CN111487334A - Detection method of low-limit canagliflozin impurities - Google Patents
Detection method of low-limit canagliflozin impurities Download PDFInfo
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Abstract
The invention discloses a method for detecting a low-limit canagliflozin impurity, wherein the low-limit impurity is a genotoxic impurity F. The method adopts a high performance liquid chromatography-mass spectrometry combined analysis method and uses [ M + NH ]4 +]Ammonium acetate is added as a parent ion to a diluent, and a volatile ammonium acetate solution and acetonitrile are used as mobile phases, so that the genotoxic impurity F can be separated and detected more efficiently. The method has the advantages of strong specificity, high sensitivity, accurate result and simple operation, and has important significance on quality control and medication safety of canagliflozin.
Description
Technical Field
The invention belongs to the technical field of medical analysis, and particularly relates to a method for detecting low-limit canagliflozin impurities.
Background
Canagliflozin is a potent, reversible and high-selectivity human kidney sodium glucose co-transporter (SG L T2) inhibitor developed by a strong original research, and can promote glucose excretion through urine by inhibiting the reabsorption of glucose by kidney, so as to reduce blood sugar, and the chemical name of the hemihydrate is (1S) -1, 5-anhydro-1- [3- [ [5- (4-fluorophenyl) -2-thienyl]Methyl radical]-4-methylphenyl radical]-D-glucitol hemihydrate, formula C24H25FO5S·1/2H2O, molecular weight 453.5, structural formula as follows:
the Kagelliflozin tablet is approved by 29 U.S. food and drug administration (FDA for short) in 2013, and has the specification of 0.1g and 0.3g and the trade name of INVOKANA. Canagliflozin tablets were approved by the australian drug administration (TGA for short) on 9/12/2013 and by the european union drug administration (EMA for short) on 20/9/the same year.
The genotoxic impurity F is an oxidative degradation impurity of canagliflozin, and particularly a hydroperoxy group (-O-OH) generated by the oxidation of a methylene adjacent to a thienyl group, and the group has genetic toxicity. Therefore, the residue of the impurity F must be strictly controlled.
However, the quality standard of the impurities is not recorded in the domestic and foreign pharmacopoeias. According to the guidelines for the limits of genotoxic impurities issued by the European pharmacopoeia administration (EMEA), the maximum limit of genotoxic impurity intake is 1.5. mu.g/day, based on the Threshold of Toxicological Concerns (TTC) as the threshold for evaluating the majority of genotoxic impurities. The control limit for this impurity is 5ppm based on a maximum canagliflozin dose of 300 mg/day. Conventional gas phase and liquid phase detection methods cannot meet the detection limit requirement.
Disclosure of Invention
The invention aims to overcome the defect that the prior art can not detect genotoxic impurity F, and provides a method for detecting the genotoxic impurity of canagliflozin.
The specific technical scheme adopted for achieving the purpose is as follows:
a method for detecting low-limit canagliflozin impurities comprises the following steps: diluting a canagliflozin sample by using a diluent, and eluting by using an acetonitrile and ammonium acetate aqueous solution as a mobile phase by using a high performance liquid chromatography-mass spectrometer;
the low-limit canagliflozin impurity is a genotoxic impurity F, and the chemical formula of the low-limit canagliflozin impurity is as follows:
wherein the ion mode adopted by the mass spectrum is a positive ion mode; the ion pairs used were: m/z 494.2>380.9, m/z 494.2> 222.9.
The mobile phase needs to contain ammonium acetate or other substances capable of generating [ M + NH ]4 +]The solvent of (1). The solvent such as ammonium acetate can yield 494.1>380.9 and 494.2>222.9, or other ion pairs with better responsiveness.
Wherein the volume ratio of the ammonium acetate aqueous solution in the mobile phase is 30-70%.
Preferably, the ratio of acetonitrile to the ammonium acetate aqueous solution in the mobile phase is specifically:
when the proportion of the ammonium acetate aqueous solution in the mobile phase is 30-70%, the tailing and separation time can be reduced while the separation efficiency is ensured. Wherein the mobile phase can be isocratic or gradient. The proportion of the aqueous ammonium acetate solution may be 30%, 45%, 50%, 55%, 70%, or may vary among the above proportions. In a specific embodiment, the gradient mobile phase of the above table is used. In the specific implementation process, the adjustment can be performed to a certain extent according to conditions such as the concentration and the temperature of the impurity F.
Wherein the concentration of the ammonium acetate aqueous solution is 1-10 mM, preferably 2-6 mM, and more preferably 5 mM.
The concentration of the ammonium acetate aqueous solution may be any value of 1 to 10mM, and may be further limited to 2, 3, 4, 5, 6 mM.
Wherein the elution rate of the mobile phase is 0.5-2 m L/min, preferably 1m L/min.
Wherein, the chromatographic column is: agilent Eclipse XDB-C18.
Wherein the temperature of the chromatographic column during elution is 25-35 ℃, and preferably 30 ℃.
The flow rate of the mobile phase can be 0.5, 1, 1.5 or 2m L/min, when the column capacity of the chromatographic column is larger, the flow rate of the mobile phase can be properly increased, and when the column capacity is smaller, the flow rate of the mobile phase is also properly reduced, so that the reduction of the separation effect caused by the over-high flow rate is prevented.
Preferably, the diluent is a mixed solution of acetonitrile and 5mM ammonium acetate aqueous solution in a volume ratio of 1:1, wherein the concentration of the ammonium acetate aqueous solution is 5 mM.
The diluent must contain ammonium acetate, or otherwise produce [ M + NH ]4 +]The solvent of (1). But excluding aqueous ammonium formate, formic acid, and the like.
Wherein the ionization technology used by the mass spectrum is a spray voltage ionization technology, the spray voltage is 5.5kV, and the ionization temperature is 550 ℃.
The spraying voltage is not limited to 5.5kV, and is preferably selected from 2-8 kV, and preferably 5.5 kV. The ionization temperature can be selected preferably from 300-800 ℃, and is preferably 550 DEG C
The invention has extremely low detection limit and can meet the detection requirement of toxic impurities of canagliflozin genes. The invention uses [ M + NH ]4 +]As a parent ion, ammonium acetate is added into a diluent, and an ion pair with high selectivity and high responsiveness is obtained by screening: m/z 494.2>380.9，m/z 494.2>222.9, trace amounts of impurity F can be detected using this ion pair with detection limits down to 0.05ng/ml and quantitation limits down to 0.125 ng/ml. The method has the advantages of strong specificity, high sensitivity, accurate result and simple operation, and has important significance for quality control and medication safety of canagliflozin
Detailed Description
The invention is further illustrated with reference to specific examples, which are not intended to limit the invention in any way.
1. The instrument comprises the following steps:
the type of the high performance liquid chromatograph: agilent 1260 Infinity;
the mass spectrometer model: AB SCIEX 4500;
chromatographic column Agilent Eclipse XDB-C18, 4.6 × 250mm, 5 um;
c18, 4.6 × 150mm, 2.7um, octadecyl bonded silica gel as filler;
2. reagent: acetonitrile (merck, chromatographically pure), formic acid (Fisher, chromatographically pure), ammonium formate (Fisher, chromatographically pure), ammonium acetate (Fisher, chromatographically pure), ultrapure water (Milli-Q purified);
the diluent 1 is a mixed solution of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 55: 45.
The diluent 2 is a formic acid solution with a volume fraction of 0.1% (1 ml formic acid is made up to 1000ml with water).
The diluent 3 is 5mM ammonium acetate water solution-acetonitrile with the volume ratio of 1: 1.
3. Reference substance of impurity F
① batch No. 178599C-HB-08(STD)
A solution of impurity F in acetonitrile at a concentration of 83.3. mu.g/ml was used as control stock solution 1.
② batch No. 20170301
Accurately weighing a proper amount of impurity reference substance F, adding acetonitrile: the mixed solution of water (45:55) was diluted to 7.52. mu.g/ml as a control stock solution 2.
Example 1: selection of ion pairs
(1) Preparing a reference substance solution of the impurity F:
taking 100 μ L reference stock solution 1 in 10ml volumetric flask, adding diluent 1 to desired volume;
taking 100 mu L reference stock solution 1 in a 10ml volumetric flask, adding diluent 2 to a constant volume;
control solution 3(416 ng/ml): 5ml of the control solution 1 was placed in a 10ml volumetric flask and 10mM ammonium formate buffer was added to the flask for volume determination.
(2) Screening ion pairs:
determining parent ions through Q1 Scan, and respectively scanning response peaks of the control solutions 1, 2 and 3 at 50-800 Da in a positive ion mode. And scanning the parent ion MS2 to screen the daughter ion with high responsiveness.
The results are shown in table 1:
TABLE 1
Each control solution has a high-response parent ion, and three pairs of ion pairs are obtained through further screening. Wherein, [ M + Na+]The response in the assay was decreasing and therefore control solutions 2, 3 were selected for further validation.
(3) Verification and results
The chromatographic mass spectrometry conditions used were:
flow rate: 1.0ml/min
Column temperature: 30 deg.C
Sample injection volume of 10 mu L
Mobile phase: acetonitrile, 0.1% aqueous formic acid 70: 30;
mass spectrometry conditions are as in table 2: MRM mode
TABLE 2
And respectively taking 10 mu L reference substance solutions 2 and 3 for injection, recording spectrograms, continuously diluting the reference substance solutions 2 and 3, and verifying the signal-to-noise ratio of the respective high-responsiveness ion pairs under low concentration.
The results are shown in Table 3:
TABLE 3
Example 2:
(1) preparing a reference substance solution of the impurity F:
control solution 4(376 ng/ml): taking 0.5ml of impurity reference substance stock solution 2 into a 10ml volumetric flask, and adding diluent 3 to a constant volume;
control solution 5(37.6 ng/ml): 1ml of the reference solution 4 is put into a 10ml volumetric flask, and the diluent 3 is added to a constant volume.
(2) Screening ion pairs:
the parent ion is determined by Q1 Scan, and the response peak of the control solution 4 at 50-800 Da is scanned in the positive ion mode. And scanning the parent ion MS2 to screen the daughter ion with high responsiveness.
The results are shown in table 4:
TABLE 4
(3) Verification and results
The chromatographic mass spectrometry conditions used were:
flow rate: 1.0ml/min
Column temperature: 30 deg.C
Sample injection volume of 5 mu L
The mobile phases are as in table 5:
TABLE 5
Mass spectrometry conditions are as in table 6: MRM mode
TABLE 6
5 μ L control solution was injected 5 times and the spectra recorded for 6 replicates.
As a result: the ion pair 494.2>380.9 has high responsiveness, the S/N ratio is as high as 2457.9 when tested by using a control solution 5 with the concentration of 37.6ng/ml, and the responsiveness is stable after 6 times of repetition.
Example 3: method verification
(1) Preparing a reference substance solution of the impurity F:
control solution 6(62.67 ng/ml): and (3) taking 0.5ml of the reference substance stock solution 2, adding 2.5ml of the diluent 3, uniformly mixing, precisely measuring 2.5ml of the solution in a 50ml measuring flask, metering to a certain volume by using the diluent 3, and shaking uniformly.
Control solution 7(2.5 ng/ml): taking 2ml of the reference substance solution 6(62.67ng/ml) in a 50ml volumetric flask, fixing the volume to the scale with the diluent 3, and shaking up.
(2) The method conditions are as follows:
chromatographic conditions are as follows:
column temperature: 30 deg.C
Flow rate: 1.0ml/min
Sample injection volume of 5 mu L
The mobile phases are as in table 7:
TABLE 7
Mass spectrometry conditions are as in table 8: MRM mode
TABLE 8
(3) Methodology validation
a. Specificity test
And (3) taking a diluent 3 for sample injection and recording a chromatogram, wherein the base line is stable, and the specificity of the method is shown.
b. System applicability
And taking a reference substance solution 7(2.5ng/ml) as a system applicability solution, continuously sampling 6 needles, recording a chromatogram, calculating the RSD of impurity peak areas, and obtaining RSD results which are all less than or equal to 5%, wherein the RSD results meet the requirements.
c. Limit of detection of quantitative limit
And diluting the reference substance solution 6 step by step and injecting a sample, and detecting the signal-to-noise ratio of the impurity peak. The pharmacopoeia stipulates that the signal-to-noise ratio (S/N) of the detection limit is 3, and the signal-to-noise ratio (S/N) of the quantification limit is 10. The experimental results show that the detection limit concentration of the method is 0.05ng/ml, and the quantification limit concentration is 0.125ng/ml, as shown in Table 9.
TABLE 9
d. Linearity and range
Control solution 6 was removed by precision pipetting and diluted to a concentration of 0.125ng/ml, 0.25ng/ml, 0.50ng/ml, 1.25ng/ml, 2.51ng/ml, 3.76ng/ml and 5.01ng/ml, and 5. mu. L samples were taken from each concentration solution and chromatograms were recorded, and the results are shown in Table 10.
Watch 10
Linear regression was performed with the concentration of impurity F as the x-axis and the peak area as the y-axis. The regression equation for concentration versus peak area was 0.5772x-0.005 with a correlation coefficient R of 0.9999. The genotoxic impurity F is proved to have good linearity in the concentration range of 0.125 ng/ml-5.013 ng/ml.
e. Recovery rate
Sample solution: weighing about 25mg of canagliflozin, placing the canagliflozin in a 50ml volumetric flask, and fixing the volume by using the diluent 3.
The recovery solution is precisely weighed to be about 25mg of canagliflozin, placed in a 50m L volumetric flask, precisely transferred 61.0 ml, 2.0ml and 3.0ml of reference substance solution respectively, and prepared into solutions containing 50%, 100% and 150% of impurities by using diluent 3 to fix the volume to a scale, wherein the solutions are used as the recovery solutions in three parts.
Precisely measuring 5 mul of each of the reference solution 7, the sample solution and the recovery solution, and recording data. The above measured values of the recovery solution are the total measured values. The sample solution measurement is the background amount. The control solution 7 was used as an external standard for calculating the total amount measured and the background amount.
According to the following formula, the contents and recovery rates of genotoxic impurities in the samples are respectively calculated. The results are shown in Table 11.
The formula:
total measured value (external standard concentration/external standard peak area) peak area measured
Background amount (external standard concentration/external standard peak area) background peak area
The addition was measured as total amount-background amount, and the recovery was measured as addition/actual addition.
TABLE 11
The result shows that the recovery rate and the total average recovery rate of the genotoxic impurity F in the canagliflozin are both between 100.8 and 102.2 percent, the RSD and the total RSD are not more than 1.9 percent, all indexes meet the requirement, and the method has good accuracy.
f. Precision degree
Repeatability of
Precisely weighing about 25mg of canagliflozin, placing the canagliflozin into a 50m L volumetric flask, precisely transferring 2.0ml of a reference substance solution 6, adding the reference substance solution 6, using a diluent 3 to scale, paralleling six parts to serve as solutions with 100% recovery rate, respectively sampling 5 mu l of the reference substance solution, recording a chromatogram, and according to the calculation formula of the recovery rate, obtaining a result shown in table 12, wherein the recovery rate of genotoxic impurities F is 98.2-104.8%, and the relative standard deviation is 2.6%, and the method has good repeatability.
Intermediate precision
Six 100% recovery solutions were prepared on different dates according to the above procedure, chromatograms were recorded, and the results of the calculations are shown in table 12. The relative standard deviation of the recovery rate of 12 parts of solution on different dates is 2.0 percent, which meets the requirement and shows that the method has good intermediate precision.
TABLE 12
g. Durability
Changes in HP L C flow Rate
Changing the flow rate to 0.9ml/min and 1.1ml/min, keeping other mass spectrum and chromatographic conditions unchanged, continuously injecting 6 needles of the control solution 8, and calculating the impurity peak area RSD, wherein the results are shown in Table 13.
Watch 13
Change in HP L C column temperature
The column temperature was changed to 25 ℃ and 35 ℃ and other mass spectrum and chromatographic conditions were not changed, 6 samples of the control solution 8 were continuously injected, and the impurity peak area RSD was calculated and the results are shown in table 14.
TABLE 14
And (4) conclusion: after the flow rate and the column temperature are respectively and properly changed, the system applicability meets the regulations, and the method has good durability.
The method is verified to be good in linearity, recovery rate, precision and durability, simple and effective, and can be used for detecting the content determination of genotoxic impurities in canagliflozin.
Example 4: sample assay
Referring to the mass spectrum and the chromatographic conditions in example 3, 5. mu.l of each of the sample solution and the control solution 8 was injected, and the chromatogram was recorded, and the content of genotoxic impurities in the sample was calculated by an external standard method.
Watch 15
| Batch number | Content of impurities |
| C031-51701001 | Not detected out |
| C031-51701002 | Not detected out |
| C031-51701003 | Not detected out |
As a result, no impurities were detected in each sample, and the samples of each batch were acceptable, as shown in Table 15.
The present invention has been described in detail with reference to the above examples using specific embodiments and experiments, but it will be apparent to those skilled in the art that modifications or improvements can be made thereto without departing from the spirit of the present invention. Accordingly, such modifications and improvements do not depart from the spirit of the invention and are intended to be included within the scope of the invention.
Claims (10)
1. A method for detecting low-limit canagliflozin impurities is characterized by comprising the following steps: diluting a canagliflozin sample by using a diluent, and eluting by using an acetonitrile and ammonium acetate aqueous solution as a mobile phase by using a high performance liquid chromatography-mass spectrometer;
the low-limit canagliflozin impurity is a genotoxic impurity F, and the chemical formula of the low-limit canagliflozin impurity is as follows:
2. the detection method according to claim 1, wherein the ion mode adopted by the mass spectrometry is a positive ion mode; the ion pairs used were: m/z 494.2>380.9, m/z 494.2> 222.9.
3. The detection method according to claim 1, wherein the volume ratio of the ammonium acetate aqueous solution in the mobile phase is 30-70%.
4. The detection method according to claim 3, wherein the ratio of acetonitrile to the aqueous ammonium acetate solution in the mobile phase is in particular:
5. the detection method according to any one of claims 1 to 4, wherein the concentration of the ammonium acetate aqueous solution is 1 to 10mM, preferably 2 to 6mM, and more preferably 5 mM.
6. The detection method according to any one of claims 1 to 4, wherein the elution rate of the mobile phase is 0.5 to 2m L/min, preferably 1m L/min.
7. The detection method according to any one of claims 1 to 4, wherein the chromatographic column is: agilenteclipse XDB-C18.
8. The detection method according to claim 7, wherein the column temperature of the chromatographic column at the time of elution is 25 to 35 ℃, preferably 30 ℃.
9. The detection method according to any one of claims 1 to 4, wherein the diluent is a mixed solution of acetonitrile and an aqueous solution of ammonium acetate at a volume ratio of 1:1, wherein the concentration of the aqueous solution of ammonium acetate is 5 mM.
10. The detection method according to any one of claims 1 to 4, wherein the ionization technique used in the mass spectrometry is a spray voltage ionization technique, the spray voltage is 5.5kV, and the ionization temperature is 550 ℃.
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| CN108530434A (en) * | 2017-03-03 | 2018-09-14 | 重庆医药工业研究院有限责任公司 | Impurity compound of canagliflozin and preparation method thereof |
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