CN112209882A - Levoornidazole impurity C and preparation method and application thereof - Google Patents
Levoornidazole impurity C and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a levoornidazole impurity C and a preparation method and application thereof. The preparation method comprises the following steps: (1) reacting the levoornidazole and an oxidant in an organic solvent; (2) and carrying out post-treatment on the reaction liquid to obtain the ornidazole impurity C. Also discloses the application of the impurity C as an impurity reference substance in the quality research of the bulk drug of the levoornidazole.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a levoornidazole impurity C and a preparation method and application thereof.
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:
nanjing sheng and pharmaceutical industry Co Ltd discloses a method for detecting an ornidazole optical enantiomer by high performance liquid chromatography in Chinese patent application CN1752749A, which comprises the following steps: (1) chromatographic conditions are as follows: the chromatographic column adopts cellulose esters as a chiral column of a stationary phase; the mobile phase is n-hexane-methyl tert-butyl ether-isopropanol-glacial acetic acid; the detection wavelength is 280 nm-340 nm. (2) And preparing the sample into a solution containing 0.05-0.5 mg/ml ornidazole racemate by adopting an organic solvent. (3) Measuring and recording a chromatogram.
Chengdu Jindian medicine science and technology development Limited company discloses a detection method and a content determination method for ornidazole injection impurities in Chinese patent application CN102539564A, and the detection method is used for detecting the impurities 2-methyl-5-nitroimidazole and 1- (3-chloro-propenyl) -2-methyl-5-nitroimidazole in ornidazole injection; HPLC detection conditions: the mobile phase is acetonitrile-water (or methanol-water) in a volume ratio of: 15-25: 75-85, and the detection wavelength of the impurity 2-methyl-5-nitroimidazole and the maximum impurity is 305-315 nm.
A quality control method of ornidazole is disclosed in Chinese patent application CN102565271A by Yangziang pharmaceutical industry group Nanjing Hailing pharmaceutical industry Limited, and high performance liquid chromatography (chromatographic conditions: chromatographic column: reversed phase C18 column, mobile phase: methanol-water-glacial acetic acid with volume ratio of 30: 70: 0.2, flow rate of 1.0ml/min, detection wavelength of 310nm, and column temperature of 30 ℃) is adopted to detect ornidazole and 2-methyl-5-nitroimidazole.
Shaanxi synthetic medicine industry, Inc. discloses an HPLC method for separating and analyzing a levoornidazole isomer in Chinese patent application CN107917979A, which adopts high performance liquid chromatography, takes amylose bonded silica gel as a filler, combines a water phase (pH value of 2-9.0) and an organic phase in a certain proportion as a mobile phase, and performs elution and separation by using gradient or isocratic elution, wherein the flow rate is 0.1-1.0 ml/min, the column temperature is 0-40 ℃, and the sample injection volume is 0.1-100 mu l.
In order to ensure the clinical medication safety of the levonidazole, the field still needs to comprehensively detect the quality of the levonidazole, particularly the detection of related substances.
Disclosure of Invention
The invention provides a levoornidazole impurity C, namely a reference substance IMP-8, which is analyzed by nuclear magnetism and mass spectrometry to confirm the chemical structure:
in a second aspect, the present invention provides a method for preparing the above-mentioned levoornidazole impurity C, i.e. the reference product IMP-8, comprising the following steps:
(1) reacting the levoornidazole and an oxidant in an organic solvent;
(2) the reaction liquid is post-treated to obtain the related impurity C of the ornidazole, namely the reference product IMP-8.
In the above production method of the present invention, the reaction temperature of the step (1) is 10 ℃ to reflux temperature, preferably 20 ℃ to 30 ℃.
In the above production method of the present invention, the reaction time of the step (1) is 12 to 24 hours, preferably 20 hours.
In the preparation method of the invention, the oxidant in the step (1) is one of hydrogen peroxide, potassium permanganate, potassium dichromate and m-chloroperoxybenzoic acid; preferably, it is m-chloroperoxybenzoic acid.
In the above preparation method of the present invention, the reaction of step (1) is carried out in an organic solvent, the organic solvent is an aprotic organic solvent, preferably, the aprotic organic solvent is one or a mixture of two or more selected from tetrahydrofuran, acetone and dichloromethane; more preferably, it is dichloromethane.
In the preparation method of the present invention, the molar ratio of the oxidant to the levoornidazole in the step (1) is (1-3): 1, preferably (1-2): 1.
In the above preparation method of the present invention, the post-treatment of step (2) is: filtering, collecting filtrate, and purifying by column chromatography to obtain impurity C, i.e. IMP-8 as reference substance.
In the above preparation method of the present invention, the column chromatography purification is: the volume ratio is 70: eluting with dichloromethane and methanol at the ratio of 1-10: 1.
In a third aspect, the invention provides the reference product IMP-8, which is the levoornidazole impurity C with a purity meeting the requirement, prepared by the preparation method, and the reference product IMP-8 is used as an impurity reference product in the quality research of the levoornidazole raw material medicine and/or is used for controlling the quality of the levoornidazole raw material medicine.
Has the advantages that: the quality control method of the levoornidazole impurity C provided by the invention has the following advantages:
according to the structural properties and physicochemical characteristics of various related substance components in the levoornidazole, the analysis conditions such as the optimal detection wavelength, mobile phase screening, degradation test and the like are screened out through a large number of experiments, and multiple experimental verifications show that the quality control method of the related substance in the levoornidazole, provided by the invention, can effectively detect the increase of 3 known impurities to 8 known impurities in the existing method by adopting a dual-wavelength and gradient elution mode, has good stability and good separation degree on various analysis components, and can sensitively and accurately quantitatively detect and analyze various compounds. Therefore, the quality control method of the related substances in the levoornidazole can objectively, comprehensively and accurately evaluate the quality of the active ingredient of the levoornidazole sodium chloride injection, and has important significance for controlling the quality of the levoornidazole and ensuring the safety of clinical medication.
Drawings
FIG. 1 shows a UV scanning spectrum of IMP01 as a control in test example 1;
FIG. 2A is a chart showing the suitability of the system for HPLC at a wavelength of 318nm in test example 2;
FIG. 2B is a chart showing a control HPLC of the impurity at a wavelength of 318nm in test example 2;
FIG. 2C is a HPLC chart of a sample at a wavelength of 318nm in test example 2;
FIG. 2D is a 100% standard sample HPLC plot at 318nm in test example 2;
FIG. 2E is a chart showing the suitability of the system for HPLC at a wavelength of 210nm in test example 2;
FIG. 2F shows a control HPLC plot of the impurity at 210nm wavelength in test example 2;
FIG. 2G is a HPLC chart of a sample at a wavelength of 210nm in test example 2;
FIG. 2H shows a 100% standard sample HPLC plot at 210nm in test example 2;
FIG. 3A is a chart showing the applicability of the system at a wavelength of 318nm in HPLC in comparative example 1;
FIG. 3B is a chart showing the applicability of the system at a wavelength of 210nm in comparative example 1 by HPLC;
FIG. 3C shows a HPLC plot of IMP01 at 318nm in comparative example 1;
FIG. 3D shows a HPLC plot of IMP08 at a wavelength of 210nm in comparative example 1.
Detailed Description
The technical scheme of the invention is further illustrated by the following specific examples; it should be understood that the following examples are not intended to limit the scope of protection.
The determination of MS in the following examples of the control IMP08 used a time-of-flight mass spectrometer (ESI), manufacturer: waters, model: LCT Premier. Nuclear magnetic measurements were performed using a nuclear magnetic resonance spectrometer, manufacturer: bruker, model Bruker AV 400.
Example 1
Adding levoornidazole (5 g, 22.7 mmol) and m-chloroperoxybenzoic acid (7.86 g, 45.4 mmol) into 100ml of dichloromethane, controlling the temperature to be 20-30 ℃, and reacting for 20 hours. After the reaction, insoluble matter was removed by filtration. The filtrate was collected, column chromatographed (eluent change dichloromethane: methanol = 70: 1) and concentrated to dryness to give 5g of a yellow solid. The yield thereof was found to be 93.8%.
1H-NMR（400MHz; DMSO）：δ8.512(s,1H), 5.910～5.923(d,1H), 4.650～4.692(d,1H), 4.229～4.289(t,1H), 4.048～4.078(s,1H), 3.681～3.776(m,2H), 2.459(s,3H)。
13C-NMR（400MHz; DMSO）：δ142.50, 131.93, 123.21, 69.17, 50.84, 47.01, 9.10。
Detecting positive ions by adopting an ESI source:
obtaining a reference substance IMP08 [M+H]+236 peak, [2M + H]+471 peaks, [2M + Na]+493 peak.
Example 2
Adding levoornidazole (5 g, 22.7 mmol) and m-chloroperoxybenzoic acid (7.86 g, 45.4 mmol) into 100ml of tetrahydrofuran, controlling the temperature to be 20-30 ℃, and reacting for 20 hours. After the reaction, insoluble matter was removed by filtration. Collecting the filtrate, and purifying by column chromatography. Eluent changes were in order dichloromethane: methanol = 70: 1, concentrated to dryness to give 4.5g of the yellow solid control IMP08, 84.9% yield.
Test example 1
Selection of ultraviolet wavelength
In the test examples of the present application, scanning was performed using an ultraviolet analyzer Shimadzu UV2450, a 20% methanol aqueous solution as a solvent, an IMP01 concentration as a control of 10. mu.g/ml, and an ultraviolet spectrum shown in FIG. 1, in which the wavelength of 1 was 309.50.
The reference product IMP01, the reference product IMP02, the reference product IMP03, the reference product IMP04, the reference product IMP05, the reference product IMP06 and the levoornidazole have maximum absorption near 318nm, the reference product IMP07 and the reference product IMP08 have maximum absorption near 210nm, so that the detection wavelength of the related substances is determined to be 318nm, and the detection wavelength of the reference product IMP07 and the reference product IMP08 is 210 nm.
Test results show that the maximum absorption of IMP 01-IMP 06 and the maximum absorption of the levoornidazole are within the range of 309 nm-320 nm, the maximum absorption of IMP07 and IMP08 are within the range of 200 nm-220 nm, and the wavelength of 318nm/210nm is selected as the detection wavelength for condition inspection of related substances of the product.
Test example 2
The test conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler (4.6X 250mm X5 μm)
Mobile phase: phase A: methanol phase B: water (W)
Gradient elution was performed as per the following table.
Detection wavelength: 318 nm; flow rate: 1.2 ml/min;
sample introduction volume: 40 mu l; column temperature: 30 ℃;
the specific test operation is as follows:
and (3) testing the applicability of the system: accurately weighing a proper amount of the levoornidazole and impurity reference substances IMP01, IMP02, IMP03, IMP04 and IMP06, dissolving and diluting the mixture by using a methanol water solution with the volume ratio of 20:80 to prepare a solution containing 2.5mg of the levoornidazole and 2.5 mug of each impurity per 1ml, and injecting 40 mug of the solution into a liquid chromatograph, wherein in the figure 2A, the separation degree between the levoornidazole and adjacent impurity peaks and among the impurity peaks is in accordance with the regulation.
Test solution: dissolving the product with methanol water solution with methanol-water volume ratio of 20:80, and diluting to obtain solution containing levoornidazole (C) per lml7H10ClN3O3) 2.5mg of the solution as a test solution.
Control solution: precisely measuring 1ml of test solution, placing into a 100ml measuring flask, and diluting to scale with methanol water solution with methanol-water volume ratio of 20:80 to obtain control solution.
Impurity control solution: taking appropriate amount of IMP01, IMP02, IMP03, IMP04 and IMP06 reference substances respectively, dissolving and diluting with methanol solution with the volume ratio of methanol to water of 20:80 to prepare solution containing 0.2 mug/ml of IMP02 impurity and 2.5 mug of IMP01, IMP03, IMP04 and IMP06 impurity per 1ml as impurity reference solution.
Preparing a sample labeling solution: taking about 25mg of the levoornidazole, precisely weighing, placing in a 10ml measuring flask, adding the solution of the reference substance solution 1, dissolving, diluting to scale, shaking uniformly, and taking the solution as a sample and a standard solution.
Precisely measuring 40 mu l of each of the sample solution, the reference solution, the sample standard solution and the impurity reference solution, respectively injecting into a liquid chromatograph, recording a chromatogram (the impurity reference HPLC is shown in figure 2B, the sample HPLC is shown in figure 2C, and the 100% sample standard HPLC is shown in figure 2D), deducting a solvent peak and a gradient peak in the chromatogram of the sample solution, wherein the impurity peak is shown in the chromatogram of the sample solution, IMP01, IMP03, IMP04 and IMP06 cannot exceed 0.1% by the peak area according to an external standard method, the IMP02 cannot exceed 0.008% by the peak area according to the external standard method, the peak area of other single impurities cannot be larger than 0.1% of the main component peak area of the reference solution, and the total amount of the impurities cannot exceed 0.2%.
Reference product IMP05
The test conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler (such as Waters sunfire C18, 4.6 × 150mm × 3.5 μm)
Mobile phase: methanol-water (volume ratio of 22: 78)
Detection wavelength: 310 nm; flow rate: 1.0 ml/min; sample introduction volume: 40 mu l; column temperature: 30 ℃;
the specific test operation is as follows:
and (3) testing the applicability of the system: accurately weighing a proper amount of the levoornidazole and an impurity reference product IMP05, dissolving and diluting the proper amount of the levoornidazole and the impurity reference product IMP05 by using a methanol water solution with the volume ratio of methanol to water of 20:80 to prepare a solution containing 2.5mg of the levoornidazole and 2.5 mug of each impurity per 1ml as a system applicability solution, injecting 40 mul of the system applicability solution into a liquid chromatograph, and ensuring that the separation degrees between the levoornidazole and adjacent impurity peaks and between the IMP05 peaks and adjacent impurity peaks meet the regulations.
Test solution: dissolving the product with methanol water solution with methanol-water volume ratio of 20:80, and diluting to obtain solution containing levoornidazole (C) per lml7H10ClN3O3) 2.5mg of the solution as a test solution.
Impurity control solution: taking a proper amount of IMP05 reference substances, dissolving the reference substances by using a methanol solution with the volume ratio of methanol to water being 20:80, and diluting the reference substances to prepare a solution containing 0.2 microgram/ml of IMP05 impurity per 1ml as an impurity reference solution.
Precisely measuring 40 mu l of each of the test solution and the impurity control solution, respectively injecting the test solution and the impurity control solution into a liquid chromatograph, recording the chromatogram until the retention time of the main component peak is 2 times, deducting the solvent peak and the gradient peak in the chromatogram of the test solution, wherein the IMP05 is not more than 0.008% calculated by the peak area (the sum of peak areas of double peaks) according to an external standard method if the impurity peak is present in the chromatogram of the test solution.
Reference product IMP07 and reference product IMP08
Chromatographic conditions are as follows:
a chromatographic column: octadecylsilane chemically bonded silica gel as filler (4.6X 250mm X5 μm)
Mobile phase: phase A: methanol phase B: water (W)
Gradient elution was performed as per the following table.
Detection wavelength: 210 nm; flow rate: 1.2 ml/min;
sample introduction volume: 40 mu l; column temperature: 30 ℃;
the specific test operation is as follows:
and (3) testing the applicability of the system: accurately weighing a proper amount of the levoornidazole and impurity reference products IMP07 and IMP08, dissolving and diluting the mixture by using a methanol water solution with the volume ratio of methanol to water of 20:80 to prepare a solution which contains 2.5mg of the levoornidazole and 2.5 mug of each impurity per 1ml and is used as a system applicability solution, and injecting 40 mug of the system applicability solution into a liquid chromatograph, wherein the separation degree between the levoornidazole and adjacent impurity peaks and among the impurity peaks is required to meet the specification as shown in figure 2E.
Test solution: dissolving the product with methanol water solution with methanol-water volume ratio of 20:80, and diluting to obtain solution containing levoornidazole (C) per lml7H10ClN3O3) 2.5mg of the solution as a test solution.
Impurity control solution: an appropriate amount of IMP07 and IMP08 reference substances are respectively taken, dissolved and diluted by a methanol solution with the volume ratio of methanol to water being 20:80 to prepare a solution containing 0.2 mug/ml of IMP08 impurity and 2.5 mug of IMP07 impurity per 1ml as an impurity reference solution.
Preparing a sample labeling solution: taking about 25mg of the levoornidazole, precisely weighing, placing in a 10ml measuring flask, adding the solution of the reference substance solution 3, dissolving, diluting to scale, shaking uniformly, and taking the solution as a sample and a standard solution.
Precisely measuring 40 mu l of each of the sample solution, the sample standard solution and the impurity control solution, respectively injecting into a liquid chromatograph (the impurity control HPLC is shown in figure 2F, the sample HPLC is shown in figure 2G, and the 100% sample standard HPLC is shown in figure 2H), recording a chromatogram, deducting a solvent peak and a gradient peak in the chromatogram of the sample solution, wherein the impurity peak is shown in the chromatogram of the sample solution, the IMP07 is not more than 0.1% calculated by the peak area according to an external standard method, and the IMP08 is not more than 0.008% calculated by the peak area according to the external standard method.
Specific results are shown in table 1.
TABLE 1 detection results of related substances in levoornidazole
The experimental results in table 1 show that the compounds and the reference substance in the method for detecting the related substance of the levoornidazole provided by the invention have good matching degree and good separation degree, and the experimental results show that the percentage contents of IMP01 and IMP02 impurities in the prepared levoornidazole sample are less than 0.1%, and other impurities are not detected, so that the quality reliability of the sample is also shown.
The quality control method of the ornidazole provided by the invention has good stability and repeatability, can objectively, comprehensively and accurately evaluate the quality of the ornidazole injection, and has important significance for controlling the quality of active ingredients of the ornidazole sodium chloride injection and ensuring the safety of clinical medication.
In the examples of the present invention, the chemical names and structures of the reference products IMP-1 to IMP-8 are as follows:
reference product IMP01
reference product IMP02
reference product IMP03
reference product IMP04
reference product IMP05
reference product IMP06
reference product IMP07
reference product IMP08
Comparative example 1
The experimental conditions are as follows:
mobile phase: methanol-water (20: 80 by volume);
a chromatographic column: penomenex Luna C18 (2), 4.6X 250mm, 5 μm;
flow rate: 1.2 ml/min; detection wavelength: 318nm/210 nm;
column temperature: 30 ℃; sample introduction amount: 40 μ l.
318nm system applicability HPLC chart as in FIG. 3A, 210nm system applicability HPLC chart as in FIG. 3B, experimental conclusion: the separation degree of the main peak levoornidazole and the reference products IMP 01-IMP 08 meets the regulation, but the separation degree of the impurity reference product IMP01 and the impurity reference product IMP08 is poor, the separation degree is 0.809 (210 nm, as shown in figure 3C) or 0.770 (318 nm, as shown in figure 3D), and the separation degree cannot be effectively separated.
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 (10)
1. The impurity C of the ornidazole, namely the reference product IMP-8, has a chemical structure as follows:
2. the method of preparing levoornidazole impurity C as claimed in claim 1, including the steps of:
(1) reacting the levoornidazole and an oxidant in an organic solvent;
(2) the reaction liquid is post-treated to obtain the related impurity C of the ornidazole, namely the reference product IMP-8.
3. The preparation method according to claim 2, wherein the reaction temperature of the step (1) is 10 ℃ to reflux temperature, preferably 20 ℃ to 30 ℃.
4. The preparation method according to claim 2, wherein the reaction time of the step (1) is 12 to 24 hours, preferably 20 hours.
5. The preparation method according to claim 2, wherein the oxidant in step (1) is one of hydrogen peroxide, potassium permanganate, potassium dichromate and m-chloroperoxybenzoic acid; preferably, it is m-chloroperoxybenzoic acid.
6. The production method according to any one of claims 2 to 5, wherein the reaction of step (1) is carried out in an organic solvent which is an aprotic organic solvent, preferably a mixture of one or two or more selected from tetrahydrofuran, acetone and dichloromethane; preferably, dichloromethane.
7. The preparation method of any one of claims 2 to 5, wherein the molar ratio of the oxidant to the levoornidazole in step (1) is (1-3): 1, preferably (1-2): 1.
8. The production method according to any one of claims 2 to 5, wherein the post-treatment of step (2) is: filtering, collecting filtrate, and purifying by column chromatography to obtain impurity C, i.e. IMP-8 as reference substance.
9. The preparation method of claim 8, wherein the column chromatography purification is: the volume ratio is 70: 1 to 10:1 of dichloromethane was eluted with methanol.
10. Use of the levoornidazole impurity C as claimed in claim 1 as an impurity control in a levoornidazole drug substance quality study, and/or to control the quality of a levoornidazole drug substance.
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| CN107917979A (en) * | 2016-10-11 | 2018-04-17 | 陕西合成药业股份有限公司 | A kind of HPLC methods for separating analysis l-ornidazole isomers |
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