CN117169392B - Pretreatment method for detecting impurity content in nifedipine controlled release tablet, detection method and application thereof - Google Patents
Pretreatment method for detecting impurity content in nifedipine controlled release tablet, detection method and application thereof Download PDFInfo
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- 239000012535 impurity Substances 0.000 title claims abstract description 97
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 229960001597 nifedipine Drugs 0.000 title claims abstract description 83
- 238000013270 controlled release Methods 0.000 title claims abstract description 38
- 238000001514 detection method Methods 0.000 title claims abstract description 34
- 238000002203 pretreatment Methods 0.000 title claims abstract description 12
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 9
- 238000004090 dissolution Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 47
- WXYIONYJZVWSIJ-UHFFFAOYSA-N acetonitrile;methanol;hydrate Chemical group O.OC.CC#N WXYIONYJZVWSIJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002861 polymer material Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- -1 polyoxyethylene Polymers 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims 1
- 229940069328 povidone Drugs 0.000 claims 1
- 239000000523 sample Substances 0.000 abstract description 18
- 239000012488 sample solution Substances 0.000 abstract description 16
- 238000002360 preparation method Methods 0.000 abstract description 9
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- 239000000126 substance Substances 0.000 abstract description 7
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- 238000004458 analytical method Methods 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 description 36
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- 238000002156 mixing Methods 0.000 description 7
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000012085 test solution Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000005520 cutting process Methods 0.000 description 4
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- 239000013074 reference sample Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
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- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 231100000357 carcinogen Toxicity 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
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- 229920000642 polymer Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
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- 238000012216 screening Methods 0.000 description 1
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- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003403 water pollutant Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of chemical analysis, and discloses a pretreatment method for detecting impurity content in nifedipine controlled release tablets, a detection method and application thereof, wherein the pretreatment method comprises the following specific steps: firstly adding the nifedipine controlled release tablet into a perchloric acid solution for dissolution, and then adding a mobile phase for constant volume filtration. According to the invention, the pretreatment process of the sample is optimized, the preparation time of the sample is shortened, the viscosity of the sample solution is reduced, the recovery rate of active substances is improved, the high performance liquid chromatography condition is established, the content of impurities in the nifedipine controlled release tablet is detected by a high performance liquid chromatograph, and the detection accuracy is improved.
Description
Technical Field
The invention belongs to the technical field of chemical analysis, and particularly relates to a pretreatment method for detecting impurity content in nifedipine controlled release tablets, and a detection method and application thereof.
Background
Nifedipine controlled release tablet is dihydropyridine calcium ion channel antagonist antihypertensive drug, and is marketed in Italy in 1992 and in China in 1994, and is mainly used for treating hypertension, coronary heart disease and chronic stable angina (exertional angina). Generally, the drug release is controlled by a penetrating agent through double-layer tabletting and laser drilling, so that the purpose of stable release and continuous effect is achieved within 24 hours.
Nifedipine has chemical name of 2, 6-dimethyl-4- (2-nitrophenyl) -1, 4-dihydro-3, 5 pyridine dicarboxylic acid dimethyl ester, and molecular formula of C 17 H 18 N 2 O 6 The chemical structural formula is。
The nifedipine is unstable, and is easy to degrade under the condition of illumination to produce impurities I and II, so that the product quality is influenced, and in order to ensure the product quality, impurities possibly existing in the nifedipine controlled release tablet are required to be separated and quantitatively detected, so that the nifedipine controlled release tablet has important significance for effectively controlling the product quality of the nifedipine controlled release tablet and improving the safety in use.
However, since the highly hydrophilic polymer material is added during the production of the existing nifedipine controlled release tablet product, the release is regulated, the sample solution is sticky during the impurity inspection, the impurities possibly existing are not easy to be effectively extracted, the impurities cannot be effectively or accurately detected, the nifedipine is unstable, the impurities are easily increased due to complex sample treatment, in the prior art, for example, CN113267583A is an HPLC-based nifedipine related substance analysis method, a detection method of nifedipine raw material related substance is provided, chloroform is added for grinding during the preparation of the sample, but the chloroform 2017 is listed in a list of 2B type carcinogens by WHO, and 2019 is listed in a list of first toxic and harmful water pollutants and is an easy-to-make toxic reagent, and the method is very unfriendly to the environment and experimental staff by taking the nifedipine as a solvent; CN110231429 is a method for screening nifedipine by using high-efficiency thin-layer chromatography and bioluminescence method, which is a food detection technology, and detects nifedipine as a main component, but can not accurately detect impurities possibly existing.
Therefore, the provision of a simple and safe pretreatment method for detecting the impurity content in the nifedipine controlled release tablet and a detection method thereof is a problem which needs to be solved by the person skilled in the art.
Disclosure of Invention
In view of the above, the invention provides a pretreatment method for detecting the content of impurities in a nifedipine controlled release tablet and a detection method thereof, which effectively solve the problems that in the prior art, a sample solution is sticky, impurities possibly existing are not easy to extract effectively, the impurities cannot be detected effectively or accurately, nifedipine is unstable, and the impurities are easy to increase due to complex sample treatment.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a pretreatment method for detecting impurity content in nifedipine controlled release tablets comprises the steps of adding a perchloric acid solution into nifedipine controlled release tablets for dissolution, adding a mobile phase for constant volume filtration.
The perchloric acid solution can effectively destroy the high molecular auxiliary materials added in the controlled release tablet, so that nifedipine, impurities I and impurities II are quickly released, and the nifedipine can be effectively extracted; meanwhile, the perchloric acid solution damages the structure of the high polymer auxiliary material, so that the viscosity of the solution is reduced, the filtering difficulty is reduced, and the detection accuracy is improved.
Preferably, the perchloric acid content is more than or equal to 0.05ml calculated by 30mg of nifedipine controlled release tablets.
Preferably, the mass ratio of the nifedipine to the high polymer material in the nifedipine controlled release tablet is 30:50-200.
Preferably, the polymer material is at least one of polyoxyethylene, crospovidone, low-substituted hydroxypropyl cellulose, hypromellose, croscarmellose sodium and the like.
Preferably, the concentration of the perchloric acid solution is 0.1-0.5%, preferably 0.1%, which allows to extract the impurities possibly present efficiently without damaging the fittings of the instrument.
Preferably, the dissolution is light-proof for 30-120min, preferably 60min, so that the impurities can be effectively extracted, and the obtained solution is convenient to filter.
Preferably, the mobile phase is acetonitrile-methanol-water with the volume ratio of 20:30:50, so that different components can be effectively separated, and the detection specificity is improved.
Preferably, the filtration is carried out using a 0.45 μm microfiltration membrane.
A detection method for detecting the impurity content in nifedipine controlled release tablets adopts the pretreatment method.
Preferably, the detection method is high performance liquid chromatography.
Preferably, the conditions of the high performance liquid chromatography are:
chromatographic column: octadecylsilane chemically bonded silica chromatographic column;
mobile phase: acetonitrile-methanol-water in a volume ratio of 20:30:50;
flow rate: 1.0ml/min;
sample injection amount: 50 μl;
detection wavelength: 235nm;
column temperature: 30 ℃.
235nm is taken as detection wavelength, maximum absorption of nifedipine, impurities I and II is considered, the impurity detection sensitivity is high, acetonitrile-methanol-water (20:30:50) is taken as mobile phase, and auxiliary material peaks and various impurities can be effectively separated.
Preferably, the chromatographic column is Phenomenex Luna C (2) 100 a, 4.6mm×250mm×5 μm, or a chromatographic column of comparable performance.
The detection method is applied to the detection of the impurity content in the nifedipine controlled release tablet.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the invention, the pretreatment process of the sample is optimized, the preparation time of the sample is shortened, the viscosity of the sample solution is reduced, the recovery rate of active substances is improved, the high-performance liquid chromatography condition is established, the content of impurities in the nifedipine controlled release tablet is detected by a high-performance liquid chromatograph, and the detection method has the advantages of high specificity and high sensitivity;
(2) According to the invention, the perchloric acid solution is selected as the extraction solvent, the pretreatment process is optimized, the viscosity of the sample solution is reduced, the damage to the high performance liquid chromatographic column is reduced, the stable sample solution is prepared, the experimental efficiency is improved, the harm caused by the organic reagent is avoided, the detection cost is reduced, and the content of impurities in the nifedipine controlled release tablet can be effectively detected by adopting the detection method disclosed by the invention, so that the detection accuracy is improved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a chromatogram of a specific experimental test of the present invention;
FIG. 2 is a linear relationship of nifedipine according to the present invention;
FIG. 3 is a linear relationship of impurity I according to the present invention;
FIG. 4 is a linear relationship of impurity II according to the present invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The detection method for detecting the impurity content in the nifedipine controlled release tablet specifically comprises the following steps:
the structures of impurity I and impurity II are shown in Table 1 below:
TABLE 1 impurity I and impurity II Structure
High performance liquid chromatography (chinese pharmacopoeia 2020 edition, fourth edition general rule 0512) determination:
control solution: respectively taking a proper amount of an impurity I reference substance, an impurity II reference substance and a nifedipine reference substance, precisely weighing, and quantitatively diluting with acetonitrile-methanol-water (20:30:50) to obtain mixed solutions containing 0.3 mug of impurity I, 0.3 mug of impurity II and 0.12 mug of nifedipine in each 1 ml;
test solution: taking 1 nifedipine controlled release tablet (manufacturer: huarun Shuanghe Jimin pharmaceutical industry (Jinan) Limited company, specification 30 mg), cutting into 4 parts with a blade cleaned by normal hexane, placing into a 500ml brown measuring flask, adding 50ml 0.1% perchloric acid solution, oscillating for 1h at room temperature, diluting to scale with acetonitrile-methanol-water (20:30:50), fully mixing, filtering with microporous membrane (0.45 μm), and collecting subsequent filtrate;
sensitivity solution: precisely measuring 5ml of reference substance solution, placing into a 50ml brown measuring flask, diluting to scale with acetonitrile-methanol-water (20:30:50), and shaking;
the conditions of the high performance liquid chromatography are as follows:
chromatographic column: phenomenex Luna C18 (2) 100A, 4.6mm×250mm×5 μm, with guard posts;
acetonitrile-methanol-water (20:30:50) as mobile phase;
the column temperature is 30 ℃; the flow rate is 1.0ml per minute;
detection wavelength 235nm;
the sample injection volume is 50 μl;
assay: precisely measuring the solution of the sample, the solution of the reference substance and the solution of the sensitivity, respectively injecting into a liquid chromatograph, recording a chromatogram, and recording the chromatogram to 2 times of the retention time of the nifedipine peak;
system applicability requirements: in the reference substance solution chromatogram, the peak-out sequence is an impurity I, an impurity II and nifedipine in sequence; the separation degree among the impurity I peak, the impurity II peak and the nifedipine peak meets the requirement; in the sensitivity solution chromatogram, the signal to noise ratio of nifedipine should be not less than 10.
Example 1
1) Specificity test
Solvent: solvent I [0.1% perchloric acid solution ]; solvent ii [ acetonitrile-methanol-water (volume ratio 20:30:50) ];
blank auxiliary materials: taking a proper amount of blank auxiliary materials, adding about 50ml of a solvent I into a 500ml brown measuring flask, oscillating for 1h, diluting to a scale with a solvent II, fully mixing, and filtering to obtain the finished product;
test solution: taking 1 nifedipine controlled release tablet (manufacturer: huarun Shuanghe Jimin pharmaceutical industry (Jinan) Limited company, specification 30 mg), cutting into 4 parts with a blade cleaned by n-hexane, placing into a 500ml brown measuring flask, adding 50ml solvent I, oscillating at room temperature for 1h, diluting to scale with solvent II, mixing thoroughly, and filtering to obtain the final product;
impurity I locating solution: taking a proper amount of an impurity I reference substance, precisely weighing, placing the reference substance into a 100ml brown measuring flask, adding a solvent II for dissolution and dilution to a scale, precisely weighing a proper amount, diluting the reference substance with the solvent II to prepare a solution of 0.3 mug/ml, and shaking uniformly;
impurity II locating solution: taking a proper amount of impurity II reference substance, precisely weighing, placing the reference substance into a 100ml brown measuring flask, adding a solvent II for dissolution and dilution to a scale, precisely weighing a proper amount, diluting the reference substance with the solvent II to prepare a solution of 0.3 mug/ml, and shaking uniformly;
nifedipine positioning solution: taking a proper amount of nifedipine reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding a solvent II for dissolution and dilution to a scale, precisely weighing a proper amount, diluting with the solvent II to prepare a solution of 1.2 mug/ml, and shaking uniformly;
mixing solution: placing a proper amount of the impurity I reference substance, the impurity II reference substance and the nifedipine reference substance into a 100ml brown measuring flask, dissolving and diluting a scale by adding the solvent II, precisely measuring a proper amount, and diluting by using the solvent II to prepare a solution containing 1.2 mug/ml of nifedipine, 0.3 mug/ml of impurity I and 0.3 mug/ml of impurity II;
and (3) measuring: precisely measuring 50 μl of each solution, respectively injecting into a liquid chromatograph, and recording the chromatogram; the relevant conclusions are shown in fig. 1 and table 2;
TABLE 2 results of specificity experiments
As can be seen from the test results in Table 2 and FIG. 1, the blank auxiliary materials show peaks before 6.5min under the chromatographic condition, and the measurement of each impurity and nifedipine is not interfered; the impurity peaks and the nifedipine peak can be effectively separated, and no impurity is detected at the main peak of each component, so that the method has good specificity.
2) Quantitative limit and detection limit test
Quantitative limit: and taking a proper amount of nifedipine, an impurity I and an impurity II reference substance, precisely weighing, gradually diluting to a proper concentration, and obtaining a solution concentration which is a quantitative limit concentration when the signal to noise ratio is about 10:1, wherein the related results are shown in the following table 3.
TABLE 3 quantitative limit test results
Limit of detection: the solutions under the quantitative limit are precisely measured, the solutions are gradually diluted to proper concentrations by solvents, the concentration of the solutions is the detection limit concentration when the signal to noise ratio is about 3:1, and the related results are shown in the following table 4.
TABLE 4 detection limit test results
As is clear from tables 3 and 4, under the chromatographic conditions, the impurity I and impurity II were detected when the contents thereof were 0.003% of the sample; when the contents of the impurity I and the impurity II are equivalent to 0.012 percent of the sample, the accurate quantification can be realized, and the method is proved to have higher sensitivity.
3) Linearity and range
Solvent: solvent I [0.1% perchloric acid solution ]; solvent II [ acetonitrile-methanol-water (20:30:50) ];
preparation of impurity I control stock solution: taking about 25mg of impurity I reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding solvent II to dissolve and dilute to scale, and shaking uniformly to obtain the final product;
preparing an impurity II reference stock solution: taking about 25mg of impurity II reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding solvent II to dissolve and dilute to scale, and shaking uniformly to obtain the final product;
preparation of nifedipine reference stock solution: taking about 24mg of nifedipine reference substance, precisely weighing, placing into a 200ml brown measuring flask, adding a solvent II, dissolving, diluting to scale, and shaking uniformly to obtain the nifedipine reference substance;
preparation of linear relation stock solution: precisely measuring 5ml of nifedipine reference sample stock solution, 6ml of impurity I and impurity II reference sample stock solutions, placing into a 200ml brown measuring flask, diluting to scale with solvent II, and shaking;
preparing a linear relation solution: precisely measuring 0.2, 0.4, 0.6, 0.8, 1.0 and 1.5ml of the linear stock solution, respectively placing into 25ml brown measuring bottles, diluting to scale with a solvent II, shaking uniformly, and respectively numbering 1, 2, 3, 4, 5 and 6 to obtain the final product; the correlation results are shown in FIGS. 2-4, which show that the peak area-concentration of impurity I, impurity II and nifedipine are in good linear relationship within the range of 150% of the limit concentration.
4) Precision test
The method is characterized in that 6 test sample solutions are prepared from 1 piece of nifedipine controlled release tablet (manufacturer: huarun Shuanghe Jimin pharmaceutical industry (Jinan) Limited, 30 mg) with the same batch number, measurement is carried out, a chromatogram is recorded, the result is shown in the table 5 below, and by adopting the sample treatment method, the detection result RSD is less than 10% under the chromatographic condition, and the precision is good.
TABLE 5 precision test results
5) Accuracy test
Impurity i control stock solution: taking about 20mg of impurity I reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding solvent II to dissolve and dilute to scale, and shaking uniformly to obtain the final product;
impurity II control stock solution: taking about 20mg of impurity II reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding solvent II to dissolve and dilute to scale, and shaking uniformly to obtain the final product;
nifedipine stock solution: taking about 24mg of nifedipine reference substance, precisely weighing, placing into a 100ml brown measuring flask, adding a solvent II, dissolving, diluting to scale, and shaking uniformly to obtain the nifedipine reference substance;
impurity control stock solution: precisely measuring 2.5ml of each of the impurity I and impurity II reference substance stock solutions, placing the stock solutions into a same 50ml brown measuring flask, diluting to scale with a solvent II, and shaking uniformly to obtain the final product;
nifedipine control stock solution: precisely measuring 2.5ml of nifedipine stock solution, placing in a 50ml brown measuring flask, diluting with solvent II, and shaking;
preparing a reference substance solution: precisely measuring 1ml of nifedipine reference substance stock solution and 3ml of impurity reference substance stock solution, placing into the same 100ml brown measuring flask, diluting to scale with solvent II, and shaking;
sensitivity solution: precisely measuring 5ml of reference substance solution, placing into a 50ml brown measuring flask, diluting to scale with solvent II, and shaking;
preparing a test solution: taking 1 nifedipine controlled release tablet (manufacturer: huarun Shuanghe Jimin pharmaceutical industry (Jinan) Limited company, specification 30 mg), cutting into 4 parts with a blade cleaned by normal hexane, placing into a 500ml brown measuring flask, adding 50ml solvent I, shaking for 1h, diluting with water to scale, fully mixing, transferring into a beaker, and mixing uniformly to obtain the nifedipine controlled release tablet;
preparation of 10% accuracy solution: precisely measuring 0.3ml of impurity reference substance stock solution, placing into a 100ml brown measuring flask, diluting to scale with sample solution, shaking, and filtering to obtain 3 parts by the same method;
preparation of 100% accuracy solution: precisely measuring 3ml of impurity reference substance stock solution, placing into a 100ml brown measuring flask, diluting with sample solution to scale, shaking, and filtering; 3 parts of the mixture were prepared in the same manner.
Preparation of 150% accuracy solution: precisely measuring 4.5ml of impurity reference substance stock solution, placing into a 100ml brown measuring flask, diluting with sample solution to scale, shaking, and filtering; 3 parts of the components are prepared by the same method;
the results are shown in tables 6 and 7,
TABLE 6 results of impurity I recovery test
TABLE 7 results of impurity II recovery test
6) Solution stability test
Preparing a test solution: taking 1 nifedipine controlled release tablet (manufacturer: huarun Shuanghe Jimin pharmaceutical industry (Jinan) Limited company, specification 30 mg), cutting into 4 parts with a blade cleaned by n-hexane, placing into a 500ml brown measuring flask, adding 50ml solvent I, shaking for 1h, diluting to scale with solvent II, mixing thoroughly, and filtering to obtain the final product;
the sample solutions are precisely measured and placed for 36 hours at room temperature, 50 μl is precisely measured and injected into a liquid chromatograph when the sample solutions are respectively 0, 2, 4, 6, 8, 10, 12, 24 and 36 hours, and the results are shown in Table 8, and the sample solutions have good stability in 36 hours at room temperature.
TABLE 8 test results of stability of test solutions
7) Durability test
Precisely measuring 50 μl of each of the reference solution and the sensitivity solution under different test conditions by adjusting the proportion of mobile phase, the temperature of the column and the chromatographic column, respectively injecting into a liquid chromatograph, and recording the chromatogram; comparing the retention time of nifedipine peak, the number of theoretical plates and the separation condition of the nifedipine peak and the front and back impurity peaks, and the test results are shown in tables 9 and 10;
TABLE 9 results of durability test conditions for examination of substances
Table 10 durability test results of the degree of separation of each peak
According to the above, under the conditions of mobile phase proportion, column temperature and different chromatographic column changes, the signal to noise ratio of the nifedipine peak in the sensitivity test solution is more than 10, the separation degree of the impurity I, the impurity II and the nifedipine peak meets the requirements, and the durability is good;
by adjusting the sample treatment method, the sample precisely measures 50 μl of the sample solution under different temperature and time conditions, and then the sample solution is injected into a liquid chromatograph to record the chromatogram; comparing the retention time of nifedipine peak, the number of theoretical plates and the separation condition of the nifedipine peak and the front and back impurity peaks, and the results are shown in tables 11 and 12;
TABLE 11 test results of sample solutions from different sample treatments
TABLE 12 detection results of different sample processing methods
Note that: * The main component nifedipine has obviously lower peak, about one fourth of the protection method, and incomplete extraction
From the above, the ultrasonic treatment needs a long time by adopting other different extraction methods, so that the impurities I and II are increased in the sample treatment process; the impurity I and the impurity II cannot be effectively extracted by soaking, and the detection result is low; the method comprises the steps of oscillating for 30min to 2h by 0.1% perchloric acid solution, effectively extracting impurities to be detected in a short time, and preferably oscillating for 1h in consideration of the difficulty of filtration and the timeliness of operation; and the concentration of the perchloric acid solution (more than or equal to 0.1%) can be used for effectively extracting impurities, and the concentration of the perchloric acid solution is preferably 0.1% in consideration of the damage to instrument accessories caused by the excessive concentration of the acid.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (6)
1. A pretreatment method for detecting impurity content in nifedipine controlled release tablets is characterized in that nifedipine controlled release tablets are added into perchloric acid solution to be dissolved, and then mobile phase constant volume filtration is carried out;
wherein, calculated by 30mg of nifedipine controlled release tablets, the perchloric acid content is more than or equal to 0.05ml;
the concentration of the perchloric acid solution is 0.1-0.5%;
the mobile phase is acetonitrile-methanol-water, and the volume ratio of the acetonitrile-methanol-water is 20:30:50;
the mass ratio of nifedipine to the polymer material in the nifedipine controlled release tablet is 30:50-200, and the polymer material is at least one of polyoxyethylene, crosslinked povidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose and crosslinked sodium carboxymethyl cellulose.
2. The pretreatment method for detecting the impurity content in the nifedipine controlled release tablet according to claim 1, wherein the dissolution is light-proof and is performed by shaking for 30-120min at room temperature.
3. A method for detecting the impurity content in nifedipine controlled release tablets, which is characterized in that the pretreatment method of any one of claims 1-2 is adopted.
4. The method for detecting the impurity content in the nifedipine controlled release tablet according to claim 3, wherein the detection method is high performance liquid chromatography.
5. The method for detecting the impurity content in the nifedipine controlled release tablet according to claim 4, wherein the conditions of the high performance liquid chromatography are as follows:
chromatographic column: octadecylsilane chemically bonded silica chromatographic column;
mobile phase: acetonitrile-methanol-water in a volume ratio of 20:30:50;
flow rate: 1.0ml/min;
sample injection amount: 50 μl;
detection wavelength: 235nm;
column temperature: 30 ℃.
6. Use of the detection method according to any one of claims 3 to 5 for detecting the impurity content in nifedipine controlled release tablets.
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