CN110208431B - Method for detecting residual chloropropanol compound in medicine - Google Patents
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Abstract
The invention discloses a method for detecting residual chloropropanol compounds in a medicament, which adopts a gas chromatography, and the diluent of the medicament is a mixed solvent of acetone and n-hexane. The detection method can effectively detect the residual situation of the chloropropanol compound possibly existing in the medicine such as ornidazole or levoornidazole.
Description
Technical Field
The invention belongs to the technical field of drug analysis, and particularly relates to a method for detecting residual chloropropanol compounds in drugs.
Background
The chemical name of the levoornidazole is as follows: s- (-) - (3-chloro-2-hydroxypropyl) -2-methyl-5-nitroimidazole, the structure of the compound is as follows:
at present, the preparation which is sold on the market and takes the levo-ornidazole as an active component at home only comprises a levo-ornidazole sodium chloride injection, and the preparation belongs to nitroimidazole derivative anti-anaerobe medicines and is a levo-form body of the ornidazole. Clinical test results show that compared with the ornidazole sodium chloride injection, the levoornidazole sodium chloride injection has clinical statistical significance in reducing the incidence rate of adverse reactions of dizziness and somnolence.
The 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol belong to chloropropanol, and are introduced from S-epichlorohydrin which is the starting raw material of levoornidazole. Chloropropanols have carcinogenic and sperm-inhibiting activities, are internationally recognized food pollutants, and are classified as class 2 and class 5 impurities respectively by ICH M7. Therefore, a method capable of detecting residual chloropropanol compounds therein is very important for controlling the quality of a pharmaceutical product.
S- (-) epoxy chloropropane and R- (+) epoxy chloropropane are basic chemical raw materials and are widely applied to the preparation and synthesis of medicine raw materials. As a potential metabolic regulator for the synthesis of fatty acid oxidation inhibitors; for the total synthesis of macquamicins and of macrolide RK-397; chiral building blocks for the enantioselective synthesis of hydroxyisoxazolidines and (+) -cis-sylvanin, a potential antineoplastic agent; drugs such as anti-infective drugs (levoornidazole, ornidazole), the precursor 4-chloro-3-hydroxybutyrate (atorvastatin),βPreparation of chiral epichlorohydrin and its application in-adrenoceptor antagonist (atenolol), L-carnitine, reflex sensitizer (angiogenesis inhibitors 39 a-39 c), and other drugs (anesthetic baclofen)The use of S- (-) epichlorohydrin or R- (+) epichlorohydrin in the synthesis of "organic chemistry", vol 29, No. 8, p1209-1216 ") was referred to.
The Chinese pharmacopoeia 2015 edition discloses a method for detecting a residual solvent of 3-chloro-1, 2-propanediol, which adopts n-hexane and ultrasound, but because iohexol is not dissolved in the n-hexane, trace 3-chloro-1, 2-propanediol impurities contained in the iohexol are easily adsorbed or wrapped by iohexol particles and are not dissolved out, so that false negative results of actual measurement are caused. Zhengjinqi et al (an improvement of a method for measuring 3-chloro-1, 2-propanediol in iohexol, China Standard for pharmaceutical products, No. 2013, No. 06, p 437-439) adopt ethyl acetate for extraction, thereby realizing accurate detection.
However, in the existing detection method, the separation degree of untreated levoornidazole and a target substance does not meet the requirement, a used solvent contrast cannot be prepared, and 3-chloro-1, 2-propanediol and 1, 3-dichloro-2-propanol cannot be simultaneously measured, so that the method cannot be applied to detecting the residual amount of chloropropanol in the levoornidazole, and in order to control the clinical safety of the levoornidazole sodium chloride injection and maintain the benefits of patients, the invention is necessary to invent a detection method for detecting genotoxic impurities 1, 3-dichloro-2-propanol and 3-chloro-1, 2-propanediol remained in the active ingredient levoornidazole of the levoornidazole sodium chloride injection.
Disclosure of Invention
The invention provides a method for detecting residual chloropropanol compounds in a medicament, which adopts a gas chromatography, wherein a diluent of the medicament is a mixed solvent of acetone and n-hexane, preferably, the volume ratio of the acetone to the n-hexane in the mixed solvent is 1: 9.
The invention provides a method for detecting residual chloropropanol compounds in a medicament, which adopts gas chromatography, wherein the diluent of the medicament is a mixed solvent of acetone and n-hexane, and preferably, the volume ratio of the acetone to the n-hexane in the mixed solvent is 1: 9.
The invention provides a method for detecting residual chloropropanol compounds in a medicament, which adopts a gas chromatography and detects according to the following detection conditions and operations:
the detection conditions include:
a chromatographic column: capillary tubing (DIKMA DM-1701 column, 30 m. times.0.32 mm. times.0.5 μm) with 14% cyanopropylene and 86% dimethylpolysiloxane as fixative
Carrier: nitrogen gas
Flow rate of carrier gas: 1 ml/min-3 ml/min, preferably, 1.5ml/min
A detector: hydrogen Flame Ionization Detector (FID)
Detector temperature: 220 ℃ to 280 ℃, preferably 250 DEG C
Sample inlet temperature: 200 to 250 ℃, preferably 230 DEG C
Sample introduction volume: 1.0-5.0. mu.l, preferably 2.0. mu.l
Column temperature: the initial temperature is 50 ℃, the temperature is maintained for 5 minutes, the temperature is raised to 140 ℃ at the rate of 12 ℃ per minute, the temperature is maintained for 5 minutes, the temperature is raised to 160 ℃ at the rate of 20 ℃ per minute, and the temperature is maintained for 2 minutes;
dissolving the medicine with acetone-n-hexane mixed solvent to obtain a test solution; dissolving one or two of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol with acetone-n-hexane mixed solvent ketone to obtain reference solution;
sampling the reference solution, and recording a chromatogram; sampling the sample solution and the reference solution, and recording the chromatogram.
In some embodiments of the invention, the detection conditions comprise:
a chromatographic column: DIKMA DM-1701 column 30 m.times.0.32 mm.times.0.5. mu.m
Carrier: high purity nitrogen gas
Flow rate of carrier gas: 1.5ml per minute
A detector: hydrogen Flame Ionization Detector (FID)
Detector temperature: 250 deg.C
Sample inlet temperature: 230 deg.C
Sample introduction volume: 2.0. mu.l
Column temperature: the starting temperature was 50 ℃ for 5 minutes, 12 ℃ per minute to 140 ℃ for 5 minutes, and 20 ℃ per minute to 160 ℃ for 2 minutes.
In some embodiments of the invention, the chloropropanol compound is one or both of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol.
In some embodiments of the invention, the drug is ornidazole or levoornidazole, rivaroxaban, atorvastatin, atenolol, or levocarnitine, etc.; preferably, the drug is a levoornidazole drug substance or an ornidazole drug substance.
In some embodiments of the invention, the gas chromatography employs split feed, preferably at a split ratio of 2: 1.
In some embodiments of the invention, wherein the test solution is formulated as: precisely weighing about 1.0g of the medicine, placing the medicine in a 10ml iodine measuring flask, adding 4.0ml of mixed solvent namely acetone-n-hexane (volume ratio is 1: 9), sealing, oscillating for 10 minutes at 50 times per minute by a speed-regulating oscillator, carrying out ice-water bath for 30 minutes, filtering by a 0.22 mu m nylon membrane, and taking the subsequent filtrate to return to room temperature to be used as a test solution.
In some embodiments of the invention, wherein the control solution is formulated as: taking a proper amount of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol, precisely weighing, and quantitatively diluting with a mixed solvent, namely acetone and n-hexane (volume ratio is 1: 9) to prepare a solution containing about 7.5 mu g of 1, 3-dichloro-2-propanol and 12.5 mu g of R-3-chloro-1, 2-propanediol in each 1ml as a reference stock solution. Precisely measuring the reference substance stock solutions 0.2ml, 0.5ml, 0.8ml, 1.0ml, 1.2ml and 1.5ml respectively, placing in a 10ml measuring flask, and diluting to scale with a blank solvent to obtain the reference substance series standard solution.
In a preferred embodiment of the invention, the invention provides a method for detecting residual chloropropanol compounds in ornidazole, which adopts headspace gas chromatography and detects according to the following detection conditions and operations:
precisely weighing about 1.0g of ornidazole, placing in a 10ml iodine flask, adding 4.0ml of mixed solvent namely acetone and n-hexane (1: 9), sealing, oscillating for 10 minutes at 50 times per minute by a speed-regulating oscillator, carrying out ice water bath for 30 minutes, filtering with a 0.22 mu m nylon membrane, and taking the subsequent filtrate to return to room temperature to serve as a sample solution;
taking another appropriate amount of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol, precisely weighing, and quantitatively diluting with blank solvent to obtain a solution containing about 7.5 μ g of 1, 3-dichloro-2-propanol and 12.5 μ g of R-3-chloro-1, 2-propanediol per 1ml as a reference stock solution;
precisely measuring the reference substance stock solutions 0.2ml, 0.5ml, 0.8ml, 1.0ml, 1.2ml and 1.5ml respectively, placing in a 10ml measuring flask, and diluting to scale with a blank solvent to obtain a reference substance series standard solution;
capillary (DIKMA DIKMA DM-1701 column 30 m. times.0.32 mm. times.0.5 μm) using 14% cyanopropylene and 86% dimethylpolysiloxane as a fixing solution as a column for chromatography, support: high-purity nitrogen; flow rate of carrier gas: 1.5ml per minute; a detector: a hydrogen Flame Ionization Detector (FID); detector temperature: 250 ℃; sample inlet temperature: 230 ℃; sample introduction volume: 2.0 μ l; column temperature: the initial temperature is 50 ℃, the temperature is maintained for 5 minutes, the temperature is increased to 140 ℃ at the rate of 12 ℃ per minute, the temperature is maintained for 5 minutes, the temperature is increased to 160 ℃ at the rate of 20 ℃ per minute, and the temperature is maintained for 2 minutes;
carrying out split-flow sample injection with a split-flow ratio of 2:1, taking 2.0 μ l of each control strain solution, respectively injecting into a gas chromatograph, and recording a chromatogram map, wherein the linear correlation coefficient of a target object is more than 0.990; precisely measuring the sample solutions with 2.0 μ l each, respectively injecting into a gas chromatograph, and recording the chromatogram;
calculated by peak area according to a standard curve method, the 1, 3-dichloro-2-propanol is not more than 0.0015 percent, and the R-3-chloro-1, 2-propanediol is not more than 0.0025 percent.
In a preferred embodiment of the invention, the ornidazole may be levoornidazole.
The boiling point of 1, 3-dichloro-2-propanol is 174 ℃, the boiling point of R-3-chloro-1, 2-propanediol is 213 ℃, the sensitivity of headspace sample injection cannot meet the measurement requirement, and the sample injection mode selects liquid to directly inject samples. The results of thermogravimetric analysis experiments of the levoornidazole show that the sample begins to lose after 140 ℃, which indicates that the direct sample injection may interfere the peak generation of the target substance. In order to strictly control the quality of the levonidazole and efficiently detect the residual quantity of the 1, 3-dichloro-2-propanol and the 3-chloro-1, 2-propanediol in the active ingredients of the levonidazole and sodium chloride injection, the invention screens a sample pretreatment mode, a detector type, a diluting solvent and a chromatographic column through a large number of experiments.
1. The invention respectively considers two sample pretreatment modes of extraction concentration and dispersion extraction for the sample pretreatment mode. The test result shows that the sample preparation method of dispersive extraction is adopted, the influence of sample residues on the subsequent analysis procedure is small, and the interference on the target object is avoided.
2. The invention respectively considers the types of the dilution solvents, namely dimethyl sulfoxide and water, normal hexane and dichloromethane, and normal hexane and acetone. The result shows that when the mixed solvent of normal hexane and acetone is used as the diluting solvent, the requirements of solution homogeneous phase and separation degree from a target object can be met, and the difference of the solubility of a control and a sample is effectively utilized to realize the requirement of determination.
3. The invention respectively considers the proportion of acetone in n-hexane to be 8%, 10% and 12% for the proportion of the diluting solvent. The test result shows that the acetone proportion is 10%, the linear correlation coefficient is good, the dissolving capacity of the mixed solvent to the target object meets the determination requirement, and the sample interference is within the acceptable range.
4. The present invention looks at the hydrogen Flame Ionization Detector (FID) and the Electron Capture Detector (ECD) separately for the detectors. The target has tailing phenomenon on the ECD detector, tailing factor is larger than 3.0, peak type on FID is good, and the FID is selected as the detector.
5. In the present invention, DB-5 column (30 m.times.0.53 mm.times.1.0 μm), HP-5 column (30 m.times.0.32 mm.times.0.5 μm), DB-WAXETR column (60 m.times.0.32 mm.times.1.0 μm), and DM-1701 column (30 m.times.0.32 mm. times.0.5 μm) were examined for each column. The experimental results show that the Dima DM-1701 (30 m multiplied by 0.32mm multiplied by 0.5 μm) meets the requirements of separation degree, sensitivity and tailing factor.
Has the advantages that: the quality control method of chloropropanol in levoornidazole provided by the invention has the following advantages:
according to the structural property physicochemical characteristics of residual genotoxic impurity components in the levoornidazole, a large number of experiments screen out special sample pretreatment modes, the proportion of a mixed solvent, the optimal detector type, chromatographic columns and other analysis conditions, and multiple experimental verifications show that the quality control method for chloropropanol in the levoornidazole provided by the invention has good stability and good separation degree of various analysis components, effectively solves the interference of the levoornidazole on a target object, and can sensitively and accurately quantitatively detect and analyze various compounds. Therefore, the quality control method of chloropropanol in the levoornidazole provided by the invention can objectively, comprehensively and accurately evaluate the quality of the active ingredient of the levoornidazole sodium chloride injection, and has extraordinary significance for controlling the quality of the levoornidazole and ensuring the safety of clinical medication.
Drawings
FIG. 1 is a gas chromatography analysis chart of a control mixture of 1, 3-dichloro-2-propanol and 3-chloro-1, 2-propanediol obtained in example 1.
Fig. 2 is a gas chromatography detection analysis diagram of the l-ornidazole sample of example 1.
Detailed Description
Embodiments of the present invention are further illustrated by the following specific examples. The invention is capable of modifications in various equivalent manners, such as those skilled in the art, which fall within the scope of the invention.
Example 1
The quality control method of chloropropanol in the ornidazole comprises the following steps:
(1) diluting the solution: the volume ratio of acetone to n-hexane is 1:9
(2) Preparing a levoornidazole sample solution: the method comprises the steps of precisely weighing about 1.0g of levoornidazole 5 batches (YF 02-FP-01 batch, YF02-FP-02 batch, YF02-FP-03 batch, YF02-FP-04 batch and YF02-FP-05 batch) produced by Jiangsu Yunyang group pharmaceutical Co., Ltd, placing the weighed levoornidazole into a 10ml iodine measuring flask, adding 4.0ml of mixed solvent namely acetone and n-hexane (volume ratio is 1: 9), sealing the flask, oscillating the flask for 10 minutes 50 times per minute by a speed-regulating oscillator, carrying out ice water bath for 30 minutes, filtering the flask by a 0.22 mu m nylon membrane, and taking a subsequent filtrate to return to room temperature to be used as a sample solution.
(3) Preparing a standard curve of a reference substance: taking a proper amount of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol, precisely weighing, and mixing with a mixed solvent, namely acetone: n-hexane (volume ratio of 1: 9) was quantitatively diluted to a solution containing about 7.5. mu.g of 1, 3-dichloro-2-propanol and 12.5. mu.g of R-3-chloro-1, 2-propanediol per 1ml, and used as a stock solution of a control. Precisely measuring the reference substance stock solutions 0.2ml, 0.5ml, 0.8ml, 1.0ml, 1.2ml and 1.5ml respectively, placing in a 10ml measuring flask, and diluting to scale with a blank solvent to obtain the reference substance series standard solution.
(4) And (3) determining the residual amount of chloropropanol in a sample: sampling the reference solution, and recording a chromatogram; sampling the sample solution and the reference solution, and recording the chromatogram. Chromatographic conditions are as follows: a chromatographic column: a capillary tube (DIKMA DM-1701 column 30 m. times.0.32 mm. times.0.5 μm) using 14% cyanopropylene and 86% dimethylpolysiloxane as a fixing solution; carrier: high-purity nitrogen; flow rate of carrier gas: 1.5ml per minute, split sample injection, split ratio 2: 1; a detector: a hydrogen Flame Ionization Detector (FID); detector temperature: 250 ℃; sample inlet temperature: 230 ℃; sample introduction volume: 2.0 μ l; column temperature: the starting temperature was 50 ℃ for 5 minutes, 12 ℃ per minute to 140 ℃ for 5 minutes, and 20 ℃ per minute to 160 ℃ for 2 minutes.
Respectively injecting 2.0 μ l of each control strain solution into a gas chromatograph, and recording the chromatogram, wherein the linear correlation coefficient of the target object is more than 0.990; then, 2.0. mu.l of each sample solution was measured precisely and injected into a gas chromatograph, and the chromatogram was recorded (reference sample shown in FIG. 1, sample shown in FIG. 2).
In the quality control method of chloropropanol, step (3), the peak area of 1, 3-dichloro-2-propanol is used as ordinate, the concentration (mug/ml) is used as abscissa, and a standard curve is drawn as: Y-5.5492X-1.2618, r-0.9997; taking the peak area of the 3-chloro-1, 2-propanediol as the ordinate and the concentration (mug/ml) as the abscissa, a standard curve is drawn as follows: Y3.2627X-7.4146 and r 0.9968.
Through the analysis, the linear relation of the standard curves of the compounds is good, and the r value reaches more than 0.99. Therefore, the analysis method provided by the invention is accurate and reliable, can be used for sensitively, accurately, qualitatively and quantitatively detecting the chloropropanol, the detected amount of the impurity 1, 3-dichloro-2-propanol is less than 0.0015 percent, and the detected amount of the 3-chloro-1, 2-propanediol is less than 0.0025 percent, and also shows the quality reliability of the sample. Provides scientific basis for the quality control of the levoornidazole.
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 (7)
1. A detection method for residual chloropropanol compounds in a medicine is characterized in that the medicine is a levoornidazole raw material medicine or an ornidazole raw material medicine, and the detection method adopts a gas chromatography and carries out detection according to the following detection conditions and operations:
the detection conditions include:
a chromatographic column: DIKMADM-1701 column, 30 m.times.0.32 mm.times.0.5 μm
Carrier gas: nitrogen gas
Flow rate of carrier gas: 1 ml/min-3 ml/min
A detector: hydrogen flame ionization detector
Detector temperature: 220-280 deg.C
Sample inlet temperature: 200-250 deg.C
Sample introduction volume: 1.0-5.0 mul
Column temperature: the initial temperature is 50 ℃, the temperature is maintained for 5 minutes, the temperature is raised to 140 ℃ at the rate of 12 ℃ per minute, the temperature is maintained for 5 minutes, the temperature is raised to 160 ℃ at the rate of 20 ℃ per minute, and the temperature is maintained for 2 minutes;
dissolving the medicine by using a mixed solvent of acetone and n-hexane in a volume ratio of 1:9 to obtain a test solution; dissolving one or two of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol by using a mixed solvent of acetone and n-hexane in a volume ratio of 1:9 as a reference solution;
sampling the reference solution, and recording a chromatogram; sampling the sample solution and the reference solution, and recording the chromatogram.
2. The assay of claim 1, wherein the test solution is formulated as: precisely weighing about 1.0g of the medicine, placing the medicine in a 10ml iodine measuring flask, adding 4.0ml of acetone-n-hexane with the volume ratio of 1:9, sealing, oscillating for 10 minutes at 50 times per minute by a speed-regulating oscillator, carrying out ice-water bath for 30 minutes, filtering by a 0.22 mu m nylon membrane, and taking the subsequent filtrate to return to room temperature to serve as a test solution.
3. The assay of claim 2, wherein the control solution is formulated as: taking a proper amount of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol, precisely weighing, quantitatively diluting with acetone and n-hexane in a volume ratio of 1:9 to prepare a solution containing 7.5 mu g of 1, 3-dichloro-2-propanol and 12.5 mu g of R-3-chloro-1, 2-propanediol in each 1ml, and taking the solution as a reference substance stock solution; precisely measuring the reference substance stock solutions 0.2ml, 0.5ml, 0.8ml, 1.0ml, 1.2ml and 1.5ml respectively, placing in a 10ml measuring flask, and diluting to scale with a blank solvent to obtain the reference substance series standard solution.
4. The detection method according to any one of claims 1 to 3, wherein the chloropropanol compound is one or both of 1, 3-dichloro-2-propanol and R-3-chloro-1, 2-propanediol.
5. The detection method according to any one of claims 1 to 3, wherein the gas chromatography employs split-flow injection.
6. The detection method according to claim 5, wherein the split ratio of the split sample injection is 2: 1.
7. The detection method according to any one of claims 1 to 3, wherein the carrier gas flow rate is 1.5ml/min, the detector temperature is 250 ℃, the injection port temperature is 230 ℃, and the injection volume is 2.0 μ l.
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