CN114034804A - Method for measuring proline content in captopril tablet - Google Patents
Method for measuring proline content in captopril tablet Download PDFInfo
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- CN114034804A CN114034804A CN202111282297.1A CN202111282297A CN114034804A CN 114034804 A CN114034804 A CN 114034804A CN 202111282297 A CN202111282297 A CN 202111282297A CN 114034804 A CN114034804 A CN 114034804A
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
The invention discloses a method for measuring proline content in captopril tablets. The invention has strong specificity and high sensitivity; the method has accurate and reliable detection result and can be used for quality control of the captopril tablet sample.
Description
Technical Field
The invention belongs to the field of chemical drug analysis and detection, and particularly relates to a detection method for determining proline in captopril tablets.
Background
Captopril is an angiotensin converting enzyme inhibitor and is often used in the treatment of hypertension and certain types of congestive heart failure. In the production of captopril, proline is often used as a raw material, or during production and storage, the content of proline is also monitored to ensure the quality of captopril.
Proline is an alpha-imino acid, can be regarded as a heterocyclic structure formed by substituting a hydrogen atom on self amino group by a side chain of the alpha-amino acid, and is one of common amino acids constituting proteins. The structural formula is as follows:
due to the fact that proline is low in captopril tablets, ultraviolet absorption of proline is poor, liquid chromatography detection cannot meet detection requirements, the common amino acid detection means is derivatization detection at present, operation is complex, interference exists, and reproducibility is poor.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a method for determining proline in captopril tablets by adopting LC-MS (liquid chromatography-mass spectrometry).
The technical scheme is as follows:
an LC-MS analysis method for determining the proline content in captopril tablets is characterized by comprising the following steps: and determining the preparation of a sample solution of the captopril tablet, and accurately measuring the proline content in the captopril tablet by using a liquid phase-mass spectrometer and adopting an external standard method.
The method specifically comprises the following steps:
(1) taking the captopril tablet, weighing, grinding, precisely weighing about 20mg (about equivalent to 5mg of captopril) of captopril tablet powder, putting the captopril tablet powder into a 10ml measuring flask, diluting with a blank solution, fixing the volume to a scale, shaking up, filtering, and taking a subsequent filtrate as a test solution.
(2) The captopril tablet sample solution was measured by LC-MS:
a chromatographic column: waters xselectricity HSS T3, 5 μm, 4.6mm 250 mm;
water phase: 0.05% aqueous formic acid; organic phase: acetonitrile
Column temperature: 30 ℃; flow rate: 1 mL/min; sample introduction volume: 5 mu L of the solution;
an ion source: ESI; the scanning mode is as follows: a SIM;
mass spectrum acquisition time: 0min to 5 min;
collected ion (m/z): 116;
elution procedure:
| time (min) | 0 | 5 | 5.5 | 8.5 | 8.6 | 11 |
| Organic phase (%) | 0 | 0 | 90 | 90 | 0 | 0 |
(3) Accurately weighing a certain amount of proline to prepare a reference solution, injecting a sample, recording a chromatogram, and calculating the proline content in the captopril tablet by measuring the peak area and the concentration of the proline in the test solution according to an external standard method.
Has the advantages that: (1) the invention develops a method for detecting the content of proline in the captopril by using a liquid phase-mass spectrometer, and simultaneously adopts an external standard method, so that the detection process is simple, and the detection result is accurate and reliable. The detection method has high response and strong specificity, and can be used for quality control of the captopril tablets; (2) the invention optimizes and selects LC-MS operation parameters in the detection process, has short detection time, and simultaneously ensures the specificity, accuracy and sensitivity of detection.
Drawings
FIG. 1 is a graph showing the results of detection of a sample by the method of the present invention in example 1.
Detailed Description
For the purpose of enhancing the understanding of the present invention, the present invention will be further described in detail with reference to the following examples and the accompanying drawings, which are only used for explaining the present invention and are not to be construed as limiting the scope of the present invention.
The main instruments used in the following examples are: LC-MS (model: Thermo Vanqish UHPLC/Thermo TSQ QUANTIS, manufacturer: Saimer Feishell science and technology (China) Co., Ltd.); one in ten thousand electronic balance (model: XS205DU, manufacturer: Mettler Toledo)
The control solutions used in the following examples were: proline (source: Meline; purity: 99%)
The solvents used in the following examples are: formic acid (source: TEDIA; purity: chromatographic grade), ultrapure water (Milli-Q), methanol (source: Merck; purity: chromatographic grade), acetonitrile (source: Merck; purity: chromatographic grade)
EXAMPLE 1 testing of captopril tablet samples from a manufacturer
(1) Preparation of captopril tablet samples:
respectively taking 5 captopril tablets of different batches of different manufacturers, weighing, grinding, precisely weighing an appropriate amount of captopril tablet powder (equivalent to 5mg of captopril), putting the captopril tablet powder into a 10ml measuring flask, diluting with a blank solution, fixing the volume to a scale, shaking up, filtering, and taking a subsequent filtrate as a sample solution. Two test solutions were prepared in parallel for each batch.
(2) Preparation of proline control solution:
blank solution: 50% methanol.
Control stock solutions: accurately weighing 5.378mg of proline reference substance, placing in a 100ml measuring flask, dissolving with blank solution, fixing volume to scale, and shaking up to obtain reference substance stock solution.
Standard limit control solution: precisely measuring 1ml of the reference substance stock solution, placing the reference substance stock solution in a 100ml measuring flask, diluting with a blank solution, fixing the volume to a scale, and shaking up to serve as a standard limit reference substance solution.
(3) The instrument method comprises the following steps:
liquid phase system: thermo Vanqish UHPLC
A chromatographic column: waters XSelect HSS T3, 5 μm, 4.6mm 250mm
Column temperature: 30 deg.C
Sample injector temperature: 10 deg.C
Flow rate: 1ml/min
Sample introduction volume: 5 μ l
Water phase: 0.05% aqueous formic acid solution
Organic phase: acetonitrile
Elution conditions:
| time (min) | 0 | 5 | 5.5 | 8.5 | 8.6 | 11 |
| Organic phase (%) | 0 | 0 | 90 | 90 | 0 | 0 |
Operating time: 11min
Mass spectrometry: thermo TSQ QUANTIS Mass spectrometer
An ion source: ESI source
The scanning mode is as follows: SIM Positive ion mode
Mass to charge ratio (m/z): 116
Mass spectrum acquisition time: 0-5 min
Ionization voltage: 3500V (+)
Sheath gas: 60Arb
Auxiliary gas: 15Arb
Tail blowing: 2Arb
Ion source temperature: 350 deg.C
Interface temperature: 350 deg.C
(4) And (3) analysis results:
the blank solution is not interfered at the retention time of the object to be detected; and (4) continuously feeding 6 needles of the standard limit reference substance solution, wherein the peak area RSD and the retention time RSD of the object to be detected both meet the requirements. Proline in each test sample batch is not detected.
Example 2 accuracy examination
(1) Preparing a solution:
blank solution: 50% methanol.
Control stock-1: accurately weighing 5.475mg of proline reference substance, placing in a 100ml measuring flask, dissolving with blank solution, fixing volume to scale, and shaking up to obtain reference substance stock solution-1.
Standard limit control solution: precisely measuring 11 ml of the reference substance stock solution, placing the reference substance stock solution in a 100ml measuring flask, diluting with a blank solution, fixing the volume to a scale, and shaking up to obtain a standard limit reference substance solution.
Test solution: weighing 20 captopril tablets, grinding, precisely weighing 20.26mg and 20.52mg (equivalent to 5.010mg and 5.075mg of captopril) of captopril tablet powder, respectively placing the captopril tablet powder and the captopril tablet powder in a 10ml measuring flask, diluting the solution with a blank solution, fixing the volume to a scale, shaking up, filtering, and taking a subsequent filtrate as two test solution.
Standard 50% limit add standard test solution: taking 20 captopril tablets, weighing, grinding, precisely weighing 20.05mg, 20.21mg and 20.60mg (equivalent to captopril 4.958mg, 4.998mg and 5.094mg) of captopril tablet powder, respectively placing the captopril tablet powder, the captopril powder and the 20.60mg in a 10ml measuring flask, diluting the captopril tablet powder with 50% linear horizontal test solution under 4.4.1, fixing the volume to a scale, shaking uniformly, filtering, and taking subsequent filtrate as three parts of 50% standard limit added standard test solution.
Standard test solution addition at 100% standard limit: weighing 20 captopril tablets, grinding, precisely weighing captopril tablet powder of 20.08mg, 20.26mg and 20.12mg (corresponding to captopril of 4.966mg, 5.010mg and 4.976mg), respectively placing into a 10ml measuring flask, diluting with standard limit control solution, fixing the volume to scale, shaking up, filtering, and taking the subsequent filtrate as three standard limit added standard sample solutions.
Standard limit of 150% plus standard test article solution: taking 20 captopril tablets, weighing, grinding, precisely weighing 19.99mg, 20.55mg and 20.28mg (equivalent to captopril 4.944mg, 5.082mg and 5.015mg) of captopril tablet powder, respectively placing the captopril tablets powder in a 10ml measuring flask, diluting the captopril tablet powder with 150% linear horizontal test solution under 4.4.1, fixing the volume to the scale, shaking up, filtering, and taking the subsequent filtrate as three 150% standard limit standard sample solutions.
(2) The instrument method comprises the following steps:
liquid phase system: thermo Vanqish UHPLC
A chromatographic column: waters XSelect HSS T3, 5 μm, 4.6mm 250mm
Column temperature: 30 deg.C
Sample injector temperature: 10 deg.C
Flow rate: 1ml/min
Sample introduction volume: 5 μ l
Water phase: 0.05% aqueous formic acid solution
Organic phase: acetonitrile
Elution conditions:
| time (min) | 0 | 5 | 5.5 | 8.5 | 8.6 | 11 |
| Organic phase (%) | 0 | 0 | 90 | 90 | 0 | 0 |
Operating time: 11min
Mass spectrometry: thermo TSQ QUANTIS Mass spectrometer
An ion source: ESI source
The scanning mode is as follows: SIM Positive ion mode
Mass to charge ratio (m/z): 116
Mass spectrum acquisition time: 0-5 min
Ionization voltage: 3500V (+)
Sheath gas: 60Arb
Auxiliary gas: 15Arb
Tail blowing: 2Arb
Ion source temperature: 350 deg.C
Interface temperature: 350 deg.C
(3) And (3) analysis results:
a sample is added into the sample solution at three concentration levels, the recovery rate of each substance to be tested is 94.84-101.61%, the receiving standard (85-110%) of the accuracy parameter recovery rate is met, and the specific results are shown in the following table.
Example 3 repeatability test
(1) Preparing a solution:
blank solution: 50% methanol.
Control stock-1: accurately weighing 5.475mg of proline reference substance, placing in a 100ml measuring flask, dissolving with blank solution, fixing volume to scale, and shaking up to obtain reference substance stock solution-1.
Standard limit control solution: precisely measuring 11 ml of the reference substance stock solution, placing the reference substance stock solution in a 100ml measuring flask, diluting with a blank solution, fixing the volume to a scale, and shaking up to obtain a standard limit reference substance solution.
Standard limit plus standard test solution: weighing 20 captopril tablets, grinding, precisely weighing 20.08mg, 20.26mg, 20.12mg, 20.52mg, 20.14mg and 19.95mg (corresponding to captopril 4.966mg, 5.010mg, 4.976mg, 5.075mg, 4.981mg and 4.934mg) of captopril tablet powder, respectively placing the captopril tablets in 10ml measuring bottles, diluting the measuring bottles with a standard limit control solution, fixing the volume to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as six standard limit added standard sample solutions.
(2) The instrument method comprises the following steps:
liquid phase system: thermo Vanqish UHPLC
A chromatographic column: waters XSelect HSS T3, 5 μm, 4.6mm 250mm
Column temperature: 30 deg.C
Sample injector temperature: 10 deg.C
Flow rate: 1ml/min
Sample introduction volume: 5 μ l
Water phase: 0.05% aqueous formic acid solution
Organic phase: acetonitrile
Elution conditions:
| time (min) | 0 | 5 | 5.5 | 8.5 | 8.6 | 11 |
| Organic phase (%) | 0 | 0 | 90 | 90 | 0 | 0 |
Operating time: 11min
Mass spectrometry: thermo TSQ QUANTIS Mass spectrometer
An ion source: ESI source
The scanning mode is as follows: SIM Positive ion mode
Mass to charge ratio (m/z): 116
Mass spectrum acquisition time: 0-5 min
Ionization voltage: 3500V (+)
Sheath gas: 60Arb
Auxiliary gas: 15Arb
Tail blowing: 2Arb
Ion source temperature: 350 deg.C
Interface temperature: 350 deg.C
(3) And (3) analysis results:
one injection is added into each of six standard limit sample solutions, the content of proline RSD is 1.16%, the receiving standard (less than or equal to 10%) of the repeatability parameter RSD is met, and the specific results are shown in the following table.
In conclusion, the method for detecting the proline in the captopril by the LC-MS is high in response and high in specificity; the method has accurate and reliable detection result and can be used for quality control of the captopril tablets.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
1. A method for measuring proline content in captopril tablets is characterized in that a liquid chromatography-mass spectrometer is used, and an external standard method is adopted to realize accurate measurement of proline content in captopril tablets.
2. The method according to claim 1, characterized in that it comprises in particular the steps of:
1) preparation of captopril tablet samples: taking captopril tablets, grinding, diluting with a blank solution, fixing the volume to a scale, shaking up, filtering, taking a subsequent filtrate, and preparing into a solution containing 0.5mg of captopril per 1 mL;
2) preparing a reference solution: taking a proper amount of proline reference substance, and adding a blank solution to prepare a solution containing 500ng of proline per 1 mL;
3) and (3) sampling a test sample solution and a reference substance solution, recording a chromatogram, and calculating the content of proline in the captopril tablet by measuring the peak area and the concentration of proline in the test sample solution according to an external standard method.
3. The method as claimed in claim 2, wherein the blank solution in step 1) is a methanol aqueous solution with a mass fraction of 50%.
4. The method according to claim 2, wherein the detection conditions of the step 2) liquid chromatography-mass spectrometer are as follows:
liquid chromatography conditions:
a chromatographic column: waters xselectricity HSS T3, 5 μm, 4.6mm 250 mm;
mobile phase: water phase: 0.05% aqueous formic acid; organic phase: acetonitrile;
column temperature: 30 ℃; flow rate: 1 mL/min; sample introduction volume: 5 mu L of the solution;
the water phase and the organic phase are mixed mobile phases for gradient elution, and the mobile phase gradient elution parameters are as follows: 0min, 0% organic phase; 5min, 0% organic phase; 5.5min, 90% organic phase; 8.5min, 90% organic phase; 8.6min, 0% organic phase; 11min, 0% organic phase;
mass spectrum conditions: in an electrospray ionization detection mode, a mass spectrum scanning mode of multi-reaction monitoring and a positive ionization mode are adopted, wherein the ionization voltage (IS) IS 3500V, and the ion source Temperature (TEM): 350 ℃, sheath gas: 60Arb, assist gas: 15Arb, tail blowing: 2Arb, ion collected (m/z): 116.
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