CN110487918A - The analysis method of genotoxicity impurity in Pantoprazole Sodium and its starting material - Google Patents
The analysis method of genotoxicity impurity in Pantoprazole Sodium and its starting material Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N30/14—Preparation by elimination of some components
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
Abstract
The invention belongs to Pharmaceutical Analysis chemical fields, and in particular to two kinds of methods analysis measurement Pantoprazole Sodium and its synthesize latent gene toxic impurities in starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole.This method uses octadecylsilane chemically bonded silica for stationary phase, carries out analysis measurement using mass detector；The mobile phase is the aqueous solution containing acetonitrile, methanol and organic ammonium salt；The structure type of the latent gene toxic impurities includes halogenated methyl pyridines, azepine aryl N- oxide-based, N- acylated amino group benzene class, aromatic amine and nitrobenzene compounds.This method is not only able to achieve Pantoprazole Sodium and its synthesizes latent gene toxic impurities in starting material and efficiently separates, and can accurately be quantitative determined to the genotoxicity impurity, the high sensitivity of method, and specificity is strong；Experimental implementation is easy, quick, has great importance to the quality control of Pantoprazole Sodium and drug safety.
Description
Technical field
The invention belongs to Pharmaceutical Analysis chemical fields, and in particular to the analysis measurement side of two kinds of latent gene toxic impurities
Method is respectively used to potential base in Pantoprazole Sodium and its synthesis starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Analysis and Limit Test because of toxic impurities.
Background technique
Pantoprazole Sodium (Pantoprazole Sodium), entitled 5- difluoro-methoxy -2- [[(3, the 4- dimethoxies of chemistry
Base -2- pyridyl group)-methyl] sulfinyl] -1H- benzimidazole sodium-hydrate, molecular formula C16H14F2N3O4S·H2O,
Structural formula are as follows:
Pantoprazole Sodium is a kind of proton pump inhibitor, can act on DA-2 receptor, selectively acting highly selectively
In gastric mucosa parietal cell, inhibit H in cell wall+/K+Atpase activity makes the H in parietal cell+It cannot be transported in stomach, to press down
The secretion of gastric acid processed.Pantoprazole Sodium be bleeding caused by treating peptic ulcer and acute gastric mucosal it is a kind of safely, have
The drug of effect has very high curative rate to peptic ulcer and Reflux exophagitis.The medicine compares Omeprazole under conditions of weak acid
Stablize with Lansoprazole, does not influence metabolism of the other drugs in liver.The medical instrument has higher selectivity and bioavilability, In
Foreign countries are widely used to the acid-related diseases such as treatment peptic ulcer, Zhuo-Ellison syndrome and reflux esophagitis, and take
Obtain satisfied curative effect.Pantoprazole Sodium powder ampoule agent for injection (is now renamed as military field by German hectogram pharmaceutical factory (Byk Gulden)
Pharmaceutical factory) it takes the lead in succeeding in developing, in October, 1994 in South Africa Initial Public Offering, trade name Pantoloc；And in December, 1998
Administrative protection was obtained in China in 30th, is terminated in June, 2005.Up to the present, 16 pharmacy corporation productions of SFDA approved
Pantoprazole sodium, share 141 pharmacy corporations be approved to produce its enteric coatel tablets, capsulae enterosolubilis, powder injection formulation and enteric it is micro-
The preparation of a variety of dosage forms such as pill capsule.
About the synthesis of Pantoprazole Sodium, document report majority with 2- chloromethyl-3,4-dimethoxypyridine hydrochloride and
5- difluoro-methoxy -2-mercaptobenzimidazole is starting material.The compound and synthesis technology patent for being related to this product mainly have: closing
In the compound patent of Pantoprazole Sodium be by BYK GULDEN LOMBERG company in application on June 16th, 1984 (priority
Day), Patent No. EP0166287；Compound patent about Pantoprazole sodium-hydrate is EP0533790.
Latent gene toxic impurities (Potential Genotoxic Impuriti, PGI) refer to alert with genetoxic
Show the impurity of structure, but and without experiment test model verifying." potentiality " said here refers to the potentiality of genetoxic,
Rather than the potentiality of impurity.In the synthesis process of Pantoprazole Sodium, used starting material 2- chloromethyl -3,4- dimethoxy
Issuable by-product Pantoprazole sulfone N- oxide in ylpyridine hydrochloride and synthesis process is deposited in chemical structure
In the caution structure segment of latent gene toxicity.Simultaneously it was also found that another starting material 5- difluoro first of Pantoprazole Sodium
In the synthetic route of oxygroup -2- sulfydryl -1H- benzimidazole, it is related in multiple chemical structures that there are genotoxicity caution structures
Starting material, intermediate and the possible by-product of segment.These impurity structures and title with latent gene toxicity indicate such as
Under:
The structure (impurity A, impurity B) of latent gene toxic impurities in Pantoprazole Sodium:
Structure (the impurity C~impurity of 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole and its latent gene toxic impurities
H):
5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Impurity A: 2- chloromethyl -3,4- dimethoxy pyridine hydrochloride impurity B: Pantoprazole sulfone N- oxide
Impurity C:4- difluoro-methoxy-aniline impurity D:N- (4- difluoro-methoxy phenyl) acetyl
Amine
Impurity E: difluoro-methoxy -1,2 4-,-phenylenediamine impurity F: N- [2- nitro -4- difluoromethoxy phenyl
Base] acetamide
Impurity G:2- nitro -4- difluoro-methoxy-aniline impurity H:4- amino-phenol
In order to preferably control the quality of Pantoprazole Sodium finished product, the safety of medication is improved, is needed to therein potential
Genotoxicity impurity carries out separation determination, according to the relevant regulations of guideline ICH M7, checks that latent gene toxic impurities are
It is no to go beyond the limit.It is 80mg according to the maximum of taking daily of Pantoprazole preparation of sodium, it is small with genotoxicity limit of impurities level
It is calculated in 1.5 μ g/day, the control limit of the genotoxicity impurity (impurity A and impurity B) in Pantoprazole Sodium is set as
0.001%, genotoxicity impurity (impurity C~impurity H) in starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Control limit is set as 0.002%.
Currently, the method for separating and assaying about genotoxicity impurity in separation determination Pantoprazole Sodium and its starting material is not
Seeing has disclosed report.Therefore, we are respectively used to Pantoprazole Sodium using two kinds of analysis methods of LC-MS technological development
And its synthesize the analysis and limit of latent gene toxic impurities in starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Measurement.It is extremely important to the quality control and the safety assurance of drug of Pantoprazole Sodium.
Summary of the invention
The purpose of the present invention is to provide the analysis determining methods of two kinds of latent gene toxic impurities, can effectively realize and dissolve
Support draws azoles sodium and its synthesizes point of latent gene toxic impurities in starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
From measurement and running water.The sensitivity of both methods is high, and specificity is strong；Examination on experimental operation is easy, quick simultaneously.
To achieve the above object, the technical solution of the present invention is as follows:
Separation determination Pantoprazole Sodium, 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole and latent gene toxic impurities
Method, the method is separated by solid-liquid separation using 18 silane group silica gel as stationary phase, and the mobile phase is to contain acetonitrile, first
The aqueous solution of pure and mild ammonium acetate.
The structural formula of the Pantoprazole Sodium and its starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole is such as
Under:
Latent gene toxic impurities (PGI) refer to the impurity with genetoxic caution structure, but and test without experiment
Model verifying." potentiality " said here refers to the potentiality of genetoxic, rather than the potentiality of impurity.In Pantoprazole Sodium
Synthesis process in, can in used starting material 2- chloromethyl-3,4-dimethoxypyridine hydrochloride and synthesis process
The by-product Pantoprazole sulfone N- oxide that can be generated, chemical structure
It is middle that there are the caution structure segments of latent gene toxicity.Simultaneously it was also found that another starting of Pantoprazole Sodium
In the synthetic route of raw material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole, it is related in multiple chemical structures that there are genes
Starting material, intermediate and the possible by-product of toxicity caution structure segment.
Further, the latent gene toxic impurities include that halogenated methyl pyridines, azepine aryl N- be oxide-based, N- acyl
Change the one or more of aminobenzene class, aromatic amine and nitrobenzene compounds.Impurity structural formula is as follows:
The structure (impurity A, impurity B) of latent gene toxic impurities in Pantoprazole Sodium:
Structure (the impurity C~impurity of latent gene toxic impurities in 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
H):
Further, ammonium acetate solution-acetonitrile mixed solution is used to carry out isocratic elution as mobile phase I, to dissolving Tuo La
Two kinds of latent gene toxic impurities in azoles sodium are analyzed；It is molten with ammonium acetate solution-methanol mixing containing 0.1% formic acid
Liquid carries out isocratic elution as mobile phase II, to six kinds in starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Latent gene toxic impurities are analyzed.
Further, the volume ratio of ammonium acetate solution and acetonitrile is 30:70~50:50 in the mobile phase I；Flowing
Ammonium acetate solution (containing 0.1% formic acid) and the volume ratio of methanol are 50:50~70:30 in phase II.
Further, the concentration of ammonium acetate solution is 0.01mol/L~0.1mol/L in the mobile phase.
Further, the specification of the chromatographic column be 150mm × 4.6mm, 5 μm or 250mm × 4.6mm, 5 μm or 150mm ×
3.0mm,3.5μm。
Further, the detector of the method is mass detector, using electric spray ion source (ESI), cation scanning
Mode, MRM detection pattern are determined according to the chemical structure of each latent gene toxic impurities and cracking rule using respectively exclusive
It measures ion pair and carries out qualitative and quantitative analysis.
The quota ion pair and lytic pathway of each latent gene toxic impurities are as follows:
Further, the measuring method of the gene poison impurity, comprising the following steps:
(1) take Pantoprazole sodium sample appropriate, it is accurately weighed, it is dissolved with solvent and dilutes that concentration is made is the molten of 1mg/mL
Liquid is as test solution；It separately takes impurity A and impurity B sample appropriate, dissolved with solvent and dilutes that concentration is made is 10ng/mL's
Solution is as contrast solution；Test solution and contrast solution 10uL sample introduction are taken respectively, record each impurity quota ion pair respectively
Under ion flow graph, according to external standard method press calculated by peak area impurity content.
(2) take 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole sample appropriate, it is accurately weighed, it is dissolved with solvent and dilute
Release be made concentration be 10mg/mL solution as test solution；It separately takes impurity C~impurity H sample each appropriate, is dissolved with solvent
And dilute be made concentration be 200ng/mL solution as contrast solution；Take respectively test solution and contrast solution 10uL into
Sample records the ion flow graph under each impurity quota ion pair respectively, presses calculated by peak area impurity content according to external standard method.
Further, the solvent is methanol or acetonitrile solution.
Further, the flow velocity of the mobile phase is 0.3ml/min~1.0ml/min.
Further, the chromatographic column column oven temperature of stating is 30 DEG C~50 DEG C.
Stationary phase and mobile phase in the present invention is in separation determination Pantoprazole Sodium and its synthesis starting material (5- difluoro first
Oxygroup -2- sulfydryl -1H- benzimidazole) in latent gene toxic impurities chromatography in application, the stationary phase be octadecane
Base silane bonded silica gel, mobile phase are the aqueous solution containing acetonitrile, methanol and organic ammonium salt, and the chromatography specifically includes efficiently
Liquid chromatogram, LC-MS chromatography, thin-layer chromatography etc..
The beneficial effects of the present invention are: the present invention provides the analysis methods of two kinds of latent gene toxic impurities, respectively
For latent gene in pantoprazole sodium and its synthesis starting material 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
The analysis of toxic impurities and Limit Test.The structure type of the latent gene toxic impurities includes halogenated methyl pyridines, nitrogen
Heteroaryl N-oxide class, N- acylated amino group benzene class, aromatic amine and nitrobenzene compounds.This method can not only be realized
Latent gene toxic impurities efficiently separate in Pantoprazole Sodium and its synthesis starting material, and can be to the gene poison
Property impurity accurately quantitative determined, the specificity of method is strong, and accuracy is high；Examination on experimental operation is easy, quick simultaneously, right
The quality control and the safety assurance of drug of Pantoprazole Sodium are extremely important.
Detailed description of the invention
Fig. 1 be Pantoprazole Sodium in embodiment 1 HPLC-MS figure (chromatographic peak in Fig. 1 is the ion stream of Pantoprazole Sodium
Peak, retention time are 4.1min or so).
Fig. 2 is that (chromatographic peak in Fig. 2 is the ion stream peak of impurity A, when reservation for the HPLC-MS figure of impurity A in embodiment 1
Between for 5.1min or so).
Fig. 3 is that (chromatographic peak in Fig. 3 is the ion stream peak of impurity B, when reservation for the HPLC-MS figure of impurity B in embodiment 1
Between for 3.2min or so).
Fig. 4 is that the HPLC-MS of Pantoprazole Sodium and impurity A and impurity B mixed solution schemes the (chromatography in Fig. 4 in embodiment 1
Peak is followed successively by the ion stream peak of impurity B, Pantoprazole Sodium and impurity A, retention time be followed successively by 3.203min, 4.135min and
5.148min)。
Fig. 5 is that the HPLC-MS of 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole in embodiment 2 schemes the (chromatography in Fig. 5
Peak is the ion stream peak of 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole, and retention time is 15.4min or so).
HPLC-MS that Fig. 6 is impurity C in embodiment 2 figure (the ion stream peak that the chromatographic peak in Fig. 6 is impurity C, when reservation
Between for 8.5min or so).
HPLC-MS that Fig. 7 is impurity D in embodiment 2 figure (the ion stream peak that the chromatographic peak in Fig. 7 is impurity D, when reservation
Between for 20.2min or so).
Fig. 8 is that (chromatographic peak in Fig. 8 is the ion stream peak of impurity E, when reservation for the HPLC-MS figure of impurity E in embodiment 2
Between for 5.9min or so).
Fig. 9 is that (chromatographic peak in Fig. 9 is the ion stream peak of impurity F, when reservation for the HPLC-MS figure of impurity F in embodiment 2
Between for 26.2min or so).
(the ion stream peak that the chromatographic peak in Figure 10 is impurity G retains the HPLC-MS figure that Figure 10 is impurity G in embodiment 2
Time is 36.8min or so).
(the ion stream peak that the chromatographic peak in Figure 11 is impurity H retains the HPLC-MS figure that Figure 11 is impurity H in embodiment 2
Time is 3.0min or so).
Figure 12 is 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole and each impurity (impurity C~impurity H) in embodiment 2
(chromatographic peak in Figure 12 is followed successively by impurity H, impurity E, impurity C, 5- difluoro-methoxy -2- mercapto to the HPLC-MS figure of mixed solution
The ion stream peak of base -1H- benzimidazole, impurity D, impurity F and impurity G, retention time be followed successively by 3.005min, 5.896min,
8.484min, 15.442min, 20.099min, 25.996min and 36.177min).
Specific embodiment
Below with reference to attached drawing, the present invention is further elaborated in conjunction with specific embodiments, and illustrated embodiment is in order to more
The contents of the present invention are illustrated well, rather than are limited the invention.Institute is experimentally such as without spy in embodiment
Different explanation, is conventional method；Used material, reagent etc. unless otherwise specified, can obtain from commercial channels.Therefore
Those skilled in the art carry out nonessential modifications and adaptations according to foregoing invention content, still fall within protection of the invention
Range.
The method of separating and assaying of latent gene toxic impurities in embodiment 1, Pantoprazole Sodium
(1) instrument and condition
The triple level four bars mass spectrometer of Shimadzu LC-MS/MS8050 type high performance liquid chromatography；
Chromatographic column: Alltima C18Chromatographic column (150mm × 4.6mm, 5 μm)；
Mobile phase: 0.02mol/L ammonium acetate: acetonitrile (40: 60)；
Flow velocity: 0.5ml/min；
Column temperature: 40 DEG C；
Sampling volume: 10 μ L；
Solvent: acetonitrile-water (50:50).
Mass Spectrometry Conditions: it uses electric spray ion source (ESI), cation scan pattern；
Atomization gas, dry gas, heating gas are nitrogen, and collision gas is argon gas；
Atomization gas flow velocity is 3L/min；
Dry gas stream speed is 10.0L/min；
Heating gas velocity is 10.0L/min；
Interface temperature is 300 DEG C；
Curved heating tube (DL) temperature is 250 DEG C；
Heating resistance temperature is 400 DEG C；
Collision induced dissociation (CID) air-flow is 270Kpa；
MRM detection pattern: impurity A quota ion pair 188.00 → 92.10, capillary voltage (CE): -23.0；Impurity B is fixed
Measure ion pair 416.00 → 168.00, CE:-25.0；Pantoprazole Sodium quota ion pair 384.00 → 138.00, CE:-30.0.
(2) experimental procedure
Pantoprazole Sodium positions solution: precision weighs Pantoprazole sodium sample 10.06mg, sets in 10mL volumetric flask, solubilization
Scale is dissolved and is diluted in agent, is shaken up, as Pantoprazole Sodium stock solution；Precision measures 10 μ L of stock solution and sets 100mL volumetric flask
In, solubilizer is diluted to scale, shakes up to obtain the final product.
Impurity A positions solution: precision weighs impurity A sample 10.01mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity A stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity B positions solution: precision weighs impurity B sample 10.03mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity B stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Mixed solution: precision measures Pantoprazole Sodium stock solution, impurity A stock solution and each 10 μ L of impurity B stock solution, sets same
In one 100mL volumetric flask, solubilizer is diluted to scale, shakes up to obtain the final product.
Test solution: with Pantoprazole Sodium stock solution.
Contrast solution: precision measures impurity A stock solution and each 10 μ L of impurity B stock solution, sets in same 100mL volumetric flask,
Solubilizer is diluted to scale, shakes up；For the accurate 1mL that measures into 10mL volumetric flask, solubilizer is diluted to scale, shakes up again to obtain the final product.
Measuring method: precision measures test solution and each 10 μ l of contrast solution, is injected separately into liquid chromatograph, record from
Son is contained to 188.00 → 92.10 and the ion flow graph of ion pair 416.00 → 168.00, according to external standard method by calculated by peak area impurity
Amount.
(3) experimental result
By Fig. 4 result it is found that Pantoprazole and impurity A and impurity B can reach baseline separation with this condition, method it is special
Attribute is good.
The content of impurity A and impurity B in the Pantoprazole Sodium of four batches is calculated using this method, by following table result
It is found that in each batch of Pantoprazole Sodium the content of impurity A and impurity B well below limit concentration (0.001%), method it is sensitive
Degree is high, and accuracy is good.
The separation determination side of latent gene toxic impurities in embodiment 2,5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole
Method
(1) instrument and condition
Shimadzu Agilent 6410B Triple Quadrupole LC-MS high performance liquid chromatography-triple quadrupole bar series connection
Mass spectrometer；
Chromatographic column: Alltima C18Chromatographic column (150mm × 4.6mm, 5 μm)；
Mobile phase: 0.005Mol/L ammonium acetate solution (contains 0.1% formic acid): methanol (60:40)
Flow velocity: 0.5ml/min；
Column temperature: 40 DEG C；
Sampling volume: 10 μ L；
Solvent: methanol.
Mass Spectrometry Conditions: ion source is electric spray ion source, cation scan pattern；
Gas Temp:300℃；
Gas Flow:10L/min；
Nebulizer:30psi；
Capillary:5500V。
MRM detection pattern, parameter are as follows:
(2) experimental procedure
Sample (5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole) positions solution: precision weighs sample 100.04mg, sets
In 10mL volumetric flask, solubilizer dissolves and is diluted to scale, shakes up, as stock sample solution；Precision measures 20 μ L of stock solution and sets
In 100mL volumetric flask, solubilizer is diluted to scale, shakes up, then the accurate 1mL that measures is set in 10mL volumetric flask, and solubilizer is diluted to
Scale shakes up to obtain the final product.
Impurity C positions solution: precision weighs impurity C sample 19.98mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity C stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity D positions solution: precision weighs impurity D sample 20.01mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity D stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity E positions solution: precision weighs impurity E sample 20.03mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity E stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity F positions solution: precision weighs impurity F sample 20.05mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity F stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity G positions solution: precision weighs impurity G sample 19.96mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity G stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Impurity H positions solution: precision weighs impurity H sample 20.01mg, sets in 10mL volumetric flask, and solubilizer dissolution is simultaneously dilute
It releases to scale, shakes up, as impurity H stock solution；Precision measures 10 μ L and sets in 100mL volumetric flask, and solubilizer is diluted to scale, shakes
It is even to obtain the final product.
Mixed solution: precision measures stock sample solution 2mL and sets in 10mL volumetric flask, and solvent is diluted to scale and shakes up；It is smart again
10 μ L of close measurement and each impurity (impurity C, D, E, F, G and H) each 10 μ L of stock solution, set in same 100mL volumetric flask, solubilization
Dilution agent shakes up to scale to obtain the final product.
Test solution: with 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole stock solution.
Contrast solution: precision measures each impurity (impurity C, D, E, F, G and H) each 10 μ L of stock solution, sets same 100mL capacity
In bottle, solubilizer is diluted to scale, shakes up to obtain the final product.
Measuring method: precision measures test solution and each 10 μ l of contrast solution, is injected separately into liquid chromatograph, and record is each
The spectrogram peak area of impurity quota ion pair presses each impurity content of calculated by peak area according to external standard method.
(3) experimental result
By Figure 12 result it is found that 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole and each impurity (impurity C~impurity H)
Baseline separation, the high-specificity of method can be reached with this condition.
It is calculated using content of this method to each impurity in three batch starting materials, by following table result it is found that each batch
The content of each impurity is well below limit concentration (0.002%) in starting material, the high sensitivity of method, and accuracy is good.
Finally, it is stated that above embodiments are only used in order to explain the technical scheme of the invention in detail rather than are limited, this field
Professional technician can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the technology of the present invention side
The objective and range of case, are intended to be within the scope of the claims of the invention.
Claims (12)
1. the analysis determining method of latent gene toxic impurities in Pantoprazole Sodium and its synthesis starting material, which is characterized in that
Chromatography point is carried out to latent gene toxic impurities under the conditions of suitable column temperature using octadecylsilane chemically bonded silica as stationary phase
From using mass detector progress analysis detection；The mobile phase is the aqueous solution containing acetonitrile, methanol and organic ammonium salt, institute
It states synthesis starting material and is selected from 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole.
2. the method according to claim 1, wherein the latent gene toxic impurities are selected from halogenated methyl pyridine
Class, azepine aryl N- be oxide-based, N- acylated amino group benzene class, aromatic amine and nitrobenzene compounds it is one or more.
3. according to the method described in claim 2, it is characterized in that, the halogenated methyl pyridines, azepine aryl N- are aoxidized
Species, N- acylated amino group benzene class, aromatic amine and nitrobenzene compounds are selected from 2- chloromethyl -3,4- dimethoxy-pyridine salt
Hydrochlorate, Pantoprazole sulfone N- oxide, 4- difluoro-methoxy-aniline, N- (4- difluoro-methoxy phenyl) acetamide, 4- difluoro first
Oxy-1,2,-phenylenediamine, N- [2- nitro -4- difluoro-methoxy phenyl] acetamide, 2- nitro -4- difluoro-methoxy-aniline and
4-aminophenol.
4. the method according to claim 1, wherein the organic ammonium salt be ammonium acetate, it is water-soluble with ammonium acetate
The mixed solution of liquid and acetonitrile carries out isocratic elution as mobile phase, to two kinds of latent gene toxic impurities in Pantoprazole Sodium
2- chloromethyl -3,4- dimethoxy pyridine hydrochloride and Pantoprazole sulfone N- oxide are analyzed；With the ammonium acetate containing formic acid
The mixed solution of aqueous solution and methanol carries out isocratic elution as mobile phase, to starting material 5- difluoro-methoxy -2- sulfydryl -
Six kinds of latent gene toxic impurities in 1H- benzimidazole are analyzed, and six kinds of latent gene toxic impurities are 4- difluoro respectively
Aminoanisole, N- (4- difluoro-methoxy phenyl) acetamide, 4- difluoro-methoxy -1,2,-phenylenediamine, N- [2- nitro -4- two
Fluorine methoxyl group phenyl] acetamide, 2- nitro -4- difluoro-methoxy-aniline and 4-aminophenol, the ammonium acetate water containing formic acid
The volume ratio of formic acid and ammonium acetate solution is 1:1000 in solution.
5. according to the method described in claim 4, it is characterized in that, the flow velocity of the mobile phase is 0.3ml/min~1.0ml/
min。
6. according to the method described in claim 4, it is characterized in that, in the mobile phase ammonium acetate solution and acetonitrile body
Product ratio is 30:70~50:50；The volume ratio of ammonium acetate solution and methanol containing formic acid is 50:50~70:30, described
The volume ratio of formic acid and ammonium acetate solution is 1:1000 in ammonium acetate solution containing formic acid.
7. according to the method described in claim 4, it is characterized in that, the concentration of ammonium acetate solution be 0.01mol/L~
0.1mol/L。
8. the method according to claim 1, wherein the mass detector carry out analysis detection when, using electricity
Esi ion source, cation scan pattern, multiple-reaction monitoring pattern according to the chemical structure of each latent gene toxic impurities and are split
Solution rule carries out qualitative and quantitative analysis using respectively exclusive quota ion pair.
9. the method according to claim 1, wherein the specification for the chromatographic column that the chromatographic isolation uses for
150mm × 4.6mm, 5 μm or 250mm × 4.6mm, 5 μm or 150mm × 3.0mm, 3.5 μm.
10. the method according to claim 1, wherein the following steps are included:
(1) take Pantoprazole sodium sample appropriate, it is accurately weighed, it is dissolved with solvent and dilutes the solution work for being made that concentration is 1mg/mL
For test solution；Separately take impurity 2- chloromethyl -3,4- dimethoxy pyridine hydrochloride and Pantoprazole sulfone N- oxide samples
In right amount, it uses solvent to dissolve and dilutes and solution that concentration is 10ng/mL is made as contrast solution；Test solution and right is taken respectively
According to solution 10uL sample introduction, the ion flow graph under each impurity quota ion pair is recorded respectively, presses calculated by peak area impurity according to external standard method
Content.
(2) take 5- difluoro-methoxy -2- sulfydryl -1H- benzimidazole sample appropriate, it is accurately weighed, it is dissolved with solvent and dilutes system
At the solution that concentration is 10mg/mL as test solution；Separately take six impurity samples each appropriate, six impurity samples are respectively
4- difluoro-methoxy-aniline, N- (4- difluoro-methoxy phenyl) acetamide, 4- difluoro-methoxy -1,2,-phenylenediamine, N- [2- nitre
Base -4- difluoro-methoxy phenyl] acetamide, 2- nitro -4- difluoro-methoxy-aniline and 4-aminophenol, are dissolved and dilute with solvent
Release be made concentration be 200ng/mL solution as contrast solution；Test solution and contrast solution 10uL sample introduction are taken respectively, point
The ion flow graph under each impurity quota ion pair is not recorded, presses calculated by peak area impurity content according to external standard method.
11. according to the method described in claim 10, it is characterized in that, the solvent is methanol or acetonitrile solution.
12. the method according to claim 1, wherein the suitable column temperature condition is 30 DEG C~50 DEG C.
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