CN111175413B - Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof - Google Patents
Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof Download PDFInfo
- Publication number
- CN111175413B CN111175413B CN202010191452.8A CN202010191452A CN111175413B CN 111175413 B CN111175413 B CN 111175413B CN 202010191452 A CN202010191452 A CN 202010191452A CN 111175413 B CN111175413 B CN 111175413B
- Authority
- CN
- China
- Prior art keywords
- temperature
- acetate
- chlorobutanol
- sample
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
- G01N30/6073—Construction of the column body in open tubular form
- G01N30/6078—Capillaries
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention relates to the technical field of detection, in particular to a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta-cyclodextrin sodium raw material or a preparation thereof. The method comprises the following steps: detecting by adopting a gas chromatography technology, wherein the gas chromatography technology conditions are as follows: (35% -trifluoropropyl) -methyl polysiloxane chromatography column or chromatography column with similar polarity; the initial temperature of the chromatographic column is 68-72 ℃, the temperature is increased to 120 ℃ at the rate of 3-7 ℃ per minute for 1 minute, the temperature is increased to 260 ℃ at the rate of 48-52 ℃ per minute for 7 min; a hydrogen flame ionization detector; the temperature of the detector is 260-280 ℃; the temperature of the sample inlet is 190-210 ℃. The method determines the content of the 4-chlorobutanol acetate through a proper sample introduction mode and chromatographic conditions, can effectively separate the sample from impurities, and has the advantages of strong specificity, high precision, good linear relation, repeatability, accuracy, stability and durability and high detection sensitivity.
Description
Technical Field
The invention relates to the technical field of genotoxic impurity detection, in particular to a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta cyclodextrin sodium raw material or a preparation thereof.
Background
SBE-beta-CD, chemical name of which is sulfobutyl betacyclodextrin sodium, is a novel pharmaceutical preparation auxiliary material and belongs to a sulfonic derivative of anionic high water-solubility cyclodextrin. It can be well included with drug molecules to form a non-covalent complex, thereby improving the stability, water solubility and safety of the drug, effectively improving the biological activity of the drug molecules, having small nephrotoxicity, alleviating the hemolysis of the drug and controlling the release rate of the drug. At present, the nitrogen-containing compound has been commercialized, is applied to injection drugs, oral drugs, nasal drugs, ophthalmic drugs and the like, and has special affinity and inclusion property for nitrogen-containing drugs.
Sulfobutyl betacyclodextrin sodium is an etherate of betacyclodextrin and 1, 4-butane sultone under alkaline conditions, and 4-chlorobutanol acetate and acetyl chloride react in the 1, 4-butane sultone to obtain chlorobutyl acetate; heating, refluxing and hydrolyzing the chlorobutyl acetate and the anhydrous sodium sulfite in water to obtain 4-hydroxybutanesulfonic acid sodium salt and acetic acid as a byproduct; distilling to remove water and acetic acid, adding methanol, introducing hydrogen chloride, and acidifying to obtain 4-hydroxy butanesulfonic acid methanol solution; distilling the 4-hydroxy butyl sulfonic acid methanol solution to remove methanol, and adding 4-chlorobutanol acetate for esterification; distilling to remove 4-chlorobutanol acetate, and rectifying to obtain the product. 4-chlorobutanol acetate is a potential impurity in 1, 4-butane sultone.
4-chlorobutanol acetate, also known as 4-chlorobutyl acetate, acetic acid 4-chlorobutyl ester, 4-chlorobutyl acetate, 1-acetoxy-4-chlorobutane, 4-chlorobutyl ethyl acetate belong to genotoxic impurities, have strict control limit in medicine.
The sulfobutyl betacyclodextrin sodium is used as an auxiliary material of a pharmaceutical preparation for injection, and the use scene of the sulfobutyl betacyclodextrin sodium can directly enter blood. The potential genotoxicity of the sulfobutyl-beta-cyclodextrin sodium is strictly controlled. Therefore, an accurate detection method for the content of 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium is established, and is necessary for safe medication of the sulfobutyl-beta-cyclodextrin sodium. For example, voriconazole for injection, which is prepared by using sulfobutyl-betadex sodium at present, is required to have 4-chlorobutanol acetate not more than 36 mu g/day according to the dosage of a human body.
In the prior art, gas chromatography is a better means for detecting low-concentration and low-content substances, and is a method for detecting and analyzing gas substances or substances which can be converted into gas under certain conditions. Because of different properties of substances, the distribution coefficients of all components in a sample at the gas phase and the fixed liquid-liquid phase are different, when the vaporized sample is carried into a chromatographic column by carrier gas to operate, the components are repeatedly distributed between the two phases, although the carrier gas flow rate is the same, the operating speeds of all the components in the chromatographic column are different due to different adsorption or dissolution capacities of the fixed relative components, the components are separated from each other after flowing for a certain time, leave the chromatographic column in sequence and enter a detector, and generated signals are amplified and then the chromatographic peaks of all the components are drawn on a recorder. According to the peak position, the name of the component is determined, and the concentration is determined according to the peak area.
Because the content of the detected sample is very low when the detected sample is a trace substance in a solid state, how to effectively detect the 4-chlorobutanol acetate with low content by adopting a gas chromatography technology is a difficult task for researchers. At present, no report of a detection method of 4-chlorobutanol acetate, especially low-content detection, is found.
Disclosure of Invention
In view of the above, the invention provides a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta-cyclodextrin sodium raw material or a preparation thereof. The method has the advantages of strong specificity, high precision, good linear relation, repeatability, accuracy, stability and durability and high detection sensitivity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta-cyclodextrin sodium raw material or a preparation thereof, which comprises the following steps:
dissolving a sample to be detected in methanol to obtain a test sample solution;
dissolving a reference substance in methanol to obtain a reference substance solution;
respectively detecting the test solution and the reference solution by adopting a gas chromatography technology, recording chromatograms, and obtaining the content of 4-chlorobutanol acetate by an external standard method; the conditions of the gas chromatography technique were as follows:
a chromatographic column: (35% -trifluoropropyl) -methyl polysiloxane chromatography column, 14% cyanopropyl phenyl-86% methyl polysiloxane chromatography column or chromatography column with similar polarity;
temperature program of chromatographic column: the initial temperature is 68-72 ℃, the temperature is increased to 120 ℃ at the rate of 3-7 ℃ per minute, the temperature is maintained for 1 minute, the temperature is increased to 260 ℃ at the rate of 48-52 ℃ per minute, and the temperature is maintained for 7 minutes;
a detector: a hydrogen flame ionization detector;
detector temperature: 260-280 ℃;
sample inlet temperature: 190-210 ℃;
carrier gas: nitrogen gas.
The method adopts gas chromatography, takes a polar capillary column as a separation means, takes a hydrogen flame detector as a detection means, and adopts a proper sample introduction mode and chromatographic conditions to measure the content of 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium. Therefore, the problem of detecting the 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium is solved. The method has the advantages of less sample consumption, high detection sensitivity, high reproducibility and reliable result.
Preferably, the concentration of the sample solution is 0.01 to 0.03 g/mL.
Preferably, the concentration of the test solution is 0.02 g/mL.
Preferably, the concentration of the control solution is 0.00102-0.10770 mug/mL.
Preferably, the concentration of the control solution is 0.072 μ g/mL.
Preferably, the column temperature-increasing program: the initial temperature was 70 ℃, the temperature was raised to 120 ℃ at a rate of 5 ℃ per minute for 1 minute, and the temperature was raised to 260 ℃ at a rate of 50 ℃ per minute for 7 min.
Preferably, the gas chromatography apparatus is Shimadzu GC2010plus gas chromatograph.
Preferably, the flow rate of the gas chromatography is 1.4-1.6 mL/min.
Preferably, the column flow rate of the gas chromatography technique is 1.5 mL/min.
Preferably, the sample size of the gas chromatography technique is: 0.8 to 1.2. mu.L.
Preferably, the sample size of the gas chromatography technique is: 1 μ L.
Preferably, the detector temperature is 270 ℃.
Preferably, the injection port temperature is 200 ℃.
Preferably, the sample injection method is a direct sample injection method.
Preferably, the direct sample injection method is an automatic or manual direct sample injection method.
The invention provides a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta-cyclodextrin sodium raw material or a preparation thereof. The method comprises the following steps: dissolving a sample to be detected in methanol to obtain a test sample solution; dissolving a reference substance in methanol to obtain a reference substance solution; respectively detecting the test solution and the reference solution by adopting a gas chromatography technology, recording chromatograms, and obtaining the content of 4-chlorobutanol acetate by an external standard method; the conditions of the gas chromatography technique were as follows: a chromatographic column: (35% -trifluoropropyl) -methyl polysiloxane chromatography column, 14% cyanopropyl phenyl-86% methyl polysiloxane chromatography column or chromatography column with similar polarity; temperature program of chromatographic column: the initial temperature is 68-72 ℃, the temperature is increased to 120 ℃ at the rate of 3-7 ℃ per minute, the temperature is maintained for 1 minute, the temperature is increased to 260 ℃ at the rate of 48-52 ℃ per minute, and the temperature is maintained for 7 minutes; a detector: a hydrogen flame ionization detector; detector temperature: 260-280 ℃; sample inlet temperature: 190-210 ℃; carrier gas: nitrogen gas. The invention has the following advantages:
the method adopts gas chromatography, takes a polar capillary column as a separation means, takes a hydrogen flame detector as a detection means, measures the content of the 4-chlorobutanol acetate in the sulfobutyl-betadex sodium by a proper sample introduction mode and chromatographic conditions, can effectively separate the sample from impurities, and has the advantages of strong specificity, high precision, linear relation, repeatability, accuracy, stability and durability, high detection sensitivity and high minimum detection limit of the 4-chlorobutanol acetate up to the level of 0.001 ng/mL.
Drawings
FIG. 1 is a blank solution profile of example 1;
FIG. 2 is a control solution profile of example 1;
FIG. 3 is a test solution profile of example 1;
FIG. 4 is a standard curve map;
FIG. 5 white solvent spectrum in comparative example 1;
FIG. 6 is a spectrum of a control solution of comparative example 1;
FIG. 7 is a spectrum of a control solution of comparative example 1;
FIG. 8 white solvent profile (headspace sample) in comparative example 2;
FIG. 9 is a spectrum of a control solution in comparative example 2 (headspace sample injection-stationary 30 min);
FIG. 10 is a spectrum of a control solution in comparative example 2 (headspace sample injection-stationary 60 min);
FIG. 11 is a solution map (direct injection) of the control in comparative example 2;
FIG. 12 is a graph of control solution profile (rate of 10 ℃ per minute) in comparative example 3;
FIG. 13 is a graph of control solution profile (rate of 8 ℃ per minute) in comparative example 3;
FIG. 14 is a graph of control solution profile (rate of 5 ℃ per minute) in comparative example 3;
FIG. 15 is a control solution profile (maintained for 10 minutes) for comparative example 3;
FIG. 16 white solvent spectrum in example 11;
FIG. 17 spectrum of control solution in example 11.
Detailed Description
The invention discloses a method for detecting the content of 4-chlorobutanol acetate in a sulfobutyl-beta-cyclodextrin sodium raw material or a preparation thereof, and a person skilled in the art can realize the detection by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
Sulfobutyl betacyclodextrin sodium term interpretation:
common name of Chinese: sulfobutyl betacyclodextrin sodium salt
The name of English: betadex Sulfobutyl Ether Sodium
Chinese alias: sulfobutyl-BETA-cyclodextrin sodium salt; sulfobutyl-beta-cyclodextrin; sulfobutylbetacyclodextrin; sulfobutyl ether-beta-cyclodextrin; sulfobutyl-beta-cyclodextrin sodium; sulfobutyl ether betacyclodextrin sodium salt; sulfobutyl-beta-cyclodextrin sodium salt
English abbreviation: SBECD; SBE-beta-CD
Chinese phonetic: huangdgingji Beita Huang jinganjnna
Chemical name: (4-sulfonic acid-1-butyl ether) -cyclopeptomer D-glucopyranose sodium salt
CAS NO.：182410-00-0
UNII No: 2PP9364507
The technical scheme of the invention is as follows: a method for measuring 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium is characterized by comprising the following steps:
(1) preparing a test solution: about 0.2g of the product is precisely weighed and placed in a 10mL volumetric flask, and methanol is added to dissolve and dilute the product to a scale mark to be used as a test solution.
(2) Preparing a reference substance solution: an appropriate amount of a control was precisely weighed and diluted with methanol to about 0.072 μ g of 4-chlorobutanol acetate per 1mL to serve as a control solution.
(3) A capillary column taking (35% -trifluoropropyl) -methyl polysiloxane (or similar polarity) as a stationary phase is taken as a chromatographic column; a hydrogen flame ionization detector is adopted; the carrier gas is nitrogen; respectively injecting sample solutions to be tested and a reference substance solution;
(4) respectively detecting the peak areas of 4-chlorobutanol acetate in the test solution and the reference solution;
and (4) calculating the content of 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium according to the data in the step (4).
Gas chromatography is a good means for detecting low-concentration and low-content substances, and is a method for detecting and analyzing gas substances or substances which can be converted into gas under certain conditions. Because of different properties of substances, the distribution coefficients of all components in a sample at the gas phase and the fixed liquid-liquid phase are different, when the vaporized sample is carried into a chromatographic column by carrier gas to operate, the components are repeatedly distributed between the two phases, although the carrier gas flow rate is the same, the operating speeds of all the components in the chromatographic column are different due to different adsorption or dissolution capacities of the fixed relative components, the components are separated from each other after flowing for a certain time, leave the chromatographic column in sequence and enter a detector, and generated signals are amplified and then the chromatographic peaks of all the components are drawn on a recorder. According to the peak position, the name of the component is determined, and the concentration is determined according to the peak area.
By adopting the gas chromatography system, the sample and impurities can be effectively separated, the detection sensitivity is very high, and the lowest detection limit of the 4-chlorobutanol acetate can reach the level of ng/mL. Since the limit of 4-chlorobutanol acetate in the sample is low, there is a high requirement for sensitivity.
The reagent or instrument used in the method for detecting the content of 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium raw material or the preparation thereof provided by the invention can be purchased from the market. In the detection method of the present invention, a gas chromatograph (Shimadzu corporation) is used, and the chromatographic column is a capillary column of (35% -trifluoropropyl) -methyl polysiloxane (DB-200) (or similar polarity) (Agilent corporation).
The invention is further illustrated by the following examples:
example 1: chromatographic conditions and chromatographic system of the detection method of the invention
The instrument comprises the following steps: shimadzu GC2010plus gas chromatograph
And (3) chromatographic column: is a capillary column of (35% -trifluoropropyl) -methylpolysiloxane (DB-200,30 m.times.0.25 mm.times.0.25 μm) (or of similar polarity).
Temperature program of chromatographic column: the initial temperature is 70 ℃, the temperature is increased to 120 ℃ at the rate of 5 ℃ per minute, the temperature is maintained for 1 minute, the temperature is increased to 260 ℃ at the rate of 50 ℃ per minute, and the temperature is maintained for 7 minutes;
a detector: a hydrogen flame ionization detector is arranged on the gas-liquid separator,
detector temperature: 270 ℃;
sample inlet temperature: 200 ℃;
carrier gas: nitrogen gas;
column flow rate: 1.5 mL/min;
the sample injection amount is as follows: 1 mu L of the solution;
and (3) sample introduction mode: automatic or manual direct sample introduction.
Preparing a test solution: taking about 0.2g of sulfobutyl-beta-cyclodextrin sodium raw material, precisely weighing, placing in a 10mL volumetric flask, adding methanol to dissolve and diluting to a scale mark to be used as a test solution.
Preparation of a reference solution: an appropriate amount of a control was precisely weighed and diluted with methanol to about 0.072 μ g of 4-chlorobutanol acetate per 1mL to serve as a control solution.
Example 2: the detection method of the invention is system specificity detection
The solution was prepared in the manner of solution preparation in example 1. The blank solvent and the reference solution are detected according to the method for measuring the 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium in the example 1, and the test spectra are shown in the figure 1-figure 3.
Table 1: results of the specificity test
As can be seen from the results in table 1, the blank solvent does not interfere with the main peak determination.
Example 3: the detection method of the invention detects the injection precision
According to the preparation method of the reference substance solution in example 1, the 4-chlorobutanol acetate in the sulfobutyl-beta-cyclodextrin sodium in example 1 is detected by the method, the sample injection is carried out for 6 times continuously, and the detection result is shown in Table 2.
TABLE 2 sample introduction precision
As can be seen from Table 2, 6 needles were fed continuously and the RSD was 0.27%, indicating that the system of the present invention is well suited.
Example 4: the detection method of the invention is used for detecting the quantitative limit and the detection limit.
The detection limit and the quantification limit are determined according to a signal-to-noise ratio method. The lowest concentration that can be detected is calculated by diluting a mixed control solution of known concentration to a low concentration sample, and comparing the measured signal with the signal (baseline noise) at the blank. When the S/N is approximately equal to 10, the concentration is determined as the limit of quantitation, and when the S/N is approximately equal to 3, the concentration is determined as the limit of detection. A solution was prepared in the manner as described for the solution preparation in example 1 and tested according to the method for measuring 4-chlorobutanol acetate in sulfobutylbetacyclodextrin sodium as described in example 1. The results are shown in Table 3.
TABLE 3 detection limit and quantitation limit test results
| Components | Detection limit (μ g/mL) | Limit of quantitation (ug/mL) |
| 4-chlorobutanol acetate | 0.001 | 0.004 |
Example 5: linear and range detection for the detection method of the invention
An appropriate amount of 4-chlorobutanol acetate was precisely weighed, and the solutions were quantitatively diluted with methanol to prepare solutions of serial concentrations, which were measured according to the method for measuring 4-chlorobutanol acetate in sulfobutyl-betadex sodium in example 1. The linear relationship is plotted as a function of measured response signal (peak area) versus analyte concentration, and a least squares linear regression is performed, reporting a correlation coefficient, which is required to be not less than 0.9900. The measurement results are shown in Table 4 and FIG. 4.
TABLE 4 Linear measurement results
From the results, the linear regression equation of 4-chlorobutanol acetate is:
y＝1×10 6 x-841.82(r＝0.9996；n＝6)，
the linear range is 0.00102-0.10770 mu g/mL, and the linear relationship is good.
Example 6: intermediate precision detection of the detection method of the invention
Control and test solutions were prepared according to the sample procedure as in example 1 by the analyst, and 6 needles were continuously inserted to test the% RSD of the 4-chlorobutanol acetate content. The results of the calculations are shown in Table 5.
TABLE 5 results of intermediate precision test
| Number of measurements | Weight g of sample | Content of 4-chlorobutanol acetate/%) |
| 1 | 0.2001 | ＜0.5ppm |
| 2 | 0.2005 | ＜0.5 |
| 3 | 0.1998 | ＜0.5ppm |
| 4 | 0.2003 | ＜0.5 |
| 5 | 0.2001 | ＜0.5ppm |
| 6 | 0.1997 | ＜0.5ppm |
| Average | -- | ＜0.5ppm |
| RSD(％) | ---- | 0 |
In the intermediate precision test, 12 times of measurement results show that the RSD of the 4-chlorobutanol acetate content meets the requirement (RSD percent is less than or equal to 6.0)
Example 7: repeatability detection of the detection method of the invention
According to example 1, 6 portions of the standard test solution are reconstituted by a different analyst from the experiment of example 6, and another analyst separately establishes a system at a different date. The test process and result calculation are consistent with those under the intermediate precision test item. Meanwhile, 12 times of measurement results of repeatability tests and intermediate precision tests are required, and the RSD of the content of the residual solvent is not more than 6.0%. The calculation results are shown in Table 6.
TABLE 64-Chlorobutanol acetate repeatability measurements
As can be seen from the results, the reproducibility of the method for detecting 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium in the invention is proved to be good.
Example 8: accuracy detection of the detection method of the invention
The accuracy of the method is determined by adding a reference substance to a test sample and measuring the content of 4-chlorobutanol acetate in the test sample to calculate the recovery rate of the added amount. Recovery rates between 90.0% and 108.0% are required to confirm good accuracy of the process. The results are shown in Table 7.
TABLE 74 determination of the recovery of chlorobutanol acetate
The results in Table 7 show that the recovery rate of 4-chlorobutanol acetate is between 90.0 and 108.0 percent, and the RSD is 0.67 percent; the invention has good accuracy and the recovery rate meets the expected requirement.
Example 9: solution stability detection of the detection method of the invention
The solution stability test measures the law that the content of 4-chlorobutanol acetate in the reference solution and the test solution changes along with the extension of the standing time, and the reference solution and the test solution are respectively placed at room temperature for a proper time of 0 hour to 24 hours for sample injection detection and content investigation. The results are shown in Table 8.
TABLE 8 solution stability test results
From the results, it can be seen that the control solution and the test solution were stable within 12 hours.
Example 10: durability test of the test method of the invention
And evaluating the bearing degree of the measurement result which is not influenced when the measurement condition has small fluctuation by changing the headspace temperature, the temperature rise rate of the chromatographic column and the flow rate of the chromatographic column.
TABLE 9 durability test results
As can be seen from the table, when the column temperature, the temperature rise rate of the chromatographic column and the flow rate of the chromatographic column are slightly changed, the detection of the 4-chlorobutanol acetate is not influenced.
Comparative example 1 comparison of different chromatography columns
According to the detection of residual solvent (4-chlorobutanol acetate) in cefotaxime sodium in the second part of the 'Chinese pharmacopoeia' 2015 edition, a 100% dimethyl polysiloxane capillary column (UF-1,30m multiplied by 0.25mm multiplied by 0.5 mu m) is selected for determination. The results are shown in FIGS. 5 and 6. The detection of the target product in the blank solvent is shown, i.e. the blank is interfered.
(35% -trifluoropropyl) -methylpolysiloxane (DB-200,30 m.times.0.25 mm. times.0.25 μm) of similar polarity were selected for detection by reference to the residual solvent (4-chlorobutanol acetate) in zoledronic acid of the relevant data. The results are shown in FIG. 7.
The results show that the DB-200 column is better and can meet the detection requirements.
Comparative example 2 comparison of sample introduction
And adopting a headspace sample introduction mode. The test was conducted by setting the plateau temperature to 100 ℃ according to the boiling points of 4-chlorobutanol acetate and 1, 4-butane sultone, and equilibrating for 30 minutes and 60 minutes, respectively, and the test results are shown in fig. 8 to 10.
Adopts a direct sample injection mode and uses methanol as a solvent. The test results are shown in FIG. 11.
From the above results, no matter whether the equilibrium time is 30 minutes or 60 minutes, the corresponding target peak cannot be located at the time of headspace sampling. When direct sampling is adopted, positioning can be realized, but the separation degree from adjacent peaks is not enough.
Comparative example 3 comparison of temperature program
The test results are shown in fig. 12 using a temperature program with an initial temperature of 70 c and a rate of 10 c per minute up to 260 c for 7 minutes.
The initial temperature was 70 deg.C, and the temperature was raised to 260 deg.C at a rate of 8 deg.C per minute for 7 minutes, the results of which are shown in FIG. 13.
The initial temperature was 70 deg.C, and the temperature was raised to 260 deg.C at a rate of 5 deg.C per minute for 7 minutes, the results of which are shown in FIG. 14.
The initial temperature was 70 ℃, the temperature was raised to 120 ℃ at a rate of 5 ℃ per minute for 1 minute, and then to 260 ℃ at a rate of 50 ℃ per minute for 10 minutes, and the results are shown in fig. 15.
From the results of the graphs, it was found that the method in which the initial temperature was 70 ℃ and the temperature was raised to 120 ℃ at a rate of 5 ℃ per minute for 1 minute, and then raised to 260 ℃ at a rate of 50 ℃ per minute for 10 minutes, and the separation degree was high, further increased the lifetime of the column.
In the development and development test of the invention, a plurality of chromatographic condition comparison tests are also available and are not listed.
Example 11: chromatographic conditions and chromatographic system of the detection method of the invention
The instrument comprises the following steps: shimadzu GC2010plus gas chromatograph
A chromatographic column: 14% cyanopropylphenyl-86% methylpolysiloxane as a capillary column (BP10, 0.32 mm. times.25 m, 0.5 μm) in fixed liquid.
Temperature program of chromatographic column: the initial temperature is 70 ℃, the temperature is increased to 120 ℃ at the rate of 5 ℃ per minute, the temperature is maintained for 1 minute, the temperature is increased to 260 ℃ at the rate of 50 ℃ per minute, and the temperature is maintained for 7 minutes;
a detector: a hydrogen flame ionization detector is arranged on the gas-liquid separator,
detector temperature: 270 ℃;
sample inlet temperature: 200 ℃;
carrier gas: nitrogen gas;
column flow rate: 1.5 mL/min;
the sample injection amount is as follows: 1 mu L of the solution;
and (3) sample introduction mode: automatic or manual direct sample introduction.
Preparing a test solution: taking about 0.2g of sulfobutyl-beta-cyclodextrin sodium raw material, precisely weighing, placing in a 10mL volumetric flask, adding methanol to dissolve and diluting to a scale mark to be used as a test solution.
Preparation of a reference solution: an appropriate amount of a control was precisely weighed and diluted with methanol to about 0.072 μ g of 4-chlorobutanol acetate per 1mL to serve as a control solution.
The test results are shown in FIGS. 16 and 17.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A detection method for the content of 4-chlorobutanol acetate in a sulfobutyl-betadex sodium raw material or a preparation thereof is characterized by comprising the following steps:
dissolving a sample to be detected in methanol to obtain a test sample solution; the concentration of the test solution is 0.01-0.03 g/mL;
dissolving a reference substance in methanol to obtain a reference substance solution;
respectively detecting the test solution and the reference solution by adopting a gas chromatography technology, recording chromatograms, and obtaining the content of 4-chlorobutanol acetate by an external standard method; the conditions of the gas chromatography technique are as follows:
a chromatographic column: (35% -trifluoropropyl) -methylpolysiloxane chromatography column or 14% cyanopropylphenyl-86% methylpolysiloxane chromatography column;
temperature program of chromatographic column: the initial temperature is 68-72 ℃, the temperature is increased to 120 ℃ at the rate of 3-7 ℃ per minute, the temperature is maintained for 1 minute, the temperature is increased to 260 ℃ at the rate of 48-52 ℃ per minute, and the temperature is maintained for 7 minutes;
a detector: a hydrogen flame ionization detector;
detector temperature: 260-280 ℃;
sample inlet temperature: 190-210 ℃;
carrier gas: nitrogen gas.
2. The detection method according to claim 1, wherein the concentration of the control solution is 0.00102-0.10770 μ g/mL.
3. The detection method according to claim 1, wherein the column temperature increasing program: the initial temperature was 70 ℃, the temperature was raised to 120 ℃ at a rate of 5 ℃ per minute for 1 minute, and the temperature was raised to 260 ℃ at a rate of 50 ℃ per minute for 7 min.
4. The detection method according to claim 1, wherein the apparatus used in the gas chromatography is Shimadzu GC2010plus gas chromatograph.
5. The detection method according to claim 1, wherein the column flow rate of the gas chromatography is 1.4 to 1.6 mL/min.
6. The detection method according to claim 1, wherein the sample size of the gas chromatography is as follows: 0.8 to 1.2 μ L.
7. The method of claim 1, wherein the detector temperature is 270 ℃.
8. The detection method according to claim 1, wherein the sample inlet temperature is 200 ℃.
9. The detection method according to any one of claims 1 to 8, wherein the sample injection manner is a direct sample injection manner.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010191452.8A CN111175413B (en) | 2020-03-18 | 2020-03-18 | Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010191452.8A CN111175413B (en) | 2020-03-18 | 2020-03-18 | Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111175413A CN111175413A (en) | 2020-05-19 |
| CN111175413B true CN111175413B (en) | 2022-08-02 |
Family
ID=70658551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010191452.8A Active CN111175413B (en) | 2020-03-18 | 2020-03-18 | Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111175413B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007051358A1 (en) * | 2005-11-02 | 2007-05-10 | Nanjing Normal University | HYDROXYPROPYL-SULFOBUTYL-β-CYCLODEXTRIN, THE PREPARATION METHOD,THE ANALYTICAL METHOD AND THE PHARMACUTICAL APPLICATION THEREOF |
| CN102128898A (en) * | 2010-12-09 | 2011-07-20 | 海南和德通医药科技有限公司 | Method for detecting 1,4-butane sultone in sulphur butyl betadex |
| CN103728402A (en) * | 2012-10-15 | 2014-04-16 | 北大方正集团有限公司 | GC method for detecting residual quantity of solvent in compound |
| CN109293625A (en) * | 2017-07-25 | 2019-02-01 | 荆楚理工学院 | A kind of synthetic method of high-purity 1,4- butane sultones |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003016294A1 (en) * | 2001-08-17 | 2003-02-27 | Merck & Co., Inc. | Process for preparing sultams |
-
2020
- 2020-03-18 CN CN202010191452.8A patent/CN111175413B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007051358A1 (en) * | 2005-11-02 | 2007-05-10 | Nanjing Normal University | HYDROXYPROPYL-SULFOBUTYL-β-CYCLODEXTRIN, THE PREPARATION METHOD,THE ANALYTICAL METHOD AND THE PHARMACUTICAL APPLICATION THEREOF |
| CN102128898A (en) * | 2010-12-09 | 2011-07-20 | 海南和德通医药科技有限公司 | Method for detecting 1,4-butane sultone in sulphur butyl betadex |
| CN103728402A (en) * | 2012-10-15 | 2014-04-16 | 北大方正集团有限公司 | GC method for detecting residual quantity of solvent in compound |
| CN109293625A (en) * | 2017-07-25 | 2019-02-01 | 荆楚理工学院 | A kind of synthetic method of high-purity 1,4- butane sultones |
Non-Patent Citations (4)
| Title |
|---|
| A Critical Comparison of Four Test Methods for Determining Overall and Specific Migration from Microwave Susceptor Packaging;Katrina Mountfort 等;《Journal of Food Protection》;19960501;第59卷(第5期);第534-540页 * |
| Determination of Low-ppm Levels of 1,4-Butane Sultone in Sulfobutyl Ether β-Cyclodextrin Using Liquid-Liquid Extraction and GC-MS;Meng Wang 等;《Chromatograhia》;20120705;第75卷;第937-941页 * |
| 分散液液微萃取-GC法测定磺丁基醚-β-环糊精中杂质1,4-丁烷磺内酯;王双 等;《沈阳药科大学学报》;20160430;第33卷(第4期);第298-302页 * |
| 顶空气相色谱法测定唑来膦酸的7种残留溶剂;姚曦 等;《广东药科大学学报》;20180831;第34卷(第4期);第430-433页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111175413A (en) | 2020-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105334274B (en) | Reversed-phase high performance liquid chromatography determination method for content and related substances of tofacitinib citrate | |
| CN107607632A (en) | The method of residual solvent in extraction of ginkgo biloba leaves by headspace gas | |
| CN111579689A (en) | Method for measuring content of dimethyl sulfate in clopidogrel hydrogen sulfate | |
| CN103698424B (en) | Detecting method of detecting organic solvent in slightly-soluble aluminum salt drug | |
| CN110441446B (en) | Method for effectively detecting purity of 2-chloropropionyl chloride | |
| CN114994212A (en) | High performance liquid chromatography detection method for hydroxylamine residue in medicine | |
| CN107957467B (en) | Method for separating and measuring lysophosphatidylcholine in pharmaceutical preparation | |
| CN113030285B (en) | Method for detecting residual 2-bromomethyl-1, 3-dioxolane in doxofylline | |
| CN111175413B (en) | Method for detecting content of 4-chlorobutanol acetate in sulfobutyl-beta-cyclodextrin sodium raw material or preparation thereof | |
| CN114839287B (en) | Method for detecting sodium myristate in miboplatin | |
| CN112710762B (en) | Method for measuring residual quantity of dimethyl sulfate | |
| CN115616133A (en) | Method for detecting cysteine in compound amino acid injection and application thereof | |
| CN111505163B (en) | Method for detecting phenethyl methane sulfonate substances | |
| CN114137120A (en) | Method for detecting related substances in rapamycin drug stent | |
| CN114689767A (en) | Method for detecting aripiprazole raw material and related substances of aripiprazole preparation | |
| CN113791149B (en) | Detection method of 1-chloro-3-methoxypropane related substance | |
| CN113777204B (en) | Detection method of p-hydroxyacetophenone related substances | |
| CN110849995B (en) | Detection method of DCU in indapamide bulk drug | |
| CN113219105B (en) | Detection method of 2-nitro-4-methoxyaniline in esomeprazole magnesium and intermediate thereof | |
| CN115327003B (en) | Method for detecting clopidogrel oxide related substances | |
| CN111175388B (en) | Method for determining DCC content in indapamide bulk drug | |
| CN111595954B (en) | Method for detecting content of DCC and DCU in indapamide bulk drug | |
| CN112394122B (en) | Method for detecting content of 3-hydroxypropyl demethyl tadalafil in health food | |
| CN112557541B (en) | Detection method of maropiptan citrate and related substances thereof | |
| CN113376294A (en) | Analysis method of ethyl cyanoacetate in tofacitinib citrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |