CN113533591B - GC analysis method for benzene and paraldehyde in cefprozil - Google Patents
GC analysis method for benzene and paraldehyde in cefprozil Download PDFInfo
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Abstract
The invention discloses a GC analysis method for benzene and paraldehyde in cefprozil, which takes a mixed solution of sodium hydroxide solution and dimethyl sulfoxide as a solvent; a capillary column taking 6% of cyanopropylphenyl-94% of dimethyl polysiloxane as a stationary liquid starts to be at 40 ℃ for 7min, is heated to be at 100 ℃ at the speed of 20 ℃/min for 7min, is heated to be at 220 ℃ at the speed of 25 ℃/min for 5 min; detector (FID) temperature 250 deg.C; the temperature of a sample inlet is 200 ℃; the balance temperature of the headspace bottle is 80 ℃, and the balance time is 30 min; the split ratio is 2:1, flow rate 2.5 mL/min. The method has the advantages of good separation degree, strong specificity, high sensitivity and good accuracy, can control the residual benzene and paraldehyde in the cefprozil, and ensures the quality of the final product.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and analysis, and particularly relates to a GC (gas chromatography) analysis method for benzene and paraldehyde in cefprozil.
Background
Cefprozil belongs to the second generation of cephalosporin antibiotics, which can be used to treat bronchitis or other bacterial infections. In vitro tests prove that the cefprozil has obvious effects on staphylococcus aureus (including beta-lactamase-producing strains), streptococcus pneumoniae and streptococcus pyogenes in gram-positive aerobic bacteria, and also has certain antibacterial activity on enterococcus durans, listeria monocytogenes, staphylococcus epidermidis, staphylococcus saprophyticus and staphylococcus warnenei. The chemical structural formula is as follows:
in the prior art, the synthetic route of cefprozil mainly comprises a chemical method and an enzymatic method, wherein the enzymatic method takes 7-APRA and L-p-hydroxyphenylglycine methyl ester (or other derivatives) as substrates and utilizes penicillin acylase to enzymatically synthesize cefprozil. The sunbaihu (university of tianjin master's paper 2012), CN104928340, CN 105368910 a, etc. report a method for enzymatically synthesizing cefprozil, wherein water is used as a reaction medium, the product is easy to accumulate around the enzyme, which affects the enzymatic synthesis ability, and the penicillin acylase has a relatively obvious hydrolysis in an aqueous medium, which can cause the generated cefprozil and the side chain activated by ester or amide to be inevitably decomposed into a beta-lactam nucleus and corresponding side chain acid, resulting in more impurities, low product purity, and long reaction period, if the reaction period is shortened, the conversion rate will be greatly reduced, which cannot meet the requirements of industrial production.
The synthesis of cefprozil by chemical method is based on the starting raw materials, and mainly comprises two routes of GCLE and 7-ACA, such as US patent 4694079, Chinese patent CN200810056349.1, and the synthesis of cefprozil (China journal of pharmaceutical industry, 2004,35 (7): 388, etc.).
The synthetic route using 7-ACA as the starting material needs a large amount of organic solvent, and meanwhile, the Wittig reaction has low yield, slow reaction and poor selectivity, more E-type isomer byproducts are mixed in Z-type products, and the content of trans-isomer is too high, thus affecting the drug effect and safety of the drug.
The reaction for synthesizing cefprozil by taking GCLE as the starting material is specific, byproducts are less, the product quality is better, but a large amount of solvent is also used, formula 2 is a synthetic route of cefprozil by taking GCLE as the starting material, methanol, acetone, dichloromethane, butyl acetate, isopropanol and paraldehyde are used in the synthetic process, and according to the requirements of EMEA (European drug evaluation organization), the acetone has the risk of introducing benzene, so the benzene residue in the cefprozil needs to be checked.
The classification of residual solvents in the four general rules of the current Chinese pharmacopoeia (ChP 2020) means that benzene belongs to the first class of solvents and the limit thereof is not more than 0.0002%.
Paraldehyde is evaluated by using ICH M7 evaluation software (Derek, Sarah), the prediction report shows that the Derek prediction result is negative, the Sarah prediction result is positive, and the software evaluates that ICH M7 is classified into 2 types. ICH M7 specifies that the total administration time for anti-infective therapy is 1-12 months, the acceptable intake of genotoxic impurities is 20 μ g/day, and the acceptable intake of paraldehyde TTC is 20 μ g/day; the maximum daily dose of the preparation is 1 g; the transmission is in terms of 100%, and the control limit should be 20 μ g/day/100% (1 g/day/100%) to 20ppm (0.002%), regardless of the charge ratio.
The existing Chinese pharmacopoeia (ChP 2020) does not specify the method for detecting benzene and paraldehyde in cefprozil, but in the process of drug development, the benzene and paraldehyde need to be controlled to ensure the quality of the finished product. Because the limit of benzene and paraldehyde is low, referring to a method for detecting N, N-dimethylformamide residue of cefprozil in Chinese pharmacopoeia (ChP 2020), 1, 3-dimethyl imidazolidinone is used as a solvent, although the detection sensitivity can be reached, the solvent has interference at the benzene peak position; therefore, there is a need to establish a new method for treating a sample, which can completely dissolve cefprozil and simultaneously meet the requirements of benzene and paraldehyde sensitivity.
Disclosure of Invention
The invention aims to establish a method for separating and measuring benzene and paraldehyde in cefprozil, which has the advantages of good separation degree, strong specificity, high sensitivity and good accuracy, can control the residual benzene and paraldehyde in cefprozil, and ensures the quality of the final product.
In order to achieve the purpose, the method adopts a gas chromatography to separate and detect the residual benzene and paraldehyde in the cefprozil, and is realized by the following technical scheme:
taking a mixed solution of a sodium hydroxide solution and dimethyl sulfoxide as a solvent; a capillary column taking 6% of cyanopropylphenyl-94% of dimethyl polysiloxane as a stationary liquid, in particular to a commercially available Agilent gas phase capillary column 6% of cyanopropylphenyl/94% of dimethyl polysiloxane CP-1301, wherein the 6% of cyanopropylphenyl means that the capillary column adopts a non-bonded stationary phase containing 6% of cyanopropylphenyl (mass fraction), the initial temperature is 40 ℃, the temperature is maintained for 2-10min, the temperature is raised to 100 ℃ at the speed of 20 ℃/min, the temperature is maintained for 2-10min, the temperature is raised to 220 ℃ at the speed of 25 ℃/min, and the temperature is maintained for 2-10 min; detector (FID) temperature 250 deg.C; the temperature of a sample inlet is 200 ℃; the balance temperature of the headspace bottle is 80 ℃, and the balance time is 20-45 min; the split ratio is 2:1, and the flow rate is 2-3 mL/min.
According to the invention, the solvent is a 0.2-0.5mol/L sodium hydroxide solution: dimethyl sulfoxide 70: 30. Cefprozil is difficult to dissolve in the common reagents for gas phase detection: water, formamide, acetamide, dimethyl sulfoxide and the like, the solvent can completely dissolve cefprozil, and the accuracy of benzene and paraldehyde is good.
According to the invention, a capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as a stationary liquid was started at 40 ℃ for 7min, heated to 100 ℃ at a rate of 20 ℃/min for 7min, heated to 220 ℃ at a rate of 25 ℃/min for 5 min. Benzene and paraldehyde can be effectively separated from other impurities in the sample.
According to the invention, the temperature of the injection port is 200 ℃, the split ratio is 2:1, and the sensitivity of benzene and paraldehyde is obviously improved.
According to the invention, the balance temperature of the headspace bottle is 80 ℃, the balance time is 30min, and under the condition of ensuring sufficient sensitivity of benzene and paraldehyde, a sample does not generate a thermal degradation product which affects specificity.
In addition, the sample concentration of the present invention is 100mg/ml, and the flow rate is 2.0-3.0ml/min, preferably 2.5 ml/min.
By adopting the analysis method, the method has the advantages of good separation degree, strong specificity, high sensitivity and good accuracy, can control the residual benzene and paraldehyde in the cefprozil, ensures the quality of the final product, and can provide beneficial reference and basis for other impurities with extremely low limit in the cefprozil.
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The above and/or additional aspects and advantages of the present invention will become apparent and readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings of which:
FIG. 1 is GC graphs of the blank solution, the reference solution and the test solution in example 1;
FIG. 2 is a GC spectrum of an air-white solution and a test solution in comparative example 1;
FIG. 3 is a GC spectrum of the test solution in comparative example 2;
FIG. 4 is GC graphs of the blank solution, the reference solution and the test solution in comparative example 3;
Detailed Description
The present invention will be further described by the following examples, which, however, are not intended to limit the scope of the present invention in any way. Certain changes and modifications within the scope of the claims, which may be made by one skilled in the art, are also considered to be within the scope of the invention.
Example 1
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.2mol/L sodium hydroxide solution-dimethyl sulfoxide (70:30)
A chromatographic column: capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 7min, heating to 100 deg.C at 20 deg.C/min, maintaining for 7min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 5min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 2:1
Flow rate: 2.5ml/min
Headspace equilibrium temperature: 80 ℃; the balance time is as follows: 30min
Experimental procedure
Solution preparation
Test solution: 200mg of cefprozil is precisely weighed, placed in a 20ml headspace bottle, added with 2ml of solvent, and sealed by a gland to be used as a test solution.
Control solution: accurately weighing appropriate amount of benzene and paraldehyde respectively, adding solvent, quantitatively diluting to obtain mixed solution containing benzene about 0.2 μ g and paraldehyde about 2 μ g per 1ml, accurately weighing 2ml, placing in 20ml headspace bottle, and sealing with gland.
The result is shown in figure 1, benzene and paraldehyde can be completely separated, no interference peak is generated at the positions of benzene and paraldehyde in a blank solvent and a sample, and the specificity meets the requirement; the recovery rate of the paraldehyde is 96.29 percent, and the requirement of experimental accuracy is met.
Example 2
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.3mol/L sodium hydroxide solution-dimethyl sulfoxide (70:30)
A chromatographic column: capillary column with 6% cyanopropyl phenyl-94% dimethyl polysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 2min, heating to 100 deg.C at 20 deg.C/min, maintaining for 2min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 2min
A sample inlet: 200 deg.C
A detector: 250 ℃ C
The split ratio is as follows: 2:1
Flow rate: 2mL/min
Headspace equilibrium temperature: 80 ℃; the balance time is as follows: 20min
Experimental procedure
The experimental steps are the same as those in the embodiment 1, the benzene and the paraldehyde can be completely separated, no interference peak is generated at the positions of the benzene and the paraldehyde in the blank solvent and the sample, and the specificity meets the requirement; the recovery rate of paraldehyde is 90.74%, and the requirement of experimental accuracy is met.
Example 3
Apparatus and conditions
A gas chromatograph: agilent 7890B +7697A
Solvent: 0.5mol/L sodium hydroxide solution-dimethylsulfoxide (70:30)
A chromatographic column: capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 10min, heating to 100 deg.C at 20 deg.C/min, maintaining for 10min, heating to 220 deg.C at 25 deg.C/min, maintaining for 10min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 2:1
Flow rate: 3mL/min
Headspace equilibrium temperature: 80 ℃; the balance time is as follows: 45min
Experimental procedure
The experimental steps are the same as those in the embodiment 1, the benzene and the paraldehyde can be completely separated, no interference peak is generated at the positions of the benzene and the paraldehyde in the blank solvent and the sample, and the specificity meets the requirement; the recovery rate of the paraldehyde is 95.57%, and the requirement of experimental accuracy is met.
Comparative example 1
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.25mol/L sodium hydroxide solution-1, 3-dimethyl-2-imidazolidinone (90:10)
A chromatographic column: capillary column with 6% cyanopropyl phenyl-94% dimethyl polysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 7min, heating to 100 deg.C at 20 deg.C/min, maintaining for 7min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 5min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 1:1
Flow rate: 2.5ml/min
Headspace equilibrium temperature: 80 ℃; the balance time is as follows: 30min
Experimental procedure
Precisely weighing 200mg of cefprozil, placing the cefprozil into a 20ml headspace bottle, adding 2ml of solvent, and sealing by a gland to obtain a test solution. Performing high performance liquid chromatography analysis according to the above conditions, and recording chromatogram, wherein the result is shown in figure 2, and the interference in the solvent at the benzene peak position does not meet the requirement of specificity.
Comparative example 2
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.25mol/L sodium hydroxide solution-N, N-dimethylformamide (90:10)
And (3) chromatographic column: capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 7min, heating to 100 deg.C at 20 deg.C/min, maintaining for 7min, heating to 220 deg.C at 25 deg.C/min, maintaining for 5min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 1:1
Flow rate: 2.5ml/min
Headspace equilibrium temperature: 80 ℃; the balance time is as follows: 30min
Experimental procedure
The experimental procedure is the same as that of comparative example 1, the result is shown in figure 3, and N, N-dimethylformamide is decomposed when meeting sodium hydroxide, so that the experimental determination is interfered, and the experimental determination does not meet the requirement of specificity.
Comparative example 3
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.25mol/L sodium hydroxide solution-dimethylsulfoxide (90:10)
A chromatographic column: capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 7min, heating to 100 deg.C at 20 deg.C/min, maintaining for 7min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 5min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 1:1
Flow rate: 2.5ml/min
Headspace equilibrium temperature: 80 ℃; and (3) balancing time: 30min
Experimental procedure
Solution preparation
Test solution: 200mg of cefprozil is precisely weighed, placed in a 20ml headspace bottle, added with 2ml of solvent, and sealed by a gland to be used as a test solution.
Control solution: accurately weighing appropriate amount of benzene and paraldehyde respectively, adding solvent, quantitatively diluting to obtain mixed solution containing benzene about 0.2 μ g and paraldehyde about 2 μ g per 1ml, accurately weighing 2ml, placing in 20ml headspace bottle, and sealing with gland.
Performing high performance liquid chromatography analysis according to the above conditions, recording chromatogram, and obtaining the result shown in figure 4, wherein benzene and paraldehyde can be completely separated, no interference peak is generated at benzene and paraldehyde positions in blank solvent and sample, and specificity meets requirements; however, the recovery of paraldehyde is 81.23%, and thus it is desirable to increase the recovery of paraldehyde.
Comparative example 4
Apparatus and conditions
Gas chromatograph: agilent 7890B +7697A
Solvent: 0.25mol/L sodium hydroxide solution-dimethylsulfoxide (80:20)
A chromatographic column: capillary column using 6% cyanopropylphenyl-94% dimethylpolysiloxane as stationary liquid
Temperature rising procedure: starting temperature of 40 deg.C, maintaining for 7min, heating to 100 deg.C at 20 deg.C/min, maintaining for 7min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 5min
A sample inlet: 200 deg.C
A detector: 250 deg.C
The split ratio is as follows: 1:1
Flow rate: 2.5ml/min
Headspace equilibrium temperature: 80 ℃; and (3) balancing time: 30min
The experimental steps are the same as those of the comparative example 3, the result is similar to that of the attached figure 4, the benzene and the paraldehyde can be completely separated, no interference peak exists at the positions of the benzene and the paraldehyde in the blank solvent and the sample, and the specificity meets the requirement; however, the recovery of paraldehyde was 81.47%, and thus it was desired to increase the recovery of paraldehyde.
Experimental example 1
With reference to the experimental conditions of example 4, experiments were performed respectively for specificity, sensitivity, linear range, precision (injection precision, repeatability, intermediate precision), accuracy, durability, and the results were as follows:
according to the results shown in the table, the method has the advantages of strong specificity, good accuracy and high sensitivity, so that effective quantitative monitoring on residual levels of benzene and paraldehyde in cefprozil can be reflected, and meanwhile, beneficial reference and basis are provided for other impurities with low limits in cefprozil.
Claims (8)
1. A GC analysis method for benzene and paraldehyde in cefprozil is characterized by comprising the following steps: a capillary column which takes a mixed solution of a sodium hydroxide solution and dimethyl sulfoxide as a solvent and takes 6 percent of cyanopropyl phenyl-94 percent of dimethyl polysiloxane as a stationary liquid; the temperature rising procedure is as follows: starting temperature of 40 deg.C, maintaining for 2-10min, heating to 100 deg.C at 20 deg.C/min, maintaining for 2-10min, heating to 220 deg.C at 25 deg.C/min, and maintaining for 2-10 min; the temperature of the detector is 250 ℃, the temperature of the sample inlet is 200 ℃, the equilibrium temperature of the headspace bottle is 80 ℃, and the equilibrium time is 20-45 min; the split ratio is 2:1, the flow rate is 2-3mL/min, and the residual benzene and paraldehyde in the cefprozil are separated and measured.
2. The GC analysis method according to claim 1, wherein the concentration of said sodium hydroxide solution is 0.2 to 0.5 mol/L.
3. The GC analysis method according to claim 1, wherein the volume ratio of the sodium hydroxide solution to the dimethyl sulfoxide in the solvent is 70: 30.
4. The GC analysis method according to claim 1, wherein the temperature-increasing procedure is: the initial temperature is 40 deg.C, the temperature is maintained for 5-10min, the temperature is raised to 100 deg.C at the rate of 20 deg.C/min, the temperature is maintained for 5-10min, the temperature is raised to 220 deg.C at the rate of 25 deg.C/min, and the temperature is maintained for 3-8 min.
5. The GC analysis method of claim 4, wherein the temperature ramp program is: the initial temperature is 40 ℃, the temperature is maintained for 7min, the temperature is increased to 100 ℃ at the speed of 20 ℃/min, the temperature is maintained for 7min, the temperature is increased to 220 ℃ at the speed of 25 ℃/min, and the temperature is maintained for 5 min.
6. The GC analysis method of claim 1, wherein the detector is a hydrogen flame ionization detector.
7. The GC analysis method of claim 1, wherein the equilibration time is 30 min.
8. The GC analysis method of claim 1, wherein the flow rate is 2.5 mL/min.
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