CN102109501A - Method for detecting related substances in quinapril hydrochloride and hydrochlorothiazide composition - Google Patents
Method for detecting related substances in quinapril hydrochloride and hydrochlorothiazide composition Download PDFInfo
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- CN102109501A CN102109501A CN 200910247274 CN200910247274A CN102109501A CN 102109501 A CN102109501 A CN 102109501A CN 200910247274 CN200910247274 CN 200910247274 CN 200910247274 A CN200910247274 A CN 200910247274A CN 102109501 A CN102109501 A CN 102109501A
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Abstract
The invention relates to a method for detecting related substances in a quinapril hydrochloride and hydrochlorothiazide composition by high performance liquid chromatography (HPLC). In the method, XB-cyan (-CN) or XB-C8 is taken as a chromosorb, and an organic phase and phosphoric acid buffer salt solution are used for gradient elution; related impurities in the quinapril hydrochloride and hydrochlorothiazide composition can be effectively separated and detected through one-time sample introduction; and the method is high in detection sensitivity, accuracy and specificity, and is an effective method for strictly controlling the quality of the composition.
Description
Technical field
The present invention relates to the detection method of medicine, be specifically related to a kind of detection hypertension therapeutic medicine, the method for quinapril hydrochloride and hydrochlorothiazide composition related substance.
Background technology
The compound preparation of quinapril hydrochloride and Hydrochioro belongs to the compound preparation of ACEI and the two fixed dosage composition of diuretics, and external at present listing specification has (1) quinapril/hydrochlorothiazide tablets 10mg/12.5mg (in quinapril); (2): quinapril/hydrochlorothiazide tablets 20mg/25mg (in quinapril); (3): quinapril/hydrochlorothiazide tablets 20mg/12.5mg (in quinapril).Clinical research confirmation quinapril/hydrochlorothiazide tablets can effectively bring high blood pressure down, and can reduce the spinoff of quinapril hydrochloride and Hydrochioro respectively.But, to the detection of the related substance in quinapril hydrochloride, the hydrochlorothiazide composition, all do not report both at home and abroad, therefore, the control of the compound preparation difficult quality of quinapril hydrochloride and Hydrochioro, to a certain degree influence is produced.Suddenly wait to study method for determination related substances in quinapril hydrochloride and the hydrochlorothiazide composition.
Summary of the invention
Technical matters to be solved by this invention be research and design a kind of fast, effectively, related substance detection method in the quinapril hydrochloride of high, the favorable reproducibility of precision and the hydrochlorothiazide composition.
The invention provides a kind of method that detects related substance in quinapril hydrochloride and the hydrochlorothiazide composition.Adopt XB-cyano group (CN) or XB-C8 be chromatographic column carrier, with organic phase A and phosphate buffered saline(PBS) B, according to gradient elution.Single injected sampling can effectively separate, and measures the related impurities in quinapril hydrochloride, the hydrochlorothiazide composition.
The inventive method comprises the following steps:
(1) use high performance liquid chromatograph, the ultraviolet multiwavelength detector, chromatographic column carrier granularity 3～5 μ m, aperture 4.6mm, length is 100～250mm;
(2) with XB-cyano group (CN) or XB-C8 be chromatographic column carrier, organic phase A and phosphate buffered saline(PBS) B adopt gradient elution;
(3) sample ligand is made and is contained quinapril 0.4～0.6mg/ml, contains Hydrochioro 0.25～0.65mg/ml as need testing solution, dilutes 100 times as 1% own control solution with need testing solution.
(3) after the stability and high efficiency liquid chromatograph, to chromatogram system sample introduction, sample size is 5～20 μ l; Flow velocity is 0.6～1.5ml/min, and the stratographic analysis time is 35 minutes.
(4) after sample to be tested is separated, major component 1% Self-control method of not correction up factor calculating related substance (" two appendix V of Chinese pharmacopoeia version in 2005 D).
The described organic phase A of the inventive method is selected from acetonitrile or methyl alcohol, preferred acetonitrile.Phosphate buffered saline(PBS) B is the phosphate buffer of 0.01～0.10mol/L, phosphate is selected from one or more the potpourri in sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate or the dipotassium hydrogen phosphate, preferably phosphoric acid potassium dihydrogen, preferred concentration are 0.05mol/L; Phosphate buffer B can add the peak shape improver, and the peak shape improver is selected from diethylamine, triethylamine, trifluoroacetic acid or ion-pairing agent, and (ion-pairing agent is a series of reagent, as novalgin, sodium pentanesulfonate, perfluorooctane sulfonate etc.) one or more etc.; Phosphate buffered saline(PBS) B pH value scope is 2～4, and is preferred 2.5, and the reagent of regulating the pH value is phosphoric acid; The gradient elution program is:
Can be according to above method with quinapril, Hydrochioro and its related impurities, comprise that known impurities quinapril cyclocomplex and relevant unknown impuritie effectively separate, Hydrochioro chromatographic peak retention time is about 21min, Hydrochioro chromatographic peak retention time is about 7.7min, and quinapril cyclocomplex chromatographic peak retention time is about 24.8min.
Measure and determine that the impurity peaks ownership is as follows:
6.4min about, the impurity peaks about 19.9min and about 18.5min belongs to Hydrochioro; 14.7min about, about 19.6min, the impurity peaks about 24.7min belongs to quinapril hydrochloride, under the quinapril hydrochloride super-humid conditions at 18.9min, 19.3min, the small impurities peak about 27.0min.
In the need testing solution as quinapril cyclocomplex peak occurs, its peak area must not be greater than quinapril cyclocomplex peak area (1.5%) in the contrast solution, desolventize outside the peak, as other impurity peaks greater than main peak area 0.05% appear, each impurity peak area and must not greater than Hydrochioro in the 1% own control solution, quinapril main peak area and 3 times (3.0%).
The inventive method detection sensitivity height, precision is good, and specificity is strong, is the effective ways of strict such composition quality of control.
Description of drawings
Fig. 1 quinapril cyclocomplex chromatogram
Fig. 2 quinapril hydrochloride reference substance chromatogram
Fig. 3 Hydrochioro reference substance chromatogram
Figure 41 % own control solution chromatogram
Fig. 5 need testing solution chromatogram
The blank auxiliary material solution of Fig. 6 chromatogram
0 ℃ of 5 days chromatogram of Figure 74
5 ℃ of Figure 82, RH75%5 days chromatogram
5 days chromatograms of Figure 94 500lx
0 ℃ of 10 days chromatogram of Figure 104
5 ℃ of Figure 112, RH75%10 days chromatogram
10 days chromatograms of Figure 124 500lx
Figure 13 destructive test chromatogram
Specific implementation method
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The lucifuge operation.Adopt the cyano group post, mobile phase A: acetonitrile; The potassium dihydrogen phosphate of Mobile phase B: 0.05mol/L is transferred PH to 2.5 with phosphoric acid, and according to the form below carries out gradient elution.The detection wavelength is 215nm, 40 ℃ of column temperatures, flow velocity 1ml/min.
Precision takes by weighing quinapril cyclocomplex 10mg, puts in the 100ml volumetric flask, adds 50% acetonitrile solution 30ml, ultrasonic 5min makes dissolving, with the water constant volume, shake up, precision pipettes in right amount again, and the acetonitrile solution with 15% quantitatively dilutes, and finally makes the solution that every 1ml contains the about 10 μ g of quinapril cyclocomplex, solution in contrast, get 20 μ l and inject liquid Hunan chromatograph, regulate detection sensitivity, make that the peak height of main peak is about 20% of full scale in the contrast solution.
Get quinapril hydrochloride and hydrochlorothiazide composition porphyrize powder an amount of (being equivalent to quinapril 10mg), the accurate title, decide, put in the 20ml volumetric flask, the acetonitrile solution 6ml of adding 50%, ultrasonic 5min makes dissolving, with the water constant volume, make the solution that every 1ml contains quinapril 0.5mg approximately, as need testing solution (facing) with now joining; Precision is measured need testing solution 1.0ml, put in the 100ml volumetric flask, with 15% acetonitrile solution constant volume, as 1% own control solution, measure with method, record test sample chromatogram is to 2 times of quinapril main peak retention time, in the need testing solution as quinapril cyclocomplex peak occurs, its peak area must not be greater than quinapril cyclocomplex peak area (1.5%) in the contrast solution, desolventize outside the peak, as other impurity peaks greater than main peak area 0.05% appear, each impurity peak area and must not be greater than Hydrochioro in the 1% own control solution, quinapril main peak area and 3 times (3.0%).
Belongingness problem for issuable impurity in the composition of determining quinapril hydrochloride and Hydrochioro composition, respectively under (1) 40 ℃, (2) 25 ℃, RH75%, (3) 4500lx illumination with sample (a) quinapril hydrochloride raw material, (b) Hydrochioro raw material, (c) quinapril hydrochloride hydrochlorothiazide composition (10.8mg: 12.5mg), (d) composition and blank auxiliary material were placed 10 days, took a sample respectively with 10 days in the 5th day, measure by embodiment 1 method, determine the impurity peaks ownership.
Conclusion, about 6.4min, the impurity peaks about 19.9min and about 18.5min belongs to Hydrochioro; 14.7min about, about 19.6min, the impurity peaks about 24.7min belongs to quinapril hydrochloride, under the quinapril hydrochloride super-humid conditions at 18.9min, 19.3min, the small impurities peak about 27.0min.
At the main ingredient potpourri, and the supplementary material potpourri can clear and definite its belongingness has: the impurity peaks ownership Hydrochioro about 6.4min, about 14.7min, about 24.7min, the impurity peaks about 27.0min belongs to quinapril hydrochloride.18, about 19min, the degradation product of Hydrochioro and quinapril hydrochloride is slightly overlapping, can not clear and definite its attaching problem.But two kinds of main ingredient compositions generally, and with the auxiliary material potpourri, after the setting-out of influence factor condition, do not produce new bigger degradation product.In the influence factor collection of illustrative plates of preparation, main degradation peak's attaching problem substantially can be clear and definite, and each impurity peaks and quinapril, Hydrochioro peak degree of separation meet the requirements.
Be the feasibility of checking chromatographic condition, this product and auxiliary material have been carried out sour destruction, alkali destruction, oxidation destruction, high temperature destruction and illumination failure test respectively.
Acid destroys: get quinapril hydrochloride and Hydrochioro compound fine powder an amount of (being equivalent to quinapril 10mg approximately), put in the 10ml tool plug test tube, add 0.1mol/L hydrochloric acid solution 2ml, sonicated 10min regulates the pH value to neutral with the sodium hydroxide solution of 0.1mol/L, is transferred in the 20ml measuring bottle, be diluted to scale with moving phase, shake up, filter, get subsequent filtrate and destroy need testing solution as acid.
Alkali destroys: get quinapril hydrochloride and Hydrochioro compound fine powder an amount of (being equivalent to quinapril 10mg approximately), put in the 10ml tool plug test tube, add 0.1mol/L sodium hydroxide solution 0.5ml, add water 2ml again, sonicated 10min, regulate the pH value to neutral with the hydrochloric acid solution of 0.1mol/L, be transferred in the 20ml measuring bottle, be diluted to scale, shake up with moving phase, filter, get subsequent filtrate and destroy need testing solution as alkali.
Oxidation destroys: get quinapril hydrochloride and Hydrochioro compound fine powder an amount of (being equivalent to quinapril 10mg approximately), put in the 10ml tool plug test tube, 5 of the hydrogen peroxide solutions that the adding dilution is 100 times, add and add water 2ml again, sonicated 10min is transferred in the 20ml measuring bottle, be diluted to scale with moving phase, shake up, filter, get subsequent filtrate and destroy need testing solution as oxidation.
High temperature destroys: get quinapril hydrochloride and Hydrochioro compound fine powder an amount of (being equivalent to quinapril 10mg approximately), put in the 10ml tool plug test tube, add 2ml water, place boiling water 10min, be transferred in the 20ml measuring bottle, be diluted to scale, shake up with moving phase, filter, get subsequent filtrate and destroy need testing solution as high temperature.
Illumination destroys: get quinapril hydrochloride Hydrochioro compound fine powder an amount of (being equivalent to quinapril 10mg approximately), put in the 10ml tool plug test tube, add the moving phase dissolving, shake up, put illumination 10min under the 4500LX illumination, sonicated 5 minutes, be transferred in the 20ml measuring bottle, be diluted to scale, shake up with moving phase, filter, get subsequent filtrate and destroy solution as illumination.
According to embodiment 1 respectively precision measure each 20 μ l of above solution, inject liquid chromatograph respectively, the record chromatogram.This product is destroyed and illumination has to a certain degree destruction after destroying through acid destruction, alkali, and oxidation destruction, high temperature destroy more serious, and each destroys the product peak and can separate fully with main peak, and this chromatographic condition has good selectivity, can be used for the inspection of this product related substance.
Be feasibility and the detection limit and the quantitative limit of checking chromatographic condition, this method is carried out detectability and quantitative limit mensuration
According to embodiment 1, precision is measured 1% own control solution (Hydrochioro, quinapril hydrochloride concentration is respectively 0.664 μ g/ml, 0.542 1.0ml μ g/ml), put respectively in 100ml, 25ml, the 10ml volumetric flask, be mixed with certain density solution, sample introduction 20 μ l inject liquid chromatograph respectively.
By chromatogram as seen, the signal to noise ratio (S/N ratio) of Hydrochioro was 3.1 when quantitatively 100ml was put in dilution, and the detectability concentration of Hydrochioro is 6.64ng/ml, detected and was limited to 0.1328ng.The signal to noise ratio (S/N ratio) of Hydrochioro was 9.5 when quantitatively 25ml was put in dilution, and the quantitative limit concentration of Hydrochioro is 26.56ng/ml, quantitatively is limited to 0.5312ng;
The signal to noise ratio (S/N ratio) of quinapril was 3.7 when quantitatively 25ml was put in dilution, and the detectability concentration of quinapril hydrochloride is 21.68ng/ml, detected to be limited to 0.4336ng.The signal to noise ratio (S/N ratio) of quinapril was 11.4 when quantitatively 10ml was put in dilution, and the quantitative limit concentration of quinapril hydrochloride is 54.20ng/ml, detected to be limited to 1.0840ng.
Claims (9)
1. a method that detects quinapril hydrochloride and hydrochlorothiazide composition related substance is characterized in that this method comprises the following steps:
(1) use high performance liquid chromatograph, the ultraviolet multiwavelength detector, chromatographic column carrier granularity 3～5 μ m, aperture 4.6mm, length is 100～250mm;
(2) (CN) or XB-with XB-cyano group
C8Be chromatographic column carrier, organic phase A and phosphate buffered saline(PBS) B adopt gradient elution;
(3) sample ligand is made and is contained quinapril 0.4～0.6mg/ml, contains Hydrochioro 0.25～0.65mg/ml as need testing solution, dilutes 100 times as 1% own control solution with need testing solution;
(3) after the stability and high efficiency liquid chromatograph, to chromatogram system sample introduction, sample size is 5～20 μ l; Flow velocity is 0.6～1.5ml/min, and the stratographic analysis time is 35 minutes;
(4) after sample to be tested is separated, calculate related substance with major component 1% Self-control method of the not correction up factor.
2. according to the method for claim 1, it is characterized in that described organic phase A is acetonitrile or methyl alcohol.
3. according to the method for claim 1, it is characterized in that described organic phase A is an acetonitrile.
4. according to the method for claim 1, it is characterized in that described step (2) phosphate buffered saline(PBS) B concentration is 0.01～0.10mol/L, phosphate-buffered salt is one or more the potpourri in sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium hydrogen phosphate or the dipotassium hydrogen phosphate.
5. according to the method for claim 1, it is characterized in that described step (2) phosphate buffered saline(PBS) B concentration is 0.05mol/L, phosphate-buffered salt is a potassium dihydrogen phosphate.
6. according to the method for claim 1, it is characterized in that described step (2) phosphate buffer B can add the peak shape improver, described peak shape improver is one or more a potpourri of diethylamine, triethylamine, trifluoroacetic acid, novalgin, sodium pentanesulfonate or perfluorooctane sulfonate.
7. according to claim 1,3,4 or 5 method, it is characterized in that described phosphate buffered saline(PBS) BpH value scope is 2～4, the reagent of regulating the pH value is phosphoric acid.
8. according to claim 1,3,4 or 5 method, it is characterized in that described phosphate buffered saline(PBS) BpH value scope is 2.5.
9. according to the method for claim 1, it is characterized in that the program of described step (2) gradient elution is
Time (minute) organic phase A (%) phosphate buffered saline(PBS) B (%)
0 15 85
9 15 85
19 40 60
35 40 60
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102565221A (en) * | 2011-12-26 | 2012-07-11 | 浙江大学 | Method for measuring hydrochlorothiazide drug content by ion chromatography-ultraviolet detection method |
| CN117538461A (en) * | 2024-01-10 | 2024-02-09 | 地奥集团成都药业股份有限公司 | Detection method of related substances of benazepril hydrochloride tablets |
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| US7335644B2 (en) * | 2003-03-31 | 2008-02-26 | Council Of Scientific And Industrial Research | Anti-hypertensive molecules and process for preparation thereof |
| CN101609070A (en) * | 2008-06-16 | 2009-12-23 | 北京德众万全药物技术开发有限公司 | A kind of method of measuring related substances of losastan potassium/hydrochlorothiazide tablets with HPLC |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102565221A (en) * | 2011-12-26 | 2012-07-11 | 浙江大学 | Method for measuring hydrochlorothiazide drug content by ion chromatography-ultraviolet detection method |
| CN117538461A (en) * | 2024-01-10 | 2024-02-09 | 地奥集团成都药业股份有限公司 | Detection method of related substances of benazepril hydrochloride tablets |
| CN117538461B (en) * | 2024-01-10 | 2024-03-26 | 地奥集团成都药业股份有限公司 | Detection method of related substances of benazepril hydrochloride tablets |
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