CN109856303A - The high-sensitivity analysis method of genotoxicity impurity in Pantoprazole Sodium - Google Patents
The high-sensitivity analysis method of genotoxicity impurity in Pantoprazole Sodium Download PDFInfo
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Abstract
The invention discloses a kind of high-sensitivity analysis methods of genotoxicity impurity 2- chloromethyl-3,4-dimethoxypyridine hydrochloride (CMDP) in Pantoprazole Sodium.Using the analysis method of high performance liquid chromatography-mass spectrometry, with the mixed solution of ammonium bicarbonate soln and acetonitrile come dilute sample, and using volatile carbonate solution and acetonitrile as mobile phase, detection limit and quantitative limit are respectively 0.2ppm and 0.6ppm, it can more efficiently separate and detect impurity CMDP, strong, high sensitivity, advantage simple and fast, at low cost with specificity.
Description
Technical field
The invention belongs to Pharmaceutical Analysis detection technique fields, and in particular to genotoxicity impurity in a kind of Pantoprazole Sodium
Analysis method, relate more specifically to it is a kind of with tablets by HPLC-MS to 2- chloromethyl -3,4- dimethoxy-pyridine
The method that hydrochloride (CMDP) is separated and quantitative determined.
Background technique
Pantoprazole Sodium is a kind of novel proton pump inhibitor, for treating gastric ulcer, duodenal ulcer, esophagitis
Deng with safe and reliable, the small feature of toxic side effect.
Compound 2- chloromethyl-3,4-dimethoxypyridine hydrochloride (CMDP) is the important intermediate of Pantoprazole Sodium,
For genotoxicity impurity, it is necessary to its residual of strict control.But domestic Extra Pharmacopoeia Martindale not yet includes the quality standard of the impurity.
According to the regulation of " the genetoxic limit of impurities guideline " of European Pharmacopoeia management board (EMEA) publication, worry according to toxicology
Threshold value (TTC) is as the threshold value for evaluating most of genetoxic impurity, then genetoxic impurity intake threshold limit value
1.5ug/ it.It was counted according to Pantoprazole Sodium maximum dose 240mg/ days (40mg/ piece, 3 times/day, a two panels), the control of the impurity
Limit processed is 6.25ppm.According to testing requirements, detection limit is generally 0.1 or so of control limit, therefore detecting limit should be in 0.6ppm
Below.Conventional gas phase and liquid phase detection method is unable to satisfy this detection limit and requires, and detects and dissolves as disclosed in the prior art
Support draws the method for principal component Pantoprazole or its impurity A-F in azoles sodium raw materials or preparation.In addition, Pantoprazole Sodium and CMDP are easily sent out
Raw degradation, influences the accuracy of testing result, increases the difficulty of detection.
Document Chromatographia (2008), 68 (5/6), 481-484, which is disclosed, dissolves support with GC-MS and RP-LC detection
The method for drawing CMDP in azoles sodium.Wherein the detection of GC-MS method is limited to 1ppm, and the detection of RP-LC method is limited to 3ppm, detection spirit
Sensitivity is poor, is unable to satisfy testing requirements.
Document Journal ofPharmaceutical and Biomedical Analysis (2012), 70,592-597
It discloses and uses LCMS/MS equipment, make diluent with acetonitrile/water, acetonitrile/ammonium acetate of constant ratio does eluent, detects CMDP
Method.This method can meet testing requirements, but this method equipment is expensive, complicated for operation, not be suitable for industrialized production.
Therefore, it is the content of strict control CMDP, develops a kind of high sensitivity, detection at low cost and easily operated point
Analysis method is the problem of urgent need to resolve.
Summary of the invention
For shortcoming and deficiency existing in the prior art, the object of the present invention is to provide genes in a kind of Pantoprazole Sodium
The high-sensitivity analysis method of toxic impurities (CMDP).Present inventor uses high performance liquid chromatography-mass spectrometry equipment, leads to
It crosses to the conditions repeated screening such as mobile phase, type of elution, mass spectrum, has explored a kind of low detection limit that meets and required, and taken into account master
The detection method that ingredient is separated with impurity realizes the purpose for dividing analysis of variance CMDP simple and effectively.
The purpose of the present invention can be achieved through the following technical solutions:
The present invention provides genotoxicity impurity 2- chloromethyl-3,4-dimethoxypyridine hydrochloride in a kind of Pantoprazole Sodium
High-sensitivity analysis method, it is characterised in that: Pantoprazole sodium sample is after diluting dilution agent, using high performance liquid chromatography-
Mass Spectrometry is mobile phase elution with carbonate solution and acetonitrile.
In a preferred embodiment, the carbonate solution is ammonium bicarbonate soln or sal volatile.Due to dissolving support
Draw azoles that can be destroyed under the conditions ofs acid, highly basic, heating etc., CMDP can degrade in acid condition, to guarantee the accurate of detection
Degree, needs the pH value of strict control diluent and mobile phase.Present inventor in various alkali or salting liquid screening process,
It was found that when adjusting the pH of diluent and mobile phase by way of adding alkaline buffer solution, it is subtle during buffer preparation
Difference will cause larger difference to measurement result, therefore select single alkali or salting liquid to adjust diluent and mobile phase
pH.After a large amount of screening tests, finally found that can accurately and easily adjust pH value to conjunction using volatile carbonate solution
Suitable alkalescent, while can guarantee the stability of sample in continuous mode, meet testing requirements.
In a preferred embodiment, the concentration of the carbonate solution is 0.01-0.03mol/L, preferably 0.02mol/L.
In a preferred embodiment, the diluent is the mixed solution of ammonium bicarbonate soln and acetonitrile, sample after dilution
Product concentration is 2mg/mL.
In a preferred embodiment, the volume ratio of ammonium bicarbonate soln and acetonitrile is 5-10: 1, preferably 9: 1 in diluent.
In a preferred embodiment, the mode of mobile phase elution is gradient elution, the volume content of carbonate in eluent
For 20-80%.Point of system can be improved by adjusting the ratio of carbonate solution and acetonitrile in mobile phase using gradient elution
From ability, shorten analysis time, so that CMDP is preferably separated with other components, while more effectively guaranteeing the stabilization of sample
Property.
In a preferred embodiment, the condition of the gradient elution are as follows:
| Time (minute) | Carbonate solution (%V/V) | Acetonitrile (%V/V) |
| 0 | 80 | 20 |
| 7 | 55 | 45 |
| 10 | 20 | 80 |
| 10.01 | 80 | 20 |
| 15 | 80 | 20 |
In a preferred embodiment, 0.8~1.2mL/min of elution rate of mobile phase, the temperature of chromatographic column are 38~42
℃。
In a preferred embodiment, chromatographic column used in high performance liquid chromatography is Agilent Proshell HPH C18 column,
150*4.6mm 2.7 μm.
In a preferred embodiment, the ionization techniques of the mass spectrographic ion source are electro-spray ionization technology, spraying
Voltage is 3KV, be atomized chamber pressure 35psi, 350 DEG C of dry gas temperature.
Further, Mass Spectrometry Conditions are as shown in the table:
Compared with prior art, what the method for the present invention obtained has the beneficial effect that:
1, analysis method provided by the invention can effectively detect Pantoprazole Sodium genotoxicity impurity CMDP, specificity
By force；
2, analysis method provided by the invention can carry out quantitative analysis to CMDP, meet the requirement of detection limit 0.6ppm, spirit
Sensitivity is high；
3, analysis method provided by the invention is easy to operate, and the used time is short, reduces the decomposition of sample, and detection accuracy is high；
4, the quality and drug safety of Pantoprazole Sodium can be improved in the determination method of CMDP provided by the invention；
5, the determination method of CMDP provided by the invention, to other may in the drug containing CMDP genotoxicity it is miscellaneous
The detection of matter CMDP provides good reference.
Detailed description of the invention
Fig. 1 is the mass spectrogram of 150301PS batch sample in embodiment 1；
Fig. 2 is the linear relationship chart of CMDP during embodiment 2 is linearly investigated.
Specific embodiment
Below with reference to specific implementation the present invention is further elaborated, but these embodiments to the present invention do not constitute it is any
Limitation.
1, instrument:
Assay balance, model: Sartorius CPA225D (d=0.01mg)；BSA224S (d=0.1mg)；
High performance liquid chromatograph model Agilent Infinity1260, chromatographic column are Agilent Proshell HPH
C18,4.6 × 150mm, 2.7um, using octadecyl silane as filler；
Mass spectrum model: the single level four bars mass spectrograph of Agilent 6120.
2, reagent:
Acetonitrile (chromatographically pure), manufacturer: Fisher
Ammonium hydrogen carbonate (chromatographically pure), manufacturer: MREDA
Water (ultrapure water), manufacturer: Watson
2- chloromethyl-3,4-dimethoxypyridine hydrochloride (CMDP), lot number: 09514HDV, source: Sigma, purity:
97%
3, sample:
Pantoprazole Sodium, lot number: 150301PS, 150302PS, 150303PS, 150701PS, 150702PS,
150703PS。
Embodiment 1
Chromatographic condition:
Mobile phase: 0.02mol/L ammonium bicarbonate soln is mobile phase A, and acetonitrile is Mobile phase B；
Column temperature: 40 DEG C；
Flow velocity: 1.0mL/min；
Sample volume: 10uL；
Elution requirement is as shown in table 1 below:
Table 1
1, solution is prepared and is detected
A, the preparation of test solution:
Diluent:
3.16g ammonium hydrogen carbonate solid is taken, the ammonium bicarbonate soln that 2L obtains 0.02mol/L is added water to, takes 900mL0.02mol/
L ammonium bicarbonate soln adds 100mL acetonitrile to obtain diluent.
Test solution:
Take test sample appropriate (containing about Pantoprazole Sodium 20mg), it is accurately weighed, it sets in 10mL measuring bottle, adds diluent dissolution simultaneously
Constant volume shakes up.
B, the preparation of reference substance solution:
CMDP impurity reference substance about 10mg is taken, it is accurately weighed, it sets in 10mL measuring bottle, the appropriate ultrasound of acetonitrile is added to make to dissolve, and
With dilution in acetonitrile to scale；Precision measures 0.5mL, sets in 50mL measuring bottle, adds dilution in acetonitrile to scale, shakes up, then accurate measurement
0.6mL is set in 50mL measuring bottle, is added diluent to scale, is shaken up, the solution that obtained concentration is about 120ng/mL, as CMDP pairs
According to product solution.
C, detection method:
Taking CMDP reference substance solution 0.2mL, 1.0mL, 1.3mL, 2mL, 2.4mL to set 20mL measuring bottle respectively adds diluent fixed
Hold.Each 10 μ L of above-mentioned solution is taken, liquid chromatograph-mass spectrometer is injected, records SIM mode map.With CMDP under SIM mode
Peak area carry out linear regression, establish standard curve.10 μ L of test solution is separately taken, liquid chromatograph-mass spectrometer is injected,
Record SIM mode map.CMDP content in test sample is calculated according to standard curve.
2, measurement result
According to the method described above, 6 batches of Pantoprazole Sodium test samples are detected, the results are shown in Table 2:
Table 2
2 methodology validation of embodiment
1, specificity is investigated
A, solution is prepared
CMDP reference substance solution: CMDP reference substance solution is prepared according to method in embodiment 1.
Other impurities reference substance solution: it is prepared according to limit specified in USP40.Take Pantoprazole Sodium impurity A, B,
C, D&F mixing and impurity E reference substance are appropriate, and respectively plus diluent is quantitatively diluted in every 1mL impure A about 40ug, impurity B about
The solution of 30ug, impurity C about 20ug, impurity D&F mixing about 40ug, impurity E about 20ug, shake up, respectively as pair of each impurity
According to product solution.
Impurity positions solution: taking each impurity reference substance solution 1mL respectively, sets in 10mL measuring bottle, diluent is added to be settled to quarter
Degree positions solution respectively as each impurity.
Mixed solution: taking sodium sesquihydrate appropriate (containing about Pantoprazole Sodium 20mg), accurately weighed, sets
In 10mL measuring bottle, it is separately added into each impurity reference substance solution 1mL, adds diluent constant volume, shakes up, as mixed solution.
Blank solvent: using diluent as blank solvent.
B, detection and result
Blank solvent, each impurity positioning solution, each 10uL of mixed solution are taken, LC-MS instrument is injected separately into, records spectrogram,
As a result 3 be see the table below.
Table 3
| Sample | Testing result |
| Blank solvent | Non- appearance |
| CMDP | 6.785min m/z187.9 quasi-molecular ions |
| Impurity A | Non- appearance |
| Impurity B | Non- appearance |
| Impurity C | Non- appearance |
| Impurity D&F | Non- appearance |
| Impurity E | Non- appearance |
| Mixed solution | 6.785min m/z187.9 quasi-molecular ions |
The result shows that Pantoprazole Sodium principal component, impurity A-F and blank solvent do not interfere the detection of impurity CMDP, it should
Method specificity is good.
2, detection limit and quantitative limit are investigated
The CMDP reference substance solution that precision measurement above-mentioned specificity is prepared when investigating is appropriate, and diluent is added quantitatively to dilute, point
Solution containing about CMDP1.2ng and 0.4ng is not made in every 1mL.
Precision measures each 10uL of solution of above-mentioned various concentration, LC-MS instrument is injected separately into, with quasi-molecular ions under SIM mode
Signal-to-noise ratio be 10: 1 when solution be used as quantitative limit solution, with the solution of signal-to-noise ratio 3: 1 be detection limit solution.Spectrogram is recorded,
It the results are shown in Table 4.
Table 4
The result shows that the CMDP containing 0.2ppm can be detected, containing 0.6ppm's when test sample concentration is 2mg/mL
CMDP by accurate quantitative analysis, can show that the detection sensitivity of this method is high, meet the testing requirements of control limit 6.25ppm.
3, linear to investigate
Using 12ng/mL as 100% limit strength solution.The accurate measurement CMDP reference substance solution 0.2mL, 1.0mL of difference,
1.6mL, 2mL, 2.4mL and 3.0mL set in 20mL measuring bottle respectively, diluent are added to be diluted to scale, and it is quantitative that concentration, which is respectively prepared,
The solution for limiting the limit concentration of concentration (LOQ), 50%, 80%, 100%, 120% and 150%, as linear solvent.
Precision measures linear solvent 10uL, is injected separately into LC-MS instrument, records map.As a result 5 be see the table below.
Table 5
| Series | Concentration (ng/L) | Main peak area |
| LOQ | 1.233 | 1363.9 |
| 50% | 6.163 | 6455 |
| 80% | 9.861 | 10653.8 |
| 100% | 12.327 | 13167.7 |
| 120% | 14.792 | 15643 |
| 150% | 18.490 | 19216.7 |
Using concentration as abscissa, peak area is ordinate, makees linear regression curves, and obtaining linear equation is Y=104.2X+
161.1, coefficient R=0.999.Show CMDP in 1.233~18.490ng/mL concentration range, solution concentration and peak area
In good linear relationship.
4, accuracy and precision
Accuracy
CMDP 80%, 100% and 120% 3 concentration of 100% limit concentration the rate of recovery be 90.0%~
Between 105.0%, it is 2.2 (n=9) that the evaluation rate of recovery, which is 99.49%, RSD, shows that method accuracy is high.
Precision
Sample introduction precision: CMDP quantitative limit determines strength solution, i.e. 1.233ng/mL strength solution continuous sample introduction 6 times, surveys
The peak area RSD=6.3% of the SIM quasi-molecular ions obtained shows that method sample introduction precision is high；
Repeatability: 6 part of 100% limit concentration that same batch test sample is prepared (takes and supplies with a batch for examination mark-on solution
Test product is accurately weighed containing about Pantoprazole 20mg, sets 10mL measuring bottle, CMDP mother liquor 1.0mL is added, diluent is added to dissolve and dilute
To scale, shake up), replication 6 times, the detected level of 6 CMDP measured is in 6.365ppm~6.516ppm, RSD 0.9%
(n=6), 6 testing results are consistent, and method is reproducible.
6 part of 100% limit concentration that different researchers prepare respectively for try mark-on mixed solution, in different time survey
The RSD of 12 testing results obtained is 1.2%, and this method Intermediate precision is high.
5, durability
Minor change occurs for chromatographic condition, and (40 ± 2 DEG C of column temperature, flow velocity 1.0mL/min ± 0.2mL/min and replacement be not homochromy
Compose column) when, on measurement result substantially without influence, the 100% limit concentration measured under different condition is for CMDP in examination mark-on solution
Average detected level is 6.19ppm, and the relative standard deviation RSD for detecting result is 2.0%, and method durability is good.
Embodiment 3
Only change the sal volatile that mobile phase A is 0.01M, remaining condition is same as Example 1.Using identical detection
Method detects the sample of 6 batches in embodiment 1.The result is as follows:
| Sample lot number | CMDP content (%) |
| 150301PS | Lower than 0.2ppm |
| 150302PS | Lower than 0.2ppm |
| 150303PS | Lower than 0.2ppm |
| 150701PS | Lower than 0.2ppm |
| 150702PS | Lower than 0.2ppm |
| 150703PS | Lower than 0.2ppm |
The result shows that doing mobile phase A using the sal volatile of 0.01M, testing result and embodiment 1 are almost the same.
Embodiment 4
Only change diluent and mobile phase, other conditions are same as Example 1, compare and use different diluents and mobile phase
Testing result.
The result shows that CMDP is unstable in sample when mobile phase neutral using water or ammonium acetate solution etc., detection knot is influenced
The accuracy of fruit.The sodium hydroxide solution for adding 0.01M in water makes mobile phase meta-alkalescence, it is ensured that sample has enough stabilizations
Property, but when detecting before 5 minutes not appearances, might have impurity is not detected, so that testing result is inaccurate.Also, sodium hydroxide
The non-volatile alkali such as solution is unsuitable for Mass Spectrometer Method, damages to mass spectrograph big.Ammonium hydroxide, because volatile, so that dilution and flowing
PH value in phase can change with time change, so not applicable.Triethylamine can interference inspection strongly because mass spectrum residual is serious
It surveys as a result, therefore not being suitable for Mass Spectrometer Method.Using 0.02M and 0.03M ammonium bicarbonate soln be mobile phase when, analysis time
It is short, it is solution-stabilized, it is easy to operate, it can get satisfied testing result.But when using the ammonium bicarbonate soln of 0.04M, detection knot
Fruit is not sufficiently stable, and reproducibility is undesirable, therefore does not use greater concentrations of ammonium bicarbonate soln.Comprehensive Correlation as a result, using
The ammonium hydrogen carbonate or sal volatile of 0.01-0.03M is as mobile phase A.
It should be pointed out that above-described embodiment is the further unrestricted detailed description made to technical solution of the present invention,
Only technical concept and feature to illustrate the invention.It is of the invention its object is to which person skilled in the art can understand
Content is simultaneously implemented accordingly, and it is not intended to limit the scope of the present invention.It is equivalent made by all Spirit Essences according to the present invention
Changes or modifications should be covered by the protection scope of the present invention.
Claims (10)
1. the high sensitivity of genotoxicity impurity 2- chloromethyl-3,4-dimethoxypyridine hydrochloride point in a kind of Pantoprazole Sodium
Analysis method, it is characterised in that: Pantoprazole sodium sample, using tablets by HPLC-MS, is used after diluting dilution agent
Carbonate solution and acetonitrile are mobile phase elution.
2. analysis method as described in claim 1, it is characterised in that: the carbonate solution is ammonium bicarbonate soln or carbon
Acid ammonium solution.
3. analysis method as claimed in claim 2, it is characterised in that: the concentration of the carbonate solution is 0.01-
0.03mol/L, preferably 0.02mol/L.
4. analysis method as described in claim 1, it is characterised in that: the diluent is ammonium bicarbonate soln and acetonitrile
Mixed solution, sample concentration is 2mg/mL after dilution.
5. analysis method as claimed in claim 4, it is characterised in that: ammonium bicarbonate soln and acetonitrile in the mixed solution
Volume ratio is 5-10: 1, preferably 9: 1.
6. analysis method as described in claim 1, it is characterised in that: the mode of elution is gradient elution, carbonic acid in eluent
The volume content of salt is 20-80%.
7. analysis method as claimed in claim 6, it is characterised in that: the condition of the gradient elution are as follows:
8. analysis method as claimed in claim 6, it is characterised in that: the elution rate of the elution is 0.8~1.2mL/
Min, the temperature of chromatographic column is 38~42 DEG C when elution.
9. analysis method described in claim 1, it is characterised in that: chromatographic column used in high performance liquid chromatography is Agilent
Proshell HPH C18 column, 150*4.6mm, 2.7 μm.
10. analysis method as described in claim 1, it is characterised in that: the ionization techniques of the mass spectrographic ion source are electricity
Electrospray ionisation technology, spray voltage 3KV, be atomized chamber pressure 35psi, 350 DEG C of dry gas temperature.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111812253A (en) * | 2020-09-10 | 2020-10-23 | 天津汉一医药科技有限公司 | Method for detecting potential genotoxic impurities in compound containing benzimidazole structure |
| CN113125583A (en) * | 2019-12-30 | 2021-07-16 | 成都百裕制药股份有限公司 | Method for detecting content of genotoxic impurities in pantoprazole sodium for injection |
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| CN101475561A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing pantoprazole and salt thereof |
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| CN101475561A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Method for synthesizing pantoprazole and salt thereof |
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| CN113125583A (en) * | 2019-12-30 | 2021-07-16 | 成都百裕制药股份有限公司 | Method for detecting content of genotoxic impurities in pantoprazole sodium for injection |
| CN113125583B (en) * | 2019-12-30 | 2022-06-21 | 成都百裕制药股份有限公司 | Method for detecting content of genotoxic impurities in pantoprazole sodium for injection |
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