CN112697910B - Method for measuring acetic acid in isothio blue by headspace-gas chromatography - Google Patents
Method for measuring acetic acid in isothio blue by headspace-gas chromatography Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for determining acetic acid in isothio blue through headspace-gas chromatography. The method adopts methyl isobutyl ketone to prepare a test solution and a reference solution, and then carries out headspace-gas chromatography detection. The analysis method adopted by the invention does not need pretreatment, and has the advantages of simple operation, high sensitivity, good reproducibility and accurate result.
Description
Technical Field
The invention belongs to the field of pharmaceutical analysis, and particularly relates to a method for determining acetic acid in isothio blue through headspace-gas chromatography.
Background
Acetic acid can be used as a substrate solvent for drug synthesis reaction, when the reaction is finished or the next reaction is carried out, the residual quantity of the acetic acid can influence the quality of the drug and the next synthesis reaction, and according to the regulation of ICH, the limit of the acetic acid in the drug is regulated within 5000ppm, so that for important types of drugs containing acetic acid residues, especially for important types of drugs such as the acetic acid residue in isothioblue, whether the acetic acid content in the drug reaches the standard or not is very important to detect.
The existing analysis methods for acetic acid comprise: gas chromatography mass spectrometry (GC-MS), liquid chromatography mass spectrometry (LC-MS), and the use of common reversed phase liquid ultraviolet chromatography (RPLC-UV) is mentioned in chinese pharmacopoeia, version 2015. In the gas chromatography, the common chromatographic column causes the tailing of chromatographic peaks due to the high polarity of acetic acid, and most of the chromatographic columns adopt some polarity such as WAX and FFAP-WAX. GC-MS needs to perform derivatization on acetic acid for detection analysis in order to improve the detection sensitivity, but mass spectrometry is expensive, and is not widely used in most common pharmaceutical enterprises. In addition, the solubility of the isothio blue in water and a conventional solvent is low, the residual quantity of acetic acid is in ppm level, the analysis sensitivity is not high by using liquid chromatography, the operation of headspace gas chromatography is simple, and the detection of volatile compounds is suitable, and the solvent does not need to consider compounds with high boiling point and weak alkalinity such as DMF, NMP and the like when the headspace gas chromatography is adopted because the acetic acid is weak in acidity.
Chinese application patent 201610113454.9 discloses a method for simultaneously detecting residual solvents acetic acid and ethyl acetate, and the method adopts headspace gas chromatography, but the pretreatment is relatively complex.
Disclosure of Invention
The method adopts methyl isobutyl ketone as a solvent, adopts a headspace gas chromatography hydrogen flame ion detection method to realize the analysis of the acetic acid, does not need pretreatment, has simple operation, high sensitivity, good reproducibility and accurate result, and has few reports in the industry at present on the analysis method for detecting the acetic acid residue in the isothio blue.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a method for determining acetic acid in isothio blue by headspace-gas chromatography, which comprises the following steps:
(1) Preparation of a test solution: accurately weighing isothio blue, placing the isothio blue in a headspace bottle, and adding methyl isobutyl ketone to dissolve the isothio blue to be used as a test solution;
(2) Preparation of standard solution: accurately weighing a reference substance acetic acid, placing into a headspace bottle, adding methyl isobutyl ketone for dissolving to obtain a reference substance solution;
(3) Setting headspace-gas chromatography conditions:
headspace conditions: the temperature of the hatching chamber is 85-95 ℃;
chromatographic conditions are as follows: carrier gas: nitrogen gas; and (3) chromatographic column: polyethylene glycol is used as stationary liquid (30m, 0.53mm,1 μm); sample inlet temperature: 235-245 ℃, adopting programmed temperature rise: the initial temperature is 75-85 deg.C, maintaining for 0-2min, increasing to 105-115 deg.C at 6-8 deg.C/min, maintaining for 4-6min, increasing to 225-235 deg.C at 19-21 deg.C/min, and maintaining for 3-5min;
detection conditions are as follows: the detector temperature is 265-275 ℃.
(4) Content determination: and (3) detecting the residual amount of acetic acid in the isothio blue by using an external standard method, taking a test solution and a reference solution, respectively injecting samples in a headspace manner, recording a chromatogram, and calculating the residual amount of acetic acid in the isothio blue by using a peak area according to the external standard method.
Preferably, the concentration of the test solution is 200mg/ml.
Preferably, the dosing loop temperature in the headspace conditions is 105-115 ℃ and the transfer line temperature is 115-125 ℃.
Preferably, in the headspace condition, the headspace bottle equilibrium time is more than or equal to 20min, the pressurization time is 0.4-0.6min, the quantitative ring filling time is 0.2min, and the quantitative equilibrium time is 0.05min.
Preferably, in the headspace condition, the sample injection time is 0.5-1.5min, the column temperature equilibrium time is 0.05min, the sample bottle pressure is 21psi, and the quantitative loop volume is 1mL.
Preferably, the chromatographic conditions are such that the nitrogen purity is 99-100% and the carrier gas flow rate is 3.5-4.5mL/min.
Preferably, the sample injection mode in the chromatographic conditions is as follows: split-flow sample injection, and the split-flow ratio is 9-11.
Preferably, the hydrogen flow rate is 28-32mL/min and the air flow rate is 290-310mL/min in the detection condition.
Preferably, the nitrogen is blown as a tail gas under the detection conditions, and the flow rate is 28-32mL/min.
According to the method for determining the residual solvent in the isothio blue, the ratio of the mean values of all response factors of acetic acid in the system adaptability control solution is 101.49%, and in all standard solutions 1, the RSD of the acetic acid response factors is 4.62%, so that the requirement of system adaptability is met; the special hollow white has no other impurity peaks, and the separation degree of a main peak is more than 1.5; the recovery rate of the method is 100.5-122.5%, the RSD of 9 recovery rates is 6.84%, and the method has good accuracy and precision.
Drawings
FIG. 1-1: determining a complete chromatogram of the special blank solution of the acetic acid method in the isothio blue by using a headspace-gas chromatography;
FIGS. 1-2: determining a complete chromatogram of the acetic acid method specific standard solution in the isothio blue by using a headspace-gas chromatography;
FIGS. 1 to 3: measuring a local amplification chromatogram of the acetic acid method specific standard solution in the isothio blue by using a headspace-gas chromatography;
FIG. 2: determining an acetic acid method acetic acid linear relation chromatogram in the isothio blue by using a headspace-gas chromatography;
FIG. 3-1: a complete chromatogram for quantitative limit detection of acetic acid in isothio blue is determined by headspace-gas chromatography;
FIG. 3-2: a partial enlarged view of quantitative limit detection of an acetic acid method in the isothio blue is determined by headspace-gas chromatography;
FIG. 4-1: determining a complete chromatogram of an isothio blue sample by using headspace-gas chromatography;
FIG. 4-2: and (3) measuring a local amplification chromatogram of the isothio blue sample by headspace-gas chromatography.
The invention will now be further illustrated with reference to the accompanying drawings and examples:
Detailed Description
The present invention is further illustrated by the following examples. It is to be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention.
The detection method used in the following examples is headspace chromatography:
headspace conditions: the temperature of the hatching chamber is 90 ℃, and the balance time of the headspace bottle is more than or equal to 20min; the temperature of the quantitative ring is 110 ℃, and the temperature of the transmission line is 120 ℃; pressurizing for 0.5min, quantitatively filling for 0.2min, and quantitatively balancing for 0.05min; sample introduction time is 1.0min, column temperature equilibrium time is 0.05min, sample bottle pressure is 21psi, and quantitative loop volume is 1mL.
Chromatographic conditions are as follows: carrier gas: nitrogen with the purity of 99.999 percent and the flow rate of carrier gas of 4.0mL/min; the sample introduction mode is divided sample introduction, and the flow dividing ratio is 10: agilent DB-WAX (30m, 0.53mm,1 μm); sample inlet temperature: temperature programming is adopted at 240 ℃, and temperature is increased: the initial temperature is 80 ℃, the temperature is maintained for 0min, the temperature is increased to 110 ℃ at 7 ℃/min, the temperature is maintained for 5min, the temperature is increased to 230 ℃ at 20 ℃/min, and the temperature is maintained for 4min;
detection conditions are as follows: the detector temperature is 270 ℃, the hydrogen flow rate is 30mL/min, the air flow rate is 300mL/min, the hydrogen flow rate is 30mL/min, and the air flow rate is 300mL/min.
EXAMPLE 1 selection of solvent
When acetonitrile is used as a solvent, the tailing factor of acetic acid is between 0.95 and 1.05, but the boiling point of the acetic acid is low (81.6 ℃), the air tightness of the headspace is influenced, and the selection range of the equilibrium temperature of the headspace is narrow. When DMSO is used as a solvent, although the boiling point is high, the acetic acid peak type tailing is serious (3.35), the response is poor, and the sensitivity is low. When methyl isobutyl ketone is used as a solvent, the difference between the boiling point of the methyl isobutyl ketone and the boiling point of acetic acid is not large, the sensitivity is high, and the tailing factor is 1.51, so that the solvent is selected to carry out methodology verification on the acetic acid.
Example 2 examination of System Adaptation
Accurately weighing 200mg of acetic acid, placing the acetic acid into a 10mL volumetric flask, adding methyl isobutyl ketone solvent, shaking up, fixing the volume, and marking as standard stock solution. Remove 1mL of standard stock solution into 10mL volumetric flask, dilute with diluent methyl isobutyl ketone and fix volume, this label is standard solution. Two standard solutions, designated STD1 and STD2, were prepared in the same manner, and analyzed by sample injection under the chromatographic conditions described above, in sequence table 1. The method comprises the following steps: the ratio of the mean value of each response factor of the two-pin standard solution 2 to the first 4-pin standard solution 1 is 95-105%; in all standard solutions 1, the RSD of the acetic acid response factor is less than or equal to 5.0%.
The results of the experiment are shown in Table 2. As shown in table 2, the ratio of the mean value of the response factors of acetic acid in the two-pin standard solution 2 and the first 4-pin standard solution 1 is 101.49%, and the RSD of the acetic acid response factor in all the standard solutions 1 is 4.62%, which satisfies the requirement of system adaptability.
TABLE 1 adaptive sample introduction sequence for system
The last needle of the 'Tuo' needle is used as the system blank, and the others are used as the balance system.
TABLE 2 adaptive results table of system
Example 3 specificity test
Transferring 2mL of diluent methyl isobutyl ketone into a headspace bottle, covering and sealing the headspace bottle, and marking the headspace bottle as a blank solution; accurately weighing 2500mg of acetic acid, placing the acetic acid in a 100mL volumetric flask, dissolving the acetic acid by using a diluent methyl isobutyl ketone, diluting the acetic acid to a constant volume to a scale, and shaking up to obtain a standard solution 1; transferring 1.0mL of standard solution into a volumetric flask of 1-25 mL, diluting with a diluent methyl isobutyl ketone, fixing the volume to a scale, and shaking up to obtain a standard solution 2; and then further transferring 1.0mL of standard solution into a 2-10 mL volumetric flask, diluting with a diluent methyl isobutyl ketone, fixing the volume to a scale, and shaking up to obtain a standard solution 3. 2ml of the standard solution 3 was removed precisely to a headspace bottle, capped and sealed (acetic acid: 0.1 mg/ml), labeled LOQ, and analyzed by sample introduction after the instrument was ready. The result shows that the position of the acetic acid peak is not interfered with the blank compared with the blank (the percentage of the peak area of the interference peak at the position of the acetic acid peak in the blank to the peak area of LOQ is less than 50%), which is shown in figure 1-1, figure 1-2 and figure 1-3.
Example 4 examination of the Linear relationship
Preparation of Standard Curve
Accurately weighing 500mg of acetic acid, placing the acetic acid into a 50mL volumetric flask, diluting the acetic acid with a diluent methyl isobutyl ketone to a constant volume, and marking the acetic acid as a linear stock solution. Linear stock solutions with different volumes were transferred into 25mL volumetric flasks, respectively, according to table 3, and the volume was fixed with methyl isobutyl ketone as a diluent to obtain linear solutions. Respectively transferring 2mL of linear solutions with different concentrations into a 20mL headspace bottle, carrying out sample injection analysis according to the chromatographic conditions after the instrument is stabilized, and horizontally walking 2 needles with the same concentration. Taking the average peak area as an ordinate (Y axis) and the concentration as an abscissa (X axis), carrying out linear regression analysis on the series acetic acid linear solution to obtain a linear equation of the acetic acid, wherein the linear equation is Y =256.93x +17.082, R 2 Concentration response of 6.13% with intercept at 100% indicating good linearity of acetic acid with peak area in the range of 0.1-2mg/mL, results are shown in table 4 and fig. 2.
TABLE 3 dilution chart of acetic acid linear solution
Table 4 results of acetic acid linear solutions
Example 5 limit of quantitation test
The limit of quantitation is 500ppm, and the preparation method of the limit solution is as follows:
accurately weighing 2500mg of acetic acid, placing the acetic acid in a 100mL volumetric flask, dissolving the acetic acid by using a diluent methyl isobutyl ketone, diluting the acetic acid to a constant volume to a scale, and shaking up to obtain a standard solution 1; transferring 1.0mL of standard solution into a volumetric flask with the volume ranging from 1mL to 25mL, diluting with a diluent methyl isobutyl ketone, fixing the volume to a scale, and shaking up to obtain a standard solution 2; and then further transferring 1.0mL of standard solution into a 2-10 mL volumetric flask, diluting with a diluent methyl isobutyl ketone, fixing the volume to a scale, and shaking up to obtain a standard solution 3. Precisely transferring 2ml of standard solution 3 to a headspace bottle, capping and sealing, (acetic acid: 0.1 mg/ml), marking as LOQ, injecting into headspace GC for analysis, and quantitatively limiting the signal-to-noise ratio of the acetic acid peak in the solution to be more than 10. The results are shown in FIGS. 3-1 and 3-2.
EXAMPLE 6 examination of accuracy
Preparation of sample recovery rate
Accurately weighing 12 parts of isothioblue sample, 400mg each, in a 20mL headspace bottle, wherein 3 parts are used as blanks, 3 parts are used as acetic acid LOQ solution adding standards, 3 parts are used as acetic acid solution 100% adding standards, 3 parts are used as acetic acid solution 160% adding standards, and the accuracy of the method is examined by calculating the recovery value of each adding standard according to an external standard method by using the average value of the first 4 pins of the standard solution STD1 with system adaptability, and the result is shown in Table 5. As shown in Table 5, the recovery rate of the method was 100.5% to 122.5%, and the RSD of 9 recovery rates was 6.84%, indicating that the method had good accuracy and precision.
Accuracy of the method of Table 5
Example 7 detection of acetic acid residue in test article
Preparation of control solutions: accurately weighing 2500mg of acetic acid, placing the acetic acid in a 100mL volumetric flask, dissolving the acetic acid by using a diluent methyl isobutyl ketone, diluting the acetic acid to a constant volume to a scale, and shaking up to obtain a standard solution 1; and transferring the 1.0mL standard solution into a 1-25 mL volumetric flask, diluting with a diluent methyl isobutyl ketone, fixing the volume to a scale, and shaking up to obtain a standard solution 2. 2ml of the standard solution 2 was removed precisely to a headspace bottle, which was capped and sealed. Two portions were prepared in the same way, and labeled STD1 and STD2, respectively. (acetic acid: 1 mg/ml)
Preparation of a test solution: accurately weighing 400mg of an isothio blue sample, placing the isothio blue sample in a 20ml headspace bottle, precisely transferring 2ml of diluent into the headspace bottle, capping and sealing the headspace bottle, and preparing two parts by the same method, wherein the parts are respectively marked as TS1 and TS2. (AP 2263-4 sample
After the instrument was ready, the sample was analyzed as in the sequence listing of Table 6, and the results are shown in Table 7 and FIGS. 4-1 and 4-2.
TABLE 6 sample introduction sequence table for acetic acid residue detection in test sample
Calculating the formula:
calculated by an external standard method, the formula is as follows:
wherein
X-is- -acetic acid residual solvent content, ppm;
R i -response factor of acetic acid in the sample solution
R S -the mean value of the response factors for acetic acid in the front 4 control solutions 1;
TABLE 7 residual amount of acetic acid in test article
The above detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but rather the scope of the invention is intended to include all equivalent implementations or modifications without departing from the scope of the invention.
Claims (10)
1. A method for measuring acetic acid in isothio blue by headspace-gas chromatography is characterized by comprising the following steps:
(1) Preparation of a test solution: adding isothio blue into methyl isobutyl ketone to be used as a test solution;
(2) Preparation of control solutions: adding methyl isobutyl ketone into acetic acid to serve as a reference solution;
(3) Setting headspace-gas chromatography conditions:
headspace conditions: the temperature of the hatching chamber is 90 ℃;
chromatographic conditions are as follows: carrier gas: nitrogen gas; a chromatographic column: polyethylene glycol is used as stationary liquid, the length of a chromatographic column is 30m, the inner diameter is 0.53mm, and the thickness of the membrane is 1 μm; sample inlet temperature: 235-245 ℃, adopting programmed temperature rise: the initial temperature is 75-85 deg.C, maintaining for 0-2min, increasing to 105-115 deg.C at 6-8 deg.C/min, maintaining for 4-6min, increasing to 225-235 deg.C at 19-21 deg.C/min, and maintaining for 3-5min;
detection conditions are as follows: the temperature of the detector is 265-275 ℃;
(4) Content determination: and detecting the residual amount of acetic acid in the isothio blue by using an external standard method.
2. The method for determining acetic acid in isothioblue by headspace-gas chromatography as claimed in claim 1, wherein the concentration of the test solution in (1) is 200mg/ml.
3. The method for determining acetic acid in isothio blue according to claim 1, wherein said (3) headspace conditions further comprise: the temperature of the quantitative ring is 105-115 ℃ and the temperature of the transmission line is 115-125 ℃.
4. The method for determining acetic acid in isothio blue according to claim 1, wherein said (3) headspace conditions further comprise: the balance time of the headspace bottle is more than or equal to 20min, the pressurization time is 0.4-0.6min, the quantitative ring filling time is 0.2min, and the quantitative balance time is 0.05min.
5. The method for determining acetic acid in isothio blue according to claim 1, wherein said (3) headspace conditions further comprise: sample injection time is 0.5-1.5min, column temperature equilibrium time is 0.05min, sample bottle pressure is 21psi, and quantitative loop volume is 1mL.
6. The headspace-gas chromatography method for determining acetic acid in isothio blue as claimed in claim 1, wherein said (3) chromatographic conditions further comprise: the purity of nitrogen is 99-100%, and the flow rate of carrier gas is 3.5-4.5mL/min.
7. The headspace-gas chromatography method for determining acetic acid in isothio blue as claimed in claim 1, wherein said (3) chromatographic conditions further comprise: the sample introduction mode is as follows: split-flow sample injection, and the split-flow ratio is 9-11.
8. The headspace-gas chromatography method for determining acetic acid in isothio blue as claimed in claim 1, wherein said (3) chromatographic conditions further comprise: the hydrogen flow rate is 28-32mL/min, and the air flow rate is 290-310mL/min.
9. The headspace-gas chromatography method for determining acetic acid in isothio blue as claimed in claim 1, wherein said (3) chromatographic conditions further comprise: nitrogen gas is used as tail gas blowing, and the flow rate is 28-32mL/min.
10. Use of the headspace-gas chromatography method according to any one of claims 1 to 9 for the determination of acetic acid in isothio blue for the detection of the residual amount of acetic acid in isothio blue.
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