Method for near-infrared rapid detection of contents of two components in piperacillin sodium and tazobactam sodium for injection

Abstract

The invention discloses a method for near-infrared rapid detection of contents of two components in piperacillin sodium and tazobactam sodium for injection, and belongs to the field of detection methods. Comprising the following steps: collecting near infrared spectrums of piperacillin sodium and tazobactam sodium samples for injection, screening and removing abnormal spectrums, reasonably dividing sample sets, preferably selecting modeling parameters, establishing and verifying a quantitative correction model and the like. The model constructed by the invention can simultaneously realize detection of two components in piperacillin sodium and tazobactam sodium for injection, the method is accurate and rapid, nondestructive detection of a sample can be realized, and rapid quantitative analysis of the drug can be realized.

Description

Technical Field

[0001] The invention belongs to the field of detection methods, and relates to a method for detecting the content of components in piperacillin sodium and tazobactam sodium for injection, and in particular to a method for quickly detecting the content of components in piperacillin sodium and tazobactam sodium for injection by using near-infrared spectroscopy. Background Art

[0002] Piperacillin is a semi-synthetic penicillin antibiotic, and tazobactam is a β-lactamase inhibitor. It has a strong inhibitory effect on β-lactamase. When used together with piperacillin, it produces a synergistic effect and improves the antibacterial efficacy.

[0003] Piperacillin Sodium and Tazobactam Sodium for Injection is a two-component compound preparation suitable for moderate and severe infections caused by piperacillin-sensitive bacteria and β-lactamase-producing bacteria that are sensitive to piperacillin and piperacillin-tazobactam. Currently, the main method for determining its content is high performance liquid chromatography, which has complex pretreatment, cumbersome operation, and large amount of organic solvents, and is not suitable for rapid determination of piperacillin sodium and tazobactam sodium for injection.

[0004] Near-infrared spectroscopy is an efficient and rapid modern analytical technology. It comprehensively uses the knowledge and techniques of spectroscopy, computer and chemometrics, and has the advantages of not destroying samples, being fast, accurate and pollution-free. A near-infrared spectrometer is used to directly and non-destructively collect sample information in ampoules, and a universal rapid quantitative analysis model for piperacillin sodium and tazobactam sodium for injection is established. Summary of the invention

[0005] In view of the defects existing in the prior art, the present invention aims to achieve the above objectives. The technical solution adopted by the present invention is: 1. A method for rapid near-infrared detection of the contents of two components (piperacillin sodium and tazobactam sodium) in piperacillin sodium and tazobactam sodium for injection, comprising the following steps: 1) Using Fourier transform near infrared spectrometer to obtain near infrared spectrum of piperacillin sodium and tazobactam sodium for injection; 2) using the determination method specified in the national drug standard to obtain the content determination values ​​of the two components of the piperacillin sodium and tazobactam sodium for injection described in step 1); 3) screening and eliminating abnormal spectra of the near infrared spectrum obtained in step 1); 4) Dividing the remaining near-infrared spectral samples in step 3) into a sample set and a validation set; 5) Preprocessing the spectrum in step 3), selecting characteristic bands and the number of principal components, and establishing a quantitative analysis model; 6) The model established in step 5) is used to predict and verify the content of piperacillin sodium and tazobactam sodium for injection.

[0006] The piperacillin sodium and tazobactam sodium for injection is a sterile powder for injection, which is a compound preparation of two components: piperacillin sodium and tazobactam sodium.

[0007] The spectrum collection method in step 1) is: the sample does not need to be processed, and the solid optical fiber probe is directly pressed against the bottom of the vial for collection. Spectral collection range: 12000~4000cm -1 , resolution 8cm -1 , the number of scans was 32 times, 3 bottles of each batch of samples were measured, each bottle was measured 6 times, and the average spectrum was taken as the modeling spectrum.

[0008] The determination method specified in the national drug standard is based on the HPLC determination method specified in Part II of the 2020 edition of the "Chinese Pharmacopoeia", and the determination indicators are two components: piperacillin sodium and tazobactam sodium.

[0009] The method for screening abnormal spectra is based on the Hotelling T2 test and the predicted concentration residual method.

[0010] The method for dividing the sample set is the SPXY method.

[0011] The spectral preprocessing method described in step 5) is: the spectral preprocessing methods of piperacillin sodium and tazobactam sodium models are multivariate scattering correction, first-order derivative, and SG smoothing method. The characteristic interval of the piperacillin sodium model is: 4802.1~5203.3cm -1 、5604.4~8011.3cm -1 、8813.6~9214.7cm -1 11205~11602.3cm -1 The characteristic interval of the tazobactam sodium model is 4802.1~7610.1cm -1 、8813.6~9214.7cm -1 11205~11602.3cm -1 The number of principal components of the piperacillin sodium and tazobactam sodium models were 8 and 5, respectively.

[0012] The corrected correlation coefficient (R C 2 ) is 0.9970, and the prediction correlation coefficient (R p 2 ) was 0.9988, the corrected mean square error (RMSEC) was 2.13, and the predicted mean square error (RMSEP) was 2.20; the R C 2 is 0.9975, R p 2 It is 0.9989, RMSEC is 1.35, and RMSEP is 1.42.

[0013] The model established in step 5) is used to predict the content of the components in piperacillin sodium and tazobactam sodium for injection, and compared with the values ​​measured by the determination method specified in national standards.

[0014] Compared with the prior art, the advantages of the present invention are: The present invention provides a non-destructive, accurate, and environmentally friendly rapid universal detection method for the content of components in piperacillin sodium and tazobactam sodium for injection. The technical solution of the present invention does not need to destroy the sample, does not consume any chemical reagents, greatly shortens the detection time and cost, and can simultaneously detect the contents of two components in piperacillin sodium and tazobactam sodium for injection. BRIEF DESCRIPTION OF THE DRAWINGS In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work. Figure 1 is a near infrared spectrum of piperacillin sodium and tazobactam sodium for injection used for modeling in the method of the present invention; Figure 2 This is a characteristic band screening result diagram of the piperacillin sodium model in the method of the present invention; Figure 3 This is a characteristic band screening result diagram of the tazobactam sodium model in the method of the present invention; Figure 4 It is a result diagram of selecting the principal component number of the piperacillin sodium model in the method of the present invention; Figure 5 It is a result diagram of selecting the principal component number of the tazobactam sodium model in the method of the present invention; Figure 6 This is a calibration modeling result diagram of piperacillin sodium in the method of the present invention; Figure 7 This is a calibration modeling result diagram of tazobactam sodium in the method of the present invention; DETAILED DESCRIPTION In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments of the present application will be clearly and completely described below in combination with the specific embodiments of this specification and the corresponding drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of this application. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art.

[0015] The present invention discloses a method for rapid near-infrared detection of the content of components in piperacillin sodium and tazobactam sodium for injection, which comprises the following steps: Step 1: Collection of near infrared spectra of piperacillin sodium and tazobactam sodium for injection samples

[0016] The near infrared spectrometer is used to collect the near infrared spectral data of the piperacillin sodium and tazobactam sodium for injection sample. Before the near infrared spectral data collection, the piperacillin sodium and tazobactam sodium for injection sample does not need to be processed in any way. In addition, the near infrared spectrometer can also record the serial number, manufacturer, production date, sample name and other relevant information of the piperacillin sodium and tazobactam sodium for injection sample.

[0017] Among them, the near-infrared spectrometer uses the MATRIX-F near-infrared spectrometer type Fourier transform near-infrared spectrometer produced by BRUKER, Germany, to scan the near-infrared spectrum of the sample. The spectrum acquisition method is to directly use a solid optical fiber probe to press against the bottom of the vial to collect the near-infrared diffuse reflectance spectrum of the sample. Spectral acquisition range: 12000~4000cm -1 , resolution 8cm -1 , scanning times 32 times, 3 bottles of each batch of samples were measured, each bottle was measured 6 times, and the average spectrum was taken as the modeling spectrum. Figure 1 Spectra of 78 batches of samples are shown.

[0018] Step 2. The contents of the two components of the piperacillin sodium and tazobactam sodium samples for injection were determined by the HPLC method specified in Part II of the 2020 edition of the Chinese Pharmacopoeia to obtain the content data of the two components of all piperacillin sodium and tazobactam sodium samples for injection.

[0019] Step 3: Establishment of near infrared spectroscopy model The original spectral data of 78 batches of samples were imported into SIMCA 14.1 analysis software for Hotelling T2 test. After screening and eliminating 5 abnormal spectra, and then eliminating 4 abnormal samples based on the principle of predicted concentration residual, the correlation coefficient between the predicted value of the piperacillin correction model and the reference value increased to 0.9467, and the RMSECV decreased to 6.82. The correlation coefficient between the predicted value of the tazobactam correction model and the reference value increased to 0.9599, and the RMSECV decreased to 5.81.

[0020] Furthermore, the remaining 69 samples after removing abnormal samples are divided into a calibration set and a validation set based on the SPXY method. The SPXY method is implemented by Matlab R2022b software. The division is shown in Table 1. Table 1 Division of calibration set and validation set

[0021] Furthermore, the interval partial least squares method is used to optimize the characteristic bands. If the RMSECV value of a certain band is less than the RMSECV value of the full spectrum modeling, the band is determined to be a characteristic band. The characteristic bands of the piperacillin sodium model are as follows: Figure 2 As shown, the characteristic bands of the tazobactam sodium model are as follows Figure 3 As shown;

[0022] Furthermore, the interaction validation method was used to investigate the effect of different principal component numbers on the RMSECV value. The number corresponding to the inflection point when the RMSECV value decreased was taken as the optimal principal component number. The optimal principal component number of the piperacillin sodium model is as follows: Figure 4 As shown in Figure 2, the optimal number of principal components for the tazobactam sodium model is as follows: Figure 5 As shown;

[0023] The optimal spectral preprocessing parameters for the piperacillin sodium and tazobactam sodium models were both MSC+FD+SG(3). The optimal modeling parameters are summarized in Table 2. Table 2 Optimal modeling parameters

[0024] Then, based on the partial least squares method, TQAnalyst 9 infrared spectroscopy analysis software was used to call in the near infrared spectra of 69 samples of piperacillin sodium and tazobactam sodium for injection, and the quantitative components: piperacillin sodium and tazobactam sodium were added. The content values ​​determined by the method specified in the pharmacopoeia standard were assigned one by one, and the near infrared quantitative analysis model was established according to the parameters in Table 2. The calibration model result of piperacillin sodium is shown in the figure Figure 6 The calibration model results of tazobactam sodium are shown in Figure 7 . R of the piperacillin sodium model C 2 is 0.9970, R p 2 The R of the tazobactam sodium model was 0.9988, RMSEC was 2.13, and RMSEP was 2.20. C 2 is 0.9975, R p 2 The RPD values ​​of the two models are both greater than 5.0, indicating that the prediction effect of the model meets the practical application requirements, as shown in Table 3. Table 3 Main evaluation parameters of the content determination model

[0025] Step 4: Near infrared spectroscopy model prediction and verification Six batches of piperacillin sodium and tazobactam sodium samples for injection were taken, and original near-infrared spectra were collected using the spectrum collection method described in Example 1.

[0026] TQAnalyst 9 infrared spectroscopy analysis software was used to transfer the established model method, transfer the spectral results, and automatically analyze to obtain the data of the predicted content in 6 batches of piperacillin sodium and tazobactam sodium samples for injection. The actual data of the component content in 6 batches of piperacillin sodium and tazobactam sodium samples for injection were determined by using the method for determining the content of piperacillin sodium and tazobactam sodium samples for injection in Example 2. The predicted results were compared with the actual values ​​of the content obtained by HPLC test, as shown in Table 4. The errors between the predicted values ​​and the actual values ​​were within the allowable range, which proved the reliability of the prediction model obtained in the embodiment of the present invention. Table 4 Comparison of measured values ​​of piperacillin sodium and tazobactam sodium for injection and model predicted values

[0027] It should be noted that, in this application, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the presence of other identical elements in the process, method, article or device including the elements.

[0028] The above description is only a specific implementation of the present application, so that those skilled in the art can understand or implement the present application. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to the embodiments shown herein, but will conform to the widest range consistent with the principles and novel features applied for herein.

Claims

1. A method for rapid near-infrared detection of the contents of two components (piperacillin sodium and tazobactam sodium) in piperacillin sodium and tazobactam sodium for injection, comprising the following steps: 1) Using Fourier transform near infrared spectrometer to obtain near infrared spectrum of piperacillin sodium and tazobactam sodium for injection; 2) using the determination method specified in the national drug standard to obtain the content determination values ​​of the two components of the piperacillin sodium and tazobactam sodium for injection described in step 1); 3) screening and eliminating abnormal spectra of the near infrared spectrum obtained in step 1); 4) Dividing the remaining near-infrared spectral samples in step 3) into a sample set and a validation set; 5) Preprocessing the spectrum in step 3), selecting characteristic bands and the number of principal components, and establishing a quantitative analysis model; 6) The model established in step 5) is used to predict and verify the content of piperacillin sodium and tazobactam sodium for injection.

2. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The piperacillin sodium and tazobactam sodium for injection is a sterile powder for injection, which is a compound preparation of two components: piperacillin sodium and tazobactam sodium.

3. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The spectrum acquisition method in step 1) is: the sample does not need to be processed, and the solid optical fiber probe is directly pressed against the bottom of the vial for collection. The spectrum acquisition range is: 12000~4000cm -1 , resolution 8cm -1 , the number of scans was 32 times, 3 bottles of each batch of samples were measured, each bottle was measured 6 times, and the average spectrum was taken as the modeling spectrum.

4. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The determination method specified in the national drug standard is based on the HPLC determination method specified in Part II of the 2020 edition of the "Chinese Pharmacopoeia", and the determination indicators are two components: piperacillin sodium and tazobactam sodium.

5. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The method for screening abnormal spectra is based on the Hotelling T2 test and the predicted concentration residual method.

6. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The sample set partitioning method is Sample set Partitioning based on joint X Y distance (SPXY) method.

7. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The spectral preprocessing method described in step 5) is: the spectral preprocessing methods of piperacillin sodium and tazobactam sodium models are all multivariate scattering correction, first-order derivative, (Savitzky-Golay, SG) smoothing method, and the characteristic interval of piperacillin sodium model is: 4802.1~5203.3cm -1 、5604.4~8011.3cm -1 、8813.6~9214.7cm -1 11205~11602.3cm -1 ; The characteristic interval of the tazobactam sodium model is 4802.1~7610.1cm -1 、8813.6~9214.7cm -1 11205~11602.3cm -1 The number of principal components of the piperacillin sodium and tazobactam sodium models were 8 and 5, respectively.

8. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: Adjusted correlation coefficients for the piperacillin model The predicted correlation coefficient is 0.9970. The corrected mean square error (RMSEC) was 0.9988, the predicted mean square error (RMSEP) was 2.13, and the predicted mean square error (RMSEP) was 2.

20. is 0.9975, It is 0.9989, RMSEC is 1.35, and RMSEP is 1.

42.

9. The method for rapid near-infrared detection of the content of ingredients in piperacillin sodium and tazobactam sodium for injection according to claim 1, characterized in that: The model established in step 5) is used to predict the content of the components in piperacillin sodium and tazobactam sodium for injection, and compared with the values ​​measured by the determination method specified in national standards.

Images