Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient

Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient Wei Wang, Rong Chen, Yulan Liu, Hongjian Wei, Zifei He, Xiaomin Zheng, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7203829/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In the industrial production process of avibactam sodium, the quantitative determination of residual solvents from the manufacturing process is critical for ensuring product quality and safety. This study aimed to develop and validate a headspace gas chromatography with flame ionization detector (HS-GC-FID) method for the simultaneous determination of 12 residual solvents in avibactam sodium active pharmaceutical ingredient (API). The targeted solvents include methanol (MET), ethanol (ET), acetone (ACE), isopropanol (IPA), acetonitrile (ACN), dichloromethane (DCM), tert-butanol (tBA), methyl tert-butyl ether (MTBE), ethyl acetate (EA), tetrahydrofuran (THF), toluene (Tol), and butyl acetate (BuOAc). Following method optimization, all 12 solvents were well-separated, with a resolution greater than 1.5 between closely eluting peaks. The method demonstrated excellent linearity, with mass concentrations of the solvents showing a strong correlation with chromatographic peak areas (coefficient of determination, R² ≥ 0.99). Accuracy was confirmed by the recovery study, yielding average recovery rates below 10.0%, while precision was found to be within acceptable limits. The validated method proved to be accurate, specific, and highly sensitive, making it suitable for the rapid determination of residual solvents in avibactam sodium API. This approach ensures compliance with regulatory requirements and supports quality control in pharmaceutical manufacturing. headspace gas chromatography avibactam sodium residual solvents active pharmaceutical ingredient Figures Figure 1 Figure 2 Introduction Avibactam is a diazabicyclooctane (DBO) derivative with the chemical name [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] hydrogen sulfate[ 1 ]. Unlike traditional β-lactamase inhibitors, avibactam exhibits a unique, reversible mechanism of action. The inhibition process begins when the serine residue of β-lactamases nucleophilically attacks the amide bond of avibactam, resulting in ring opening and the formation of a covalent enzyme-inhibitor complex [ 2 ]. This complex represents the inhibited state of the enzyme, yet unlike classical inhibitors, no hydrolysis occurs. Instead, avibactam can undergo recyclization, reforming its β-lactam ring and regenerating the active molecule. The rate of nucleophilic ring opening significantly exceeds that of recyclization, ensuring that β-lactamases remain predominantly inhibited. Crucially, avibactam's structure can be restored through reversible reactions, which contributes to its prolonged inhibitory effect [ 3 ]. Avibactam demonstrates broad-spectrum inhibition against multiple classes of β-lactamases, including class A enzymes (e.g., CTX-M-15, KPC-2), class C enzymes (AmpC), and some class D enzymes (e.g., OXA-48) [ 4 , 5 ]. Clinically, the ceftazidime-avibactam combination has proven effective against Enterobacteriaceae that produce AmpC, KPC, and extended-spectrum β-lactamases (ESBLs) [ 6 ]. The synthesis of avibactam and its derivatives involves complex, multi-step reactions that require various organic solvents [ 7 – 11 ]. However, the complete removal of organic solvents from final products is often unattainable, and their residual traces may compromise both therapeutic efficacy and patient safety due to inherent toxicity and irritant properties, which necessitates rigorous residual solvent analysis in the quality control of avibactam and its derivatives [ 12 , 13 ]. The International Council for Harmonisation (ICH) Q3C guideline mandates strict control of residual solvents throughout the pharmaceutical manufacturing process. The regulation classifies solvents into three categories based on their toxicity profiles and establishes permissible exposure limits for each [ 14 ]. To ensure compliance and streamline quality assessment, a robust platform method for residual solvent analysis is crucial. Such a method would serve as a versatile foundation for avibactam production, enabling rapid adaptation to specific program requirements while maintaining analytical consistency across different derivatives. However, literature on residual solvent detection in avibactam and its derivative products remains scarce, highlighting a critical gap in current analytical methodologies for this important class of β-lactamase inhibitors. Headspace capillary gas chromatography with flame ionization detection (HS-GC-FID) has emerged as the gold standard for determining residual solvents in pharmaceuticals, owing to its exceptional sensitivity, wide dynamic range, and robust performance [ 15 – 18 ]. Ramanjaneyulu et al. established a selective and sensitive HS-GC method for the simultaneous analysis of 11 residual solvents (MET, ET, ACE, DCM, MTBE, n-hexane, 1-propanol, EA, THF, DIPEA, and DMF) in rufloxacin hydrochloride. This method demonstrated excellent sensitivity at ppm levels while offering reduced runtime [ 19 ]. Similarly, Noorbasha et al. validated a GC method for paclitaxel that simultaneously quantifies MET, ET, ACE, IPA, DCM, n-hexane, EA, THF, and DIPEA. The technique proved to be simple, sensitive, and specific, with demonstrated linearity, precision, accuracy, and robustness, making it suitable for both drug substance and product analysis [ 20 ]. Gudibanda et al. further advanced the field by developing a novel HS-GC method with enhanced sensitivity for twelve solvents (MET, ET, ACN, IPA, DCM, MTBE, EA, THF, 1,4-dioxane, DMF, hexane fractions, and Tol) in oseltamivir phosphate API and dosage forms [ 21 ]. Therefore, based on the synthetic route of avibactam sodium and following the Chinese Pharmacopoeia (2020 edition) and ICH guidelines, we developed a gas chromatography method for the rapid detection and quantification of 12 potential residual organic solvents in avibactam sodium and conducted the comprehensive methodological research. This study establishes a technical foundation to ensure the safe production of high-quality avibactam sodium API and its derived formulations in future manufacturing processes. Experimental Section Chemicals and Materials HPLC-grade N-methylpyrrolidone (NMP) was purchased from Shanghai Aladdin Scientific Co., Ltd. (Shanghai, China). HPLC-grade MET, ET, IPA, and ACN were purchased from Tianjin Kemiou Chemical Reagent Co. (Shanghai, China). Analytical-grade ACE, isopropyl acetate (IPAC), and DCM were purchased from Chengdu Kelong Chemical Co. (Chengdu, China). Analytical-grade MTBE, EA, TH, Tol, and BuOAc were purchased from Chongqing Chuandong Chemical Co. (Chongqing, China). Five batches of the avibactam sodium API sample (batch numbers: L-2002210901V, L-2002210902V, L-2002210903V, L-202230701, and AP046-N00201R) were produced by Fuan Pharmaceutical Co. (Chongqing, China). Deionized water was used throughout. Instrumentation The headspace GC-FID system consisted of an auto-headspace sampler (Agilent GC 7694A, (Agilent Technology Co., Shanghai, China) connected to a GC system (Agilent GC 7890B, Shanghai, China) equipped with a hydrogen flame ionization detector (FID) and a DB-624UI capillary columns (30 m×0.32 mm×1.8 µm, Santa Clara, CA, USA). Preparation of Reference and Sample Solutions Preparation of internal standard solution A total of 100 mg of IPAC was accurately weighed, dissolved, and diluted in NMP to prepare a solution of 0.1 mg/mL, then shaken well. Preparation of reference solution A total of 0.75 g of MET, 0.1 g of ACN, 0.15 g of DCM, 0.18 g of THF, 0.22 g of Tol, and 1.25 g each of ET, ACE, IPA, tBA, MTBE, EA, and BuOAc were weighed and placed in a 50 mL volumetric flask. These organic solvents were dissolved and diluted with the internal standard solution to the mark, shaken well, and used as the reference stock solution. Accurately measured 1 mL of the reference stock solution, placed it in a 50 mL volumetric flask, diluted to the mark with the internal standard solution, shook well, and used as the reference solution. 2.3.3 Preparation of the sample solution A total of 0.2 g of avibactam sodium API samples was accurately weighed and precisely added to 2 mL of the internal standard solution. The mixture was then heated in an 80°C water bath until it was dissolved and shaken well. HS-GC-FID Analysis HS-GC-FID Analysis was performed on a GC system equipped with a FID. The programmed temperature rise was set as follows: maintain the initial temperature at 40℃ for 5 minutes, then increase the temperature at a rate of 20°C /min to 120°C and hold for 2 minutes; subsequently, increase the temperature at a rate of 20°C/min to 200°C and hold for 5 minutes. The nitrogen was used as the carrier at a flow rate of 2.0 mL/min, with a split ratio of 20:1. The detector temperature was set at 250°C, and the injection port temperature was 200°C. The conditions of the headspace sampler were set as follows: equilibrium temperature, 80°C; equilibrium time, 30 min; quantitative loop temperature, 90°C; and transmission line temperature, 100°C. 1 mL of the blank, reference solutions, and sample solutions were injected into the GC-FID system for analysis. Method Validation The developed GC-FID method was evaluated in terms of specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, and accuracy. Specificity The internal standard solution and reference solutions of 12 solvents were respectively injected into the GC system. The analysis was conducted under the set conditions, and the chromatograms were recorded. linearity The linearity parameter was demonstrated by preparing six concentration levels, ranging from the LOQ to 200% (i.e., LOQ, 40, 80, 100, 120, and 200%) of the working concentration level, through the dilution of a standard mixture stock solution. The linearity range for MET, ET, ACE, IPA, ACN, DCM, tBA, MTBE, EA, THF, Tol, and BuOAc was assessed by plotting the concentrations of the 12 solvents against the measured GC-FID response. LOD and LOQ Using a multiple dilution method, the sensitivity of the proposed HS-GC approach for the simultaneous assessment of 12 solvents was evaluated in terms of "LOD and LOQ." The LOD of this method was defined as three times the signal-to-noise ratio (S/N = 3) of the lowest concentration, and the LOQ was defined as ten times the signal-to-noise ratio (S/N = 10) of the lowest concentration. Precision The mixed reference stock solution of 12 residual solvents was diluted with an internal standard solution to prepare test solutions at mass concentrations of 300.48, 500.16, 502.96, 500.88, 37.92, 60.40, 500.64, 500.00, 500.08, 73.28, 88.00, and 502.00 µg/mL, respectively. Six aliquots of the test solution were separately injected into the GC system. The peak areas of the 12 solvents were detected and recorded, and the mean values, along with the RSD, were calculated to determine the precision of the developed method. Accuracy The QC samples were prepared by pooling and mixing a portion of each of the five batches of avibactam sodium API samples. A total of 0.2 g of the pooled avibactam sodium API samples was precisely added to 2 mL of the internal standard solution, heated in an 80°C water bath until dissolved, and then shaken well. This sample was used as the QC0 sample. Recovery control samples at three levels, i.e., quality control low-level (QCL), quality control mid-level (QCM), and quality control high-level (QCH), were prepared by spiking the reference solutions of 12 kinds of residual solvents into the QC0 samples. The levels of spiked residual solvents were 80%, 100%, and 120%, and the corresponding concentrations are shown in Table 1 . The QC samples were prepared in replicate (n = 3), and the following formula was used to calculate the recovery rate: Recovery rate = (detected three-level concentration - detected QC0 concentration) / spiked concentration × 100. The mean recovery and RSD of measurements (n = 9) were used to evaluate the method's accuracy. Table 1 The levels and corresponding concentrations of spiked residual solvents Residual Solvent Spiked concentration (µg/mL) 80% 100% 120% MET 240.22 300.28 360.34 ET 397.57 496.96 596.35 ACE 400.96 501.20 601.44 IPA 398.46 498.08 597.70 ACN 32.70 40.88 49.06 DCM 46.40 58.00 69.60 tBA 398.40 498.00 597.60 MTBE 397.12 496.40 595.68 EA 399.14 498.92 598.70 THF 59.14 73.92 88.70 Tol 68.32 85.40 102.48 BuOAc 400.13 500.16 600.19 Results and Discussion The development and optimization of a generic headspace gas chromatography with flame ionization detection (HS-GC-FID) method for the simultaneous separation of multiple residual solvents is critical for achieving efficient and reliable analytical results during pharmaceutical development.[ 22 , 23 ]. Existing studies have employed various analytical techniques to quantify avibactam sodium; however, a gas chromatographic approach tailored explicitly for residual solvent analysis has not been reported in the prior literature [ 24 – 26 ]. To demonstrate the method's applicability for routine analysis of all target solvents, we conducted comprehensive validation following ICH Q2(R2) guidelines, the Chinese Pharmacopoeia (2020 edition), and current good manufacturing practice (cGMP) requirements [ 27 – 29 ]. The validation study systematically evaluated key analytical performance characteristics, including specificity, linearity, sensitivity, precision, and accuracy. Specificity The specificity test was a critical component of the method development process, designed to verify the optimal performance of the chromatographic system. Blank solvent (1 mL), individual reference solutions (1 mL), and a mixed reference solution (1 mL) were prepared and injected into the GC system. The resulting chromatograms were carefully analyzed to determine the retention times of each component and evaluate the degree of separation achieved. This systematic approach ensured the method's ability to distinguish and quantify the target analytes without interference. The chromatographic results were presented in Fig. 1 . The solvents eluted in the following order: methanol (MET), ethanol (ET), acetone (ACE), isopropanol (IPA), acetonitrile (ACN), dichloromethane (DCM), tert–butanol (tBA), methyl tert–butyl ether (MTBE), ethyl acetate (EA), tetrahydrofuran (THF), toluene (Tol), and butyl acetate (BuOAc). The method validation confirmed excellent specificity, with no interfering peaks detected in either the blank solvent or reference solutions (Fig. 1 ). As summarized in Table 1 , all target residual solvents exhibited distinct retention times and achieved baseline separation. Resolution values for all adjacent peak pairs in the mixed reference standard solution exceeded 1.5, demonstrating complete chromatographic separation of the analytes. These validation results confirm that the developed GC method is selective and suitable for the accurate determination of residual solvents in avibactam sodium. Table 2 The retention time and separation degree of 12 residual solvents Residual Solvent Retention Time (min) Separation Degree MET 2.32 / ET 3.09 13.74 ACE 3.59 7.43 IPA 3.81 2.72 ACN 3.96 1.92 DCM 4.27 4.01 tBA 4.45 1.92 MTBE 4.78 2.79 EA 6.42 16.96 THF 6.66 3.47 Tol 7.42 11.53 BuOAc 9.14 30.18 Linearity Each concentration of the linearity solutions was injected in triplicate into the GC system, and the peak areas of the solvents were recorded for each level. The calibration curves were constructed by plotting the concentration (x-axis) against the average peak area (y-axis), followed by linear regression analysis. The solvent peak areas exhibited excellent linearity across the tested concentration range, with correlation coefficients (R²) greater than 0.999 (Table 3 ). This strong linear relationship for all 12 residual solvents ensures accurate quantification of residual solvents in avibactam sodium API using the proposed method. Table 3 Linear results for each residual solvent (n = 3) Residual Solvent Regression Equation R 2 Linearity Range (µg/mL) MET y = 0.0041x − 0.0040 0.9999 6.01 ~ 600.56 ET y = 0.0042x − 0.0021 0.9999 5.00 ~ 993.92 ACE y = 0.0160x − 0.0665 0.9999 2.01 ~ 1002.40 IPA y = 0.0042x + 0.0042 0.9999 10.02 ~ 996.16 ACN y = 0.0055x − 0.0007 0.9999 3.79 ~ 81.76 DCM y = 0.0027x − 0.0011 0.9999 12.08 ~ 116.00 tBA y = 0.0062x + 0.0169 0.9999 5.01 ~ 996.00 MTBE y = 0.0469x − 0.2099 0.9998 1.00 ~ 992.80 EA y = 0.0099x − 0.0033 1.0000 2.50 ~ 997.84 THF y = 0.0114x + 0.0032 0.9998 2.20 ~ 147.84 Tol y = 0.0088x + 0.0051 0.9999 1.76 ~ 170.80 BuOAc y = 0.0036x + 0.0205 0.9998 5.02 ~ 1000.32 LOD and LOQ The sensitivity of the HS-GC-FID method was determined based on the ICH method, with the LOD defined as a S/N ratio of 3:1 and the LOQ with a S/N ratio of 10:1. As shown in Table 4 , the LOD for all residual solvents ranged from 0.30 to 3.66 µg/mL, and the minimum achievable LOD was 0.30 µg/mL for MTBE. The LOQ for all residual solvents ranged from 1.00 to 12.08 µg/mL, and the minimum achievable LOQ was 1.00 µg/mL for MTBE. The results shown that the method established in this study can sensitively detect the residual amount of 12 solvents in in avibactam sodium API. Table 4 LOD and LOQ results for each residual solvent Residual Solvent LOD (µg/mL) LOQ (µg/mL) MET 1.82 6.01 ET 1.52 5.00 ACE 0.61 2.01 IPA 3.03 10.02 ACN 1.15 3.79 DCM 3.66 12.08 tBA 1.52 5.01 MTBE 0.30 1.00 EA 0.76 2.50 THF 0.67 2.20 Tol 0.53 1.76 BuOAc 1.52 5.02 Precision The precision of an analytical procedure reflects the degree of agreement among multiple measurements obtained from repeated sampling of a homogeneous sample under specified conditions. This parameter is typically quantified through statistical measures such as variance, standard deviation, or coefficient of variation. In the current method validation, system precision was evaluated by performing six replicate injections of standard solutions and expressed as the RSD of the obtained data. As presented in Table 5 , the precision results demonstrated excellent reproducibility, with all solvents showing RSD values below 5.0%, which was well within the predefined acceptance criterion of less than 15%. These findings confirm that the method's precision characteristics fully comply with the stringent requirements outlined in the ICH guidelines for analytical procedure validation. The consistently low RSD values across all tested solvents indicate robust system performance and reliable measurement reproducibility. Table 5 The precision results for each residual solvent Residual Solvent Concentration (ug/mL) Peak area (pA/s) Mean peak area (pA/s) RSD (%) 1 2 3 4 5 6 MET 300.48 148.83 147.50 146.64 151.05 157.33 153.45 150.80 2.45 ET 500.16 249.33 247.59 245.22 255.71 270.81 253.24 253.65 3.32 ACE 502.96 959.70 955.29 939.30 987.97 1007.05 961.71 968.50 2.31 IPA 500.88 252.66 251.29 247.18 259.79 274.15 257.42 257.08 3.37 ACN 37.92 27.15 26.96 26.59 27.72 28.99 27.83 27.54 2.82 DCM 60.40 18.45 18.33 18.01 18.99 19.57 18.94 18.72 2.74 tBA 500.64 371.10 369.83 361.42 382.32 402.48 364.27 375.24 3.69 MTBE 500.00 2827.81 2833.71 2737.06 2922.30 2970.20 2892.43 2863.92 2.62 EA 500.08 600.34 597.78 582.49 618.09 635.51 609.24 607.24 2.75 THF 73.28 102.04 101.59 99.36 105.10 107.49 104.28 103.31 2.55 Tol 88.00 90.16 89.90 87.57 92.93 97.92 93.27 91.96 3.58 BuOAc 502.00 215.31 215.59 208.43 222.34 234.67 219.32 219.28 3.69 Accuracy Accuracy is a critical validation parameter that represents the closeness of agreement between measured values obtained by the analytical method and accepted reference values, reflecting the trueness of the method. In this study, accuracy was assessed through recovery experiments by spiking standard solvents into pooled avibactam sodium API samples at three levels: 80%, 100%, and 120% of the specification limit. As detailed in Table 6 , the average recoveries for all solvents ranged from 91.76–112.87%, with all individual recovery values falling within the acceptable range of 80.0 ~ 120.0%, as stipulated by the Chinese Pharmacopoeia (2020 edition). These results demonstrate that the method exhibits excellent accuracy, with recovery rates consistently meeting regulatory requirements. Furthermore, the low relative deviations observed confirm the method's reliability and suitability for its intended analytical purpose.This validation confirms that the method provides accurate and precise measurements, ensuring confidence in its application for quality control testing. Table 6 The recovery results for each residual solvent Residual Solvent Recovery (%) Average recovery (%) RSD (%) QCL QCM QCH MET 94.37 92.86 90.84 91.76 1.59 93.56 91.52 90.10 92.24 89.06 91.33 ET 100.88 99.60 97.55 97.14 2.46 98.91 97.39 94.58 95.95 92.32 97.06 ACE 97.61 95.49 94.43 96.25 1.12 97.77 95.66 95.56 97.65 96.50 95.55 IPA 99.74 99.02 98.65 97.80 1.45 98.60 97.77 96.31 97.47 94.65 97.99 ACN 96.10 94.85 92.78 93.41 1.77 95.18 93.63 91.07 93.98 90.41 92.74 DCM 99.36 98.34 97.49 98.04 0.71 98.79 97.76 97.22 98.48 97.18 97.70 tBA 105.03 104.23 104.03 103.22 1.29 103.93 103.18 101.75 103.09 100.51 103.25 MTBE 96.72 94.40 96.29 97.71 1.72 98.19 97.22 99.12 99.60 100.26 97.59 EA 97.76 96.61 96.88 97.20 0.45 97.77 96.62 97.23 97.77 96.95 97.21 THF 98.84 97.24 96.52 97.95 0.89 99.04 97.53 97.45 99.21 98.44 97.31 Tol 107.99 107.05 106.64 105.99 1.37 106.77 105.91 104.51 105.88 103.05 106.08 BuOAc 115.20 113.98 113.54 112.87 1.54 113.74 112.96 110.96 112.98 109.72 112.73 Sample Determination The peak area was determined using the internal standard method, and the results were presented in Table 7 . The results indicate that MET, ET, ACE, and ACN were detected, while other organic solvents were not detected (ND) in the five batches of the avibactam sodium API sample. The content of MET in the sample of batch L-2002210901V was 0.002%. The content of ACN in the sample of batch L-202230701 was 0.004%. The contents of ET in the samples of batches L-2002210901V, L-2002210902V, L-2002210903V, L-202230701 and AP046-N00201R were 0.18%, 0.16%, 0.13%, 0.33% and 0.32% respectively. The ACE content in batches L-2002210901V, L-2002210902V, L-2002210903V, L-202230701, and AP046-N00201R samples were 0.02%, 0.02%, 0.003%, 0.005%, and 0.01%, respectively. The results indicated that the residual amounts of 12 solvents in the five batches of sodium averbactam API all comply with the relevant provisions of the 2020 edition of the Chinese Pharmacopoeia. Table 7 Determination results of the avibactam sodium API sample. Residual Solvent Content (%) L-2002210901V L-2002210902V L-2002210903V L-202230701 AP046-N00201R MET 0.002 ND ND ND ND ET 0.18 0.16 0.13 0.33 0.32 ACE 0.02 0.02 0.003 0.005 0.01 IPA ND ND ND ND ND ACN ND ND ND 0.004 ND DCM ND ND ND ND ND tBA ND ND ND ND ND MTBE ND ND ND ND ND EA ND ND ND ND ND THF ND ND ND ND ND Tol ND ND ND ND ND BuOAc ND ND ND ND ND Conclusion In this work, we developed and validated a robust gas chromatography method for the simultaneous detection and quantification of 12 potential residual organic solvents in avibactam sodium API. This comprehensive methodological study included full validation of all critical parameters, establishing a reliable analytical framework for quality control. The developed method provides a solid technical foundation to ensure the production of high-quality avibactam sodium API and its pharmaceutical formulations, supporting current good manufacturing practice (cGMP) requirements for pharmaceutical production. Declarations Author contributions W.W. and X.X. provided the conceptualization. R.C., Z.H. and Y.L. performed the experiments and data compilation. H.W., X.Z. and S.H. wrote the first draft text, prepared the figures and tables. Y.T. and S.H. reviewed and polished the manuscript. All authors reviewed the manuscript. Funding This research was funded by the General Project of the Chongqing Special Program for Technological Innovation and Application Development (CSTB2022TIAD-GPX0074). Data Availability The authors declare that the data supporting the findings of this study are disclosed within the paper and will be made available upon request. Conflicts of Interest The authors declare that they have no conflicts of interest. Ethical Approval This study does not involve any human or animal participants. References Wang DY, Abboud MI, Markoulides MS.; Brem J, Schofield CJ (2016) The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. 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Wang Q, Zheng Y, Liu L, Ji P, Jiang W, Zhao J, Ren J, Yang L (2023) Simultaneous determination of ceftazidime and avibactam in human plasma and cerebrospinal fluid by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS). Anal Lett 56: 816–831. Liu X, Li B, Li S, Wang X, Kong X, Chen Y, Zhang Q, Duan J, Chen W, Li P (2025) Simultaneous determination of three β-Lactam/β-lactamase inhibitor combinations in critically ill patients by UPLC-MS/MS. J Chromatogr B 1251: 124431. Martens-Lobenhoffer J, Angermair S, Bode-Böger SM (2022) Quantification of ceftazidime/avibactam in human plasma and dried blood spots: Implications on stability and sample transport. J Chromatogr B 1193: 123164. Bernardoni F, Halsey HM, Hartman R, Nowak T, Regalado EL (2019) Generic gas chromatography flame ionization detection method using hydrogen as the carrier gas for the analysis of solvents in pharmaceuticals. J Pharmaceut Biomed 165: 366–373. Shou M, Qiu, H (2021) Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1, 1, 3, 3-tetramethylguanidine residues in an active pharmaceutical ingredient. J Pharm Anal 11: 251–256. Feng XZ, Han GC, Qin J, Yin SM, Chen Z (2016). Determination of residual solvents in linezolid by static headspace GC. J Chromatogr Sci 54: 487–491. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7203829","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":496871493,"identity":"7c8efb08-5e49-4b2e-842b-9e7c6f87ab70","order_by":0,"name":"Wei Wang","email":"","orcid":"","institution":"Chongqing Industry and Trade Polytechnic","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wang","suffix":""},{"id":496871494,"identity":"5a06a3bf-ddb7-4554-acd3-0ddf4a97f751","order_by":1,"name":"Rong Chen","email":"","orcid":"","institution":"Fuan Pharmaceutical Group Chongqing Lybon Pharm-Tech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Rong","middleName":"","lastName":"Chen","suffix":""},{"id":496871495,"identity":"cf285871-db75-49e0-9f06-7579357dc385","order_by":2,"name":"Yulan Liu","email":"","orcid":"","institution":"Fuan Pharmaceutical Group Chongqing Lybon Pharm-Tech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Yulan","middleName":"","lastName":"Liu","suffix":""},{"id":496871496,"identity":"d7255d24-6b3b-4876-bf28-c6e6c8ce686d","order_by":3,"name":"Hongjian Wei","email":"","orcid":"","institution":"Chongqing Institute for Food and Drug Control, Chongqing Key Laboratory of Quality Control and Safety Evaluation of API","correspondingAuthor":false,"prefix":"","firstName":"Hongjian","middleName":"","lastName":"Wei","suffix":""},{"id":496871497,"identity":"ae9e4b24-e97e-4342-9ab5-5befe4bc7863","order_by":4,"name":"Zifei He","email":"","orcid":"","institution":"Fuan Pharmaceutical Group Chongqing Lybon Pharm-Tech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Zifei","middleName":"","lastName":"He","suffix":""},{"id":496871498,"identity":"192a4b86-8766-4d31-abfe-d560f52a54e8","order_by":5,"name":"Xiaomin Zheng","email":"","orcid":"","institution":"Chongqing Institute for Food and Drug Control, Chongqing Key Laboratory of Quality Control and Safety Evaluation of API","correspondingAuthor":false,"prefix":"","firstName":"Xiaomin","middleName":"","lastName":"Zheng","suffix":""},{"id":496871499,"identity":"4952e06d-619b-45ff-adc0-7aabdbd50216","order_by":6,"name":"Yu Tang","email":"","orcid":"","institution":"Chongqing Institute for Food and Drug Control, Chongqing Key Laboratory of Quality Control and Safety Evaluation of API","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Tang","suffix":""},{"id":496871500,"identity":"518627f3-bd95-4416-9156-f3ae14c592eb","order_by":7,"name":"Xia Xu","email":"","orcid":"","institution":"Fuan Pharmaceutical Group Chongqing Lybon Pharm-Tech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Xu","suffix":""},{"id":496871501,"identity":"2919536a-ff90-478b-a803-811408072aba","order_by":8,"name":"Sheng Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqUlEQVRIiWNgGAWjYBACAwhlQ7qWNNK1HCZBi7lE8rOHX/6cl+c7fvgBw88dRGixnJFmbizbdttw5pk0A8beM8Q47EaCmbRkw+0EgwMJBsyMbURpSf8mLfHnXILB+ecfiNWSYyb5gQ1oxY0cYm0586ZMmrEt2XDmjTcFB3uJ0nI8fZvkjz928nzn0zc++EmMFhBg5gGRB8CISMD4A6plFIyCUTAKRgFWAACw4zoqcgASqQAAAABJRU5ErkJggg==","orcid":"","institution":"Chongqing Academy of Animal Science","correspondingAuthor":true,"prefix":"","firstName":"Sheng","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2025-07-24 09:23:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7203829/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7203829/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88812222,"identity":"8bcf89f2-f475-4612-9c8e-72b29ae5105f","added_by":"auto","created_at":"2025-08-11 15:42:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79993,"visible":true,"origin":"","legend":"\u003cp\u003eThe chromatography of the 12 residual solvents and blank using the developed GC-FID method.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7203829/v1/025128a5e246f8c70a8e13a1.png"},{"id":88813945,"identity":"65ef8b61-a710-4644-8e64-ef199b5c328e","added_by":"auto","created_at":"2025-08-11 15:58:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":47274,"visible":true,"origin":"","legend":"\u003cp\u003eThe chromatogram of the sample (Batch Number: L-2002210902V).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7203829/v1/e76640ce28310c4987a73083.png"},{"id":92870667,"identity":"9758983c-3f1c-4255-8766-7f9e07fcaf29","added_by":"auto","created_at":"2025-10-06 14:02:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1161314,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7203829/v1/5cc8043b-7625-4c9b-8e68-e92238567964.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAvibactam is a diazabicyclooctane (DBO) derivative with the chemical name [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[3.2.1]oct-6-yl] hydrogen sulfate[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Unlike traditional β-lactamase inhibitors, avibactam exhibits a unique, reversible mechanism of action. The inhibition process begins when the serine residue of β-lactamases nucleophilically attacks the amide bond of avibactam, resulting in ring opening and the formation of a covalent enzyme-inhibitor complex [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This complex represents the inhibited state of the enzyme, yet unlike classical inhibitors, no hydrolysis occurs. Instead, avibactam can undergo recyclization, reforming its β-lactam ring and regenerating the active molecule. The rate of nucleophilic ring opening significantly exceeds that of recyclization, ensuring that β-lactamases remain predominantly inhibited. Crucially, avibactam's structure can be restored through reversible reactions, which contributes to its prolonged inhibitory effect [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Avibactam demonstrates broad-spectrum inhibition against multiple classes of β-lactamases, including class A enzymes (e.g., CTX-M-15, KPC-2), class C enzymes (AmpC), and some class D enzymes (e.g., OXA-48) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Clinically, the ceftazidime-avibactam combination has proven effective against Enterobacteriaceae that produce AmpC, KPC, and extended-spectrum β-lactamases (ESBLs) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe synthesis of avibactam and its derivatives involves complex, multi-step reactions that require various organic solvents [\u003cspan additionalcitationids=\"CR8 CR9 CR10\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, the complete removal of organic solvents from final products is often unattainable, and their residual traces may compromise both therapeutic efficacy and patient safety due to inherent toxicity and irritant properties, which necessitates rigorous residual solvent analysis in the quality control of avibactam and its derivatives [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The International Council for Harmonisation (ICH) Q3C guideline mandates strict control of residual solvents throughout the pharmaceutical manufacturing process. The regulation classifies solvents into three categories based on their toxicity profiles and establishes permissible exposure limits for each [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. To ensure compliance and streamline quality assessment, a robust platform method for residual solvent analysis is crucial. Such a method would serve as a versatile foundation for avibactam production, enabling rapid adaptation to specific program requirements while maintaining analytical consistency across different derivatives. However, literature on residual solvent detection in avibactam and its derivative products remains scarce, highlighting a critical gap in current analytical methodologies for this important class of β-lactamase inhibitors.\u003c/p\u003e\u003cp\u003eHeadspace capillary gas chromatography with flame ionization detection (HS-GC-FID) has emerged as the gold standard for determining residual solvents in pharmaceuticals, owing to its exceptional sensitivity, wide dynamic range, and robust performance [\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Ramanjaneyulu et al. established a selective and sensitive HS-GC method for the simultaneous analysis of 11 residual solvents (MET, ET, ACE, DCM, MTBE, n-hexane, 1-propanol, EA, THF, DIPEA, and DMF) in rufloxacin hydrochloride. This method demonstrated excellent sensitivity at ppm levels while offering reduced runtime [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Similarly, Noorbasha et al. validated a GC method for paclitaxel that simultaneously quantifies MET, ET, ACE, IPA, DCM, n-hexane, EA, THF, and DIPEA. The technique proved to be simple, sensitive, and specific, with demonstrated linearity, precision, accuracy, and robustness, making it suitable for both drug substance and product analysis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Gudibanda et al. further advanced the field by developing a novel HS-GC method with enhanced sensitivity for twelve solvents (MET, ET, ACN, IPA, DCM, MTBE, EA, THF, 1,4-dioxane, DMF, hexane fractions, and Tol) in oseltamivir phosphate API and dosage forms [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTherefore, based on the synthetic route of avibactam sodium and following the Chinese Pharmacopoeia (2020 edition) and ICH guidelines, we developed a gas chromatography method for the rapid detection and quantification of 12 potential residual organic solvents in avibactam sodium and conducted the comprehensive methodological research. This study establishes a technical foundation to ensure the safe production of high-quality avibactam sodium API and its derived formulations in future manufacturing processes.\u003c/p\u003e"},{"header":"Experimental Section","content":"\u003cp\u003e\u003cb\u003eChemicals and Materials\u003c/b\u003e\u003c/p\u003e\u003cp\u003eHPLC-grade N-methylpyrrolidone (NMP) was purchased from Shanghai Aladdin Scientific Co., Ltd. (Shanghai, China). HPLC-grade MET, ET, IPA, and ACN were purchased from Tianjin Kemiou Chemical Reagent Co. (Shanghai, China). Analytical-grade ACE, isopropyl acetate (IPAC), and DCM were purchased from Chengdu Kelong Chemical Co. (Chengdu, China). Analytical-grade MTBE, EA, TH, Tol, and BuOAc were purchased from Chongqing Chuandong Chemical Co. (Chongqing, China). Five batches of the avibactam sodium API sample (batch numbers: L-2002210901V, L-2002210902V, L-2002210903V, L-202230701, and AP046-N00201R) were produced by Fuan Pharmaceutical Co. (Chongqing, China). Deionized water was used throughout.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInstrumentation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe headspace GC-FID system consisted of an auto-headspace sampler (Agilent GC 7694A, (Agilent Technology Co., Shanghai, China) connected to a GC system (Agilent GC 7890B, Shanghai, China) equipped with a hydrogen flame ionization detector (FID) and a DB-624UI capillary columns (30 m\u0026times;0.32 mm\u0026times;1.8 \u0026micro;m, Santa Clara, CA, USA).\u003c/p\u003e\u003cp\u003e\u003cb\u003ePreparation of Reference and Sample Solutions\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePreparation of internal standard solution\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 100 mg of IPAC was accurately weighed, dissolved, and diluted in NMP to prepare a solution of 0.1 mg/mL, then shaken well.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePreparation of reference solution\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 0.75 g of MET, 0.1 g of ACN, 0.15 g of DCM, 0.18 g of THF, 0.22 g of Tol, and 1.25 g each of ET, ACE, IPA, tBA, MTBE, EA, and BuOAc were weighed and placed in a 50 mL volumetric flask. These organic solvents were dissolved and diluted with the internal standard solution to the mark, shaken well, and used as the reference stock solution. Accurately measured 1 mL of the reference stock solution, placed it in a 50 mL volumetric flask, diluted to the mark with the internal standard solution, shook well, and used as the reference solution.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3.3 Preparation of the sample solution\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA total of 0.2 g of avibactam sodium API samples was accurately weighed and precisely added to 2 mL of the internal standard solution. The mixture was then heated in an 80\u0026deg;C water bath until it was dissolved and shaken well.\u003c/p\u003e\u003cp\u003e\u003cb\u003eHS-GC-FID Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eHS-GC-FID Analysis was performed on a GC system equipped with a FID. The programmed temperature rise was set as follows: maintain the initial temperature at 40℃ for 5 minutes, then increase the temperature at a rate of 20\u0026deg;C /min to 120\u0026deg;C and hold for 2 minutes; subsequently, increase the temperature at a rate of 20\u0026deg;C/min to 200\u0026deg;C and hold for 5 minutes. The nitrogen was used as the carrier at a flow rate of 2.0 mL/min, with a split ratio of 20:1. The detector temperature was set at 250\u0026deg;C, and the injection port temperature was 200\u0026deg;C. The conditions of the headspace sampler were set as follows: equilibrium temperature, 80\u0026deg;C; equilibrium time, 30 min; quantitative loop temperature, 90\u0026deg;C; and transmission line temperature, 100\u0026deg;C. 1 mL of the blank, reference solutions, and sample solutions were injected into the GC-FID system for analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethod Validation\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe developed GC-FID method was evaluated in terms of specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), precision, and accuracy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSpecificity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe internal standard solution and reference solutions of 12 solvents were respectively injected into the GC system. The analysis was conducted under the set conditions, and the chromatograms were recorded.\u003c/p\u003e\u003cp\u003e\u003cb\u003elinearity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe linearity parameter was demonstrated by preparing six concentration levels, ranging from the LOQ to 200% (i.e., LOQ, 40, 80, 100, 120, and 200%) of the working concentration level, through the dilution of a standard mixture stock solution. The linearity range for MET, ET, ACE, IPA, ACN, DCM, tBA, MTBE, EA, THF, Tol, and BuOAc was assessed by plotting the concentrations of the 12 solvents against the measured GC-FID response.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLOD and LOQ\u003c/b\u003e\u003c/p\u003e\u003cp\u003eUsing a multiple dilution method, the sensitivity of the proposed HS-GC approach for the simultaneous assessment of 12 solvents was evaluated in terms of \"LOD and LOQ.\" The LOD of this method was defined as three times the signal-to-noise ratio (S/N\u0026thinsp;=\u0026thinsp;3) of the lowest concentration, and the LOQ was defined as ten times the signal-to-noise ratio (S/N\u0026thinsp;=\u0026thinsp;10) of the lowest concentration.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrecision\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe mixed reference stock solution of 12 residual solvents was diluted with an internal standard solution to prepare test solutions at mass concentrations of 300.48, 500.16, 502.96, 500.88, 37.92, 60.40, 500.64, 500.00, 500.08, 73.28, 88.00, and 502.00 \u0026micro;g/mL, respectively. Six aliquots of the test solution were separately injected into the GC system. The peak areas of the 12 solvents were detected and recorded, and the mean values, along with the RSD, were calculated to determine the precision of the developed method.\u003c/p\u003e\u003cp\u003e\u003cb\u003eAccuracy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe QC samples were prepared by pooling and mixing a portion of each of the five batches of avibactam sodium API samples. A total of 0.2 g of the pooled avibactam sodium API samples was precisely added to 2 mL of the internal standard solution, heated in an 80\u0026deg;C water bath until dissolved, and then shaken well. This sample was used as the QC0 sample. Recovery control samples at three levels, i.e., quality control low-level (QCL), quality control mid-level (QCM), and quality control high-level (QCH), were prepared by spiking the reference solutions of 12 kinds of residual solvents into the QC0 samples. The levels of spiked residual solvents were 80%, 100%, and 120%, and the corresponding concentrations are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The QC samples were prepared in replicate (n\u0026thinsp;=\u0026thinsp;3), and the following formula was used to calculate the recovery rate:\u003c/p\u003e\u003cp\u003eRecovery rate = (detected three-level concentration - detected QC0 concentration) / spiked concentration \u0026times; 100.\u003c/p\u003e\u003cp\u003eThe mean recovery and RSD of measurements (n\u0026thinsp;=\u0026thinsp;9) were used to evaluate the method's accuracy.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe levels and corresponding concentrations of spiked residual solvents\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eSpiked concentration (\u0026micro;g/mL)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100%\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e120%\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e240.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e300.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e360.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e397.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e496.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e596.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e400.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e501.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e601.44\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e398.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e498.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e597.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e40.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e49.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e46.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e58.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e69.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e398.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e498.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e597.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e397.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e496.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e595.68\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e399.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e498.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e598.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e59.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e73.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e88.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e68.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e85.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e102.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e400.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e500.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e600.19\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe development and optimization of a generic headspace gas chromatography with flame ionization detection (HS-GC-FID) method for the simultaneous separation of multiple residual solvents is critical for achieving efficient and reliable analytical results during pharmaceutical development.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Existing studies have employed various analytical techniques to quantify avibactam sodium; however, a gas chromatographic approach tailored explicitly for residual solvent analysis has not been reported in the prior literature [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. To demonstrate the method's applicability for routine analysis of all target solvents, we conducted comprehensive validation following ICH Q2(R2) guidelines, the Chinese Pharmacopoeia (2020 edition), and current good manufacturing practice (cGMP) requirements [\u003cspan additionalcitationids=\"CR28\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The validation study systematically evaluated key analytical performance characteristics, including specificity, linearity, sensitivity, precision, and accuracy.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSpecificity\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe specificity test was a critical component of the method development process, designed to verify the optimal performance of the chromatographic system. Blank solvent (1 mL), individual reference solutions (1 mL), and a mixed reference solution (1 mL) were prepared and injected into the GC system. The resulting chromatograms were carefully analyzed to determine the retention times of each component and evaluate the degree of separation achieved. This systematic approach ensured the method's ability to distinguish and quantify the target analytes without interference.\u003c/p\u003e\u003cp\u003eThe chromatographic results were presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The solvents eluted in the following order: methanol (MET), ethanol (ET), acetone (ACE), isopropanol (IPA), acetonitrile (ACN), dichloromethane (DCM), tert\u0026ndash;butanol (tBA), methyl tert\u0026ndash;butyl ether (MTBE), ethyl acetate (EA), tetrahydrofuran (THF), toluene (Tol), and butyl acetate (BuOAc).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe method validation confirmed excellent specificity, with no interfering peaks detected in either the blank solvent or reference solutions (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). As summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, all target residual solvents exhibited distinct retention times and achieved baseline separation. Resolution values for all adjacent peak pairs in the mixed reference standard solution exceeded 1.5, demonstrating complete chromatographic separation of the analytes. These validation results confirm that the developed GC method is selective and suitable for the accurate determination of residual solvents in avibactam sodium.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe retention time and separation degree of 12 residual solvents\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetention Time (min)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSeparation Degree\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e/\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.43\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.47\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eLinearity\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eEach concentration of the linearity solutions was injected in triplicate into the GC system, and the peak areas of the solvents were recorded for each level. The calibration curves were constructed by plotting the concentration (x-axis) against the average peak area (y-axis), followed by linear regression analysis. The solvent peak areas exhibited excellent linearity across the tested concentration range, with correlation coefficients (R\u0026sup2;) greater than 0.999 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This strong linear relationship for all 12 residual solvents ensures accurate quantification of residual solvents in avibactam sodium API using the proposed method.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLinear results for each residual solvent (n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRegression Equation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLinearity Range (\u0026micro;g/mL)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0041x \u0026minus;\u0026thinsp;0.0040\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.01\u0026thinsp;~\u0026thinsp;600.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0042x \u0026minus;\u0026thinsp;0.0021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.00\u0026thinsp;~\u0026thinsp;993.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0160x \u0026minus;\u0026thinsp;0.0665\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.01\u0026thinsp;~\u0026thinsp;1002.40\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0042x\u0026thinsp;+\u0026thinsp;0.0042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e10.02\u0026thinsp;~\u0026thinsp;996.16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0055x \u0026minus;\u0026thinsp;0.0007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.79\u0026thinsp;~\u0026thinsp;81.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0027x \u0026minus;\u0026thinsp;0.0011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12.08\u0026thinsp;~\u0026thinsp;116.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0062x\u0026thinsp;+\u0026thinsp;0.0169\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.01\u0026thinsp;~\u0026thinsp;996.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0469x \u0026minus;\u0026thinsp;0.2099\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.00\u0026thinsp;~\u0026thinsp;992.80\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0099x \u0026minus;\u0026thinsp;0.0033\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.0000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.50\u0026thinsp;~\u0026thinsp;997.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0114x\u0026thinsp;+\u0026thinsp;0.0032\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2.20\u0026thinsp;~\u0026thinsp;147.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0088x\u0026thinsp;+\u0026thinsp;0.0051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9999\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.76\u0026thinsp;~\u0026thinsp;170.80\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ey\u0026thinsp;=\u0026thinsp;0.0036x\u0026thinsp;+\u0026thinsp;0.0205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9998\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e5.02\u0026thinsp;~\u0026thinsp;1000.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eLOD and LOQ\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe sensitivity of the HS-GC-FID method was determined based on the ICH method, with the LOD defined as a S/N ratio of 3:1 and the LOQ with a S/N ratio of 10:1. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, the LOD for all residual solvents ranged from 0.30 to 3.66 \u0026micro;g/mL, and the minimum achievable LOD was 0.30 \u0026micro;g/mL for MTBE. The LOQ for all residual solvents ranged from 1.00 to 12.08 \u0026micro;g/mL, and the minimum achievable LOQ was 1.00 \u0026micro;g/mL for MTBE. The results shown that the method established in this study can sensitively detect the residual amount of 12 solvents in in avibactam sodium API.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLOD and LOQ results for each residual solvent\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLOD (\u0026micro;g/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLOQ (\u0026micro;g/mL)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e6.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e10.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.50\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2.20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrecision\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe precision of an analytical procedure reflects the degree of agreement among multiple measurements obtained from repeated sampling of a homogeneous sample under specified conditions. This parameter is typically quantified through statistical measures such as variance, standard deviation, or coefficient of variation. In the current method validation, system precision was evaluated by performing six replicate injections of standard solutions and expressed as the RSD of the obtained data. As presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, the precision results demonstrated excellent reproducibility, with all solvents showing RSD values below 5.0%, which was well within the predefined acceptance criterion of less than 15%. These findings confirm that the method's precision characteristics fully comply with the stringent requirements outlined in the ICH guidelines for analytical procedure validation. The consistently low RSD values across all tested solvents indicate robust system performance and reliable measurement reproducibility.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe precision results for each residual solvent\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eConcentration\u003c/p\u003e\u003cp\u003e(ug/mL)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"6\" nameend=\"c8\" namest=\"c3\"\u003e\u003cp\u003ePeak area (pA/s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMean peak area (pA/s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRSD (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e300.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e148.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e147.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e146.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e151.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e157.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e153.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e150.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e500.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e249.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e247.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e245.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e255.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e270.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e253.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e253.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e502.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e959.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e955.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e939.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e987.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1007.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e961.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e968.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e500.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e252.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e251.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e247.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e259.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e274.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e257.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e257.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e27.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e26.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e27.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e28.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e27.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e27.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e60.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e18.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e18.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e18.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e18.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e19.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e18.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e18.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e500.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e371.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e369.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e361.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e382.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e402.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e364.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e375.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e500.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2827.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2833.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2737.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2922.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e2970.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e2892.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e2863.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e500.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e600.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e597.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e582.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e618.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e635.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e609.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e607.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e73.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e102.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e101.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e99.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e105.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e107.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e104.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e103.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e88.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e90.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e89.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e87.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e92.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e97.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e93.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e91.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e502.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e215.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e215.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e208.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e222.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e234.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e219.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e219.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e3.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAccuracy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAccuracy is a critical validation parameter that represents the closeness of agreement between measured values obtained by the analytical method and accepted reference values, reflecting the trueness of the method. In this study, accuracy was assessed through recovery experiments by spiking standard solvents into pooled avibactam sodium API samples at three levels: 80%, 100%, and 120% of the specification limit. As detailed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e, the average recoveries for all solvents ranged from 91.76\u0026ndash;112.87%, with all individual recovery values falling within the acceptable range of 80.0\u0026thinsp;~\u0026thinsp;120.0%, as stipulated by the Chinese Pharmacopoeia (2020 edition). These results demonstrate that the method exhibits excellent accuracy, with recovery rates consistently meeting regulatory requirements. Furthermore, the low relative deviations observed confirm the method's reliability and suitability for its intended analytical purpose.This validation confirms that the method provides accurate and precise measurements, ensuring confidence in its application for quality control testing.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe recovery results for each residual solvent\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eRecovery (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAverage recovery (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eRSD (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eQCL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eQCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eQCH\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e92.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e91.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e90.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e92.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e97.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e2.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e92.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e94.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e96.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e98.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e97.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e94.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e94.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e93.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e95.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e93.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e91.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e92.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e98.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.71\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e105.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e104.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e103.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e103.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e103.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101.75\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e103.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e103.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e94.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e97.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.72\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e100.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e97.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e96.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e98.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e96.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e97.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e97.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e99.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e98.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e97.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e107.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e107.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e106.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e105.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.37\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e105.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e105.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e103.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e106.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e115.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e113.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e113.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e112.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e113.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e112.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e110.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e109.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e112.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eSample Determination\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe peak area was determined using the internal standard method, and the results were presented in Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. The results indicate that MET, ET, ACE, and ACN were detected, while other organic solvents were not detected (ND) in the five batches of the avibactam sodium API sample. The content of MET in the sample of batch L-2002210901V was 0.002%. The content of ACN in the sample of batch L-202230701 was 0.004%. The contents of ET in the samples of batches L-2002210901V, L-2002210902V, L-2002210903V, L-202230701 and AP046-N00201R were 0.18%, 0.16%, 0.13%, 0.33% and 0.32% respectively. The ACE content in batches L-2002210901V, L-2002210902V, L-2002210903V, L-202230701, and AP046-N00201R samples were 0.02%, 0.02%, 0.003%, 0.005%, and 0.01%, respectively. The results indicated that the residual amounts of 12 solvents in the five batches of sodium averbactam API all comply with the relevant provisions of the 2020 edition of the Chinese Pharmacopoeia.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab7\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 7\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDetermination results of the avibactam sodium API sample.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eResidual Solvent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e\u003cp\u003eContent (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eL-2002210901V\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eL-2002210902V\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL-2002210903V\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eL-202230701\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAP046-N00201R\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eET\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eACN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDCM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003etBA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMTBE\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTHF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBuOAc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eND\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn this work, we developed and validated a robust gas chromatography method for the simultaneous detection and quantification of 12 potential residual organic solvents in avibactam sodium API. This comprehensive methodological study included full validation of all critical parameters, establishing a reliable analytical framework for quality control. The developed method provides a solid technical foundation to ensure the production of high-quality avibactam sodium API and its pharmaceutical formulations, supporting current good manufacturing practice (cGMP) requirements for pharmaceutical production.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003eW.W. and X.X. provided the conceptualization. R.C., Z.H. and Y.L. performed the experiments and data compilation. H.W., X.Z. and S.H. wrote the first draft text, prepared the figures and tables. Y.T. and S.H. reviewed and polished the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This research was funded by the General Project of the Chongqing Special Program for Technological Innovation and Application Development (CSTB2022TIAD-GPX0074).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e The authors declare that the data supporting the findings of this study are disclosed within the paper and will be made available upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e The authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e This study does not involve any human or animal participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWang DY, Abboud MI, Markoulides MS.; Brem J, Schofield CJ (2016) The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. 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J Pharmaceut Biomed 165: 366\u0026ndash;373.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShou M, Qiu, H (2021) Development of a rapid GC-FID method to simultaneously determine triethylamine, diisopropylamine, and 1, 1, 3, 3-tetramethylguanidine residues in an active pharmaceutical ingredient. J Pharm Anal 11: 251\u0026ndash;256.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFeng XZ, Han GC, Qin J, Yin SM, Chen Z (2016). Determination of residual solvents in linezolid by static headspace GC. J Chromatogr Sci 54: 487\u0026ndash;491.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"headspace gas chromatography, avibactam sodium, residual solvents, active pharmaceutical ingredient","lastPublishedDoi":"10.21203/rs.3.rs-7203829/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7203829/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn the industrial production process of avibactam sodium, the quantitative determination of residual solvents from the manufacturing process is critical for ensuring product quality and safety. This study aimed to develop and validate a headspace gas chromatography with flame ionization detector (HS-GC-FID) method for the simultaneous determination of 12 residual solvents in avibactam sodium active pharmaceutical ingredient (API). The targeted solvents include methanol (MET), ethanol (ET), acetone (ACE), isopropanol (IPA), acetonitrile (ACN), dichloromethane (DCM), tert-butanol (tBA), methyl tert-butyl ether (MTBE), ethyl acetate (EA), tetrahydrofuran (THF), toluene (Tol), and butyl acetate (BuOAc). Following method optimization, all 12 solvents were well-separated, with a resolution greater than 1.5 between closely eluting peaks. The method demonstrated excellent linearity, with mass concentrations of the solvents showing a strong correlation with chromatographic peak areas (coefficient of determination, R\u0026sup2; \u0026ge; 0.99). Accuracy was confirmed by the recovery study, yielding average recovery rates below 10.0%, while precision was found to be within acceptable limits. The validated method proved to be accurate, specific, and highly sensitive, making it suitable for the rapid determination of residual solvents in avibactam sodium API. This approach ensures compliance with regulatory requirements and supports quality control in pharmaceutical manufacturing.\u003c/p\u003e","manuscriptTitle":"Development and Validation of a Headspace Gas Chromatography-Flame Ionization Detection Method for the Simultaneous Determination of 12 Residual Solvents in Avibactam Sodium Active Pharmaceutical Ingredient","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-11 15:42:47","doi":"10.21203/rs.3.rs-7203829/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"01272230-69fa-436c-bdb2-f83f4a9ceaf6","owner":[],"postedDate":"August 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-06T13:53:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-11 15:42:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7203829","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7203829","identity":"rs-7203829","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}