail below.

[0018] Figure 1 This is a flowchart illustrating a method for determining a correction factor according to an embodiment of this disclosure. This method can be performed by an electronic device. The electronic device can be exemplarily understood as a device such as a mobile phone, tablet computer, laptop computer, or desktop computer. Figure 1As shown, the method provided in this embodiment includes the following steps: S110. For each of the multiple test solutions with different concentrations, obtain the first UV peak area and CAD peak area of ​​each component in the test solution. The components in the test solution include the active ingredient and impurities. The first UV peak area is calculated based on the first UV detection signal, and the CAD peak area is calculated based on the CAD detection signal. The first UV detection signal and the CAD detection signal are obtained by analyzing the test solution using a liquid chromatography system equipped with a UV detector and an electro-fogging detector under the first mobile phase conditions.

[0019] Specifically, there are various methods for preparing the test solution. Typical examples are described below, but these do not constitute a limitation of this disclosure. For instance, accurately weigh 10 mg of cefotaxime, impurity A, impurity 1, and impurity C reference standards, place them in the same 10 mL volumetric flask, and dilute to the corresponding mark with 1% glacial acetic acid to prepare a standard stock solution with a concentration of 1 mg / mL. Then, measure 1 mL, 2 mL, and 3 mL of the standard stock solution into 50 mL volumetric flasks, and dilute to the corresponding mark with 1% glacial acetic acid to prepare linear solutions with concentrations of 20 μg / mL, 40 μg / mL, and 60 μg / mL (i.e., test solutions of different concentrations). However, this method is not limited to this.

[0020] Specifically, there are various analytical methods for analyzing the test solution using a liquid chromatography system. Typical examples are described below, but these do not constitute a limitation of this disclosure. For example, the chromatographic column is a Kromasil C18 (4.6 mm × 250 mm, 5 μm); the mobile phase is 1% glacial acetic acid aqueous solution – acetonitrile (87:13, v / v), with the pH adjusted to 3.0 using glacial acetic acid; the flow rate is 1.0 mL / min; the column temperature is 30°C; the UV detector is a photodiode array detector (detection wavelength 254 nm); and the evaporation tube temperature of the electro-fogging detector is 50°C. However, this is not a limitation.

[0021] Specifically, the UV detection signal refers to the raw response signal generated by a compound in a UV detector. The UV peak area refers to the value obtained by integrating the region under a certain chromatographic peak in the UV detection signal.

[0022] Specifically, the CAD detection signal refers to the raw response signal generated by a compound in an electro-fogging detector. The CAD peak area refers to the value obtained by integrating the region under a specific chromatographic peak in the CAD detection signal.

[0023] Optionally, the main drug may include antibiotics. Further optionally, the main drug may include cefotaxime.

[0024] For example, the prepared test solution with a concentration of 20 μg / mL is injected into the liquid chromatography system, and the first UV detection signal and the CAD detection signal are acquired simultaneously, such as... Figure 2 and Figure 3 As shown. For cefotiam, the UV chromatographic peak was integrated based on the first UV detection signal to obtain the corresponding first UV peak area, and the CAD chromatographic peak was integrated based on the CAD detection signal to obtain the corresponding first UV peak area. The same method was used for impurities A, impurity 1, and impurity C, which will not be repeated here. In addition, the 40 μg / mL and 60 μg / mL test solutions were treated in the same way as the "20 μg / mL test solution", which will not be repeated here.

[0025] S120. For each test solution, obtain the second UV peak area of ​​each component in the test solution. The second UV peak area is calculated based on the second UV detection signal. The second UV detection signal is obtained by analyzing the test solution using a UV detector under the second mobile phase condition. The first mobile phase and the second mobile phase are different.

[0026] Specifically, there are various analytical methods for analyzing the test solution using a UV detector. Typical examples are described below, but these do not constitute a limitation of this disclosure. For example, the chromatographic column is a Kromasil C18 (4.6 mm × 250 mm, 5 μm); the mobile phase is phosphate buffer (containing 2.76 g disodium hydrogen phosphate and 1.29 g citric acid dissolved in 1 L of water, pH adjusted to 6.0 with citric acid or phosphoric acid) – acetonitrile (83:17, v / v); the flow rate is 1.0 mL / min; the column temperature is 30°C; and the UV detector is a photodiode array detector (detection wavelength 254 nm).

[0027] For example, the prepared 20 μg / mL test solution is injected into a UV detector, and the second UV detection signal is acquired. For cefoperazone, the UV chromatographic peak is integrated based on the second UV detection signal to obtain the corresponding second UV peak area. The same procedure applies to impurities A, 1, and C, and will not be repeated here. Furthermore, the 40 μg / mL and 60 μg / mL test solutions are processed in the same way as the 20 μg / mL test solution, and will not be repeated here.

[0028] S130. For each component, based on the second UV peak area of ​​the component in each test solution, the first UV peak area of ​​the component in each test solution is corrected to obtain the third UV peak area of ​​the component in each test solution.

[0029] In this disclosure, the correction factor for impurities relative to the active pharmaceutical ingredient, established under standard HPLC conditions using phosphate buffer, is typically used as the benchmark for quantitative calculations. However, in liquid chromatography systems equipped with UV and electro-fogging detectors, acidic conditions must be maintained due to chromatographic separation requirements, column stability, or other methodological limitations. If the RRF is calculated directly under acidic conditions based on the first UV peak area and the CAD peak area, the resulting value is the response factor under acidic conditions, which cannot be directly used for impurity quantification under neutral conditions. This is because the UV absorption characteristics of the active pharmaceutical ingredient and impurities may be affected by pH to different degrees. Therefore, UV peak areas are not directly comparable under different pH conditions and require pH-adjusted correction to reasonably correlate data obtained under acidic conditions to the standard RRF system under neutral conditions.

[0030] In some embodiments, for each test solution, the UV peak area of ​​the component is divided by the UV peak area of ​​the component to obtain the UV peak area correction factor of the component, and the UV peak area of ​​the component is multiplied by the UV peak area correction factor of the component to obtain the UV peak area of ​​the component.

[0031] For example, the calculation process of the "UV peak area correction factor of cefotaxime" is as follows: Divide the "second UV peak area of ​​cefotaxime in a 20 μg / mL test solution" by the "first UV peak area of ​​cefotaxime in a 20 μg / mL test solution" to obtain the UV peak area correction factor of cefotaxime in a 20 μg / mL test solution, as shown in Table 1; divide the "second UV peak area of ​​cefotaxime in a 40 μg / mL test solution" by the "first UV peak area of ​​cefotaxime in a 40 μg / mL test solution" to obtain the UV peak area correction factor of cefotaxime in a 40 μg / mL test solution, as shown in Table 1; divide the "second UV peak area of ​​cefotaxime in a 60 μg / mL test solution" by the "first UV peak area of ​​cefotaxime in a 60 μg / mL test solution" to obtain the correction factor of 60 μg / mL test solution. The UV peak area correction factors for cefotaxime in the test solution at μg / mL are shown in Table 1. The same applies to impurities A, 1, and C, and will not be repeated here. The mean, standard deviation, and relative standard deviation of the UV peak area correction factors can also be calculated, as shown in Table 1. Table 1 shows that the relative standard deviation of the UV peak area correction factors is between 0.57% and 0.93%, indicating good repeatability and stable and reliable correction data.

[0032] Table 1

[0033] For example, the calculation process for the "third UV peak area of ​​cefoperazone" is as follows: Multiply the "first UV peak area of ​​cefoperazone in a 20 μg / mL test solution" by the "UV peak area correction factor for cefoperazone in a 20 μg / mL test solution" to obtain the third UV peak area of ​​cefoperazone in a 20 μg / mL test solution; multiply the "first UV peak area of ​​cefoperazone in a 40 μg / mL test solution" by the "UV peak area correction factor for cefoperazone in a 40 μg / mL test solution" to obtain the third UV peak area of ​​cefoperazone in a 40 μg / mL test solution; multiply the "first UV peak area of ​​cefoperazone in a 60 μg / mL test solution" by the "UV peak area correction factor for cefoperazone in a 60 μg / mL test solution" to obtain the third UV peak area of ​​cefoperazone in a 60 μg / mL test solution. The area of ​​the third UV peak in the test solution. The same applies to impurities A, 1, and C, and will not be repeated here.

[0034] In other embodiments, for each component, the first UV peak area of ​​the component in each test solution is corrected based on the second UV peak area of ​​the component in various test solutions to obtain the third UV peak area of ​​the component in each test solution. This includes: for each test solution, dividing the second UV peak area of ​​the component by the first UV peak area of ​​the component to obtain the corresponding UV peak area ratio; calculating the UV peak area correction factor of the component based on the UV peak area ratio of the component in various test solutions; and for each test solution, multiplying the first UV peak area of ​​the component by the UV peak area correction factor of the component to obtain the third UV peak area of ​​the component.

[0035] Understandably, given that differences in mobile phase pH may affect UV absorption and lead to changes in UV peak area, this disclosure corrects for the first UV peak area to adjust the UV response of the liquid chromatography system, making it equivalent to phosphate buffer conditions. Furthermore, since mobile phase pH has no effect on the CAD response, the CAD signal can serve as a stable quality reference.

[0036] S140. For each impurity, calculate the correction factor of the impurity relative to the active pharmaceutical ingredient based on the third UV peak area and CAD peak area of ​​the impurity in various test solutions and the third UV peak area and CAD peak area of ​​the active pharmaceutical ingredient in various test solutions.

[0037] Specifically, the most common method for measuring the correction factor is shown in formula (1): Formula (1) in, It is the slope of the calibration curve for the active pharmaceutical ingredient. It is the slope of the impurity calibration curve.

[0038] This method requires a reference standard with known purity. In many cases, these reference standards are not available, making quantitative calculations difficult when unknown impurities appear under specific stress conditions. To address this challenge, a mass detector (such as a CAD) can be combined with a PDA detector to determine the correction factor. In PDA detection, the compound's response is related to the analyte concentration, as defined by Beer-Lambert's law, as shown in Equation (2): Formula (2) in, The peak area obtained from the PDA detector. The molar extinction coefficient is . For path length, Let be the molar concentration. Therefore, combining the responses of the mass detector and the PDA detector, the correction factor can be expressed by formula (3): Formula (3) in, The concentration of the main drug. The concentration of impurities, The peak area of ​​the main drug. Let be the peak area of ​​the impurity. Since the electro-fogging detector is a mass detector, formula (3) can be rewritten as formula (4): Formula (4) in, The peak area obtained using a PDA detector for impurities. The peak area obtained using a mass detector for impurities. The peak area of ​​the main drug obtained using a PDA detector. The peak area obtained using a quality detector for the main drug.

[0039] Formula (4) can be further rewritten as formula (5): Formula (5) in, The slope of the UV linear calibration curve of the main drug The slope of the CAD linear calibration curve for the main drug, The slope of the UV linear calibration curve for impurities, The slope of the CAD linear calibration curve for impurities.

[0040] Based on this, in some embodiments, for each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and CAD peak area of ​​the impurity in various test solutions and the third UV peak area and CAD peak area of ​​the active pharmaceutical ingredient in various test solutions, including: S1411. Based on the third UV peak area of ​​the active pharmaceutical ingredient in various test solutions, perform linear regression calculation with concentration as the abscissa and UV peak area as the ordinate to obtain the slope of the UV linear calibration curve of the active pharmaceutical ingredient. Also, based on the third CAD peak area of ​​the active pharmaceutical ingredient in various test solutions, perform linear regression calculation with concentration as the abscissa and CAD peak area as the ordinate to obtain the slope of the CAD linear calibration curve of the active pharmaceutical ingredient.

[0041] For example, based on the third UV peak area of ​​cefotaxime in test solutions of 20 μg / mL, 40 μg / mL, and 60 μg / mL, a linear regression analysis was performed with concentration as the x-axis and the third UV peak area as the y-axis to obtain a calibration curve (i.e., the UV linear calibration curve of cefotaxime). The slope of this calibration curve is the slope of the UV linear calibration curve of the active pharmaceutical ingredient, as shown in Table 2. Similarly, based on the CAD peak area of ​​cefotaxime in test solutions of 20 μg / mL, 40 μg / mL, and 60 μg / mL, a linear regression analysis was performed with concentration as the x-axis and the CAD peak area as the y-axis to obtain a calibration curve (i.e., the CAD linear calibration curve of cefotaxime). The slope of this calibration curve is the slope of the CAD linear calibration curve of the active pharmaceutical ingredient, as shown in Table 2.

[0042] Table 2

[0043] S1412. For each impurity, based on the third UV peak area of ​​the impurity in various test solutions, perform linear regression calculation with concentration as the abscissa and UV peak area as the ordinate to obtain the slope of the UV linear calibration curve of the impurity. Based on the CAD peak area of ​​the impurity in various test solutions, perform linear regression calculation with concentration as the abscissa and CAD peak area as the ordinate to obtain the slope of the CAD linear calibration curve of the impurity.

[0044] For example, based on the third UV peak area of ​​impurity A in the test solutions at concentrations of 20 μg / mL, 40 μg / mL, and 60 μg / mL, a linear regression analysis was performed with concentration as the x-axis and the third UV peak area as the y-axis to obtain a calibration curve (i.e., the UV linear calibration curve for impurity A). The slope of this calibration curve is the slope of the UV linear calibration curve for the active pharmaceutical ingredient, as shown in Table 2. Similarly, based on the CAD peak area of ​​impurity A in the test solutions at concentrations of 20 μg / mL, 40 μg / mL, and 60 μg / mL, a linear regression analysis was performed with concentration as the x-axis and the CAD peak area as the y-axis to obtain a calibration curve (i.e., the CAD linear calibration curve for impurity A). The slope of this calibration curve is the slope of the CAD linear calibration curve for the active pharmaceutical ingredient, as shown in Table 2. The same applies to impurities 1 and C, and will not be elaborated further here.

[0045] S1413. For each impurity, calculate the correction factor of the impurity relative to the main drug based on the slope of the UV linear calibration curve of the main drug, the slope of the CAD linear calibration curve of the main drug, the slope of the UV linear calibration curve of the impurity, and the slope of the CAD linear calibration curve of the impurity.

[0046] For example, the slopes of the UV linear calibration curve of the active pharmaceutical ingredient (e.g., 0.2543 in Table 2), the slopes of the CAD linear calibration curve of the active pharmaceutical ingredient (e.g., 0.1039 in Table 2), the slopes of the UV linear calibration curve of impurity A (e.g., 0.2223 in Table 2), and the slopes of the CAD linear calibration curve of impurity A (e.g., 0.0856 in Table 2) can be substituted into formula (5) to obtain the correction factor of impurity A relative to the active pharmaceutical ingredient (e.g., 1.05 in Table 2). The same applies to impurity 1 and impurity C, and will not be elaborated here.

[0047] For example, the correction factor was calculated using formula (5). The differences before and after UV peak area correction are shown in Table 3. The correction factors of impurity 1 and impurity C relative to the active pharmaceutical ingredient did not change significantly. This is because the subjects of this study are β-lactam compounds with highly similar structures, and they have similar chromophores and UV absorption characteristics at a wavelength of 254 nm. Changes in mobile phase pH mainly affect the absolute UV response of the compound, while having a limited impact on the relative UV response ratio between the active pharmaceutical ingredient and the impurities. In addition, since CAD provides an approximate mass response as a reference, the impact of mobile phase pH differences on RRF calculation results is further weakened. Therefore, UV peak area correction is mainly used to improve the comparability of the method under different chromatographic systems, rather than significantly changing the numerical value of the correction factor. Furthermore, the correction factor after UV peak area correction is closer to the actual response with CAD detection as a reference, indicating that by adjusting the UV response under acidic mobile phase conditions through peak area correction factor, the deviation caused by mobile phase pH on UV absorption is effectively eliminated, and the accuracy and comparability of quantitative results are improved.

[0048] Table 3

[0049] Specifically, in actual analysis, when the active pharmaceutical ingredient and impurities are measured under the same analytical conditions, the slope ratio of the linear calibration curve can be approximately represented by the peak area ratio of the corresponding detectors. Therefore, the RRF can also be directly calculated from the UV peak area and the CAD peak area, as shown in the following formula (6): Formula (6) in, The UV peak area of ​​the main drug. The CAD peak area of ​​the main drug. The UV peak area of ​​the impurities. This represents the CAD peak area of ​​the impurities.

[0050] Based on this, in other embodiments, for each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and CAD peak area of ​​the impurity in various test solutions and the third UV peak area and CAD peak area of ​​the active pharmaceutical ingredient in various test solutions, including: S1421. For each test solution, calculate the number of samples in the test solution based on the following formula. i Single correction factor for each impurity relative to the active pharmaceutical ingredient: Formula (7) in, The first in the solution to be tested i The single-correction factor of each impurity relative to the active pharmaceutical ingredient. The area of ​​the third UV peak of the active pharmaceutical ingredient in the test solution. This represents the CAD peak area of ​​the active pharmaceutical ingredient in the test solution. The first in the solution to be tested i The area of ​​the third UV peak of the impurity, The first in the solution to be tested i The CAD peak area of ​​each impurity.

[0051] Specifically, a single correction factor refers to a correction factor calculated based on a test solution of a certain concentration.

[0052] For example, for a 20 μg / mL test solution, the UV peak area of ​​the active pharmaceutical ingredient in a 20 μg / mL test solution, the CAD peak area of ​​the active pharmaceutical ingredient in a 20 μg / mL test solution, the third UV peak area of ​​impurity A in a 20 μg / mL test solution, and the CAD peak area of ​​impurity A in a 20 μg / mL test solution are substituted into formula (7) to obtain the single correction factor of impurity A in a 20 μg / mL test solution; the UV peak area of ​​the active pharmaceutical ingredient in a 40 μg / mL test solution, the CAD peak area of ​​the active pharmaceutical ingredient in a 40 μg / mL test solution, the third UV peak area of ​​impurity A in a 40 μg / mL test solution, and the CAD peak area of ​​impurity A in a 40 μg / mL test solution are substituted into formula (7) to obtain the single correction factor of impurity A in a 40 μg / mL test solution; the UV peak area of ​​the active pharmaceutical ingredient in a 60 μg / mL test solution, the CAD peak area of ​​the active pharmaceutical ingredient in a 60 μg / mL test solution, the third UV peak area of ​​impurity A in a 40 μg / mL test solution, and the CAD peak area of ​​impurity A in a 40 μg / mL test solution are substituted into formula (7) to obtain the single correction factor of impurity A in a 40 μg / mL test solution; the UV peak area of ​​the active pharmaceutical ingredient in a 60 μg / mL test solution, the third UV peak area of ​​impurity A in a 60 μg / mL test solution, and the CAD peak area of ​​impurity A in a 60 μg / mL test solution are substituted into formula (7) to obtain the single correction factor of impurity A in a 40 μg / mL test solution; the UV peak area of ​​the active pharmaceutical ingredient in a 60 μg / mL test solution, the third UV peak area of ​​impurity A in a 60 μg / mL test solution, and the Substituting the CAD peak area of ​​impurity A in a 60 μg / mL test solution, the third UV peak area of ​​impurity A in a 60 μg / mL test solution, and the CAD peak area of ​​impurity A in a 60 μg / mL test solution into formula (7), we obtain the single correction factor of impurity A in a 60 μg / mL test solution. The same applies to impurity 1 and impurity C, and will not be repeated here.

[0053] For example, Table 4 lists the normalized peak areas (i.e., CAD peak area / concentration) of cefotaxime, impurity A, impurity 1, and impurity C at different concentration levels (20 μg / mL, 40 μg / mL, and 60 μg / mL). The results show that under the same concentration conditions, the normalized peak areas of the CAD for different compounds are at similar levels, with relative standard deviations (RSDs) of 8.23%, 8.38%, and 8.33%, respectively, indicating that the CAD detector exhibits an approximately constant mass response characteristic for these compounds. Although there are some differences in the structures of different compounds, the CAD response is mainly determined by the mass of the analyte and has a weak correlation with the specific chemical structure. This result provides experimental basis for subsequently using CAD as a mass response reference and combining it with UV detection signals to estimate the correction factor.

[0054] Table 4

[0055] S1422, Regarding the first i The first type of impurity, based on the first type in various test solutions. i Calculate the single-correction factor of each impurity relative to the active pharmaceutical ingredient, and calculate the correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

[0056] Specifically, 1≤ i ≤ m ,in, m This represents the total number of types of impurities in the solution to be tested.

[0057] In some embodiments, for the first i The first type of impurity, based on the first type in various test solutions. i The single-correction factor of each impurity relative to the active pharmaceutical ingredient is calculated, including: the correction factor for the i-th impurity relative to the active pharmaceutical ingredient. i The first type of impurity, for various test solutions. i The average value of the single correction factors of each impurity relative to the active pharmaceutical ingredient is calculated to obtain the correction factor of the i-th impurity relative to the active pharmaceutical ingredient. Of course, in other embodiments, for the i-th impurity... i Impurities can also be categorized as "the corresponding impurities in various test solutions". i The maximum, minimum, or any value in the "single correction factor for each impurity" is used as the correction factor for the i-th impurity relative to the active pharmaceutical ingredient.

[0058] For example, for impurity A, the average, maximum, minimum, or any of the following values ​​are used as the correction factor of impurity A relative to cefotaxime: the single-time correction factor of impurity A relative to cefotaxime in a 20 μg / mL test solution, the single-time correction factor of impurity A relative to cefotaxime in a 40 μg / mL test solution, and the single-time correction factor of impurity A relative to cefotaxime in a 60 μg / mL test solution. The same applies to impurities 1 and C, and will not be elaborated further here.

[0059] Optionally, in response to the first i The first type of impurity, for various test solutions. i After averaging the single-correction factors of each impurity relative to the active pharmaceutical ingredient to obtain the correction factor of the i-th impurity relative to the active pharmaceutical ingredient, the following steps are also included: Regarding the first i Each impurity in the test solution is used as a standard, and the results are based on the first impurity in each test solution. i Calculate the peak area of ​​the third UV and CAD of each impurity, as well as the peak area of ​​the third UV and CAD of the standard in each test solution.i The correction factor for each impurity relative to the standard is calculated, and the NMR correction factor of the standard relative to the active pharmaceutical ingredient is multiplied by the first impurity. i The correction factor for each impurity relative to the standard is used to obtain the corresponding standard. i The intermediate correction factor for each impurity relative to the active pharmaceutical ingredient; Regarding the first i For each impurity, the correction factor of the i-th impurity relative to the active pharmaceutical ingredient (API) and the intermediate correction factors of the i-th impurity relative to the API under various standards are averaged to obtain the corrected correction factor of the i-th impurity relative to the API. It can be understood that through this process, intermediate correction factors of the impurity relative to the API under multiple different standards can be obtained, and then their average is calculated to obtain the corrected correction factor of the impurity relative to the API. This multi-standard averaging strategy can effectively reduce the systematic error caused by detector response bias.

[0060] Specifically, regarding the first i For each impurity, a reference standard is used sequentially. The correction factor of the impurity relative to the current standard is calculated using the third UV peak area and CAD peak area of ​​the impurity compared to the current standard (similar to "S1411-S1412" or "S1421-S1422", which will not be elaborated here). Then, the NMR correction factor of the current standard relative to the drug is multiplied by the correction factor of the impurity relative to the current standard to obtain the intermediate correction factor of the impurity relative to the drug for the current standard. Thus, the intermediate correction factor of the impurity relative to the drug for each standard can be obtained. The "NMR correction factor of the standard relative to the drug" is a correction factor determined by NMR; please refer to the section on "NMR (qNMR) determination of correction factors" below, which will not be elaborated here.

[0061] Specifically, regarding the first iWhen the active pharmaceutical ingredient is used as a reference standard for a certain impurity, it is not necessary to multiply the correction factor of the impurity relative to the active pharmaceutical ingredient by the NMR correction factor of the active pharmaceutical ingredient relative to the active pharmaceutical ingredient. In other words, it is not necessary to process the correction factor of the impurity relative to the active pharmaceutical ingredient. For example, for impurity A, based on the third UV peak area and CAD peak area of ​​impurity A in various test solutions, and the third UV peak area and CAD peak area of ​​impurity A in various test solutions, the correction factor of impurity A relative to impurity A is calculated. Then, the NMR correction factor of impurity A relative to cefotaxime is multiplied by the correction factor of impurity A relative to impurity A to obtain the "intermediate correction factor of impurity A relative to cefotaxime" (as shown in Table 5, 1.06) when impurity A is used as a standard. Based on the third UV peak area and CAD peak area of ​​impurity A in various test solutions, and the third UV peak area and CAD peak area of ​​impurity 1 in various test solutions, the correction factor of impurity A relative to impurity 1 is calculated. Then, the NMR correction factor of impurity 1 relative to cefotaxime is multiplied by the correction factor of impurity A relative to impurity 1 to obtain the "intermediate correction factor of impurity A relative to cefotaxime" (as shown in Table 5, 1) when impurity 1 is used as a standard. Based on the third UV peak area and CAD peak area of ​​impurity A in various test solutions, and the third UV peak area and CAD peak area of ​​impurity 1 in various test solutions, the correction factor of impurity A relative to impurity 1 is calculated. Then, the NMR correction factor of impurity 1 relative to cefotaxime is multiplied by the correction factor of impurity A relative to impurity 1 to obtain the "intermediate correction factor of impurity A relative to cefotaxime" (as shown in Table 5, 1) when impurity A is used as a standard. The third UV peak area and CAD peak area of ​​impurity A in various test solutions, as well as the third UV peak area and CAD peak area of ​​impurity C in various test solutions, are used to calculate the correction factor of impurity A relative to impurity C. The NMR correction factor of impurity C relative to cefotaxime is then multiplied by the correction factor of impurity A relative to impurity C to obtain the "intermediate correction factor of impurity A relative to cefotaxime" when impurity C is used as the standard (1.02 as shown in Table 5). Finally, the average values ​​of the "intermediate correction factor of impurity A relative to cefotaxime" when impurity A is used as the standard, the "intermediate correction factor of impurity A relative to cefotaxime" when impurity 1 is used as the standard, the "intermediate correction factor of impurity A relative to cefotaxime" when impurity C is used as the standard, and the "correction factor of impurity A relative to cefotaxime" when cefotaxime is used as the standard (1.01 as shown in Table 5) are calculated to obtain the corrected correction factor of impurity A relative to cefotaxime. The same applies to impurity 1 and impurity C, and will not be repeated here, as shown in Table 5.

[0062] Table 5

[0063] To demonstrate the accuracy of the method for determining the correction factor provided in the embodiments of this disclosure, two more sets of verification experiments were conducted.

[0064] I. Determination of Correction Factors by qNMR To perform NMR analysis, three NMR standard stock solutions were prepared: 7.74 mg of impurity A reference standard and 10.41 mg of cefoperazone reference standard, 5.93 mg of impurity 1 reference standard and 10.65 mg of cefoperazone reference standard, and 6.65 mg of impurity C reference standard and 11.48 mg of cefoperazone reference standard were each dissolved in 1.0 mL of deuterated methanol. Each NMR stock solution was divided into two aliquots: 0.5 mL was used directly for NMR determination; the other 0.5 mL was diluted to 100 mL with 1% glacial acetic acid solution, and then 1.0 mL of this solution was further diluted to 10 mL for liquid chromatography analysis. This fractionation strategy ensured that the samples measured by NMR and HPLC originated from the same stock solution and had completely consistent concentration ratios.

[0065] Nuclear magnetic resonance (NMR) measurements were performed using a Bruker Avance II Biospin 400 MHz NMR spectrometer under optimized quantitative conditions: a 90° pulse width of 12.86 μs, a relaxation delay of 10 s, and 16 cumulative scans. Phase and baseline corrections of the spectra were performed manually. qNMR, based on the principle that "the area of ​​the NMR peak is proportional to the number of corresponding hydrogen atoms," can directly and accurately determine the true content ratio of each component in a mixture without relying on the ultraviolet absorption characteristics of the compound. For example, Table 6 lists the correction factors for impurities A, 1, and C relative to cefotaxime, determined by NMR, with values ​​of 1.06, 0.97, and 1.24, respectively. Since NMR measurements are not affected by detector response bias, the obtained correction factors are considered a high-accuracy reference and can be used to determine the reliability of the correction factors measured using the method provided in this disclosure. Tables 5 and 6 compare the corrected RRF with the RRF' measured by NMR, and the relative deviation is within [missing information]. The result is between 3.78% and 3.07% (the relative deviation is calculated as corrected RRF - RRF') / RRF' × 100%), indicating that the method for determining the correction factor provided in the embodiments of this disclosure is acceptable for rapidly determining the RRF.

[0066] Table 6

[0067] II. Determination of Correction Factor for Digested Cefotaxime Take 25 mg of cefotaxime reference standard, place it in a 50 mL volumetric flask, dissolve it in water and dilute to volume to prepare a solution of approximately 0.5 mg / mL; heat the solution in a 90°C water bath for 30 minutes, and after cooling, obtain the thermally degraded cefotaxime sample. Under the same experimental conditions as the test sample, the corrected factors of impurities A, 1, and C relative to the active pharmaceutical ingredient in the digested cefotaxime sample were analyzed, as shown in Table 7. The results show that the RRF calculated under different reference standard conditions are generally close in value, and the relative deviation between them and the RRF' determined by NMR is within a certain range. The concentration ranges from 0.45% to 1.18%. Compared with the results of the test solutions in Table 5, the dispersion of the corrected RRF corresponding to the digestion of cefotaxime is slightly increased, but still within an acceptable range. This indicates that under conditions of complex coexisting components and matrix effects, the UV-CAD combined with multi-standard averaging strategy provided in the embodiments of this disclosure still has good stability and practicality.

[0068] Table 7

[0069] In summary, the relative deviations of the UV peak area-corrected RRF and the RRF' measured by NMR were calculated using Tables 3 and 6, and the relative deviations of the multi-standard-based corrected RRF and the RRF' measured by NMR were calculated using Tables 5 and 6, as shown in Table 8. The results show that the correction factors obtained by the two methods are generally similar in value, and the differences are within an acceptable range.

[0070] Table 8

[0071] In summary, the correction factor determination method based on the combined HPLC-UV-CAD technology provided in this disclosure can be used for the quantitative analysis of antibiotic drugs and related substances, especially suitable for situations where impurity standards are lacking or impurity responses vary significantly. The technical solution provided in this disclosure has the following advantages: 1) It eliminates the need for high-purity impurity standards, significantly reducing analytical costs and implementation difficulty: By combining a UV detector and an electro-cavitation detector in the same chromatographic analysis, the relative response relationship between impurities and the active pharmaceutical ingredient is established using the approximate mass response characteristics of the electro-cavitation detector. Even when high-purity impurity standards are lacking or unavailable, the correction factor of impurities can still be accurately determined, overcoming the technical bottleneck of the traditional HPLC-UV method's strong dependence on impurity standards. 2) Simultaneously corrects for differences in UV response and system characteristics, improving the accuracy and comparability of correction factor determination results: Addressing the issue of UV detection being easily affected by mobile phase pH, compound structure, and detection conditions, a correction strategy based on UV peak area correction and a combination of UV peak area / CAD peak area is proposed. While ensuring reasonable correction of the UV response, the CAD peak area is introduced as a stable quality response reference, effectively eliminating the influence of differences in different analytical systems and conditions on quantitative results. 3) The method is simple to operate and suitable for routine quality control and rapid detection scenarios: The correction factor can be estimated by calculating the UV peak area / CAD peak area. The analytical process is simplified, the calculation method is intuitive, and it is easy to promote and apply in drug development, quality research, and routine quality control. It is especially suitable for situations with complex impurity spectra or the presence of unknown impurities. 4) The results are stable and reliable, with good methodological robustness: Experimental results show that the correction factor results obtained by the method of this disclosure are consistent with those obtained under different concentration levels, different standard selections, and actual degradation sample conditions. They are highly consistent with the results of quantitative nuclear magnetic resonance determination, indicating that the method has good stability. 5) It has strong applicability and good expansion potential: This disclosure is not only applicable to the determination of correction factors for cefotaxime and its related substances, but can also be extended to the quantitative analysis of impurities in other antibiotics and non-volatile small molecule drugs, providing a general technical solution for establishing a unified and reliable strategy for determining impurity correction factors.

[0072] Figure 4 This is a schematic diagram of a correction factor measuring device provided in an embodiment of this disclosure. This correction factor measuring device can be understood as the aforementioned electronic device or a functional module within the aforementioned electronic device. For example... Figure 4 As shown, the apparatus for measuring the correction factor includes: The first acquisition module 410 is used to acquire the first UV peak area and CAD peak area of ​​each component in each of a variety of test solutions with different concentrations, wherein the components in the test solution include the active ingredient and impurities, the first UV peak area is calculated based on the first UV detection signal, the CAD peak area is calculated based on the CAD detection signal, and the first UV detection signal and the CAD detection signal are obtained by analyzing the test solution using a liquid chromatography system equipped with an ultraviolet detector and an electro-fogging detector under the first mobile phase conditions; The second acquisition module 420 is used to acquire the second UV peak area of ​​each component in each of the test solutions for each of the test solutions, wherein the second UV peak area is calculated based on the second UV detection signal, and the second UV detection signal is obtained by analyzing the test solution using the UV detector under the second mobile phase condition, and the first mobile phase and the second mobile phase are different; The first correction module 430 is used to correct the first UV peak area of ​​the component in each of the various test solutions based on the second UV peak area of ​​the component in each of the various test solutions, so as to obtain the third UV peak area of ​​the component in each of the test solutions. The first calculation module 440 is used to calculate, for each impurity, a correction factor relative to the active pharmaceutical ingredient based on the third UV peak area and the CAD peak area of ​​the impurity in each of the various test solutions and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in each of the various test solutions.

[0073] Optionally, the first correction module 430 is specifically used to, for each of the test solutions, divide the second UV peak area of ​​the component by the first UV peak area of ​​the component to obtain a UV peak area correction factor for the component, and multiply the first UV peak area of ​​the component by the UV peak area correction factor to obtain the third UV peak area of ​​the component.

[0074] Optionally, the first calculation module 440 includes: a first calculation submodule, used to calculate, for each of the test solutions, the number of the first sample in the test solution based on the following formula. i The single-correction factor of the impurity relative to the active pharmaceutical ingredient:

[0075] in, The first in the solution to be tested i The single-correction factor of the impurity relative to the active pharmaceutical ingredient. The area of ​​the third UV peak of the active pharmaceutical ingredient in the test solution. The CAD peak area of ​​the active pharmaceutical ingredient in the test solution. The first in the solution to be tested i The area of ​​the third UV peak of the aforementioned impurity, The first in the solution to be tested i The CAD peak area of ​​the impurity; The second calculation submodule is used for the first... i The impurities mentioned above, based on the first impurity in each of the various test solutions. i Calculate the single-correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

[0076] Optional, a second calculation submodule, specifically used for the first... i The impurities mentioned above, for the first impurity in each of the various test solutions. i The average value of the single correction factor of each impurity relative to the active pharmaceutical ingredient is calculated to obtain the correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

[0077] Optionally, the device further includes a correction module for use in the case of the first... i The impurities mentioned above, for the first impurity in each of the various test solutions. i After averaging the single correction factors of the impurities relative to the active pharmaceutical ingredient to obtain the correction factor of the i-th impurity relative to the active pharmaceutical ingredient, the correction factor for the i-th impurity is then calculated for the i-th impurity. i Each of the aforementioned impurities in the test solution is used as a standard, based on the first impurity in each of the aforementioned impurities in the test solution. i The third UV peak area and the CAD peak area of ​​the impurity, and the third UV peak area and the CAD peak area of ​​the standard in each of the test solutions, are used to calculate the... i The correction factor of the impurity relative to the standard is determined to obtain the correction factor of the impurity relative to each of the standards; Regarding the first i For each of the impurities, the correction factor of the i-th impurity relative to the active pharmaceutical ingredient and the correction factor of the i-th impurity relative to each of the standards are averaged to obtain the corrected correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

[0078] Optionally, the first calculation module 440 is specifically used to perform linear regression calculation with concentration as the abscissa and UV peak area as the ordinate based on the third UV peak area of ​​the active pharmaceutical ingredient in various test solutions, to obtain the slope of the UV linear calibration curve of the active pharmaceutical ingredient, and to perform linear regression calculation with concentration as the abscissa and CAD peak area as the ordinate based on the third CAD peak area of ​​the active pharmaceutical ingredient in various test solutions, to obtain the slope of the CAD linear calibration curve of the active pharmaceutical ingredient. For each impurity, a linear regression calculation is performed based on the third UV peak area of ​​the impurity in each of the various test solutions, with concentration as the abscissa and UV peak area as the ordinate, to obtain the slope of the UV linear calibration curve of the impurity. A linear regression calculation is also performed based on the CAD peak area of ​​the impurity in each of the various test solutions, with concentration as the abscissa and CAD peak area as the ordinate, to obtain the slope of the CAD linear calibration curve of the impurity. For each impurity, a correction factor for the impurity relative to the drug is calculated based on the slope of the UV linear calibration curve of the drug, the slope of the CAD linear calibration curve of the drug, the slope of the UV linear calibration curve of the impurity, and the slope of the CAD linear calibration curve of the impurity.

[0079] Optionally, the main drug may include antibiotics.

[0080] The apparatus provided in this embodiment can execute the methods of any of the above embodiments, and its execution method and beneficial effects are similar, so they will not be described again here.

[0081] This disclosure also provides an electronic device, which includes: a memory storing a computer program; and a processor for executing the computer program, wherein when the computer program is executed by the processor, it can implement the methods of any of the above embodiments.

[0082] Example, Figure 5 This is a schematic diagram of the structure of an electronic device according to an embodiment of this disclosure. See below for details. Figure 5 The diagram illustrates a structural schematic suitable for implementing the electronic device 500 in the embodiments of this disclosure. The electronic device 500 in the embodiments of this disclosure may include, but is not limited to, mobile terminals such as mobile phones, laptops, digital broadcast receivers, PDAs (personal digital assistants), PADs (tablet computers), PMPs (portable multimedia players), in-vehicle terminals (e.g., in-vehicle navigation terminals), and fixed terminals such as digital TVs and desktop computers. Figure 5 The electronic device shown is merely an example and should not be construed as limiting the functionality and scope of the embodiments disclosed herein.

[0083] like Figure 5 As shown, electronic device 500 may include a processing unit (e.g., a central processing unit, a graphics processing unit, etc.) 501, which can perform various appropriate actions and processes according to a program stored in read-only memory (ROM) 502 or a program loaded from storage device 508 into random access memory (RAM) 503. RAM 503 also stores various programs and data required for the operation of electronic device 500. Processing unit 501, ROM 502, and RAM 503 are interconnected via bus 504. Input / output (I / O) interface 505 is also connected to bus 504.

[0084] Typically, the following devices can be connected to I / O interface 505: input devices 506 including, for example, touchscreens, touchpads, keyboards, mice, cameras, microphones, accelerometers, gyroscopes, etc.; output devices 507 including, for example, liquid crystal displays (LCDs), speakers, vibrators, etc.; storage devices 508 including, for example, magnetic tapes, hard disks, etc.; and communication devices 509. Communication device 509 allows electronic device 500 to communicate wirelessly or wiredly with other devices to exchange data. Although Figure 5 An electronic device 500 with various devices is shown; however, it should be understood that it is not required to implement or possess all of the devices shown. More or fewer devices may be implemented or possessed alternatively.

[0085] In particular, according to embodiments of this disclosure, the processes described above with reference to the flowcharts can be implemented as computer software programs. For example, embodiments of this disclosure include a computer program product comprising a computer program carried on a non-transitory computer-readable medium, the computer program containing program code for performing the methods shown in the flowcharts. In such embodiments, the computer program can be downloaded and installed from a network via a communication device 509, or installed from a storage device 508, or installed from a ROM 502. When the computer program is executed by the processing device 501, it performs the functions defined in the methods of embodiments of this disclosure.

[0086] It should be noted that the computer-readable medium described in this disclosure can be a computer-readable signal medium or a computer-readable storage medium, or any combination thereof. A computer-readable storage medium can be, for example,—but not limited to—an electrical, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any combination thereof. More specific examples of a computer-readable storage medium may include, but are not limited to: an electrical connection having one or more wires, a portable computer disk, a hard disk, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), optical fiber, portable compact disk read-only memory (CD-ROM), optical storage device, magnetic storage device, or any suitable combination thereof. In this disclosure, a computer-readable storage medium can be any tangible medium containing or storing a program that can be used by or in conjunction with an instruction execution system, apparatus, or device. In this disclosure, a computer-readable signal medium can include a data signal propagated in baseband or as part of a carrier wave, carrying computer-readable program code. Such propagated data signals can take various forms, including but not limited to electromagnetic signals, optical signals, or any suitable combination thereof. A computer-readable signal medium can be any computer-readable medium other than a computer-readable storage medium, which can send, propagate, or transmit a program for use by or in connection with an instruction execution system, apparatus, or device. The program code contained on the computer-readable medium can be transmitted using any suitable medium, including but not limited to: wires, optical fibers, RF (radio frequency), etc., or any suitable combination thereof.

[0087] In some implementations, clients and servers can communicate using any currently known or future-developed network protocol such as HTTP (Hypertext Transfer Protocol) and can interconnect with digital data communication (e.g., communication networks) of any form or medium. Examples of communication networks include local area networks (“LANs”), wide area networks (“WANs”), the Internet (e.g., the Internet of Things), and peer-to-peer networks (e.g., ad hoc peer-to-peer networks), as well as any currently known or future-developed networks.

[0088] The aforementioned computer-readable medium may be included in the aforementioned electronic device; or it may exist independently and not assembled into the electronic device.

[0089] The aforementioned computer-readable medium carries one or more programs, which, when executed by the electronic device, cause the electronic device to perform the method described in any of the above embodiments.

[0090] Computer program code for performing the operations of this disclosure can be written in one or more programming languages ​​or a combination thereof, including but not limited to object-oriented programming languages ​​such as Java, Smalltalk, and C++, as well as conventional procedural programming languages ​​such as the "C" language or similar programming languages. The program code can be executed entirely on the user's computer, partially on the user's computer, as a standalone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In cases involving remote computers, the remote computer can be connected to the user's computer via any type of network—including a local area network (LAN) or a wide area network (WAN)—or can be connected to an external computer (e.g., via the Internet using an Internet service provider).

[0091] The flowcharts and block diagrams in the accompanying drawings illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of this disclosure. In this regard, each block in a flowchart or block diagram may represent a module, segment, or portion of code containing one or more executable instructions for implementing a specified logical function. It should also be noted that in some alternative implementations, the functions indicated in the blocks may occur in a different order than those indicated in the drawings. For example, two consecutively indicated blocks may actually be executed substantially in parallel, and they may sometimes be executed in reverse order, depending on the functions involved. It should also be noted that each block in the block diagrams and / or flowcharts, and combinations of blocks in the block diagrams and / or flowcharts, can be implemented using a dedicated hardware-based system that performs the specified function or operation, or using a combination of dedicated hardware and computer instructions.

[0092] The units described in the embodiments of this disclosure can be implemented in software or hardware. The names of the units are not, in some cases, intended to limit the specific unit.

[0093] The functions described above in this document can be performed at least in part by one or more hardware logic components. For example, exemplary types of hardware logic components that can be used, without limitation, include: field-programmable gate arrays (FPGAs), application-specific integrated circuits (ASICs), application-specific standard products (ASSPs), system-on-a-chip (SoCs), complex programmable logic devices (CPLDs), and so on.

[0094] In the context of this disclosure, a machine-readable medium can be a tangible medium that may contain or store a program for use by or in conjunction with an instruction execution system, apparatus, or device. A machine-readable medium can be a machine-readable signal medium or a machine-readable storage medium. A machine-readable medium can be, but is not limited to, electronic, magnetic, optical, electromagnetic, infrared, or semiconductor systems, apparatus, or devices, or any suitable combination of the foregoing. More specific examples of machine-readable storage media include electrical connections based on one or more wires, portable computer disks, hard disks, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), optical fiber, portable compact disk read-only memory (CD-ROM), optical storage devices, magnetic storage devices, or any suitable combination of the foregoing.

[0095] This disclosure also provides a computer-readable storage medium storing a computer program. When the computer program is executed by a processor, it can implement the methods of any of the above embodiments. The execution method and beneficial effects are similar, and will not be described again here.

[0096] It should be noted that, in this document, relational terms such as "first" and "second" are used merely to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0097] The above description is merely a specific embodiment of this disclosure, enabling those skilled in the art to understand or implement it. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this disclosure. Therefore, this disclosure is not to be limited to the embodiments described herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for determining a correction factor, characterized in that, include: For each of the multiple test solutions with different concentrations, the first UV peak area and CAD peak area of ​​each component in the test solution are obtained, wherein the components in the test solution include the active ingredient and impurities, the first UV peak area is calculated based on the first UV detection signal, the CAD peak area is calculated based on the CAD detection signal, and the first UV detection signal and the CAD detection signal are obtained by analyzing the test solution using a liquid chromatography system equipped with a UV detector and an electrospray detector under the first mobile phase conditions; For each of the test solutions, the second UV peak area of ​​each component in the test solution is obtained, wherein the second UV peak area is calculated based on a second UV detection signal, which is obtained by analyzing the test solution using the UV detector under the second mobile phase condition, and the first mobile phase and the second mobile phase are different; For each component, the first UV peak area of ​​the component in each test solution is corrected based on the second UV peak area of ​​the component in each of the various test solutions to obtain the third UV peak area of ​​the component in each test solution. For each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and the CAD peak area of ​​the impurity in each of the various test solutions and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in each of the various test solutions.

2. The method according to claim 1, characterized in that, For each component, the step of correcting the first UV peak area of ​​the component in each of the various test solutions based on the second UV peak area of ​​the component in each of the various test solutions to obtain the third UV peak area of ​​the component in each of the test solutions includes: For each of the test solutions, the UV peak area of ​​the component is divided by the UV peak area of ​​the component to obtain the UV peak area correction factor of the component, and the UV peak area of ​​the component is multiplied by the UV peak area correction factor of the component to obtain the third UV peak area of ​​the component.

3. The method according to claim 1, characterized in that, For each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and the CAD peak area of ​​the impurity in each of the various test solutions, and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in each of the various test solutions, including: For each of the test solutions, the number of the first sample in the test solution is calculated based on the following formula. i The single-correction factor of the impurity relative to the active pharmaceutical ingredient: in, The first in the solution to be tested i The single-correction factor of the impurity relative to the active pharmaceutical ingredient. The area of ​​the third UV peak of the active pharmaceutical ingredient in the test solution. The CAD peak area of ​​the active pharmaceutical ingredient in the test solution. The first in the solution to be tested i The area of ​​the third UV peak of the aforementioned impurity, The first in the solution to be tested i The CAD peak area of ​​the impurity; Regarding the first i The impurities mentioned above, based on the first impurity in each of the various test solutions. i Calculate the single-correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

4. The method according to claim 3, characterized in that, The above refers to the first i The impurities mentioned above, based on the first impurity in each of the various test solutions. i The calculation of the single-correction factor of the i-th impurity relative to the active pharmaceutical ingredient includes: Regarding the first i The impurities mentioned above, for the first impurity in each of the various test solutions. i The average value of the single correction factor of each impurity relative to the active pharmaceutical ingredient is calculated to obtain the correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

5. The method according to claim 4, characterized in that, In the context of the first i The impurities mentioned above, for the first impurity in each of the various test solutions. i After calculating the average of the single correction factors of the i-th impurity relative to the active pharmaceutical ingredient, the method further includes: Regarding the first i Each of the aforementioned impurities in the test solution is used as a standard, based on the first impurity in each of the aforementioned impurities in the test solution. i The third UV peak area and the CAD peak area of ​​the impurity, and the third UV peak area and the CAD peak area of ​​the standard in each of the test solutions, are used to calculate the... i The correction factor for the impurity relative to the standard is determined, and the NMR correction factor of the standard relative to the active pharmaceutical ingredient is multiplied by the first... i The correction factor of the impurity relative to the standard is used to obtain the first impurity corresponding to the standard. i The intermediate correction factor for the impurities relative to the active pharmaceutical ingredient; Regarding the first i For each of the impurities, the average value of the correction factor of the i-th impurity relative to the active pharmaceutical ingredient and the intermediate correction factor of the i-th impurity relative to the active pharmaceutical ingredient corresponding to each of the standards is calculated to obtain the corrected correction factor of the i-th impurity relative to the active pharmaceutical ingredient.

6. The method according to claim 1, characterized in that, For each impurity, a correction factor relative to the active pharmaceutical ingredient is calculated based on the third UV peak area and the CAD peak area of ​​the impurity in each of the various test solutions, and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in each of the various test solutions. This includes: Based on the third UV peak area of ​​the active pharmaceutical ingredient in various test solutions, a linear regression calculation is performed with concentration as the abscissa and UV peak area as the ordinate to obtain the slope of the UV linear calibration curve of the active pharmaceutical ingredient. Based on the third CAD peak area of ​​the active pharmaceutical ingredient in various test solutions, a linear regression calculation is performed with concentration as the abscissa and CAD peak area as the ordinate to obtain the slope of the CAD linear calibration curve of the active pharmaceutical ingredient. For each impurity, a linear regression calculation is performed based on the third UV peak area of ​​the impurity in each of the various test solutions, with concentration as the abscissa and UV peak area as the ordinate, to obtain the slope of the UV linear calibration curve of the impurity. A linear regression calculation is also performed based on the CAD peak area of ​​the impurity in each of the various test solutions, with concentration as the abscissa and CAD peak area as the ordinate, to obtain the slope of the CAD linear calibration curve of the impurity. For each impurity, a correction factor for the impurity relative to the drug is calculated based on the slope of the UV linear calibration curve of the drug, the slope of the CAD linear calibration curve of the drug, the slope of the UV linear calibration curve of the impurity, and the slope of the CAD linear calibration curve of the impurity.

7. The method according to any one of claims 1-6, characterized in that, The main drugs include antibiotics.

8. A device for measuring a correction factor, characterized in that, include: The first acquisition module is used to acquire the first UV peak area and CAD peak area of ​​each component in each of a variety of test solutions with different concentrations, wherein the components in the test solutions include the active ingredient and impurities, the first UV peak area is calculated based on a first UV detection signal, the CAD peak area is calculated based on a CAD detection signal, and the first UV detection signal and the CAD detection signal are obtained by analyzing the test solutions using a liquid chromatography system equipped with a UV detector and an electrospray detector under first mobile phase conditions; The second acquisition module is used to acquire the second UV peak area of ​​each component in each of the test solutions for each of the test solutions. The second UV peak area is calculated based on the second UV detection signal. The second UV detection signal is obtained by analyzing the test solution using the UV detector under the second mobile phase condition. The first mobile phase and the second mobile phase are different. The first correction module is used to correct the first UV peak area of ​​the component in each of the various test solutions based on the second UV peak area of ​​the component in each of the various test solutions, so as to obtain the third UV peak area of ​​the component in each of the test solutions. The first calculation module is used to calculate, for each impurity, a correction factor relative to the active pharmaceutical ingredient based on the third UV peak area and the CAD peak area of ​​the impurity in various test solutions and the third UV peak area and the CAD peak area of ​​the active pharmaceutical ingredient in various test solutions.

9. An electronic device, characterized in that, include: A processor and a memory, wherein the memory stores a computer program that, when executed by the processor, performs the method of any one of claims 1-7.

10. A computer-readable storage medium, characterized in that, The storage medium stores a computer program that, when executed by a processor, implements the method as described in any one of claims 1-7.

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