Method for determining the content of sodium fosfomycin for injection based on spectral analysis

Abstract

The present application relates to the field of material testing and analysis technology, and particularly relates to a method for determining the content of sodium fosfomycin for injection based on spectral analysis, which determines a second reference content of sodium fosfomycin component with local chemical characteristics for each target wave band by analyzing the spectral data of sodium fosfomycin for injection samples with different contents, the second reference content being a reference content with certain degree of excipient influence elimination and obvious chemical characteristics of sodium fosfomycin; the peak type error value of each target wave band of the sample to be tested is determined by the difference between the spectral peak type characteristic indexes of the sample to be tested and the different content samples, so as to quantify the influence degree of the spectral data of the sample to be tested by the excipient, and take it as a correction weight, and then combined with the second reference content and the third reference weight, the final sodium fosfomycin content of the sample to be tested with higher accuracy can be obtained.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of material testing and analysis technology, in particular to a kind of based on spectral analysis's sodium fosfomycin for injection component determination method. BACKGROUND

[0002] Sodium fosfomycin for injection is a broad-spectrum antibiotic, widely used in the treatment of various serious infections caused by sensitive bacteria, and its clinical efficacy and drug content are closely related.In the field of drug component determination, the existing method for determining the content of sodium fosfomycin for injection by spectral analysis technology usually adds a certain amount of auxiliary materials, such as buffer, stabilizer or antioxidant, to improve the physical and chemical stability and solubility of the preparation.

[0003] The structure of sodium fosfomycin molecule is special, containing epoxy group and C-P bond, which makes it usually show end absorption or weak absorption in the ultraviolet region, and it is easily disturbed by the solvent effect of auxiliary materials.Specifically, auxiliary components often have certain absorption or scattering properties in the ultraviolet-visible spectral region, especially compounds containing carboxyl, hydroxyl, phosphate and other functional groups, which may have obvious electronic transition absorption peaks in certain wavelength range, so the absorption peaks of these auxiliary materials and the characteristic absorption range of sodium fosfomycin main component partially overlap, which will cause the superposition and distortion of spectral signal, so that the actual measured absorbance is mixed with the optical response of auxiliary materials, thereby affecting the accuracy of quantitative calculation. SUMMARY

[0004] In order to solve the technical problems of the existing sodium fosfomycin for injection component determination process, such as the deviation of the generated spectral data, resulting in low accuracy of the determination results, the purpose of the present application is to provide a kind of based on spectral analysis's sodium fosfomycin for injection component determination method, the technical scheme adopted is as follows:

[0005] One embodiment of the present application provides a kind of based on spectral analysis's sodium fosfomycin for injection component determination method, which comprises the following steps:

[0006] Selecting the spectral data of several different content sodium fosfomycin for injection samples;According to the spectral data of each content sample, determine the spectral peak type characteristic index of each target wave band in different content samples;The target wave band is the wave band of sodium fosfomycin component in spectrum;

[0007] According to the change stability of the plurality of spectral peak type characteristic indexes corresponding to the same target wave band and the synchronous change between the absorbance of each wavelength point in the target wave band and the concentration of sodium fosfomycin, determine the chemical characteristic index of each wavelength point in each target wave band;

[0008] determine a second reference content of the fosfomycin sodium component corresponding to each target waveband according to the chemical characteristic index of each wavelength point in each target waveband and the first reference content; the first reference content is obtained through a linear regression model between absorbance and fosfomycin sodium content;

[0009] determine a spectral peak type characteristic index of each target waveband in the sample to be measured; determine a peak type error value of each target waveband of the sample to be measured according to the difference between the spectral peak type characteristic indexes corresponding to the sample to be measured and different content samples of each target waveband;

[0010] based on the peak type error value, the second reference content and the third reference content of each target waveband are weighted and fused to obtain a waveband corrected content, and the final fosfomycin sodium content of the sample to be measured is determined by fusing all waveband corrected contents; the third reference content is obtained by analyzing the target waveband through a quantitative analysis model.

[0011] Further, the determination of the spectral peak type characteristic index of each target waveband in the different content samples comprises:

[0012] respectively for each content sample, based on the second derivative data of the sample spectrum, the boundary of each absorption peak is determined by locating the zero-crossing point of the second derivative, and the spectral interval defined by the boundary is taken as the target waveband;

[0013] determine the spectral peak type characteristic index of each target waveband in the corresponding content sample according to the shape characteristics of the spectral peak of each target waveband.

[0014] Further, the determination of the chemical characteristic index of each wavelength point in each target waveband comprises:

[0015] respectively for each target waveband, according to the difference between the spectral peak type characteristic indexes of the target waveband in two different content samples, determine the stability index of the spectral peak type characteristic of the target waveband in multiple different content samples;

[0016] respectively for each wavelength point in the target waveband, obtain the absorbance and the sequence of fosfomycin sodium concentration of the sample of the wavelength point in different content samples, analyze the change similarity between the absorbance sequence and the sequence of fosfomycin sodium concentration to determine the synchronous change index;

[0017] determine the chemical characteristic index of each wavelength point in each target waveband according to the stability index of each target waveband and the synchronous change index of each wavelength point.

[0018] Further, the determination of the stability index of the spectral peak type characteristic of the target waveband in multiple different content samples comprises:

[0019] In the sample sequence, the absolute value of the difference between the spectral peak type feature index of the previous content sample and the spectral peak type feature index of the next content sample is calculated for the target wavelength range;

[0020] All the difference absolute values corresponding to the target wavelength range are determined, and the average value of all the difference absolute values is negatively correlated and normalized to obtain the stability index of the spectral peak type feature of the target wavelength range in multiple different content samples.

[0021] Further, the analysis of the change similarity between the absorbance sequence and the fosfomycin sodium concentration sequence determines a synchronous change index, comprising:

[0022] The DTW distance between the absorbance sequence and the fosfomycin sodium concentration sequence is calculated.

[0023] The DTW distance is negatively correlated and normalized to obtain the synchronous change index of the corresponding wavelength point.

[0024] Further, the determination of the second reference content of the fosfomycin sodium component corresponding to each target wavelength range comprises:

[0025] For each target wavelength range, the chemical contribution degree of each wavelength point in the target wavelength range is determined according to the chemical characteristic index of each wavelength point in the target wavelength range.

[0026] The first reference content of the fosfomycin sodium component corresponding to the corresponding wavelength point is weighted and fused by using the chemical contribution degree of each wavelength point in the target wavelength range to obtain the second reference content of the fosfomycin sodium component corresponding to the target wavelength range.

[0027] Further, the determination of the chemical contribution degree of each wavelength point in the target wavelength range comprises:

[0028] The chemical characteristic index of each wavelength point in the target wavelength range is normalized by maximum-minimum normalization to obtain the specificity index of each wavelength point.

[0029] The product of the chemical characteristic index and the specificity index of each wavelength point in the target wavelength range is calculated as the chemical contribution degree of the corresponding wavelength point.

[0030] Further, the determination of the peak type error value of each target wavelength range of the to-be-tested sample comprises:

[0031] For each target wavelength range, the average value of the spectral peak type feature index of the target wavelength range in different content samples is calculated as a reference peak type feature index.

[0032] The difference between the spectral peak type feature index of the target wavelength range in the to-be-tested sample and the reference peak type feature index is calculated, and the difference is normalized to obtain the peak type error value of the target wavelength range.

[0033] Further, the final fosfomycin sodium content of the sample to be measured is determined by:

[0034] For each target wave band of the sample to be measured, the peak type error value of the target wave band is taken as the weight of the second reference content, denoted as the first weight;

[0035] The complement of the peak type error value of the target wave band is taken as the weight of the third reference content, denoted as the second weight;

[0036] According to the first weight, the second weight, the second reference content and the third reference content of the target wave band, the wave band correction content of the target wave band is obtained.

[0037] The wave band correction content of each target wave band is weighted and fused to obtain the final fosfomycin sodium content of the sample to be measured.

[0038] Further, the wave band correction content of the target wave band is obtained by:

[0039] The product of the first weight and the second reference content of the target wave band is calculated, denoted as the first product; and the product of the second weight and the third reference content of the target wave band is calculated, denoted as the second product;

[0040] The sum of the first product and the second product is taken as the wave band correction content of the corresponding target wave band.

[0041] The present application has the following beneficial effects:

[0042] The application provides a kind of based on spectral analysis's fosfomycin sodium for injection component determination method, the method first obtains the spectral data of different content of fosfomycin sodium for injection sample, then based on the spectral data of known standard content sample, determine the multiple target wave bands of fosfomycin sodium component in spectrum;Its multi-wave band collaborative analysis strategy makes when a certain wave band is interfered by adjuvant or impurity, other wave bands that are not interfered or less interfered can provide reliable correction, so as to effectively overcome the interference of adjuvant in complex preparation, ensure the accuracy of detection in real and complex sample matrix.The stability of spectral peak shape characteristic index under different concentrations is used, and the synchronous change of absorbance and concentration of wavelength point is combined to dynamically screen and evaluate the reliability of each target wave band, which can automatically identify the high-quality wave bands and wavelength points that truly reflect the chemical intrinsic structure of fosfomycin sodium and are less interfered, and discard unreliable signal area, thereby improving the quality of modeling data from the source.Finally, the application constructs a double verification system including second reference content (based on chemical contribution degree weighting) and third reference content (based on traditional quantitative model), and uses peak type error value to dynamically evaluate the consistency of spectral shape between test sample and standard sample, and accordingly adaptively adjusts the weight of two reference contents;Through peak type error value, when the peak shape is consistent, the third reference content is more reliable, and when the peak shape varies, the second reference content with stronger anti-interference ability is more dependent, which makes the final content determination result show excellent robustness when facing various uncertainties.Therefore, the application not only significantly improves the accuracy of fosfomycin sodium for injection component determination, but also shows strong anti-interference ability and robustness in complex practical application scenarios, and provides reliable technical support for high-precision control of drug quality. BRIEF DESCRIPTION OF DRAWINGS

[0043] In order to more clearly illustrate the technical solutions in the embodiments of the application or the prior art, and the advantages thereof, below, a brief introduction will be given to the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are only some embodiments of the application, and for those skilled in the art, other drawings can be obtained without creative labor based on these drawings.

[0044] Figure 1 A flow chart of a kind of based on spectral analysis's fosfomycin sodium for injection component determination method of an embodiment of the application;

[0045] Figure 2 A spectral diagram of a fosfomycin sodium sample in an embodiment of the application;

[0046] Figure 3 A step flow chart for determining the chemical characteristic index of each wavelength point in each target wave band in an embodiment of the application;

[0047] Figure 4 The flow chart of the step of determining the second reference content of the fosfomycin sodium component corresponding to each target wave band in the embodiment of the present application. DETAILED DESCRIPTION

[0048] In order to further clarify the technical means and effects taken by the present application to achieve the predetermined object of the application, the specific embodiments, structures, features and effects of the technical solutions proposed by the present application are described in detail below in combination with the drawings and preferred embodiments. In the following description, different "one embodiment" or "another embodiment" do not necessarily refer to the same embodiment. In addition, the specific features, structures or characteristics in one or more embodiments can be combined in any suitable form.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs.

[0050] One embodiment of the present application provides a method for determining the content of fosfomycin sodium for injection based on spectral analysis, as shown in Figure 1 The method comprises the following steps:

[0051] S1, selecting spectral data of a plurality of different content samples of fosfomycin sodium for injection; determining the spectral peak type characteristic index of each target wave band in different content samples according to the spectral data of each content sample.

[0052] The molecular formula of fosfomycin sodium is , which contains an oxetane ring ( , a strong Raman peak), a phosphate group ( , a strong IR absorption), a sodium carboxylate ( , , an anti-symmetric stretching), these characteristic functional group peaks are easily affected by moisture, excipients and crystal form. In order to improve the accuracy of the determination of the content of fosfomycin sodium for injection, the present embodiment analyzes the influence of excipients on fosfomycin sodium to obtain a determination result of the content of fosfomycin sodium to a certain extent. First, obtain spectral data of a plurality of content samples, and analyze the spectral peak type characteristics of each type of target wave band in different content samples based on the spectral data.

[0053] As an exemplary embodiment, spectral data of a plurality of different content samples of fosfomycin sodium for injection are selected, including:

[0054] The first step is sample preparation. Different concentration gradients (contents) of fosfomycin sodium for injection samples are selected. Specifically, a known amount of fosfomycin sodium is added to the real sample matrix in stages, and the sample is dissolved in an appropriate solvent (such as water for injection or a buffer solution) according to the requirements of the preparation instructions. The sample is ensured to be completely dissolved and the solution is clear and transparent. The same solvent system and dilution factor are used for all samples, and the system is allowed to stand for a period of time under constant temperature conditions to reach a stable state. The content types of the fosfomycin sodium for injection can be set by the implementer according to the specific actual situation, such as selecting 10 different contents of fosfomycin sodium for injection samples.

[0055] The second step is instrument setting. The ultraviolet-visible spectrophotometer is used for spectrum acquisition. The scanning wavelength range is set to 190-800 nm, the optical path is set to 1 cm of quartz cuvette, and the scanning interval is generally set to 0.5-1 nm. Before testing, baseline correction is performed with a blank solvent to eliminate the background absorption effects of the solvent, cuvette and light source fluctuations, and to ensure that the subsequent spectrum reflects only the true absorption characteristics of the sample.

[0056] The third step is spectrum acquisition. The prepared fosfomycin sodium samples are sequentially placed in the cuvette for full-band scanning, and the absorbance value at each wavelength is recorded to obtain the complete absorption spectrum curve. To improve the signal-to-noise ratio, multiple scans are used to take the average to reduce the effects of transient light source fluctuations and instrument noise on signal stability. After acquisition, the spectrum data is saved as a standard format file for subsequent data analysis.

[0057] The fourth step is spectrum data preprocessing. The original spectrum data collected is preprocessed to remove interference caused by non-chemical factors. Specifically, baseline drift correction is used to eliminate overall offset caused by unstable light sources, smoothing filtering is used to suppress high-frequency noise, and standard normal variable transformation correction is used to correct scattering effects caused by small differences in sample concentration or optical path. The preprocessing of the spectrum data is a process of the prior art, and will not be described here.

[0058] After obtaining the spectrum data of each content sample, the spectral characteristics of the fosfomycin sodium component need to be analyzed to determine the spectral peak type characteristic index of each target waveband in different content samples. The target waveband is the waveband of the fosfomycin sodium component in the spectrum.

[0059] Fosfomycin sodium for injection contains multiple groups that can produce electronic transition, and has characteristic absorption peaks in the ultraviolet region, while the position, intensity and shape of the absorption peak can reflect the chemical structure characteristics and molecular environment changes. In the actual preparation, fosfomycin sodium coexists with excipients, and the excipients can also produce absorption signals in the same or adjacent waveband, causing spectral overlap and interference. Therefore, by systematically analyzing the spectral characteristics of fosfomycin sodium, the characteristic absorption peak position and peak shape characteristics of fosfomycin sodium in the mixed spectrum can be identified, which helps to distinguish the main component and excipient interference signals.

[0060] As an exemplary embodiment, according to the spectral data of each content sample, the spectral peak shape characteristic index of each target waveband in different content samples is determined, including:

[0061] First, for each content sample respectively, based on the second derivative data of the sample spectrum, the boundary of each absorption peak is determined by locating the zero-crossing point of the second derivative, and the spectral interval bounded by the boundary is taken as the target waveband.

[0062] The waveband of fosfomycin sodium related components in the spectrum is divided, that is, the absorption peak interval that can stably characterize the chemical structure characteristics of fosfomycin sodium related components is extracted from the mixed spectrum as the target waveband. The spectral diagram of fosfomycin sodium sample is shown in Figure 2 The horizontal coordinate of the spectral diagram is wavelength, and the vertical coordinate is absorbance.

[0063] Among them, the target waveband includes but is not limited to: corresponding to P=O bond stretching vibration (Infrared) or related ultraviolet characteristic peak; corresponding to the symmetrical / antisymmetrical stretching vibration of the epoxy ring C-O-C And Nearby waveband; characteristic ultraviolet absorption band related to phosphate group. The target waveband is the fingerprint region of fosfomycin sodium molecule, but its peak shape is easily interfered by the hydrogen bond interaction of common excipients (such as citrate, amino acid) in injection.

[0064] In one embodiment, first, the spectral data of the sample is smoothed and second derivative processed to enhance the peak shape characteristics and weaken the baseline influence; then, the starting, peak top and ending positions of the absorption peak are accurately positioned by using the extreme points of the second derivative spectrum, so as to determine a complete absorption peak interval, i.e. a waveband, by corresponding to three extreme points, thereby obtaining each target waveband. The implementation process of smoothing and second derivative processing, determination of the extreme points of the second derivative spectrum is all prior art, which will not be repeated here.

[0065] Since the citrate, amino acid and other excipients in the fosfomycin sodium injection formulation produce wide band absorption in the infrared spectrum, which seriously overlaps with the characteristic peaks of fosfomycin sodium, the original spectrum cannot be directly used to accurately define the boundary of the characteristic peaks. Therefore, the spectrum of each content sample in this embodiment is pre-processed by second derivative, which can effectively separate the sharp characteristic peaks of fosfomycin sodium from the wide band absorption of the excipients, and accurately define the starting and ending wavelengths of each absorption peak by locating the zero-crossing point of the second derivative. More notably, the target waveband thus determined corresponds to the vibration mode of a specific chemical bond in the fosfomycin sodium molecule, to some extent, excluding the interference of excipient absorption, providing a pure chemical information carrier for subsequent peak shape analysis.

[0066] Secondly, according to the shape characteristics of the spectral peaks in each target waveband, the spectral peak shape characteristic index of each target waveband in the corresponding content sample is determined.

[0067] The chemical characteristics of the fosfomycin sodium molecule should maintain the same spectral shape in different content samples. By analyzing the shape characteristics of the spectral peaks of each target waveband in different content samples, the interference of the excipients can be distinguished.

[0068] In one embodiment, in spectral analysis, the peak shape characteristics should generally focus on the width, height, area or symmetry of the peak. For example, the half-height width or the left-right peak area ratio can better reflect the inherent electronic transition behavior of the molecule. Therefore, the spectral peak shape characteristic index can include the peak height ratio (the ratio of the heights of adjacent peaks), the half-peak width or the peak symmetry index.

[0069] Among them, the peak symmetry is sensitive to the degree of complexation of the phosphate group with the cations in the solution; the half-peak width can reflect the uniformity of intramolecular / intermolecular vibration coupling, which is affected by the concentration and the viscosity of the matrix; the calculation of the spectral peak shape characteristic index is a conventional technique known to those skilled in the art, and the specific calculation process is not described here.

[0070] Up to now, the spectral peak shape characteristic index of each target waveband in the corresponding content sample has been obtained.

[0071] S2, according to the change stability of the multiple spectral peak shape characteristic indexes corresponding to the same target waveband and the simultaneous change between the absorbance of each wavelength point in the target waveband and the concentration of fosfomycin sodium, the chemical characteristic index of each wavelength point in each target waveband is determined.

[0072] In the preparation of fosfomycin sodium for injection, the type and proportion of excipients are generally fixed, and the spectral absorption characteristics remain basically constant among samples. Fosfomycin sodium as the main component, the concentration change will directly cause the proportional change of the corresponding absorption peak intensity in the spectrum. Therefore, by analyzing the correlation of the spectral curves of samples with different contents, the wavelength points and wave bands that change synchronously with the concentration of fosfomycin sodium can be identified. The absorption change of these wave bands is highly consistent with the concentration change of the target component, and the spectral peak shape characteristics of the wave bands remain consistent under different concentrations of fosfomycin sodium standard samples, indicating that they can reflect the characteristic electronic transition behavior of fosfomycin sodium molecules. They can effectively distinguish the response region in the spectrum that is truly related to the chemical structure of the target component, thereby eliminating the interference of excipients, solvents or impurities. By selecting the synchronous change wave band for feature extraction and modeling, the quantification accuracy of the chemical characteristic index can be ensured, and the accuracy and robustness of the spectral determination of fosfomycin sodium component can be improved.

[0073] As an exemplary embodiment, the chemical characteristic index of each wavelength point in each target wave band is determined, as shown in the following formula: Figure 3 As shown in the following formula:

[0074] S21, for each target wave band respectively, according to the difference of the spectral peak shape characteristic index of the target wave band in two different content samples, the stability index of the spectral peak shape characteristic of the target wave band in multiple different content samples is determined.

[0075] To ensure that the selected target wave band truly reflects the inherent chemical information of fosfomycin sodium rather than excipient interference, the stability of the spectral peak shape characteristic under the concentration gradient can be analyzed. The intrinsic vibration of the specific functional group of fosfomycin sodium should remain highly stable (e.g., peak position shift <1 nm, intensity ratio variation coefficient CV <3%) in different concentration standard samples. Such stable characteristics are derived from relatively isolated vibration modes within the molecule, which are less disturbed by the solution environment. On the contrary, characteristics related to intermolecular interactions (such as aggregation, strong solvation) (such as main peak half-peak width) show obvious concentration dependence. Therefore, this embodiment calculates the stability index of the peak shape characteristic of each target wave band by systematically analyzing the concentration sequence. The greater the stability index, the more likely it is a reliable target wave band that carries the intrinsic structural information of fosfomycin sodium, and the more likely it is used for subsequent quantitative modeling and correction.

[0076] First, in the sample sequence, the absolute value of the difference between the spectral peak shape characteristic index of the target wave band in the previous content sample and the spectral peak shape characteristic index of the target wave band in the next content sample is calculated.

[0077] The second step is to determine the absolute values ​​of all differences corresponding to the target band, and to perform negative correlation normalization on the average value of all differences to obtain the stability index of the spectral peak characteristics of the target band in multiple samples with different contents.

[0078] In one embodiment, the formula for calculating the stability index of the spectral peak shape characteristics of the i-th target band in multiple samples with different contents (standard fosfomycin sodium series samples) can be:

[0079] In the formula, Let represent the stability index of the spectral peak shape characteristics of the i-th target band in multiple samples with different contents, exp represent an exponential function with the natural constant e as the base, exp(-) is used to perform negative correlation normalization of the data, and O represents the number of samples with different contents. This represents the spectral peak shape characteristic index of the i-th target band in the o-th content sample. This represents the spectral peak shape characteristic index of the i-th target band in the (o+1)-th content sample. This represents the function for finding the absolute value. This represents the average value of the spectral peak shape characteristic index of the i-th target band in all O content samples, used to achieve normalization and eliminate dimensions.

[0080] In the formula for calculating the stability index, The smaller the value, the more similar the spectral peak characteristics of the i-th target band are under two standard samples of fosfomycin sodium at different concentrations; The smaller the value, the more stable the spectral peak characteristics of the i-th target band are under different concentrations of sodium fosfomycin standard samples, and the greater the stability index of the spectral peak characteristics of the i-th target band in multiple samples with different contents; by performing negative correlation mapping through the exponential function exp(-x), the... Convert it to a stability or similarity index between 0 and 1, with smaller values ​​indicating greater stability.

[0081] S22, for each wavelength point within the target band, acquire the absorbance and sodium fosfomycin concentration sequences of the samples at different concentrations, and analyze the similarity of changes between the absorbance sequence and the sodium fosfomycin concentration sequence to determine the synchronous change index.

[0082] Under ideal conditions that strictly adhere to the Lambert-Beer law, the absorbance at each wavelength within the characteristic absorption band of the target component should exhibit a strictly linear relationship with its concentration. However, in actual systems of injectable fosfomycin sodium, this premise is often violated: for example, commonly used excipient buffers... The interval contains C–O and The stretching vibration overlaps, and its addition amount often changes with the pH regulation requirement, resulting in a non-proportional deviation of the local band absorbance-concentration relationship. Therefore, in the fosfomycin sodium spectrum, when the absorbance at a certain wavelength in the target waveband changes synchronously with the fosfomycin sodium concentration, it indicates that the absorption signal at the wavelength is derived from the molecular characteristic absorption of the target component, not the interference of the excipient. The synchronous change index is determined, including:

[0083] First, the DTW distance between the absorbance sequence and the fosfomycin sodium concentration sequence is calculated.

[0084] Second, the DTW distance is normalized in a negative correlation to obtain the synchronous change index of the corresponding wavelength point.

[0085] In one embodiment, the calculation formula of the synchronous change index between the absorbance at the jth wavelength point in the ith target waveband and the fosfomycin sodium concentration can be:

[0086] ; in the formula, indicates the synchronous change index between the absorbance at the jth wavelength point in the ith target waveband and the fosfomycin sodium concentration, exp indicates the exponential function with the natural constant e as the base, exp(-) indicates the normalization processing for realizing the negative correlation of the data, and DTW is used to calculate the dynamic time warping distance between two sequences. indicates the absorbance sequence at the jth wavelength point in the ith target waveband, the absorbance sequence is composed of the absorbance of the jth wavelength point in the ith target waveband in different content samples, N indicates the fosfomycin sodium concentration sequence of the standard fosfomycin sodium series sample, and k is a preset scaling coefficient for realizing the elimination of the dimension influence in the exponential function.

[0087] In the calculation formula of the synchronous change index, indicates the synchronous change between the absorbance at the jth wavelength point in the ith target waveband and the fosfomycin sodium concentration, The smaller the value is, the more likely the absorbance at the jth wavelength point changes synchronously with the fosfomycin sodium concentration, the larger the synchronous change index is, and the calculation process of the DTW distance is the prior art, which will not be described here.

[0088] Of course, the implementer can also calculate the change synchronization between the absorbance sequence and the fosfomycin sodium concentration sequence in other ways, which is not specifically limited here.

[0089] S23, according to the stability index of each target waveband and the synchronous change index of each wavelength point, the chemical characteristic index of each wavelength point in each target waveband is determined.

[0090] In the production of standard injection, the excipients of sodium fosfomycin for injection are added according to a fixed proportion, and the content variation of sodium fosfomycin usually does not cause the content variation of the excipients. When the spectral peak shape characteristics of the target waveband remain stable in the standard samples of different sodium fosfomycin concentrations, and the synchronous variation between the absorbance of each wavelength point in the target waveband and the concentration of sodium fosfomycin is high, it indicates that the chemical characteristics of the wavelength point in the target waveband are significant. Therefore, the chemical characteristic index of each wavelength point in each target waveband can be determined by the stability index and the synchronous variation index.

[0091] Specifically, the stability index and the synchronous variation index are positively correlated with the chemical characteristic index, and the greater the stability index and the synchronous variation index, the greater the chemical characteristic index. Therefore, the product of the synchronous variation index and the stability index of each wavelength point in each target waveband is calculated, and the product of the two indexes is taken as the chemical characteristic index of the corresponding wavelength point in the corresponding target waveband.

[0092] In one embodiment, the calculation formula of the chemical characteristic index of the jth wavelength point in the ith target waveband can be:

[0093] In the formula, the chemical characteristic index of the jth wavelength point in the ith target waveband is represented by the stability index of the spectral peak shape characteristics of the ith target waveband in the plurality of different content samples is represented by the synchronous variation index between the absorbance of the jth wavelength point in the ith target waveband and the concentration of sodium fosfomycin is represented by

[0094] So far, referring to the calculation process of the chemical characteristic index of the jth wavelength point in the ith target waveband, the chemical characteristic index of each wavelength point in each target waveband can be obtained.

[0095] S3, determining the second reference content of the sodium fosfomycin component corresponding to each target waveband according to the chemical characteristic index of each wavelength point in each target waveband and the first reference content.

[0096] Here, the first reference content can represent the preliminary content estimate value obtained based on the single-wavelength point linear regression model, and the second reference content can represent the content estimate value obtained based on the weighted fusion of the chemical contribution degrees of the wavelength points in the target waveband, which can be used to correct the sodium fosfomycin content of the sample to be measured whose spectral data deformation is more serious due to the influence of the excipients. The absorbance of different wavelength points is affected differently by the excipients, so the authenticity of the sodium fosfomycin component content represented by the first reference content of different wavelength points is different. The second reference content of the sodium fosfomycin component corresponding to the target waveband can be determined according to the chemical characteristic index of the wavelength point and the first reference content.

[0097] ​As an exemplary embodiment, a second reference content of the fosfomycin sodium component corresponding to each target waveband is determined, such as Figure 4 as shown, comprising:

[0098] S31, for each target waveband, respectively, according to the chemical characteristic index of each wavelength point in the target waveband, determining the chemical contribution degree of each wavelength point in the target waveband.

[0099] When there is an excipient interference, the spectral signal of the main component and the spectral signal of the excipient will be superimposed, so that the spectral characteristics of most wavelength points are covered or distorted. If the spectral characteristics of a certain wavelength point can still be clearly distinguished and are highly related to the concentration of the fosfomycin sodium component, it means that the wavelength point is less affected by the excipient interference and has higher specificity, which further indicates that it has significant contribution to the determination accuracy of the molecular content of the target waveband. Therefore, the chemical contribution degree of each wavelength point needs to be determined according to the chemical characteristic index of each wavelength point in the target waveband.

[0100] First, the maximum and minimum value normalization is used to normalize the chemical characteristic index of each wavelength point in the target waveband, to obtain the specificity index of each wavelength point.

[0101] In this embodiment, the maximum and minimum value normalization is performed on the chemical characteristic index of each wavelength point in each target waveband, aiming to eliminate the absolute value deviation caused by the difference in vibration intensity and molar absorption coefficient between different wavebands, so as to evaluate the relative importance of each wavelength point on the same chemical reference. The greater the specificity index, i.e. the closer to 1, the smaller the corresponding wavelength point is affected by the solvent effect or excipient hydrogen bond interference in all target wavebands, and the more it can represent the intrinsic vibration characteristics of the chemical bond.

[0102] It should be noted that by determining the specificity index, it is possible to select the best from the best within the same chemical structural unit (spectral band generated by vibration of the same functional group), and to ensure that the subsequent screening is not biased due to the inherent signal intensity difference of different functional groups.

[0103] Second, the product of the chemical characteristic index and the specificity index of each wavelength point in the target waveband is calculated as the chemical contribution degree of the corresponding wavelength point.

[0104] The chemical characteristic index can represent the absolute quality of the chemical signal at the wavelength point, including its response intensity to concentration change and peak stability. The higher the chemical characteristic index, the greater the potential value of the wavelength point as a quantitative characteristic. The specificity index represents the relative reliability of the wavelength point in the current chemical environment. The higher the value, the more likely it is to be a pure representation of the vibration mode. Through multiplication calculation, it can be required that the wavelength point has both high absolute quality and outstanding performance in the same type of characteristics. For example, even if the absolute chemical characteristic of a wavelength point is strong, if the overall signal in the waveband is strong (i.e., the relative performance is general), its contribution will be appropriately reduced, so as to avoid over-reliance on a few strong absorption points and neglect other high-specificity points.

[0105] Therefore, in this embodiment, the absolute intensity of the chemical characteristic of the wavelength point (i.e., the chemical characteristic index) and the relative outstanding degree of the wavelength point in the waveband (i.e., the specificity index) are considered at the same time, to realize synergistic enhancement and ensure that only the wavelength points with strong signal and high specificity can obtain high contribution.

[0106] In one embodiment, the calculation formula of the chemical contribution of the jth wavelength point in the ith target waveband can be:

[0107] In the formula, represents the chemical contribution of the jth wavelength point in the ith target waveband, represents the chemical characteristic index of the jth wavelength point in the ith target waveband, represents the minimum chemical characteristic index in the ith target waveband, represents the maximum chemical characteristic index in the ith target waveband, represents the specificity index of the jth wavelength point in the ith target waveband. In the extreme case, equals , there is a possibility that is zero, directly assigning the chemical contribution of the jth wavelength point in the ith target waveband to , and no longer considering the relative outstanding degree of the jth wavelength point in the ith target waveband.

[0108] In the calculation formula of the chemical contribution, the greater, the stronger the chemical correlation between the jth wavelength point and the target component, which can ensure that only the wavelength points with sufficient signal intensity can obtain a higher contribution; The chemical contribution degree of each wavelength point in each target waveband can be calculated, which can be used to evaluate the relative prominence of the jth wavelength point in the ith target waveband, which is conducive to identifying the specific wavelength point in the target waveband; through maximum and minimum value normalization, the dimension can be eliminated, the specificity index is mapped between 0 and 1, and the distribution difference of the characteristic value in the target waveband is also amplified, and the peak characteristics are highlighted; through the multiplication of the chemical feature index and the specificity index, the synergistic enhancement and double inhibition can be realized, that is, when the absolute intensity and the relative specificity are both high, the product will produce a multiplication effect, and if any factor is close to zero, the overall contribution will be significantly inhibited.

[0109] It should be noted that the spectral absorption of the excipient is usually a wide spectrum band with low intensity, and the characteristic absorption of sodium fosfomycin is usually strong absorption at a specific wavelength point, so the above calculation formula of the chemical contribution degree can quantify the chemical contribution degree of each wavelength point in each target waveband. Determining the chemical contribution degree can ensure that the data analysis mainly depends on the spectral information that is derived from the intrinsic chemical structure of sodium fosfomycin and is sensitive and reliable to the change of the concentration.

[0110] It should be further noted that the wide spectrum band absorption of the excipient can cover the entire target waveband. Through the calculation of the chemical contribution degree, those wavelength points that can maintain a high chemical feature index (i.e., sensitive to the change of the concentration of sodium fosfomycin and stable peak type) even in the excipient absorption background will obtain a high contribution degree due to their high specificity index (indicating that they are relatively less susceptible to interference in the waveband).

[0111] For the wavelength points that are susceptible to pH or ionic strength, their spectral peak stability index can be low, resulting in a low chemical feature index; at the same time, because the signal is variable and relatively unreliable, their specificity index in the waveband can also be low. Multiplying the two, the contribution degree will be further reduced, thereby naturally weakening the influence of these unstable features.

[0112] S32, using the chemical contribution degree of each wavelength point in the target waveband, the first reference content of the corresponding wavelength point to the sodium fosfomycin component is weighted and fused to obtain the second reference content of the target waveband to the sodium fosfomycin component.

[0113] Each target waveband contains a plurality of wavelength points, and different wavelength points have different contributions to the determination accuracy of the component. For example, when the chemical contribution degree of the wavelength point is large, the interference of the excipient is small, and the reference effect to the evaluation of the molecular content is greater. Therefore, based on the chemical contribution degree and the first reference content of each wavelength point, the second reference content of the target waveband to the sodium fosfomycin component is determined.

[0114] As an exemplary embodiment, the first reference content of each wavelength point in the target waveband is obtained, including:

[0115] Based on the standard sample series, a simple linear regression model between the absorbance of the wavelength point and the content of fosfomycin sodium is established, and the relationship between the absorbance of the wavelength point and the content of fosfomycin sodium corresponding to the target wave band is obtained; by substituting the absorbance of the wavelength point into the simple linear regression model, the first reference content of the fosfomycin sodium component corresponding to each wavelength point in the target wave band can be determined.

[0116] wherein the standard sample series refers to a group of standard samples with known accurate content of fosfomycin sodium, and the content should cover the expected detection range. The construction of the simple linear regression model is a conventional technique known to those skilled in the art, and the specific construction process is not described here.

[0117] Different wavelength points in the target wave band are interfered by different modes of excipients, some wavelength points may be sensitive to specific interference, and other wavelength points may be immune, so by fusing multiple points, random interference can be eliminated and the true signal can be retained.

[0118] In one embodiment, the calculation formula of the second reference content of the fosfomycin sodium component corresponding to the i-th target wave band can be:

[0119] ; wherein, the second reference content of the fosfomycin sodium component corresponding to the i-th target wave band, M represents the number of wavelength points in the target wave band, the chemical contribution degree of the j-th wavelength point in the i-th target wave band, the first reference content of the fosfomycin sodium component corresponding to the j-th wavelength point in the i-th target wave band.

[0120] In the calculation formula of the second reference content, the chemical contribution degree is used as a weight, indicating the reliability measure of each first reference content, and the first reference content is used as an observation value, indicating that each wavelength point provides an independent content estimate, and the sum of the weights is used as a normalization factor, and subsequent weighted average can obtain a more robust joint estimate, i.e., the second reference content of the fosfomycin sodium component corresponding to the target wave band.

[0121] It should be noted that, unlike the traditional fixed weight, the chemical contribution degree is a data-driven adaptive weight. Through the adaptive weight, the wavelength points with strong signal and small interference can automatically obtain a high weight; the adaptive weight is independently calculated in each target wave band, which can adapt to the characteristics of different spectral regions. Therefore, the numerical accuracy and utilization value of the second reference content determined by the adaptive determination are higher, which can be used to correct the content of the fosfomycin sodium component to be measured.

[0122] Thus, the second reference content of the fosfomycin sodium component corresponding to the i-th target waveband can be obtained by referring to the second reference content of the fosfomycin sodium component corresponding to the above i-th target waveband.

[0123] S4, determining a spectral peak shape characteristic index of each target waveband in the sample to be measured; and determining a peak shape error value of each target waveband in the sample to be measured according to a difference between the spectral peak shape characteristic index of each target waveband in the sample to be measured and the spectral peak shape characteristic index corresponding to the different content samples.

[0124] Here, the peak shape error value can be used to at least represent a degree of spectral peak variation of each target waveband in the sample to be measured caused by the interference of the excipient. For the quantitative analysis of fosfomycin sodium, the peak shape error is more valuable than the absolute absorbance. The reason is that the excipient background absorption usually exhibits a wide spectral band, which changes the baseline and apparent peak shape of the characteristic peak of fosfomycin sodium, but has a relatively fixed influence mode on the symmetry and fine structure of the peak shape; the pH fluctuation in the production process of the injection directly affects the protonation state of the phosphate group in the fosfomycin sodium molecule, causing the characteristic peak to shift or split, and this change is directly reflected in the peak shape index; the difference in intermolecular hydrogen bond causes the characteristic peak to broaden, and the change in half-peak width is a sensitive indication. Therefore, the peak shape error value essentially quantifies the difference in the micro-chemical environment between the sample to be measured and the standard sample, and provides a physical basis for subsequent content correction.

[0125] In the process of spectral determination, the excipient added in the preparation process of the fosfomycin sodium for injection can produce absorption or emission signals in the spectrum, which overlap with the signals of fosfomycin sodium and interfere with the determination. If the uncorrected absorbance is directly used for quantitative modeling, the model may mistakenly regard these systematic errors as component changes, thereby reducing the determination accuracy and robustness. Therefore, through absorbance correction, the signal can be weighted and adjusted based on the chemical characteristic contribution of each wavelength, highlighting the key wavebands sensitive to the content of fosfomycin sodium and suppressing the invalid wavebands greatly affected by interference or noise.

[0126] Further, the relative position of the spectral peak shape of the fosfomycin sodium component remains consistent in different concentrations of standard samples, that is, the characteristic structure of fosfomycin sodium produces absorption in a specific wavelength region, and as long as the molecular structure does not change, the center position and basic shape of the absorption peak should be stable. Therefore, the spectral peak shape characteristic index can be used as a basis for quantitative analysis, and when the spectral peak shape characteristic of a target waveband of the sample to be measured is different from the reference spectral peak shape characteristic of the standard content sample, it indicates that the target waveband of the sample to be measured may be interfered by the spectrum of the excipient.

[0127] As an exemplary embodiment, the determination of the spectral peak shape characteristic index of each target waveband in the sample to be measured comprises:

[0128] Based on the calculation process of the spectral peak type characteristic index of each target waveband in different content samples, the spectral peak type characteristic index of each target waveband in the sample to be measured can be obtained, and the same calculation method is not described here.

[0129] As an exemplary embodiment, the peak type error value of each target waveband of the sample to be measured is determined, including:

[0130] Firstly, for each target waveband, the average value of the spectral peak type characteristic index of the target waveband in different content samples is calculated as the reference peak type characteristic index.

[0131] Secondly, the difference value between the spectral peak type characteristic index of the target waveband in the sample to be measured and the reference peak type characteristic index is calculated, and the difference value is normalized to obtain the peak type error value of the target waveband.

[0132] In one embodiment, the calculation formula of the peak type error value of the i-th target waveband can be:

[0133] In the formula, represents the peak type error value of the i-th target waveband, represents the spectral peak type characteristic index of the i-th target waveband in the sample to be measured, represents the reference peak type characteristic index of the i-th target waveband, represents the absolute value function.

[0134] In the calculation formula of the peak type error value, represents the difference value between the spectral peak type characteristic index of the i-th target waveband in the sample to be measured and the reference peak type characteristic index, and the difference value can be the absolute value of the difference between the two data; The normalization processing of the difference value is used to limit the value range of the peak type error value to 0 to 1, which is used for subsequent correction coefficients of the second reference content and the third reference content.

[0135] At this point, referring to the calculation process of the peak type error value of the i-th target waveband of the sample to be measured, the peak type error value of each target waveband of the sample to be measured can be obtained.

[0136] It should be noted that the peak type error value can more accurately express the real absorption characteristics of different target wavebands of the sample to be measured, improve the response sensitivity to the concentration change of the sample, and realize high precision and high robustness of the quantitative analysis of fosfomycin sodium components.

[0137] S5, based on the peak type error value, the second reference content and the third reference content of each target waveband are weighted and fused to obtain the waveband corrected content, and all waveband corrected contents are fused to determine the final fosfomycin sodium content of the sample to be measured.

[0138] Here, the waveband correction content is used to at least represent the correction content obtained by comprehensively considering the peak shape error.

[0139] The peak shape error value can represent the spectrum peak variation of the target waveband of the sample to be measured interfered by the excipient. When the peak shape error value tends to 0, it indicates that the spectrum quality of the corresponding target waveband of the sample to be measured is good, and the interference of the excipient is small. Since the traditional quantitative model is usually more accurate when the data quality is good, the final fosfomycin sodium content mainly depends on the result of the traditional quantitative model, i.e., the third reference content. When the peak shape error value tends to 1, it indicates that the spectrum of the corresponding target waveband of the sample to be measured is severely distorted, and the interference of the excipient is large. Therefore, the traditional quantitative model may fail at this time, and the second reference content determined based on the chemical principle is more reliable. Therefore, the final fosfomycin sodium content mainly depends on the reference content weighted by the chemical contribution, i.e., the second reference content.

[0140] As an exemplary embodiment, the final fosfomycin sodium content of the sample to be measured is determined, comprising:

[0141] In the first step, for each target waveband of the sample to be measured, the peak shape error value of the target waveband is taken as the weight of the second reference content, denoted as the first weight.

[0142] Here, when the spectrum of the target waveband of the sample to be measured is severely distorted, the correction effect of the second reference content can be amplified. Therefore, the peak shape error value of the target waveband is taken as the weight of the second reference content, so as to reduce the influence of the excipient and other substances on the spectrum data and ensure the numerical accuracy of the determination of the fosfomycin sodium content.

[0143] In the second step, the complement of the peak shape error value of the target waveband is taken as the weight of the third reference content, denoted as the second weight.

[0144] Here, the third reference content is an estimated content value of the target waveband obtained based on a traditional quantitative analysis model, such as PLS (Partial Least Squares Regression), PCR (Principal Component Regression), or a single-wavelength calibration model. The third reference content is an initial content prediction value of the fosfomycin sodium to be measured, and the complement is equal to the difference between 1 and the peak shape error value.

[0145] In an embodiment, a standard sample is used to establish a conventional quantitative calibration model of the target waveband. The spectrum data of the sample to be measured is input into the quantitative calibration model, and the model outputs the third reference content of the target waveband.

[0146] The construction and implementation process of the quantitative calibration model is a conventional technique known to those skilled in the art, and the specific construction and implementation process is not described herein.

[0147] Thirdly, according to the first weight, the second weight, the second reference content and the third reference content of the target waveband, a waveband corrected content of the target waveband is obtained.

[0148] Specifically, a product of the first weight and the second reference content of the target waveband is calculated and recorded as a first product; and a product of the second weight and the third reference content of the target waveband is calculated and recorded as a second product; and a sum of the first product and the second product is taken as the waveband corrected content of the target waveband.

[0149] In one embodiment, a calculation formula of the waveband corrected content of the i-th target waveband of the sample to be measured can be:

[0150] ; in the formula, the waveband corrected content of the i-th target waveband of the sample to be measured is represented by, the peak type error value of the i-th target waveband of the sample to be measured is represented by, the third reference content of the i-th target waveband of the sample to be measured is represented by, the second reference content of the i-th target waveband of the sample to be measured is represented by.

[0151] In the calculation formula of the waveband corrected content, the weight of the third reference content of the i-th target waveband of the sample to be measured, i.e. the second weight, is represented by, the weight of the second reference content of the i-th target waveband of the sample to be measured, i.e. the first weight, is also represented by; the second reference content of the same target waveband in different samples to be measured is the same, while the third reference content of the same target waveband in different samples to be measured is different; the third reference content is determined based on the spectral data of the sample to be measured and has uniqueness, while the second reference content is determined by analyzing the local spectral data chemical characteristics of a plurality of different standard content samples and has universality.

[0152] Referring to the calculation process of the waveband corrected content of the i-th target waveband of the sample to be measured, the waveband corrected content of each target waveband of the sample to be measured can be obtained.

[0153] Fourthly, the waveband corrected contents of each target waveband are weighted and fused to obtain the final content of the sample to be measured.

[0154] In which, the weights of different target wavebands of the sample to be measured include:

[0155] In the embodiment, the greater the peak error value, the smaller the weight of the target waveband; or the target waveband with higher signal-to-noise ratio and stronger specificity is given a greater weight; or the weight of all target wavebands is 1, and the average value of the corrected content of all wavebands is directly taken.

[0156] In one embodiment, the weight of the waveband corrected content of each target waveband can be calculated according to the complement of the peak error value, that is, The calculation formula of the final fosfomycin sodium content of the sample to be tested can be:

[0157] ; in the formula, Z represents the final fosfomycin sodium content of the sample to be tested, I represents the total number of target wavebands, represents the weight of the waveband corrected content of the i-th target waveband of the sample to be tested, represents the waveband corrected content of the i-th target waveband of the sample to be tested.

[0158] Up to now, the embodiment obtains more accurate determination results, that is, the final fosfomycin sodium content of the sample to be tested.

[0159] In summary, the present application provides a method for determining the content of sodium fosfomycin for injection based on spectral analysis, which first acquires spectral data of sodium fosfomycin for injection samples with different contents, and then determines a plurality of target wavebands of sodium fosfomycin in the spectrum based on the spectral data of samples with known standard content. The multi-waveband collaborative analysis strategy makes it possible to provide reliable correction when a certain waveband is specifically interfered by excipients or impurities, thereby effectively overcoming the interference of excipients in complex preparations and ensuring the accuracy of detection in real and complex sample matrices. The stability of spectral peak shape characteristics at different concentrations is utilized, and the simultaneous changes in absorbance and concentration of wavelength points are combined to dynamically screen and evaluate the reliability of each target waveband, which can automatically identify high-quality wavebands and wavelength points that truly reflect the chemical intrinsic structure of sodium fosfomycin and are less interfered, and discard unreliable signal regions, thereby improving the quality of modeling data from the source. Finally, the present application constructs a dual verification system containing a second reference content (based on chemical contribution degree weighting) and a third reference content (based on a traditional quantitative model), and dynamically evaluates the consistency of the spectral shape of the sample to be tested and the standard sample by using the peak type error value, and accordingly adjusts the weight of the two reference contents. Through the peak type error value, the third reference content can be relied on when the peak shape is consistent, while the second reference content with stronger anti-interference ability is preferred when the peak shape is changed, which makes the final content determination result show excellent robustness when facing various uncertainties. Therefore, the present application not only significantly improves the accuracy of the content determination of sodium fosfomycin for injection, but also exhibits strong anti-interference ability and robustness in complex practical application scenarios, thereby providing reliable technical support for high-precision control of drug quality.

[0160] The above-described embodiments are only used to illustrate the technical solutions of the present application, rather than limit them; although the foregoing embodiments of the present application have been described in detail, those skilled in the art should understand that they can modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application, and should be included in the protection scope of the present application.

Claims

1. A method for determining the content of sodium fosfomycin for injection based on spectral analysis, characterized by, The method comprises the following steps: selecting spectral data of a plurality of different content samples of fosfomycin sodium for injection; determining spectral peak type characteristic indexes of each target waveband in different content samples according to the spectral data of each content sample; the target waveband is a waveband of a fosfomycin sodium component in the spectrum; determining a chemical characteristic index of each wavelength point in each target waveband according to variation stability of a plurality of spectral peak type characteristic indexes corresponding to the same target waveband and synchronous variation between the absorbance of each wavelength point in the target waveband and the concentration of fosfomycin sodium; determining a second reference content of the fosfomycin sodium component corresponding to each target waveband according to the chemical characteristic index of each wavelength point in each target waveband and a first reference content; the first reference content is obtained through a linear regression model between the absorbance and the content of fosfomycin sodium; determining spectral peak type characteristic indexes of each target waveband in the sample to be measured; determining a peak type error value of each target waveband of the sample to be measured according to the difference between the spectral peak type characteristic indexes corresponding to the sample to be measured and different content samples; based on the peak type error value, weighting and fusing the second reference content and a third reference content of each target waveband to obtain a waveband corrected content, and then fusing all the waveband corrected contents to determine the final content of fosfomycin sodium in the sample to be measured; the third reference content is obtained by analyzing the target waveband through a quantitative analysis model.

2. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 1, characterized in that, The determination of the spectral peak type characteristic indexes of each target waveband in different content samples comprises: respectively for each content sample, based on the second derivative data of the sample spectrum, determining the boundary of each absorption peak by locating the zero-crossing point of the second derivative, and taking the spectral interval defined by the boundary as the target waveband; determining the spectral peak type characteristic index of each target waveband in the corresponding content sample according to the shape characteristics of the spectral peak of each target waveband.

3. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 1, characterized in that, The determination of the chemical characteristic index of each wavelength point in each target waveband comprises: respectively for each target waveband, determining the stability index of the spectral peak type characteristic of the target waveband in a plurality of different content samples according to the difference between the spectral peak type characteristic indexes of the target waveband in two different content samples; respectively for each wavelength point in the target waveband, obtaining the absorbance and the sequence of the concentration of fosfomycin sodium of the sample of the wavelength point in different content samples, and analyzing the variation similarity between the absorbance sequence and the sequence of the concentration of fosfomycin sodium to determine a synchronous variation index; determining the chemical characteristic index of each wavelength point in each target waveband according to the stability index of each target waveband and the synchronous variation index of each wavelength point.

4. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 3, characterized in that, The determination of the stability index of the spectral peak type characteristic of the target waveband in a plurality of different content samples comprises: in the sample sequence, calculating the absolute value of the difference between the spectral peak type characteristic index of the target waveband in the previous content sample and the spectral peak type characteristic index of the target waveband in the next content sample; determining all the absolute values of the difference corresponding to the target waveband, and performing negative correlation normalization processing on the average value of all the absolute values of the difference to obtain the stability index of the spectral peak type characteristic of the target waveband in a plurality of different content samples.

5. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 3, characterized in that, The analysis of the change similarity between the absorbance sequence and the fosfomycin sodium concentration sequence determines a synchronous change index, including: calculating the DTW distance between the absorbance sequence and the fosfomycin sodium concentration sequence; performing negative correlation normalization processing on the DTW distance to obtain a synchronous change index corresponding to a wavelength point.

6. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 1, characterized in that, The determination of the second reference content of the fosfomycin sodium component corresponding to each target waveband includes: respectively for each target waveband, determining the chemical contribution degree of each wavelength point in the target waveband according to the chemical characteristic index of each wavelength point in the target waveband; using the chemical contribution degree of each wavelength point in the target waveband to perform weighted fusion processing on the first reference content of the fosfomycin sodium component corresponding to the wavelength point, to obtain the second reference content of the fosfomycin sodium component corresponding to the target waveband.

7. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 6, characterized in that, The determination of the chemical contribution degree of each wavelength point in the target waveband includes: performing normalization processing on the chemical characteristic index of each wavelength point in the target waveband by using maximum-minimum value normalization to obtain a specificity index of each wavelength point; calculating the product of the chemical characteristic index and the specificity index of each wavelength point in the target waveband as the chemical contribution degree of the corresponding wavelength point.

8. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 1, characterized in that, The determination of the peak type error value of each target waveband of the to-be-tested sample includes: respectively for each target waveband, calculating the average value of the spectral peak type characteristic index of the target waveband at different content samples as a reference peak type characteristic index; calculating the difference value between the spectral peak type characteristic index of the target waveband at the to-be-tested sample and the reference peak type characteristic index, and performing normalization processing on the difference value to obtain the peak type error value of the target waveband.

9. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 1, characterized in that, The determination of the final fosfomycin sodium content of the to-be-tested sample includes: respectively for each target waveband of the to-be-tested sample, taking the peak type error value of the target waveband as the weight of the second reference content, denoted as a first weight; taking the complement of the peak type error value of the target waveband as the weight of the third reference content, denoted as a second weight; obtaining the waveband correction content of the target waveband according to the first weight, the second weight, the second reference content and the third reference content of the target waveband; performing weighted fusion processing on the waveband correction content of each target waveband to obtain the final fosfomycin sodium content of the to-be-tested sample.

10. The method for determining the content of sodium fosfomycin for injection based on spectral analysis according to claim 9, characterized in that, The determination of the waveband correction content of the target waveband includes: calculating the product of the first weight and the second reference content of the target waveband, denoted as a first product; and calculating the product of the second weight and the third reference content of the target waveband, denoted as a second product; taking the sum of the first product and the second product as the waveband correction content of the corresponding target waveband.

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