A method for detecting iodide impurities and / or bromide impurities in a succinoglycan sodium bulk drug

Abstract

The application discloses a method for detecting iodide impurities and / or bromide impurities in succinoglycan sodium bulk drug, and adopts high performance liquid chromatography, wherein the chromatographic conditions are as follows: an octadecylsilane bonded silica gel filling column, a flow rate of 0.8-1.2 ml / min, a detection wavelength of 205-215 nm, a column temperature of 20-30 DEG C, and a sample injection volume of 20-60 ul, and N,N-dimethyloctylamine aqueous solution-methanol is used as a mobile phase A, and methanol is used as a mobile phase B for gradient elution. The experimental results show that the method is accurate and reliable, has high sensitivity and good reproducibility, and can be used for analyzing and controlling iodide impurities and bromide impurities in succinoglycan sodium bulk drug.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical analysis and quality control, specifically relating to a method for separating and determining iodide impurities and / or bromide impurities in sugammadextrose sodium raw material by HPLC. Background Technology

[0002] Sugammadextrin sodium, a muscle relaxant, was first disclosed in patent US6670340B1. It uses γ-cyclodextrin as a starting material and triphenylphosphine as a catalyst, undergoing a halogenation reaction in DMF (N,N-dimethylformamide) to generate periodoγ-cyclodextrin. Finally, it undergoes a substitution reaction with 3-mercaptopropionic acid under alkaline conditions with sodium hydride to obtain the target product. This process may introduce iodides. Furthermore, in 1996, the literature *Tetrhedron Letters*, Vol. 37, No. 27, 4647-4650, described a method for synthesizing cyclodextrin analogs. This method directly uses bromine to react with cyclodextrin under triphenylphosphine / N,N-dimethylformamide conditions to generate 6-per-deoxy-6-per-bromocyclodextrin. The literature *SUPRAMOLECULARCHEMISTRY*, Vol. 12, also mentions this method. Pages 221-224 describe a method for preparing 6-holdeoxy-6-halocyclodextrin using N-halosuccinimide.

[0003] A search revealed that the 2025 edition of the Chinese Pharmacopoeia currently includes methods for detecting iodides and bromides primarily based on physicochemical limits or ultraviolet spectrophotometry: examples include bromide in doxophylline, bromide in sodium chloride (for injection), bromide in pentoxifylline, and iodide in sodium diatrizoate injection. Of these methods, the physicochemical limit method cannot provide quantitative detection, while the ultraviolet spectrophotometric method involves complex pretreatment of both the test and reference solutions and lacks strong specificity. Summary of the Invention

[0004] The manufacturing process of sugammadextrin active pharmaceutical ingredient (API) typically begins with gamma-cyclodextrin and proceeds through iodination or bromination to obtain a key intermediate, followed by a nucleophilic substitution reaction to finally yield the target product. This process inevitably introduces iodide or bromide impurities. Furthermore, the United States Pharmacopeia's (USP) list of related substances for sugammadextrin, 6-bromo-6-deoxy-gamma-cyclodextrin, also indicates the presence of bromide impurities in sugammadextrin.

[0005] Excessive halide ions in sugammadextrose sodium may affect the clarity and color of the injection, potentially precipitating as insoluble salts or complexes, or promoting drug molecule aggregation, leading to turbidity, opalescence, or visible white specks in the solution. Iodide ions (I... - ) or bromide ion (Br -Iodides themselves are colorless, but they are unstable and easily oxidized. Once oxidized to form elemental iodine (I₂) or bromine (Br₂), the solution will turn brownish-yellow or reddish-brown, thus failing to meet the "colorless" requirement. This principle is also reflected in iodine-containing radiopharmaceuticals, whose solutions or containers may darken due to radiation or other factors. To ensure drug safety and improve quality control, there is an urgent need to develop a simple, sensitive, stable method for detecting iodides that is suitable for the specific characteristics of sugammadextrose sodium, to overcome the shortcomings of existing technologies and ensure that the impurity limits of each batch of products meet safety requirements.

[0006] Elemental impurities refer to unintentionally added metallic and non-metallic elements that may be present in pharmaceutical products. ICH Q3D(R2) clearly states that elemental impurities in pharmaceutical products have multiple sources; they may be residues of catalysts intentionally added during synthesis, or they may be actual impurities (e.g., impurities arising from interactions with production equipment or packaging systems, or impurities present in various components of the pharmaceutical product). Because elemental impurities do not provide any therapeutic effect to patients, their content in pharmaceutical products needs to be controlled within acceptable limits. The sugammadextrose process requires the use of halogenated reagents such as iodine (iodine, N-iodosuccinimide, etc.) or brominated reagents (bromine, N-bromosuccinimide, etc.) for the reaction. For active pharmaceutical ingredients using halogenated reagents, halide ions must be detected in the drug substance. Therefore, bromide or iodide must be detected in the finished sugammadextrose sodium product depending on the process specifications.

[0007] The methods for detecting bromides or iodides in the 2025 edition of the Chinese Pharmacopoeia, including the physicochemical limit method and ultraviolet spectrophotometry, have the following problems: they cannot be quantified, the pretreatment is relatively complex, and / or the specificity is not strong.

[0008] When using conventional liquid chromatography systems (or ion-pairing reagent systems) to detect bromide in sugammadextrose sodium raw material, there are problems such as interference with ion peak elution (see Comparative Examples 1 and 2 of this application).

[0009] The inventors have developed an analytical method for detecting iodide and / or bromide impurities in sugammadextrose sodium raw material. This method has good specificity and can effectively detect possible iodide and bromide impurities. The method has high sensitivity, good repeatability, high accuracy, and good robustness. It can be used for the detection of iodide and bromide in sugammadextrose sodium raw material, effectively controlling the quality of the product.

[0010] This application provides a method for detecting iodide and / or bromide impurities in sugammadextrose sodium raw material. The method employs high-performance liquid chromatography and includes the following steps: 1) Take one or both of potassium iodide and potassium bromide, dissolve them in a diluent and dilute them to prepare iodide reference solutions and / or bromide reference solutions; 2) Take sodium sugammadextrose raw material, dissolve and dilute it with diluent to prepare a sample solution; 3) Take the reference solution from step 1) and the sample solution from step 2), inject them into the high-performance liquid chromatograph, and record the chromatograms; 4) The impurity content was calculated using the external standard method; The chromatographic conditions for the high-performance liquid chromatography method include: Column: Octadecylsilane-bonded silica gel packed column; Column temperature: 20℃~30℃; Flow rate: 0.8 ml / min ~ 1.2 ml / min; Detection wavelength: 205nm~215nm; Mobile phase: Composed of mobile phase A and mobile phase B, with N,N-dimethyloctylamine aqueous solution and methanol mixture as mobile phase A and methanol as mobile phase B, gradient elution.

[0011] In the embodiments of this application, the iodide impurities and / or bromide impurities refer to the iodides or bromides described in the 2025 edition of the Chinese Pharmacopoeia. Iodides refer to those with iodide ions (I... - Inorganic impurities existing in the form of bromide ions (Br₂O₃); bromide refers to inorganic impurities existing in the form of bromide ions (Br₂O₃). - Inorganic impurities existing in the form of ).

[0012] In the embodiments of this application, steps 1) and 2) can be interchanged, that is, step 1) prepares the sample solution, while step 2) prepares the reference solution.

[0013] In some implementations, the diluent in steps 1) and 2) is methanol, acetonitrile, water, a mixture of methanol and water, or a mixture of acetonitrile and water; in some instances, the diluent is water.

[0014] In some embodiments, step 1) is: taking an appropriate amount of one or both of potassium iodide and potassium bromide, dissolving and diluting them with a diluent to prepare an iodide reference solution containing approximately 0.05 μg to 0.60 μg per 1 ml and / or a bromide reference solution containing approximately 0.05 μg to 0.60 μg per 1 ml.

[0015] In some implementations, step 2) is: take an appropriate amount of sugammadextrose sodium raw material, add a diluent to dissolve and dilute it to prepare a sample solution containing about 2-4 mg per 1 ml.

[0016] In some implementations, step 3) is: take 20 μl to 60 μl of the reference solution from step 1) and the sample solution from step 2), inject them into the high-performance liquid chromatograph, and record the chromatograms.

[0017] In some embodiments, the volume ratio of N,N-dimethyloctylamine aqueous solution to methanol in mobile phase A is 70:30 to 80:20; in some examples, the volume ratio of N,N-dimethyloctylamine aqueous solution to methanol in mobile phase A is 75:25.

[0018] In some embodiments, the N,N-dimethyloctylamine aqueous solution in mobile phase A is prepared by taking N,N-dimethyloctylamine, adding water, and adjusting the pH value to 2.2-3.2 with phosphoric acid; in some examples, the pH is 2.4-2.8; in some examples, the pH is 2.6; in one example, the N,N-dimethyloctylamine aqueous solution in mobile phase A is prepared by taking 3 ml of N,N-dimethyloctylamine, adding 1000 ml of water, and adjusting the pH value to 2.6 with phosphoric acid.

[0019] In the embodiments of this application, the content of iodide impurities and / or bromide impurities in the sugammadextrose sodium raw material is calculated using the external standard method.

[0020] In some implementations, the gradient elution is as follows: mobile phase A is maintained at 100% volume for 15 min, mobile phase B is changed from 0% volume to 100% volume for 0.1 min, mobile phase B is maintained at 100% volume for 4.9 min, mobile phase B is returned to the original gradient for 0.1 min, and equilibration is carried out for 14.9 min. In some instances, the gradient elution is as follows: mobile phase A is maintained at 100% volume for 25 min, mobile phase B is changed from 0% volume to 100% volume for 0.1 min, mobile phase B is maintained at 100% volume for 10 min, and the gradient is returned to the original gradient for 0.1 min, with equilibration for 14.9 min. In one instance, the gradient elution is as follows: In some implementations, the column temperature is 25°C.

[0021] In some implementations, the detection wavelength is 210 nm.

[0022] In some implementations, the flow rate is 1.0 ml / min.

[0023] In some implementations, the injection volume or sample volume is 40 μl.

[0024] The determination method of the present invention is applicable to the quantitative detection of iodide impurities and / or bromide impurities in sugammadextrose sodium raw material. The method has high sensitivity and good repeatability, and can be applied to the quality control of iodide impurities and / or bromide impurities in sugammadextrose sodium raw material.

[0025] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the embodiments described in the description and the accompanying drawings. Attached Figure Description

[0026] The accompanying drawings are used to provide an understanding of the technical solutions of this application and constitute a part of the specification. They are used together with the embodiments of this application to explain the technical solutions of this application and do not constitute a limitation on the technical solutions of this application.

[0027] Figure 1 The chromatogram of potassium bromide localization solution in the phosphoric acid system of Comparative Example 1; Figure 2 The blank solvent spectrum of the phosphoric acid system in Comparative Example 1; Figure 3 The spectrum is shown for the tetrabutylammonium hydrogen sulfate system in Comparative Example 2; Figure 4 The detection chromatogram of crude sugammadextrose sodium 26050702 / QT260640 in Example 1 is shown. Figure 5 This shows the reference solution chromatograms of sodium sugammadextrose raw material iodide and bromide in Implementation Case 2; Figure 6 The image shows the detection spectra of iodide and bromide in the small-scale sample of sodium suglucose raw material in Implementation Case 2. Detailed Implementation

[0028] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that there are many more embodiments and implementations within the scope of the embodiments described herein.

[0029] Comparative Example 1 uses a common liquid-phase phosphoric acid mobile phase system Instruments and chromatographic conditions: Thermo Fisher Ultimate 3000 high-performance liquid chromatograph was used, with a Waters Xbridge C18 column; the column temperature was 25℃; and the detection wavelength was 226nm. The diluent is water; Using 0.1% phosphoric acid solution (V / V) as mobile phase A and methanol as mobile phase B, linear gradient elution was performed according to the table below: Experimental steps: Solution preparation: Potassium bromide positioning solution: Take an appropriate amount of potassium bromide, add diluent to dissolve and dilute to prepare a solution containing approximately 0.24 mg per 1 ml.

[0030] Accurately measure 30 μl of potassium bromide positioning solution, inject it into the liquid chromatograph, and record the chromatogram; The results showed that the blank solution (water) interfered with the detection, and the potassium bromide peak could not be separated from the solvent peak. This method is not suitable for bromide detection; see details below. Figure 1 (Positioning solution) Figure 2 (Blank solution). Comparative Example 1 uses a common liquid chromatography system to detect bromide. Bromide ion retention is weak, and the blank peak inversion interferes with bromide ion elution, resulting in unsatisfactory resolution.

[0031] Comparative Example 2 Instruments and chromatographic conditions: Thermo Fisher Ultimate 3000 high-performance liquid chromatograph was used, with a Waters Atlantis T3 column; the column temperature was 25℃; and the detection wavelength was 215nm. The diluent is water; The mobile phase was 10 mmol / L tetrabutylammonium hydrogen sulfate solution; Solution preparation: Reference solution: Take an appropriate amount of potassium bromide, add diluent to dissolve and dilute to prepare a solution containing approximately 0.24 mg per 1 ml.

[0032] Accurately measure 60 μl of potassium bromide reference solution and inject it into the liquid chromatograph. Record the chromatograms. See details. Figure 3 ; The results showed that the reference solution exhibited negative absorption at the potassium bromide peak, and adjusting the concentration of tetrabutylammonium hydrogen sulfate in the mobile phase did not improve this; see details. Figure 3 The ion-pair reagent system interferes with the elution of bromide ions.

[0033] Example 1 Instruments and chromatographic conditions: Thermo Fisher Ultimate 3000 high-performance liquid chromatograph was used, with a Waters Xbridge C18 column; the flow rate was 1.0 ml / min, the wavelength was 210 nm, and the column temperature was 25 °C. The diluent is water; Using N,N-dimethyloctylamine solution (3 ml of N,N-dimethyloctylamine solution was diluted with 1000 ml of water, and the pH was adjusted to 2.6 with phosphoric acid)-methanol (75:25) as mobile phase A and methanol as mobile phase B, gradient elution was performed according to the table below: Experimental steps: Solution preparation: Reference solution: Weigh approximately 18 mg of potassium iodide (batch number: 20240103 / SY24021338, source: Sinopharm Chemical Reagent Co., Ltd.) into a 100 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well, accurately measure 1 ml into a 20 ml volumetric flask, dilute to the mark with diluent, shake well, accurately measure 1 ml into a 20 ml volumetric flask, dilute to the mark with diluent, shake well, and obtain the iodide reference solution. Weigh approximately 18 mg of potassium bromide (batch number: B2148907313 / SY23121212, source: Merck & Co., Ltd.) into a 100 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well, accurately measure 1 ml into a 20 ml volumetric flask, dilute to the mark with diluent, shake well, accurately measure 1 ml into a 20 ml volumetric flask, dilute to the mark with diluent, shake well, to obtain the bromide reference solution.

[0034] Sample solutions: Weigh approximately 30 mg of sugammadextrose sodium raw material (batch number: 26031501 / QT260637, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well to obtain sample solution 1. Weigh approximately 30 mg of sugammadextrose sodium raw material (batch number: 26033001 / QT260639, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well to obtain sample solution 2. Weigh approximately 30 mg of sugammadextrose sodium raw material (batch number: 26050702 / QT260640, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well to obtain sample solution 3.

[0035] Accurately measure 40 μl each of the sample solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; the chromatogram for crude sugammadextrose sodium 26050702 / QT260640 is shown below. Figure 4 .

[0036] The retention time and bromine content of the crude bromide of sugammadextrose sodium raw material produced using the bromination process are shown in the table below: The results showed that this method can also be used for quality monitoring of bromide or iodide in sugammadextrose sodium.

[0037] Example 2 Specificity and System Suitability Test Instruments and chromatographic conditions: Thermo Fisher Ultimate 3000 high-performance liquid chromatograph was used, with a Waters Xbridge C18 column; column temperature was 25℃; flow rate was 1.0 ml / min; and detection wavelength was 210 nm. The diluent is water; Using N,N-dimethyloctylamine aqueous solution (3 ml of N,N-dimethyloctylamine was mixed with 1000 ml of water, and the pH was adjusted to 2.6 with phosphoric acid) - methanol (75:25) as mobile phase A, and methanol as mobile phase B, gradient elution was performed according to the table below: Experimental steps: Solution preparation: Reference solution: Weigh approximately 20 mg of potassium iodide (batch number: 20240103 / SY24021338, source: Sinopharm Chemical Reagent Co., Ltd.) and approximately 112 mg of potassium bromide (batch number: B2148907313 / SY23121212, source: Merck & Co., Ltd.) into the same 100 ml volumetric flask. Dissolve and dilute to the mark with diluent, shake well. Accurately measure 1 ml into the 100 ml volumetric flask, dilute to the mark with diluent, shake well. Accurately measure 1 ml into the 25 ml volumetric flask, dilute to the mark with diluent, shake well to obtain the reference solution.

[0038] Sample solution: Weigh approximately 75 mg of sodium sugammadextrose raw material (batch number: 25112901 / JSGG251194, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 25 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well to obtain the sample solution.

[0039] Accurately measure 40 μl each of the sample solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms; see [link / reference]. Figure 5 (Reference solution) and Figure 6 (Sample solution).

[0040] The retention times and peak areas of iodides and bromides in the system suitability test are shown in the table below: The results showed that the blank solution did not interfere with the detection; neither sodium suglucose nor impurities in the sample solution eluted at 15.3–15.4 min for iodide and 10.4–10.5 min for bromide, thus not interfering with the detection of iodide and bromide, indicating good specificity. The RSD of the peak area for iodide in the reference solution was 2.7%, and the RSD for the peak area for bromide was 1.1%; the RSD of the peak area for iodide in the reference solution was 1.5%, and the RSD for the peak area for bromide was 2.5%. The system has good suitability.

[0041] Example 3 Limit of Quantification and Limit of Detection Test The instruments and chromatographic conditions are the same as in Example 2. Experimental steps: The limits of quantitation (LOQ) and limit of detection (LOD) of iodides and bromides in sugammadextrose sodium raw material were determined using the signal-to-noise ratio (SNR) method. Appropriate amounts of iodide and bromide reference standards were prepared into solutions using diluent and injected into the chromatograph. The ratio of peak height to noise (SNR) was calculated. The sample detection limit was defined as the sample with a SNR of approximately 10–50, and the detection limit was defined as the sample with a SNR of approximately 3–10. The specific preparation method is as follows: The data results are shown in the table below: The results showed that the limit of quantification (LOQ) for iodide was 0.00085% and the limit of detection (LOD) was 0.00043%; the LQ for bromide was 0.0020% and the LOD was 0.0010%. This method can accurately control the content of iodide and bromide.

[0042] Example 4 Linear test The instruments and chromatographic conditions are the same as in Example 2. Experimental steps: Solution preparation: Linear stock solution: Weigh approximately 20 mg of potassium iodide (batch number: 20240103 / SY24021338, source: Sinopharm Chemical Reagent Co., Ltd.) and approximately 112 mg of potassium bromide (batch number: B2148907313 / SY23121212, source: Merck & Co., Ltd.) into the same 100 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well, accurately measure 1 ml into the 100 ml volumetric flask, dilute to the mark with diluent, shake well, and obtain the linear stock solution.

[0043] Linear solutions are prepared according to the table below: Inject the above solutions separately and record the chromatograms. Plot linear regression equations for iodides and bromides with concentration on the x-axis and peak area on the y-axis.

[0044] The linear results are as follows: The results showed that iodide exhibited good linearity in the range of 0.02554–0.19152 μl / ml, and bromide exhibited good linearity in the range of 0.06066–0.90993 μl / ml.

[0045] Example 5 Accuracy test The instruments and chromatographic conditions are the same as in Example 2. Experimental steps: Solution preparation: Spiked stock solution: Weigh approximately 20 mg of potassium iodide (batch number: 20240103 / SY24021338, source: Sinopharm Chemical Reagent Co., Ltd.) and approximately 112 mg of potassium bromide (batch number: B2148907313 / SY23121212, source: Merck & Co., Ltd.) into the same 100 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well, accurately measure 1 ml into the 100 ml volumetric flask, dilute to the mark with diluent, shake well, and obtain the spiked stock solution.

[0046] Sample solution: Weigh approximately 75 mg of sodium sugammadextrose raw material (batch number: 25112901 / JSGG251194, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 25 ml volumetric flask, dissolve and dilute to the mark with diluent, shake well to obtain the sample solution.

[0047] 50% Spiked Sample Solution: Weigh approximately 75 mg of sugammadextrose sodium raw material (batch number: 25112901 / JSGG251194, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 25 ml volumetric flask, accurately add 0.5 ml of spiking stock solution, dissolve and dilute to the mark with diluent, shake well to obtain a 50% spiked sample solution.

[0048] 100% Spiked Sample Solution: Weigh approximately 75 mg of sugammadextrose sodium raw material (batch number: 25112901 / JSGG251194, source: Jiangsu Haici Biopharmaceutical Co., Ltd.) into a 25 ml volumetric flask, accurately add 1.0 ml of spiking stock solution, dissolve and dilute to the mark with diluent, shake well to obtain a 100% spiked sample solution.

[0049] Inject the samples separately and record the chromatograms, then calculate the recovery rate.

[0050] The results are shown in the table below: The results showed that the recoveries of iodides were 94%–103% within the 50%–100% limit level, and the recoveries of bromides were 95%–104% within the 50%–100% limit level. The method demonstrated good accuracy.

[0051] Although the embodiments disclosed in this application are as described above, the content described is merely for the purpose of understanding this application and is not intended to limit this application. Any person skilled in the art to which this application pertains may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application; however, the scope of patent protection of this application shall still be determined by the scope defined in the appended claims.

Claims

1. A method for detecting iodide and / or bromide impurities in sugammadextrose sodium raw material, wherein the detection method employs high-performance liquid chromatography and includes the following steps: 1) Take one or both of potassium iodide and potassium bromide, dissolve them in a diluent and dilute them to prepare iodide reference solutions and / or bromide reference solutions; 2) Take sodium sugammadextrose raw material, dissolve and dilute it with diluent to prepare a sample solution; 3) Take the reference solution from step 1) and the sample solution from step 2), inject them into the high-performance liquid chromatograph, and record the chromatograms; 4) The impurity content was calculated using the external standard method; The chromatographic conditions for the high-performance liquid chromatography method include: Column: Octadecylsilane-bonded silica gel packed column; Column temperature: 20℃~30℃; Flow rate: 0.8 ml / min ~ 1.2 ml / min; Detection wavelength: 205nm~215nm; Mobile phase: Composed of mobile phase A and mobile phase B, with N,N-dimethyloctylamine aqueous solution and methanol mixture as mobile phase A and methanol as mobile phase B, gradient elution.

2. The detection method according to claim 1, wherein, Steps 1) and 2) can be interchanged; and / or The diluent in steps 1) and 2) is methanol, acetonitrile, water, a mixture of methanol and water, or a mixture of acetonitrile and water; or, the diluent is water.

3. The detection method according to claim 1, wherein, Step 1) is as follows: Take an appropriate amount of one or both of potassium iodide and potassium bromide, add a diluent to dissolve and dilute to prepare an iodide reference solution containing approximately 0.05 μg to 0.60 μg per 1 ml and / or a bromide reference solution containing approximately 0.05 μg to 0.60 μg per 1 ml.

4. The detection method according to claim 1, wherein, Step 2) is as follows: Take an appropriate amount of sodium sugammadextrose raw material, add a diluent to dissolve and dilute it to prepare a sample solution containing approximately 2-4 mg per 1 ml.

5. The detection method according to claim 1, wherein, Step 3) is as follows: Take 20 μl to 60 μl of the reference solution from step 1) and the sample solution from step 2), inject them into the high performance liquid chromatograph, and record the chromatograms.

6. The detection method according to any one of claims 1 to 5, wherein, The volume ratio of N,N-dimethyloctylamine aqueous solution to methanol in mobile phase A is 70:30 to 80:20; or, the volume ratio of N,N-dimethyloctylamine aqueous solution to methanol in mobile phase A is 75:25; and / or The method for preparing the N,N-dimethyloctylamine aqueous solution in the mobile phase A is as follows: take N,N-dimethyloctylamine, add water, and adjust the pH value to 2.2~3.2 with phosphoric acid; or, the pH value is 2.4~2.8; or, the pH value is 2.

6.

7. The detection method according to any one of claims 1 to 5, wherein, The gradient elution is as follows: mobile phase A is maintained at 100% volume for 15 min, mobile phase B is changed from 0% volume to 100% volume for 0.1 min, mobile phase B is maintained at 100% volume for 4.9 min, mobile phase B returns to the original gradient for 0.1 min, and equilibration is carried out for 14.9 min.

8. The detection method according to any one of claims 1 to 5, wherein, The gradient elution is as follows: mobile phase A is maintained at 100% volume for 25 min, mobile phase B is changed from 0% volume to 100% volume for 0.1 min, mobile phase B is maintained at 100% volume for 10 min, and then returned to the original gradient for 0.1 min, and equilibration is carried out for 14.9 min.

9. The detection method according to any one of claims 1 to 5, wherein, The gradient elution is as follows: 。 10. The detection method according to any one of claims 1 to 5, wherein, The chromatographic column temperature is 25°C; and / or The flow rate is 1.0 ml / min; and / or The detection wavelength is 210 nm; and / or The injection volume or sample volume is 40 μl.

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