CN102768232A - Method for producing sildenafil molecular imprinting membrane electrochemical sensor (MIES) - Google Patents

Method for producing sildenafil molecular imprinting membrane electrochemical sensor (MIES) Download PDF

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CN102768232A
CN102768232A CN2012102257213A CN201210225721A CN102768232A CN 102768232 A CN102768232 A CN 102768232A CN 2012102257213 A CN2012102257213 A CN 2012102257213A CN 201210225721 A CN201210225721 A CN 201210225721A CN 102768232 A CN102768232 A CN 102768232A
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silaenafil
rgo
molecular imprinting
solution
electrode
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CN102768232B (en
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周学敏
姜慧君
韩青
李芸
文婷婷
薛诚
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Nanjing University
Nanjing Medical University
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Nanjing Medical University
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Abstract

The invention discloses a method for producing a sildenafil molecular imprinting membrane electrochemical sensor (MIES), which can be used for producing the sildenafil MIES through the steps of electrode pretreatment, molecular layer-by-layer self-assembly for modifying an electrode, molecular imprinting membrane self-assembly, electro-polymerization reaction, template molecule elution and other steps sequentially. The sildenafil MIES produced by the method has the characteristics of high selectivity, quick response, high sensitivity, good stability and tolerance and the like, and can test sildenafil in the complex matrix efficiently, flexibly and real-timely. By the sildenafil MIES, not only can the legitimate rights and interest of most consumers be maintained, but also the health and safety of the consumers can be better guaranteed, accordingly, the consumers can get clearer understanding on selecting traditional Chinese herbal health care products and food for tonifying kidney and strengthening yang, so the national pharmacy administration and regulations completion, drug manufacturing enterprise behavior regularization and traditional Chinese herbal health care product market purification are greatly promoted.

Description

A kind of preparation method of silaenafil molecular imprinting membrane electrochemical sensor
Technical field
The invention belongs to technical field of analysis and detection, be specifically related to the preparation method of a kind of silaenafil molecular imprinting membrane electrochemical sensor (MIES).
Background technology
Sildenafil citrate is the medicine of first oral medication impotence, needs under physician guidance, to use.National Drug Administration stipulates that all food that contain sildenafil citrate are all illegal; It and monobel medicine have absolute contraindication; The patient who particularly takes monobel for suffering from hypertension angina pectoris; Can cause the blood pressure stack to descend in case take for a long time, life security is caused serious threat.Some illegal manufacturing enterprises add the sildenafil citrate of minute quantity in health food, Chinese patent drug at present, make it have effects such as antifatigue, tonifying kidney and strengthening yang, but do not show the potential hazard of product clearly for the sanction of escaping law.For guaranteeing the healthy of consumers in general, the standard health food market, the detection method of setting up the check sildenafil citrate of a sensitivity height, high specificity is very necessary and urgent problem.
Present various novel check and analysis instruments, the gas chromatography and the liquid chromatography that particularly have mass detector are all improving a lot aspect applicability and the sensitivity.But the drug ingedient that adds owing to violating a ban in health food, the Chinese patent drug is many and content is extremely low; (especially compound Chinese herbal medicinal ingredients) phase mutual interference etc. exists between the complex matrices composition; Cause present various detection method major part to have problems such as sample preparation methods is numerous and diverse, shortage selectivity, therefore detect Research on New and have very important meaning for forbidden drug in functional health care food and the medicine.
Electrochemical sensor is a kind of important electron device; Because of its simplicity of design, highly sensitive, cheap, can realize human detection, can satisfy clinical diagnosis, advantage such as environmental analysis, food analysis and product detection needs, more and more receive people's attention.
Molecular imprinting belongs to host-guest chemistry category in the supramolecular chemistry, is an interdisciplinary study that comes from subjects such as high polymer chemistry and materials chemistry.Molecular imprinting is that preparation has the technology of specific selectivity or single-minded selective polymerisation thing.Its most significant three big characteristics are: structure is imitated precordainment, specific recognition property and broad applicability.
Electropolymerization molecular imprinting sensor sensing film has certain report at present, and the electricity consumption polymerization prepares silaenafil molecular imprinting sensitive membrane sensor and do not appear in the newspapers.Detect the existing bibliographical information of silaenafil of violating a ban in the health products and adding with the enrichment of molecular imprinting method.Ding Meijuan etc. utilize Fe 3O 4As magnetic material, work out a kind of magnetic molecule marking technology and be used for detecting silaenafil and Vardenafil content in the Chinese patent drug,
Figure BDA00001833683400021
Utilize solid phase extraction techniques to study a kind of method that in the WS, can detect silaenafil content in the blood plasma Deng the people.
Health products particularly Chinese medicine class health products and add the diversity of forbidden drug kind and problem such as intellectual not because the complicacy of self component, and its analyzing and testing that contains silaenafil is had higher requirement.The detection method of existing bibliographical information has: HPLC, capillary electrophoresis, LC-MS etc.Though these traditional methods also can realize the mensuration to silaenafil, often owing to the sample substrate complicacy needs through loaded down with trivial details sample pre-treatments, this has influenced accuracy and agility that object detects greatly.The fine selectivity of binding molecule marking technology carries out the fast enriching that sample pre-treatments can realize the trace object.Once there was report to combine the silaenafil in the traditional analysis method detection of complex sample, though improved the sensitivity that detects and accuracy greatly but still faced sample preparation complicacy, shortcoming consuming time with molecular imprinting.The maximum advantage of electrochemical sensor is highly sensitive, convenient and swift, can realize real-time detection.Traditional electrochemical detects most determinands that are confined to have electrochemical activity itself; The electrochemical sensor that combines with molecular imprinting is expected to break through traditional limitation, can produce electrochemical response through the path that object to be measured combines with the specificity hole to block probe molecule.But mostly the molecular imprinting layer that voltolisation is incorporated on the electrode is non-conductive or the weakly conducting material, has influenced the sensitivity of sensor greatly.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of silaenafil molecular imprinting membrane electrochemical sensor; This method advantage of combined with electrochemical sensor and molecular imprinting is first constructed silaenafil molecular imprinting electrochemical sensor; Realization is added the fast detecting of silaenafil to violating a ban in health products, the medicine; It can not only safeguard consumers in general's legitimate rights and interests; And can ensure their healthy safety better, thus make consumers in general aspect the choosing of tonifying kidney and strengthening yang class traditional Chinese medicine health care product, have understanding more clearly, this is to improving China's pharmaceutical administration and rules; The behavior of standard pharmaceutical producing enterprise purifies traditional Chinese medicine health care product market and has very important impetus.
The object of the invention can reach through following measure:
A kind of preparation method of silaenafil molecular imprinting membrane electrochemical sensor, it may further comprise the steps:
A) electrode pre-service: glass-carbon electrode polishing back is cleaned;
B) the self-assembled modified layer by layer electrode of molecule: pretreated electrode is immersed in the WS that contains PDDA, carries out after the Electrostatic Absorption with rinsing well and drying up; Again it is immersed into electronegative redox Graphene PSS-RGO solution, floods afterwash, dry up; Continue to be immersed in the redox Graphene PDDA-RGO solution of positively charged, flood afterwash, dry up; Repeat the step of the redox Graphene PDDA-RGO solution of the electronegative redox Graphene of aforementioned immersion PSS-RGO solution and positively charged, with every RGO -/ RGO +Be one deck, 10～20 layers of repeated impregnations obtain the self-assembled modified layer by layer electrode of molecule of 10～20 layers of RGO;
C) molecular imprinting self assembly solution: preparation contains the ethanol/HAC-NaAC damping fluid of phenylenediamine function monomer and silaenafil, and it is sealed after with the nitrogen deoxygenation, places 5 ~ 20h in 20 ℃～30 ℃ lucifuge environment, obtains molecular imprinting self assembly solution.Wherein, the molar concentration rate of silaenafil and phenylenediamine function monomer is 1:1～1:50;
D) electric polymerization reaction: the molecular imprinting self assembly solution that step c) obtains is poured in the reaction vessel; Lucifuge, behind the logical nitrogen, inserting step b) the self-assembled modified layer by layer glass-carbon electrode of RGO that obtains; Under+0.2 ~ 1.0V current potential; Adopt timing electric current electropolymerization 400～800s, take out, drip washing, dry up;
E) wash-out template molecule: the electrode that step d) is obtained immerses H 2SO 4In the solution ,-0.8 ~+handle 3 ~ 10min under the 0.2V current potential.
In step a), can use the ultrasonic cleaning of second alcohol and water earlier successively after the glass-carbon electrode polishing, dry up with distilled water drip washing and with nitrogen then.
In step b), the time that the electrode after the processing is immersed in Electrostatic Absorption in the WS that contains PDDA (diallyl dimethyl ammoniumchloride) is 4～6h; Adopt distilled water to rinse well and dry up after the Electrostatic Absorption with nitrogen; The mass concentration of the WS of said PDDA is 0.5% ~ 5.0%.
In step b), the time that electrode is immersed into electronegative redox Graphene PSS (4-SSS)-RGO (redox Graphene) solution is 10 ~ 60min; The dipping back adopts distilled water to rinse well and dry up with nitrogen.The volumetric molar concentration scope of RGO is 0.1mg/mL ~ 5.0mg/mL in the said PSS-RGO solution, preferred 0.5mg/mL ~ 1.0mg/mL.
PSS-RGO can adopt existing method preparation among the present invention, like [the low temperature preparation of Graphene and electrochemical properties research] (list of references of Lv Wei [1]) and [An efficient reduction route for the production of Pd-Pt nanoparticles anchored on graphene nanosheets for use as durable oxygen reduction electrocatalysts] (list of references of people such as He W [2]).
In the step b), the time that electrode is immersed in the redox Graphene PDDA-RGO solution of positively charged is 10 ~ 60min; The dipping back is rinsed well and is dried up with nitrogen with distilled water.The volumetric molar concentration scope of RGO is 0.1mg/mL ~ 5.0mg/mL in the said PDDA-RGO solution, preferred 0.5mg/mL ~ 1.0mg/mL.
PSS-RGO can adopt existing method preparation among the present invention, as adopting [the low temperature preparation of Graphene and electrochemical properties research] (list of references of Lv Wei [1]) and people's such as He W [An efficient reduction route for the production of Pd-Pt nanoparticles anchored on graphene nanosheets for use as durable oxygen reduction electrocatalysts] (list of references [2]).
Step b) can obtain PDDA/ (RGO -/ RGO +/ ```/RGO -/ RGO +/) 10～20GCE electrode, i.e. 10～20 layers of glass-carbon electrode that RGO is self-assembled modified layer by layer.
In step c), said phenylenediamine function monomer is o-phenylenediamine, p-phenylenediamine (PPD) or m-phenylene diamine; The molar concentration rate of silaenafil and phenylenediamine function monomer is 1:1～1:50.Wherein the concentration range of silaenafil is 0.1mmol/L ~ 5.0mmol/L; The concentration range of phenylenediamine function monomer is 5.0mmol/L ~ 50.0mmol/L.The mol ratio of monomer and template molecule directly influences the formation in marking hole in the molecular imprinting film and the amount of recognition site, and then influences its absorption property.In self assembling process, silaenafil and p-phenylenediamine (PPD) make MIS to object better choice property arranged through the hydrogen bond action selective binding.Experiment finds, according to the variation of current-responsive value before and after the wash-out, when mol ratio is 1:5～1:20, particularly during 1:10, MIS current-responsive changing value is maximum.
In step d), the time that molecular imprinting self assembly solution is poured the logical nitrogen of lucifuge behind the reaction vessel into is 10 ~ 30min.Adopt timing electric current electropolymerization mode in the step d); Relatively cross silaenafil standard self assembly liquid through experiment and adopt the legal and legal electropolymerization film forming of carrying out of timing electric current voltolisation of cyclic voltammetric voltolisation respectively, contrast the variation of their electropolymerization wash-outs front and back current-responsive value.The result shows that the molecular imprinting polymeric membrane wash-out template molecule after-current response that the chronoamperometry electropolymerization forms is obviously greater than the current-responsive value behind the cyclic voltammetry electropolymerization wash-out.
In step e), adopt H 2SO 4Solution carries out wash-out to template molecule.Template molecule whether thoroughly wash-out to the mensuration of electrode important influence as a result.Traditional elution process often adopts organic solvent or buffer solution drip washing electrode, and the time that these methods generally need is long, and can not remove template molecule fully.The influence of adhesion between test potential p-phenylenediamine (PPD)-silaenafil is to explore the condition of wash-out template molecule.Experimental result shows that when the molecular imprinting polymeric membrane being applied certain positive voltage wash-out, the marking hole reappearance of wash-out rear pattern plate molecule is bad, and elute effect is obvious inadequately.Possibly be because the polymer film that initiation forms under the positive voltage polymerization is stable to positive potential.But situation is then different when applying negative potential; Negative potential can reduce hydrogen bonded power between the two through changing the inner microenvironment of protonated p-phenylenediamine (PPD) and silaenafil compound, forces template molecule to leave from the p-phenylenediamine (PPD) inside of height polymerization and reaches the wash-out purpose.The present invention is immersed H according to the mechanism of electrostatic repulsion and hydrogen bond easy fracture in acid solution with the electropolymerization rear electrode 2SO 4In the solution ,-1.0 ~+handle 3 ~ 10min under the 0.2V current potential to make and form negative charge on the polymeric membrane and assemble, preferably-0.8 ~+the 0.2V current potential handles down, further preferably-0.8 ~-the 0.2V current potential under processing.The H that adopts in this step 2SO 4The concentration range of solution is 0.2mol/L ~ 2.0mol/L.
Can detect electrochemical sensor of the present invention through following method:
Electrochemical detection method and condition:
Cyclic voltammetry (CV) method: the detection potential range is-0.2～0.6V, and sweep speed is 100mVs -1Test end liquid is 0.1molL -1KCl and 1mmolL -1K 3Fe (CN) 6Solution.
Differential pulse method (DPV) method: the detection potential range is-0.4～0.6V, and sweep speed is 50mVs -1, the current potential increment is 0.005V, and amplitude is 0.05V, and pulse width is 0.1s, and the sampling width is 0.02s, be 2s rest time.Electrode is at H before the test 2SO 4Clean in the solution to background current and recover.Test end liquid is 0.1molL -1KCl and 1mmolL -1K 3Fe (CN) 6Solution.
AC impedence method (EIS): initial potential 200mV, frequency range 0.01～10000Hz, test end liquid is 0.1molL -1KCl and 1mmolL -1K 3Fe (CN) 6Solution.
Sample determination: the silaenafil to measure in the tablet is an example, gets 5 of certain tonics tablet for kidney-reinforcing (specification 0.28g/ sheet), grinds fully with mortar, takes by weighing powder 100mg, with 10mL acetonitrile ultrasonic extraction 20min.Get filtrating 1mL after the filtration, nitrogen dries up the phosphate buffer that the back adds pH5.6, adopts DPV method in above-mentioned to measure the concentration of silaenafil in three duplicate samples.
Silaenafil is an organic weak base, and is insoluble in alkaline solution.Through test, when the PH of buffer solution was 5.6, wash-out template molecule after-current response was the highest, explained with this understanding to have formed more marking site between the p-phenylenediamine (PPD) and silaenafil, and recognition effect is best.So during sample determination the acidity of solution should can guarantee under the consoluet situation of silaenafil low as far as possible.
The silaenafil molecular imprinting membrane electrochemical sensor of this method preparation, its detectability (LOD) can reach 2.0 * 10 -8MolL -1(S/N=3), sensitivity is far above the existing sensor of having reported, its also have selectivity height, response fast, characteristics such as stability and tolerance be good, can realize the efficient, sensitive of silaenafil in the complex matrices and detect in real time.
Beneficial effect of the present invention:
1. the present invention alternately is adsorbed onto electrode surface through molecule self assembly layer by layer with the RGO of oppositely charged, and the specific surface area that this has increased electrode has greatly strengthened electronic conduction ability, has improved detection sensitivity.
2. the RGO of oppositely charged can make the nano oxidized reduction graphene molecules absorption of each layer evenly firm through self assembly layer by layer, and the number of plies is controlled, can conveniently observe the variation of electrochemical response through the control number of plies.
3. molecular imprinting is combined with electrochemical sensor, improved the specificity of electrochemical sensor, can realize the selectivity of silaenafil in the complex sample is detected.
4. the molecular imprinting layer carries out electropolymerization after through self assembly again, has formed the specificity hole rete that compact and firm comprises template molecule.
5. the function monomer of selecting for use is an aniline category matter, be function monomer be again the crosslinking chemical in traditional molecular imprinting, under electropolymerizatioconditions conditions, form the polyaniline of electric conductivity.
Description of drawings
Fig. 1 is that MIES prepares each step cycle volt-ampere comparison diagram in the process.
Among the figure, a1 is the CV curve of MIPs behind the CV curve, c1 electropolymerization of CV curve, the b1 Graphene LBL-GCE of naked-GCE, the CV curve of d1 wash-out template molecule MIES.
Fig. 2 is that MIES prepares each stage AC impedance comparison diagram in the process.
Among the figure, a2 is the CV curve of MIPs behind the CV curve, c2 electropolymerization of CV curve, the b2 Graphene LBL-GCE of naked-GCE, the CV curve of d2 wash-out template molecule MIES.
Fig. 3 is the dynamic adsorption curve figure of LBL-MIES.
Fig. 4 is the Static Adsorption curve map of LBL-MIES and LBL-NIES.
Fig. 5 is the selective adsorption curve of LBL-MIES.
Among the figure, the silaenafil of the silaenafil of a:1 μ mol/L and 1 μ mol/L Vardenafil solution absorbs curve b:1 μ mol/L and the silaenafil solution absorbs curve of 10 μ mol/L tadalafil solution absorbs curve c:1 μ mol/L.Be followed successively by c, a, b among the figure in the right side from bottom to top.
Embodiment
Medicine and reagent: Al 2O 3(0.05 μ m, Shanghai occasion China Instr Ltd.), silaenafil, Vardenafil, tadalafil (Sildenafil, Zhengzhou litchi promise bio tech ltd), potassium chloride (KCl), the potassium ferricyanide (K 3Fe (CN) 6) (analyze pure, the new precious Fine Chemical Works in Shanghai), absolute ethyl alcohol, acetonitrile (analyze pure, chemical reagent company limited of group of nations), sodium dihydrogen phosphate (NaH 2PO 4.2H 2O), sodium hydrogen phosphate (Na 2HPO 4.12H 2O, Nanjing Chemistry Reagent Co., Ltd.), 1,4-p-phenylenediamine (PPD) (ladder is uncommon likes that (Shanghai) changes into industrial development company limited for p-Phenylene diamine, p-PD), redox Graphene (RGO, self-control) sulfuric acid (H 2SO 4, Shanghai chemical reagent company limited), experimental water is a redistilled water.0.2molL -1Na 2HPO 4.12H 2O and 0.3molL -1NaH 2PO 4.2H 2The PBS of O WS preparation pH 5.8 (phosphate buffered solution, PBS).Diallyl dimethyl ammoniumchloride (Poly diallyl dimethyl ammonium chloride, PDDA, U.S. Sigma-aldrich company); Kayexalate (Poly sodium-p-styrenesulfonate; PSS, U.S. Sigma-aldrich company)
PDDA-RGO among the embodiment, PSS-RGO adopt following method preparation:
A) GO: list of references [1], get the 3.0g expanded graphite, add the 120mL concentrated sulphuric acid, ice bath stirs, and divides 3 times and adds 16.0g potassium permanganate.35 ~ 40 ℃ are stirred after 20 hours and add water 250mL in batches, 80 ℃ of hot bath stirring reactions 2 hours, and reactant gradually becomes glassy yellow.The cooling back adds 40mL hydrogen peroxide stirred overnight, makes GO (graphene oxide).Then through pickling, wash to pH near 6.Ultrasonic dispersion GO1 ~ 2 hours.
B) PDDA-RGO: list of references [2], GO quantitatively is 0.5mg/mL, ultrasonic dispersion 1h.Getting 200mL GO under the stirring condition fast, adding 28%PDDA WS 2ml, ultrasonic 2h stirs 12h fast, and the WS cleans removes unnecessary PDDA.Add monoethylene glycol, transfer PH11, more than reaction 4h under the 140 degree conditions, clean, obtain PDDA-RGO.
C) PSS-RGO:GO quantitatively is 0.5mg/mL, ultrasonic dispersion 1h.Get 200mL GO and add the ultrasonic 30min of 600mg PSS, 50 ℃ are stirred 24h.The cooling back adds ammoniacal liquor and each 4mL of hydrazine hydrate, and 95 ~ 100 ℃ are stirred 24h.Obtain PSS-RGO through washing and ultrasonic dispersion.
Embodiment 1
(1) glass-carbon electrode pre-service
(Φ=3mm) is through the Al of 0.05 μ m for glass-carbon electrode 2O 3After the suspension polishing, absolute ethyl alcohol, deionized water ultrasonic cleaning 1min are used in distilled water drip washing then respectively.
(2) the self-assembled modified layer by layer electrode of molecule
Modified electrode is immersed in the WS (0.5wt%) that contains PDDA, rinses N behind the Electrostatic Absorption 5h with distilled water well 2Dry up; (distilled water is rinsed well, N for PSS-RGO, 0.6mg/mL) 15min in the solution to immerse electronegative redox Graphene 2Dry up; (distilled water is rinsed well, N for PDDA-RGO, 0.6mg/mL) 15min in the solution to immerse the redox Graphene of positively charged then 2Dry up; Every RGO -/ RGO +Be one deck, repeat 10 times, make PDDA/ (RGO -/ RGO +/ ```/RGO -/ RGO +/) 10The GCE electrode promptly obtains 10 layers of glass-carbon electrode that RGO is self-assembled modified layer by layer
(3) molecular imprinting self assembly solution
Preparation contains 5mmolL -1P-phenylenediamine (PPD) and 1mmolL -1The ethanol of silaenafil/NaAC-HAC mixing and buffering solution seals after the inflated with nitrogen deoxygenation, keeps 20h in the room temperature lucifuge environment, accomplishes self assembly.
(4) electric polymerization reaction
Molecular imprinting self assembly solution is poured in the reaction tank, and lucifuge behind the logical nitrogen 10min, is inserted the self-assembled modified good electrode of molecular imprinting layer, under+0.8 current potential, adopts chronoamperometry electropolymerization 500s, take out, and deionized water drip washing, nitrogen dries up.
(5) wash-out template molecule
Under-0.8V the constant voltage, at 0.6molL -1H 2SO 4Handle 3min in the solution, remove template molecule.Take out, deionized water drip washing repeatedly is clean, and nitrogen dries up, and promptly gets molecular imprinting membrane electrochemical sensor (MIS).The preparation process of MIS is shown.
Embodiment 2
(1) glass-carbon electrode pre-service
(Φ=3mm) is through the Al of 0.05 μ m for glass-carbon electrode 2O 3After the suspension polishing, absolute ethyl alcohol, deionized water ultrasonic cleaning 1min are used in distilled water drip washing then respectively.
(2) the self-assembled modified layer by layer electrode of molecule
Modified electrode is immersed in the WS (1wt%) that contains PDDA, rinses N behind the Electrostatic Absorption 5h with distilled water well 2Dry up; (distilled water is rinsed well, N for PSS-RGO, 0.4mg/mL) 15min in the solution to immerse electronegative redox Graphene 2Dry up; Immerse then positively charged the redox Graphene (PDDA-RGO, 0.4mg/mL) 15min in the solution,, distilled water is rinsed well, N 2Dry up; Every RGO -/ RGO +Be one deck, repeat 20 times, make PDDA/ (RGO -/ RGO +/ ```/RGO -/ RGO +/) 20The GCE electrode obtains 20 layers of glass-carbon electrode that RGO is self-assembled modified layer by layer.
(3) molecular imprinting self assembly solution
Preparation contains 10mmolL -1P-phenylenediamine (PPD) and 1mmolL -1The ethanol of silaenafil/NaAC-HAC mixing and buffering solution seals after the inflated with nitrogen deoxygenation, keeps 10h in the room temperature lucifuge environment, accomplishes self assembly.
(4) electric polymerization reaction
Molecular imprinting self assembly solution is poured in the reaction tank, and lucifuge behind the logical nitrogen 10min, is inserted the self-assembled modified good electrode of molecular imprinting layer, under+0.6 current potential, adopts chronoamperometry electropolymerization 600s, take out, and deionized water drip washing, nitrogen dries up
(5) wash-out template molecule
Under-0.6V the constant voltage, at 0.7molL -1H 2SO 4Handle 4min in the solution, remove template molecule.Take out, deionized water drip washing repeatedly is clean, and nitrogen dries up, and promptly gets molecular imprinting membrane electrochemical sensor (MIS).
Embodiment 3
(1) glass-carbon electrode pre-service
(Φ=3mm) is through the Al of 0.05 μ m for glass-carbon electrode 2O 3After the suspension polishing, absolute ethyl alcohol, deionized water ultrasonic cleaning 1min are used in distilled water drip washing then respectively.
(2) the self-assembled modified layer by layer electrode of molecule
Modified electrode is immersed in the WS (3wt%) that contains PDDA, rinses N behind the Electrostatic Absorption 5h with distilled water well 2Dry up; (distilled water is rinsed well, N for PSS-RGO, 0.7mg/mL) 15min in the solution to immerse electronegative redox Graphene 2Dry up; Immerse then positively charged the redox Graphene (PDDA-RGO, 0.7mg/mL) 15min in the solution,, distilled water is rinsed well, N 2Dry up; Every RGO -/ RGO +Be one deck, repeat 20 times, make PDDA/ (RGO -/ RGO +/ ```/RGO -/ RGO +/) 20The GCE electrode obtains 20 layers of glass-carbon electrode that RGO is self-assembled modified layer by layer.
(3) molecular imprinting self assembly solution
Preparation contains 20mmolL -1P-phenylenediamine (PPD) and 1mmolL -1The ethanol of silaenafil/NaAC-HAC mixing and buffering solution seals after the inflated with nitrogen deoxygenation, keeps 8h in the room temperature lucifuge environment, accomplishes self assembly.
(4) electric polymerization reaction
Molecular imprinting self assembly solution is poured in the reaction tank, and lucifuge behind the logical nitrogen 10min, is inserted the self-assembled modified good electrode of molecular imprinting layer, under+0.4 current potential, adopts chronoamperometry electropolymerization 800s, take out, and deionized water drip washing, nitrogen dries up.
(5) wash-out template molecule
Under-0.4V the constant potential, at 0.5molL -1H 2SO 4Handle 5min in the solution, remove template molecule.Take out, deionized water drip washing repeatedly is clean, and nitrogen dries up, and promptly gets molecular imprinting membrane electrochemical sensor.
Embodiment 4
(1) glass-carbon electrode pre-service
(Φ=3mm) is through the Al of 0.05 μ m for glass-carbon electrode 2O 3After the suspension polishing, absolute ethyl alcohol, deionized water ultrasonic cleaning 1min are used in distilled water drip washing then respectively.
(2) the self-assembled modified layer by layer electrode of molecule
Modified electrode is immersed in the WS (2wt%) that contains PDDA, rinses N behind the Electrostatic Absorption 5h with distilled water well 2Dry up; (distilled water is rinsed well, N for PSS-RGO, 0.8mg/mL) 15min in the solution to immerse electronegative redox Graphene 2Dry up; Immerse then positively charged the redox Graphene (PDDA-RGO, 0.8mg/mL) 15min in the solution,, distilled water is rinsed well, N 2Dry up; Every RGO -/ RGO +Be one deck, repeat 20 times, make PDDA/ (RGO -/ RGO +/ ```/RGO -/ RGO +/) 20The GCE electrode obtains 20 layers of glass-carbon electrode that RGO is self-assembled modified layer by layer.
(3) molecular imprinting self assembly solution
Preparation contains 40mmolL -1P-phenylenediamine (PPD) and 1mmolL -1The ethanol of silaenafil/NaAC-HAC mixing and buffering solution seals after the inflated with nitrogen deoxygenation, keeps 6h in the room temperature lucifuge environment, accomplishes self assembly.
(4) electric polymerization reaction
Molecular imprinting self assembly solution is poured in the reaction tank, and lucifuge behind the logical nitrogen 10min, is inserted the self-assembled modified good electrode of molecular imprinting layer, under+1.0 current potentials, adopts chronoamperometry electropolymerization 400s, take out, and deionized water drip washing, nitrogen dries up.
(5) wash-out template molecule
Under-0.2V the constant potential, at 0.4molL -1H 2SO 4Handle 6min in the solution, remove template molecule.Take out, deionized water drip washing repeatedly is clean, and nitrogen dries up, and promptly gets molecular imprinting membrane electrochemical sensor.
MIES prepares the sign of process
1. the electrochemical Characterization of electrode modification process
1.1 different modifying glass-carbon electrode cyclic voltammetric map analysis before the electropolymerization:
Contrast the variation of two kinds of method modified glassy carbon current-responsive values.Same glass-carbon electrode successively operated (a1 is the CV curve of MIPs behind the CV curve, c1 electropolymerization of CV curve, the b1 Graphene LBL-GCE of naked-GCE, the CV curve of d1 wash-out template molecule MIES); After identical method pre-service, press above-mentioned CV method at deoxygenation K 3Fe (CN) 6Measure the CV curve in the/KCl test solution.The result shows that the CV area of electrode is maximum among the b1, and the current-responsive value is the highest, and it is the highest to explain that Graphene adsorbs modification back glass-carbon electrode redox reaction susceptibility layer by layer, i.e. (RGO +/ RGO -) 20The ability that/PDDA/GCE film surface transmits electric charge is stronger, possibly be that the number that the surface can move freely electronics is many, thereby has improved film electric charge transmissibility because to adsorb the Graphene electrodes specific surface area layer by layer bigger.
1.2MIES each step cycle volt-ampere contrast in the preparation process:
By above-mentioned CV method, MIES is prepared in the process each stage carried out the cyclic voltammetric sign.(Fig. 1 result shows; The cyclic voltammetric current-responsive value of Graphene absorption method modification layer by layer is higher in a1, b1, and the CV area under the curve is bigger, shows after Graphene absorption method modification layer by layer; The ability that electric charge is transmitted on the surface of glass-carbon electrode is stronger, and conductive capability strengthens.Analyze the c1 curve; The result shows the carrying out along with the electrode surface electropolymerization; The MIPs film is thickening gradually, and electrode surface has formed the fine and close weak inductive polyphenyl diamines film of one deck, has hindered the redox reaction of probe molecule; Therefore cyclic voltammetric current-responsive value reduces gradually, has explained that the molecule aggregation film can stably be modified at electrode surface.From curve d1, can find out, marking membrane electrode is immersed 0.5mol/L H 2SO 4In the solution with behind the current potential revulsion wash-out template molecule; Cyclic voltammetric current-responsive value significantly strengthens; Explain that target molecule through behind this approach wash-out, forms the marking film that has some markings hole, probe molecule can arrive electrode surface through the hole and carry out redox reaction; Therefore, the current-responsive value increases.
1.3MIES each stage AC impedance contrast in the preparation process:
Faradaic impedance can be used to survey effectively the situation on modified electrode surface.The radius of arc is big more in the AC impedance curve, and impedance is big more, otherwise impedance is more little.In testing background solution, the MIES curve (d2) of MIPs curve (c2), wash-out template molecule behind naked GCE curve (a2), Graphene LBL-GCE curve (b2), the electropolymerization has been carried out the AC impedance sign by above-mentioned AC impedence method.Fig. 2 result shows that in a2, b2, Graphene absorption method modified glassy carbon AC impedance layer by layer is less, shows that the resistance of the electron transfer of glass-carbon electrode reduces after Graphene absorption method modification layer by layer, and conductive capability strengthens.Analyze c2 figure, the result shows the carrying out along with the electrode surface self assembly, and the MIPs film is thickening gradually, and electrode impedance increases gradually.Explain that through self assembly and electropolymerization the molecule aggregation film can stably be modified at electrode surface.From d2, can find out, marking membrane electrode is immersed 0.5mol/LH 2SO 4With behind the current potential revulsion wash-out template molecule, resistance value obviously reduces in the solution, and this explanation target molecule can pass through this approach wash-out, and marking membrane electrode can be realized regeneration.
The MIES absorption property is estimated
1. dynamic adsorption test
The silaenafil standard solution of accurate respectively configuration 5 μ mol/L, 10 μ mol/L, 50 μ mol/L.Take out respectively at 1,5,10,15,20,25,30, during 40min, the electrochemical response of measuring the silaenafil sensor by above-mentioned CV method is worth changing.Curve rose than very fast in the starting stage, was tending towards saturated about 20min.Even the initial concentration of silaenafil is different, the state adsorbance that reaches capacity is basic identical, and discrimination bit is counted necessarily in the visible film, has further proved the specificity hole that has formed silaenafil in the imprint layer.
2. Static Adsorption test
With MIPs a series of concentration (0.5 μ mol/L-250 μ mol/L) silaenafil standard solution of 150 μ L is adsorbed 20min respectively.By electrode current respective change value before and after the above-mentioned CV method test absorption; Along with silaenafil concentration increases; △ Ip also increases gradually; This is because more silaenafil can occupy more marking hole, blocks probe molecule and through polymer layer generation redox reaction electric current is reduced, and the electric current changing value increases.When concentration is 50 μ molL -1The time, absorption reaches balance, and △ Ip value no longer changes, and thinks that this moment, recognition site was almost all occupied by template molecule, shows that marking hole and active binding site have height affinity and special recognition capability to silaenafil.
3. selective adsorption test
Selectivity is to investigate the important indicator of molecularly imprinted polymer marking effect and performance quality, also is that can sensor be applied to the prerequisite that actual sample detects.The experiment of design interference is used to investigate the molecular imprinting effect, studies promptly whether recognition site has specific selectivity to template molecule in the film, whether does not receive the interference of other competitive substrates.
Adopt ED compounds Vardenafil and tadalafil to carry out comparing experiment in the experiment with silaenafil.After respectively electrode being immersed in A, B, the C solution absorption 20min, at 1mmolL -1The potassium ferricyanide and 0.1molL -1Adopt the DPV method in the preamble to carry out the DPV scanning analysis in the solution of KCl.The result shows; Marking membrane electrode is close or identical to the current-responsive value of A, B, C; Be illustrated in 1 times and 10 times of concentration chaff interferences exist respectively under the condition; Marking film is constant to the adsorbance of silaenafil, and the marking hole that promptly stays behind the silaenafil wash-out does not receive the interference of Vardenafil and tadalafil to the absorption of silaenafil, thereby the silaenafil electrochemical sensor that shows preparation in this experiment has stable specific adsorption ability.
The silaenafil standard solution of the silaenafil of the silaenafil of A:1 μ mol/L and 1 μ mol/L Vardenafil standard solution B:1 μ mol/L and 10 μ mol/L tadalafil standard solution C:1 μ mol/L.
The sample determination methodology
1. typical curve and detectability
The DPV oxidation peak current of silaenafil and its concentration are 2.0 * 10 -8-5.0 * 10 -7MolL -1With 5.0 * 10 -7-5.0 * 10 -5MolL -1Scope in be good linear relationship, equation of linear regression is respectively Ip=-2.5251C+9.9314, r=0.9973.Ip=-0.0159C+8.6788，r=0.9971。
Owing to redox graphene nano granulosa layer is modified and to have been produced big specific surface area, conductivity that Graphene is good and oxidation catalytic activity, and the MIS selective enrichment and the characterization of adsorption that have make detectability (LOD) can reach 2.0 * 10 -8MolL -1(S/N=3), compare with the sensor of having reported higher sensitivity is arranged.
2.MIES stability and reappearance
Be equipped with 5 LBL-MIES with embodiment 3 legal systems, measure 10 μ molL -1△ Ip before and after the silaenafil PBS solution absorbs, RSD is 4.7%; Same LBL-MIES replication △ Ip10 time, RSD is 2.7%.Show that the LBL-MIES preparation method is stable, favorable reproducibility, and it is good to measure repeatability.
In addition the dry back 4 ° of C refrigerators of LBL-MIES were preserved 10 days, its current-responsive is reduced under 94%, the 20 after-current response when initial and is reduced to 10%.
3. actual sample analysis
The LBL-MIES that obtains with present embodiment 2 measures the silaenafil in the tablet, gets 5 of certain tonics tablet for kidney-reinforcing (specification 0.28g/ sheet), grinds fully with mortar, takes by weighing powder 100mg, with 10mL acetonitrile ultrasonic extraction 20min.Get filtrating 1mL after the filtration, nitrogen dries up the phosphate buffer that the back adds pH5.6, adopts the concentration of silaenafil in the DPV method working sample in above-mentioned, and the result shows that the silaenafil content that the Chinese medicine sex-health products are kept fit in the sheet is 7.91 μ g/g.In tonifying kidney and strengthening yang class traditional Chinese medicine health care product, add the silaenafil standard solution of basic, normal, high 3 concentration respectively, carry out the average recovery test, concrete outcome is seen table 1.
The assay of silaenafil in the table 1 kidney tonifying Johnson & Johnson sheet
Figure BDA00001833683400121

Claims (10)

1. the preparation method of a silaenafil molecular imprinting membrane electrochemical sensor is characterized in that may further comprise the steps:
A) electrode pre-service: glass-carbon electrode polishing back is cleaned;
B) the self-assembled modified layer by layer electrode of molecule: pretreated electrode is immersed in the WS that contains PDDA, carries out after the Electrostatic Absorption with rinsing well and drying up; Again it is immersed into electronegative redox Graphene PSS-RGO solution, floods afterwash, dry up; Continue to be immersed in the redox Graphene PDDA-RGO solution of positively charged, flood afterwash, dry up; Repeat the step of the redox Graphene PDDA-RGO solution of the electronegative redox Graphene of aforementioned immersion PSS-RGO solution and positively charged, with every RGO -/ RGO +Be one deck, 10～20 layers of repeated impregnations obtain the self-assembled modified layer by layer electrode of molecule of 10～20 layers of RGO;
C) molecular imprinting self assembly solution: preparation contains the ethanol/HAC-NaAC damping fluid of phenylenediamine function monomer and silaenafil, and it is sealed after with the nitrogen deoxygenation, places 5 ~ 20h in 20 ℃～30 ℃ lucifuge environment, obtains molecular imprinting self assembly solution; Wherein, the molar concentration rate of silaenafil and phenylenediamine function monomer is 1:1～1:50;
D) electric polymerization reaction: the molecular imprinting self assembly solution that step c) obtains is poured in the reaction vessel; Lucifuge, behind the logical nitrogen, inserting step b) the self-assembled modified layer by layer glass-carbon electrode of RGO that obtains; Under+0.2 ~ 1.0V current potential; Adopt timing electric current electropolymerization 400～800s, take out, drip washing, dry up;
E) wash-out template molecule: the electrode that step d) is obtained immerses H 2SO 4In the solution ,-0.8 ~+handle 3 ~ 10min under the 0.2V current potential.
2. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step a), and the ultrasonic cleaning of second alcohol and water is used earlier successively in glass-carbon electrode polishing back, dries up with distilled water drip washing and with nitrogen then.
3. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step b), and the time that the electrode after the processing is immersed in Electrostatic Absorption in the WS that contains PDDA is 4～6h; Rinse well with distilled water after the Electrostatic Absorption and dry up with nitrogen; The mass concentration of the WS of said PDDA is 0.5% ~ 5.0%.
4. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step b), and the time that electrode is immersed into electronegative redox Graphene PSS-RGO solution is 10 ~ 60min; The dipping back is rinsed well and is dried up with nitrogen with distilled water; The volumetric molar concentration scope of RGO is 0.1mg/mL ~ 5.0mg/mL in the said PSS-RGO solution.
5. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step b), and the time that electrode is immersed in the redox Graphene PDDA-RGO solution of positively charged is 10 ~ 60min; The dipping back is rinsed well and is dried up with nitrogen with distilled water; The volumetric molar concentration scope of RGO is 0.1mg/mL ~ 5.0mg/mL in the said PDDA-RGO solution.
6. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step c) said phenylenediamine function monomer is o-phenylenediamine, p-phenylenediamine (PPD) or m-phenylene diamine.
7. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step c) the molar concentration rate of silaenafil and phenylenediamine function monomer is 1:5～1:20.
8. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1; It is characterized in that in step c) the concentration range that contains silaenafil in the ethanol/HAC-NaAC damping fluid of phenylenediamine function monomer and silaenafil is 0.1mmol/L ~ 5.0mmol/L; The concentration range of phenylenediamine function monomer is 5.0mmol/L ~ 50.0mmol/L.
9. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step d), and the time that molecular imprinting self assembly solution is poured the logical nitrogen of lucifuge behind the reaction vessel into is 10 ~ 30min.
10. the preparation method of silaenafil molecular imprinting membrane electrochemical sensor according to claim 1 is characterized in that in step e) H 2SO 4The concentration range of solution is 0.2mol/L ~ 2.0mol/L.
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