CN109632921B - Detection method for content of levofloxacin in levofloxacin bulk drug, electrochemical sensor used in detection method and chiral pyrrole compound - Google Patents
Detection method for content of levofloxacin in levofloxacin bulk drug, electrochemical sensor used in detection method and chiral pyrrole compound Download PDFInfo
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- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 title claims abstract description 114
- 229960003376 levofloxacin Drugs 0.000 title claims abstract description 113
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 238000001514 detection method Methods 0.000 title claims abstract description 34
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- -1 pyrrole compound Chemical class 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 41
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- QLGORBDXWWIXNY-LLVKDONJSA-N 1-[(1R)-1-(4-methoxyphenyl)ethyl]pyrrole Chemical compound COC1=CC=C(C=C1)[C@@H](C)N1C=CC=C1 QLGORBDXWWIXNY-LLVKDONJSA-N 0.000 claims abstract description 25
- 238000002484 cyclic voltammetry Methods 0.000 claims abstract description 20
- 238000000835 electrochemical detection Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 17
- JTDGKQNNPKXKII-SSDOTTSWSA-N (1r)-1-(4-methoxyphenyl)ethanamine Chemical compound COC1=CC=C([C@@H](C)N)C=C1 JTDGKQNNPKXKII-SSDOTTSWSA-N 0.000 claims abstract description 8
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- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
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- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
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- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 206010033557 Palpitations Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
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- G01N27/416—Systems
- G01N27/42—Measuring deposition or liberation of materials from an electrolyte; Coulometry, i.e. measuring coulomb-equivalent of material in an electrolyte
- G01N27/423—Coulometry
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
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Abstract
The invention provides an electrochemical detection method for the content of levofloxacin in levofloxacin bulk drugs, a chiral polypyrrole electrochemical sensor and a chiral pyrrole compound used in the method. Preparing a novel chiral pyrrole compound (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane by using 2, 5-dimethoxytetrahydrofuran and (R) - (+) -4-methoxy-alpha-methylbenzylamine as raw materials; then, modifying the surface of the electrode by using (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane as a monomer through an electrochemical polymerization method to obtain a chiral polypyrrole electrochemical sensor; and finally, detecting the content of the levofloxacin in the levofloxacin raw material medicine by utilizing the chiral recognition function of the chiral polypyrrole electrochemical sensor and combining an electrochemical cyclic voltammetry analysis method. The electrochemical detection method has the biggest advantages of low instrument cost, convenient operation, high detection speed and high sensitivity, and basically does not discharge waste liquid.
Description
Technical Field
The invention provides a method for detecting the content of levofloxacin, in particular to an electrochemical detection method for the content of levofloxacin in levofloxacin bulk drugs, a chiral polypyrrole electrochemical sensor used in the electrochemical detection method, and a chiral pyrrole compound.
Background
Chirality (Chirality) refers to the property of an object that cannot coincide with its mirror image, and chiral compounds having this property are referred to as a pair of enantiomers. Chirality plays a unique role in the life process, and in the complex chiral environment of a biological system, the precise recognition of chiral molecules can cause the organism to generate different physiological effects, and chiral drugs are the most typical examples. In the twentieth century, the world-wide 'reaction stop' event is frightened by shock, so that people have palpitation to the heart until now, and later researches show that only the (R) -isomer of the racemate has a sedative effect, while the (S) -isomer of the racemate has a teratogenic effect. In 2000 the FDA suggested that drugs with chiral centers must be marketed as single isomers. Thus, the medicine has the advantages of definite curative effect, less side effect and less clinical dosage.
Levofloxacin (structural formula below), trade name: coke barbital; the molecular formula is as follows: c18H20FN3O4(ii) a Chemical name: (3S) - (-) -9-fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de]-[1,4]Benzoxazine-6-carboxylic acid, a third generation quinolone antibacterial drug developed by the first pharmaceutical factory in japan. The drug has chirality because the carbon atom at the 3-position is connected with four different groups, wherein, levofloxacin is an optical active (3S) -isomer of ofloxacin, the antibacterial activity of the levofloxacin is 8-128 times of the (3R) -isomer (also called as dexofloxacin or enantiomer, hereinafter all called as dexofloxacin) of the levofloxacin, the antibacterial activity of the levofloxacin is 2 times of that of racemate ofloxacin, and the toxic and side effects are small.
At present, the method for measuring the content of the levofloxacin in levofloxacin raw material medicines is mainly high performance liquid chromatography. However, the high performance liquid chromatography is often used for detecting the optical purity of chiral drugs, and expensive chiral chromatographic columns or mobile phases added with chiral inducers are often needed, so that the detection cost is high, the operation is complicated, and a large amount of mobile phase waste liquid is generated; in addition, the defects of high performance liquid chromatography are that the detection speed is slow, the detection time is long, and the detection limit and the sensitivity are low.
Disclosure of Invention
In view of the above problems, the present inventors have developed a method for electrochemically detecting the content of levofloxacin in a levofloxacin bulk drug, and prepared a novel chiral pyrrole compound (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane from 2, 5-dimethoxytetrahydrofuran and (R) - (+) -4-methoxy- α -methylbenzylamine; then, modifying the surface of the electrode by using (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane as a monomer through an electrochemical polymerization method to obtain a chiral polypyrrole electrochemical sensor; and finally, detecting the content of the levofloxacin in the levofloxacin raw material medicine by utilizing the chiral recognition function of the chiral polypyrrole electrochemical sensor and combining an electrochemical cyclic voltammetry analysis method.
Accordingly, it is an object of the present invention to provide a chiral pyrrole compound;
another object of the present invention is to provide a chiral polypyrrole electrochemical sensor;
the invention also aims to provide a rapid, simple, convenient, accurate and sensitive electrochemical detection method for detecting the content of the levofloxacin in levofloxacin bulk drugs, which utilizes the chiral recognition function of the chiral polypyrrole electrochemical sensor and can simply, conveniently and accurately detect the content of the levofloxacin in the levofloxacin bulk drugs through an electrochemical method.
According to one aspect of the present invention, there is provided a novel chiral pyrrole compound, (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, having the formula:
the chiral pyrrole compound (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is prepared by the following method:
(R) - (+) -4-methoxy- α -methylbenzylamine and 2, 5-dimethoxytetrahydrofuran to give (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, according to the following reaction equation:
under the catalysis of acid, 2, 5-dimethoxy tetrahydrofuran and (R) - (+) -4-methoxyl-alpha-methylbenzylamine are subjected to condensation reaction to obtain (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane.
Specifically, in the reaction, the molar ratio of 2, 5-dimethoxytetrahydrofuran to (R) - (+) -4-methoxy- α -methylbenzylamine is 5:1 to 1:1, and preferably 3:1 to 1: 1; the catalyst acid can be dilute sulfuric acid, dilute hydrochloric acid, glacial acetic acid or the like, and preferably glacial acetic acid; the reaction temperature is 50-100 ℃, and preferably 70-80 ℃; the reaction time is 1-4 h, and preferably 2-2.5 h.
According to another aspect of the present invention, there is provided a chiral polypyrrole electrochemical sensor, comprising: the electrode comprises a glassy carbon electrode and a poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] film layer modified on the glassy carbon electrode.
The chiral polypyrrole electrochemical sensor is prepared by the following method:
adopting an electrochemical workstation, taking a glassy carbon electrode as a working electrode, a platinum wire electrode as a counter electrode and an Ag/AgCl electrode as a reference electrode; acetonitrile solution in which (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, tetrabutylammonium perchlorate and (D) - (+) -camphor-10-sulfonic acid are dissolved is taken as electrolyte; inserting the three electrodes into electrolyte to form a one-chamber three-electrode system; and polymerizing (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane on the surface of the glassy carbon electrode by cyclic voltammetry to obtain the glassy carbon electrode modified by the poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] membrane, namely the chiral polypyrrole electrochemical sensor.
More specifically, the electrochemical workstation is a computer-controlled electrochemical analyzer, commercially available, for example, RST5000 electrochemical workstation from Risteita instruments, Inc., Suzhou.
Firstly, the electrode is pretreated, and the selected area is about 10-30 mm2The glassy carbon electrode of (5), use of Al for the glassy carbon electrode2O3Powder (e.g. 0.05 μm Al)2O3Powder), and then the glassy carbon electrode, platinum wire electrode, and Ag/AgCl electrode are ultrasonically cleaned with secondary water (e.g., ultrasonic cleaning for 5 minutes), ultrasonically cleaned with ethanol (e.g., ultrasonic cleaning for 5 minutes), and ultrasonically cleaned with secondary water (e.g., ultrasonic cleaning for 5 minutes).
Then preparing an electrolyte, adding (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, tetrabutylammonium perchlorate and (D) - (+) -camphor-10-sulfonic acid into acetonitrile, accelerating dissolution by using ultrasonic waves, and introducing nitrogen to remove oxygen to obtain the electrolyte, wherein the concentration of the (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is 0.05-0.2 mol/L, and preferably 0.09-0.12 mol/L; the concentration of tetrabutylammonium perchlorate is 0.05-0.2 mol/L, preferably 0.09-0.12 mol/L; (D) the concentration of the (+) -camphor-10-sulfonic acid is 0.05 to 0.2mol/L, preferably 0.09 to 0.12 mol/L.
Inserting the pretreated glassy carbon electrode, a platinum wire electrode and an Ag/AgCl electrode into the prepared electrolyte to form a one-chamber three-electrode system, preferably performing electrochemical polymerization by using cyclic voltammetry under the nitrogen atmosphere, wherein the potential scanning range is-0.2-2.0V, the scanning speed is 0.05V/s, the number of cycles is 30-100, preferably 40-60, and (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is polymerized on the surface of the glassy carbon electrode to obtain the glassy carbon electrode modified by the poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] film, namely the chiral polypyrrole electrochemical sensor.
According to another aspect of the invention, an electrochemical detection method for the content of the levofloxacin in the levofloxacin bulk drug is provided. Because the levofloxacin and the levofloxacin have different three-dimensional structures and the chiral polypyrrole electrochemical sensor has a three-dimensional structure recognition function, when the levofloxacin and the levofloxacin undergo redox reaction in an electrochemical system comprising the chiral polypyrrole electrochemical sensor, respective oxidation peaks respectively appear at different potentials. And then the concentration of the ofloxacin can be obtained through conversion according to the oxidation peak current value of the ofloxacin.
Specifically, the prepared chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode are inserted into a levofloxacin standard solution, a saturated calomel electrode is inserted into a saturated potassium chloride solution, a salt bridge is built between the levofloxacin standard solution and the saturated potassium chloride solution, then the electrodes are connected to an electrochemical workstation, the detection is carried out at normal temperature by adopting a cyclic voltammetry method, the potential scanning range is set to be-0.2-2.4V, the scanning speed is 0.1V/s, the number of cycles is 1 cycle, and an oxidation peak of the levofloxacin at 1.589V is detected, wherein the levofloxacin standard solution is prepared by dissolving the levofloxacin standard product in an acetonitrile solution containing tetrabutylammonium perchlorate. By the same method as above, it was found that the levofloxacin had an oxidation peak at 1.973V. The oxidation peaks of the levofloxacin and the levofloxacin appear at different potentials, namely the chiral polypyrrole electrochemical sensor can identify the levofloxacin and the levofloxacin.
The electrochemical detection method for the content of the levofloxacin in the levofloxacin raw material medicine comprises the following steps:
step 1: drawing a standard curve and establishing a linear regression equation
Solution preparation
Blank control solution: adding tetrabutylammonium perchlorate into acetonitrile to prepare acetonitrile solution containing 0.05-0.2 mol/L of tetrabutylammonium perchlorate;
standard solution: taking the blank control solution, adding an ofloxacin standard product into the blank control solution to prepare an ofloxacin standard solution with a series of concentrations (and the preferred concentration is between 1mmol/L and 0.05 mmol/L);
inserting the prepared chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode into a right ofloxacin standard solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the right ofloxacin standard solution and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting at normal temperature by adopting a cyclic voltammetry method, respectively detecting a plurality of series of right ofloxacin standard solutions with different concentrations to obtain oxidation peak current values of the right ofloxacin standard solutions with different concentrations, and drawing a right ofloxacin concentration-current standard curve according to the peak current values and the concentrations of the standard solutions to obtain a linear regression equation;
step 2: electrochemical detection of content of levofloxacin in levofloxacin bulk drug
Accurately weighing levofloxacin raw material medicines, dissolving the levofloxacin raw material medicines in the blank control solution to prepare a detection solution, inserting the prepared chiral polypyrrole electrochemical sensor and an Ag/AgCl reference electrode into the detection solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the detection solution and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting by adopting a cyclic voltammetry at normal temperature, recording the oxidation peak current value of the levofloxacin, substituting the oxidation peak current value into the regression equation, and calculating the content of the levofloxacin in the levofloxacin raw material medicines.
In the detection method, cyclic voltammetry is adopted for detection at normal temperature, and specifically, the potential scanning range is set to be-0.2-2.4V, the scanning speed is 0.1V/s, and the number of cyclic turns is 1 turn.
Advantageous effects
Compared with the prior art, the detection method has the beneficial effects that: compared with the common high performance liquid chromatography, the electrochemical detection method has the biggest advantages of low instrument cost, convenient operation, high detection speed, high sensitivity and basically no discharge of waste liquid.
Drawings
FIG. 1 is a plot of the concentration of levofloxacin versus the standard current against the peak current and the concentration of the standard solution in example 3.
Detailed Description
The preparation of chiral pyrrole compound, chiral polypyrrole electrochemical sensor, and the electrochemical detection method of levofloxacin content in levofloxacin bulk drug of the present invention are described in more detail below by examples, but the scope of the present invention is not limited to these examples.
Example 1
Preparation of (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane
Adding 20mL of water and 2.00g (0.024mol) of sodium acetate into a 100mL three-necked flask, dissolving at room temperature, and building a reflux condenser tube and a stirring device; then adding 10mL (0.17mol) of glacial acetic acid and 1.208g (0.008mol) of (R) - (+) -4-methoxy-alpha-methylbenzylamine, heating to 75 ℃, and stirring for 10 min; dropwise adding an aqueous solution dissolved with 1.5mL (0.012mol) of 2, 5-dimethoxytetrahydrofuran and 0.5g (0.006mol) of anhydrous sodium acetate into the reaction solution, keeping the temperature at 75 ℃ and stirring for 2h after the dropwise addition is finished, and stopping the reaction; cooling the reaction solution to room temperature, extracting with dichloromethane, taking an organic phase, washing with water and saturated sodium chloride solution in sequence, adding anhydrous magnesium sulfate, drying, and carrying out silica gel column chromatography purification on the organic phase, wherein the eluent is ethyl acetate: petroleum ether 1:19 (volume ratio) gave 1.1078g of the desired product (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane in 68.89% yield.
Specific optical rotation: +4.1 °;
1H-NMR(DMSO-d6，δppm)：1.811-1.828(d,3H,-CH3,J＝6.8Hz)，3.795(s, 3H,-OCH3) 5.221-5.274(q,1H, -CH-, J ═ 21.2Hz), 6.190-6.194(t,2H, pyrrole ring hydrogen, J ═ 1.6Hz), 6.745-6.755(t,2H, pyrrole ring hydrogen, J ═ 4.0Hz), 6.844-6.866(dd,2H, phencyclane, J1 ═ 2.0Hz, J2 ═ 2.0Hz), 7.050-7.071(dd,2H, phencyclane, J1 ═ 1.6Hz, J2 ═ 1.6 Hz);
13C-NMR(DMSO-d6，δppm)：21.75，55.02，56.80，108.12，114.19，119.34， 127.48，136.01，158.45；
HRMS：C13H15NO[M+H]+calculated 202.1264, found 202.1257.
Example 2
Preparation of chiral polypyrrole electrochemical sensor
Step 1: electrode pretreatment
0.05 μm Al is used for glassy carbon electrode2O3And polishing the powder, ultrasonically cleaning a glassy carbon electrode, a platinum wire electrode and an Ag/AgCl electrode for 5 minutes by secondary water, ultrasonically cleaning by ethanol for 5 minutes, and ultrasonically cleaning by secondary water for 5 minutes.
Step 2: electrochemical sensor for preparing chiral polypyrrole
Taking 1.005g (0.005mol) of (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane prepared in the above example 1, 1.709g (0.005mol) of tetrabutylammonium perchlorate, and 1.1615g (0.005mol) of (D) - (+) -camphor-10-sulfonic acid in 50mL of acetonitrile, and accelerating dissolution by ultrasonic wave to remove oxygen by introducing nitrogen gas, thereby obtaining an electrolyte; an electrochemical workstation is adopted, a glassy carbon electrode is used as a working electrode, a platinum wire electrode is used as a counter electrode, Ag/AgCl is used as a reference electrode, the three pretreated electrodes are inserted into the electrolyte to form a one-chamber three-electrode system, and electrochemical polymerization is carried out at normal temperature; and setting a potential scanning range of-0.2-2.0V, a scanning speed of 0.05V/s and 50 cycles by adopting a cyclic voltammetry to obtain the compact poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] membrane modified glassy carbon electrode, namely the chiral polypyrrole electrochemical sensor.
Example 3
Electrochemical detection of content of levofloxacin in levofloxacin bulk drug
1. Solution preparation
Blank control solution: tetrabutylammonium perchlorate is added into acetonitrile to prepare acetonitrile solution containing 0.1mol/L of tetrabutylammonium perchlorate.
Standard solution:
taking 30mL of the blank control solution, adding 0.05mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 1mmol/L of the standard solution of the levofloxacin;
preparing a standard solution of 1mmol/L levofloxacin by the same method;
and (3) taking 30mL of the blank control solution, adding 0.025mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to obtain 0.5mmol/L standard solution of the levofloxacin.
Taking 30mL of the blank control solution, adding 0.0125mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the solution by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to obtain 0.25mmol/L standard solution of the levofloxacin;
taking 30mL of the blank control solution, adding 0.00625mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 0.125mmol/L standard solution;
and (3) taking 30mL of the blank control solution, adding 0.003125mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and using the blank control solution to fix the volume to 50mL to prepare 0.0625mmol/L of the standard solution of the levofloxacin.
2. Determination of oxidation peak positions of levofloxacin and levofloxacin
Inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode prepared in example 2 into 1mmol/L levofloxacin standard solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the levofloxacin standard solution and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting at normal temperature by adopting a cyclic voltammetry method, setting a potential scanning range to be-0.2-2.4V, a scanning speed to be 0.1V/s, and a cycle number to be 1 cycle, and measuring that the levofloxacin standard solution has an oxidation peak at 1.589V. By the same method as above, it was found that the levofloxacin had an oxidation peak at 1.973V. Therefore, the chiral polypyrrole electrochemical sensor can identify levofloxacin and levofloxacin.
3. Drawing a standard curve and establishing a linear regression equation
Inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode prepared in example 2 into a right ofloxacin standard solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the right ofloxacin standard solution and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting by adopting a cyclic voltammetry at normal temperature, setting a potential scanning range of-0.2-2.4V, a scanning speed of 0.1V/s and a cycle number of 1 circle. Respectively detecting the five standard solutions with different concentrations to obtain the oxidation peak current value (see the following table 1) of the standard solution with each concentration at 1.973V, drawing a standard curve (see the following table 1) of the concentration of the right ofloxacin according to the peak current value and the concentration of the standard solution to obtain a linear regression equation of Y-0.64611X +0.10683, and calculating a correlation coefficient R2＝0.9998。
TABLE 1
4. Electrochemical detection of content of levofloxacin in levofloxacin bulk drug
Levofloxacin bulk drugs: raw material drug of commercial levofloxacin
Preparing a detection solution:
3.6137g of levofloxacin raw material medicine is precisely weighed, 30mL of the blank reference solution is added, the mixture is dissolved by ultrasonic oscillation, and the volume is fixed to 50mL by the blank reference solution to prepare the detection solution.
Inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode prepared in the embodiment 2 into the detection solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the detection solution and the saturated potassium chloride solution, connecting the electrode to an electrochemical workstation, detecting by adopting a cyclic voltammetry at normal temperature, setting a potential scanning range to be-0.2-2.4V, a scanning speed to be 0.1V/s, and 1 cycle of number. The oxidation peak current value at 1.973V is measured to be 0.5632mA, and the standard curve equation of the levofloxacin is substituted to calculate the concentration C of the levofloxacin in the detection solution to be 0.7063mmol/L, so that the content of the levofloxacin in 3.6137g of levofloxacin bulk drug is 12.762 mg; then, the content of the levofloxacin in the levofloxacin bulk drug is 3531.6 mg/kg.
Examples 4 to 7
The levofloxacin bulk drugs purchased from different manufacturers are detected according to the method of the example 3, and the results are shown in the following table 2:
TABLE 2 results of the detection of levofloxacin raw material from different manufacturers
| Sample numbering | Content of Dexproxacin (mg/kg) | |
| Example 3 | 1 | 3531.6 |
| Example 4 | 2 | 5188.4 |
| Example 5 | 3 | 3162.9 |
| Example 6 | 4 | 4170.7 |
| Example 7 | 5 | 5149.2 |
Test examples
Recovery rate of added standard
The accuracy of the detection method of the invention is examined: the three standard addition levels were 0.1mmol/L, 0.2mmol/L, and 0.3mmol/L, respectively, and samples at each level were subjected to 3 measurements, and the recovery and precision of each level were calculated from the measured amount and the standard addition amount. The results are given in Table 3 below.
TABLE 3 examination results of the detection methods
The average recovery rate of the three marked levels of the levofloxacin is 99.35-99.74%, and the detection limit of the method is 0.01ppm, which indicates that the determination result of the method is reliable.
Claims (11)
1. The chiral pyrrole compound (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane has the following structural formula:
2. a process for preparing the chiral pyrrole compound of claim 1, comprising: under the catalysis of acid, 2, 5-dimethoxy tetrahydrofuran and (R) - (+) -4-methoxyl-alpha-methylbenzylamine are subjected to condensation reaction to obtain (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane.
3. The process for preparing chiral pyrrole compound according to claim 2, wherein the molar ratio of 2, 5-dimethoxytetrahydrofuran to (R) - (+) -4-methoxy- α -methylbenzylamine is 5:1 to 1: 1; the catalyst acid is dilute sulfuric acid, dilute hydrochloric acid or glacial acetic acid; the reaction temperature is 50-100 ℃; the reaction time is 1-4 h.
4. A chiral polypyrrole electrochemical sensor, comprising: the electrode comprises a glassy carbon electrode and a poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] film layer modified on the glassy carbon electrode.
5. The chiral polypyrrole electrochemical sensor of claim 4, wherein the chiral polypyrrole electrochemical sensor is prepared by the following method:
adopting an electrochemical workstation, taking a glassy carbon electrode as a working electrode, a platinum wire electrode as a counter electrode and an Ag/AgCl electrode as a reference electrode; acetonitrile solution in which (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, tetrabutylammonium perchlorate and (D) - (+) -camphor-10-sulfonic acid are dissolved is taken as electrolyte; inserting the three electrodes into electrolyte to form a one-chamber three-electrode system; and polymerizing (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane on the surface of the glassy carbon electrode by cyclic voltammetry to obtain the glassy carbon electrode modified by the poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] membrane, namely the chiral polypyrrole electrochemical sensor.
6. The chiral polypyrrole electrochemical sensor of claim 4, wherein the chiral polypyrrole electrochemical sensor is prepared by the following method:
firstly, electrode pretreatment is carried out, and the area is selected to be 10-30 mm2The glassy carbon electrode of (5), use of Al for the glassy carbon electrode2O3Polishing the powder, then ultrasonically cleaning a glassy carbon electrode, a platinum wire electrode and an Ag/AgCl electrode by using secondary water, ultrasonically cleaning by using ethanol, and ultrasonically cleaning by using the secondary water;
then preparing electrolyte, adding (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, tetrabutylammonium perchlorate and (D) - (+) -camphor-10-sulfonic acid into acetonitrile, accelerating dissolution by using ultrasonic waves, and introducing nitrogen to remove oxygen to obtain the electrolyte, wherein the concentration of the (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is 0.05-0.2 mol/L; the concentration of tetrabutylammonium perchlorate is 0.05-0.2 mol/L; (D) the concentration of the (+) -camphor-10-sulfonic acid is 0.05 to 0.2 mol/L;
inserting the pretreated glassy carbon electrode, a platinum wire electrode and an Ag/AgCl electrode into the prepared electrolyte to form a one-chamber three-electrode system, and performing electrochemical polymerization by using a cyclic voltammetry method under the atmosphere of nitrogen, wherein the potential scanning range is-0.2-2.0V, the scanning speed is 0.05V/s, the number of cycles is 30-100, and (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is polymerized on the surface of the glassy carbon electrode to obtain the glassy carbon electrode modified by the poly [ (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane ] membrane, namely the chiral polypyrrole electrochemical sensor.
7. The chiral polypyrrole electrochemical sensor of claim 6, wherein when preparing the electrolyte, adding (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane, tetrabutyl ammonium perchlorate and (D) - (+) -camphor-10-sulfonic acid into acetonitrile, accelerating dissolution by ultrasonic wave, and introducing nitrogen to remove oxygen to obtain the electrolyte, wherein the concentration of (R) - (+) -2- (4-methoxyphenyl) -2- (1-pyrrolyl) ethane is 0.09-0.12 mol/L; the concentration of tetrabutylammonium perchlorate is 0.09-0.12 mol/L; (D) the concentration of the (+) -camphor-10-sulfonic acid is 0.09-0.12 mol/L.
8. An electrochemical detection method for the content of levofloxacin in levofloxacin bulk drugs comprises the following steps:
step 1: drawing a standard curve and establishing a linear regression equation
Solution preparation
Blank control solution: adding tetrabutylammonium perchlorate into acetonitrile to prepare acetonitrile solution containing 0.05-0.2 mol/L of tetrabutylammonium perchlorate;
standard solution: taking the blank control solution, adding an ofloxacin standard product into the blank control solution to prepare an ofloxacin standard solution with a series of concentrations, wherein the concentration is between 1mmol/L and 0.05 mmol/L;
inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode of any one of claims 4 to 6 into a standard solution of ofloxacin, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the standard solution of ofloxacin and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting by using a cyclic voltammetry method, respectively detecting the standard solutions of ofloxacin with different concentrations in a series to obtain oxidation peak current values of the standard solutions of ofloxacin with different concentrations, and drawing a standard curve of the concentration of ofloxacin-current according to the peak current values and the concentrations of the standard solutions to obtain a linear regression equation;
step 2: electrochemical detection of content of levofloxacin in levofloxacin bulk drug
Accurately weighing levofloxacin raw material medicines, dissolving the levofloxacin raw material medicines in the blank control solution to prepare a detection solution, inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode into the detection solution, inserting the saturated calomel electrode into the saturated potassium chloride solution, building a salt bridge between the detection solution and the saturated potassium chloride solution, connecting the electrodes to an electrochemical workstation, detecting by adopting a cyclic voltammetry method, recording the oxidation peak current value of the levofloxacin, substituting the oxidation peak current value into the linear regression equation, and calculating the content of the levofloxacin in the raw material medicines.
9. The electrochemical detection method according to claim 8, wherein the detection is performed by cyclic voltammetry at room temperature, the potential scanning range is set to-0.2 to 2.4V, the scanning speed is 0.1V/s, and the number of cycles is 1 cycle.
10. The electrochemical detection method according to claim 8, wherein the step 1 comprises:
1) preparation of solution
Blank control solution: adding tetrabutylammonium perchlorate into acetonitrile to prepare acetonitrile solution containing 0.1mol/L tetrabutylammonium perchlorate;
standard solution:
taking 30mL of the blank control solution, adding 0.05mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 1mmol/L standard solution of the levofloxacin;
preparing a standard solution of 1mmol/L levofloxacin by the same method;
taking 30mL of the blank control solution, adding 0.025mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the blank control solution by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 0.5mmol/L standard solution of the levofloxacin;
taking 30mL of the blank control solution, adding 0.0125mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to obtain 0.25mmol/L standard solution of the levofloxacin;
taking 30mL of the blank control solution, adding 0.00625mmol of the standard substance of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 0.125mmol/L standard solution;
taking 30mL of the blank control solution, adding 0.003125mmol of the standard product of the levofloxacin into the blank control solution, dissolving the mixture by ultrasonic oscillation, and fixing the volume to 50mL by using the blank control solution to prepare 0.0625mmol/L of the standard solution of the levofloxacin;
2) determination of the Oxidation Peak positions of levofloxacin and Ofloxacin
Inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode into a 1mmol/L levofloxacin standard solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the levofloxacin standard solution and the saturated potassium chloride solution, connecting the electrode to an electrochemical workstation, detecting at normal temperature by adopting a cyclic voltammetry method, setting a potential scanning range of-0.2-2.4V, a scanning speed of 0.1V/s and a cycle number of 1 cycle, and detecting that the levofloxacin has an oxidation peak at 1.589V; by adopting the same method, the right ofloxacin is detected to have an oxidation peak at the position of 1.973V;
3) drawing a standard curve and establishing a linear regression equation
Inserting the chiral polypyrrole electrochemical sensor and the Ag/AgCl reference electrode into a right ofloxacin standard solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the right ofloxacin standard solution and the saturated potassium chloride solution, then connecting the electrodes to an electrochemical workstation, detecting at normal temperature by adopting a cyclic voltammetry method, setting a potential scanning range to be-0.2-2.4V, a scanning speed to be 0.1V/s and a cycle number to be 1 cycle, respectively detecting the five right ofloxacin standard solutions with different concentrations to obtain an oxidation peak current value of the right ofloxacin standard solution with each concentration at a position of 1.973V, drawing a right ofloxacin concentration-current standard curve according to the peak current value and the concentration of the standard solution to obtain a linear regression equation of Y-0.64611X +0.10683, and calculating a correlation coefficient R2＝0.9998。
11. The electrochemical detection method according to claim 10, wherein in the step 2, the levofloxacin raw material is precisely weighed, the blank control solution is added, and ultrasonic oscillation is performed to dissolve the levofloxacin raw material to prepare a detection solution;
inserting the chiral polypyrrole electrochemical sensor and an Ag/AgCl reference electrode into the detection solution, inserting a saturated calomel electrode into a saturated potassium chloride solution, building a salt bridge between the detection solution and the saturated potassium chloride solution, connecting the electrode to an electrochemical workstation, detecting at normal temperature by adopting a cyclic voltammetry method, setting a potential scanning range to be-0.2-2.4V, a scanning speed to be 0.1V/s, a cycle number to be 1 circle, recording an oxidation peak current value at a position of 1.973V, bringing a right ofloxacin standard curve linear regression equation Y to 0.64611X +0.10683, calculating the concentration of the right ofloxacin in the detection solution, and converting the content of the right ofloxacin in a levofloxacin raw material medicine.
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Effective date of registration: 20220830 Address after: Room 1-601-8, Jianrui Building, Dongzha Street, Nanhu District, Jiaxing City, Zhejiang Province 314000 Patentee after: Zhejiang Quanzhu Technology Co.,Ltd. Address before: 314001 No. 56 South Yuexiu Road, Zhejiang, Jiaxing Patentee before: JIAXING University |
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Granted publication date: 20210226 |