CN105403648A - Method for detecting illegally-added fluoxetine in product - Google Patents

Method for detecting illegally-added fluoxetine in product Download PDF

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Publication number
CN105403648A
CN105403648A CN201510784041.9A CN201510784041A CN105403648A CN 105403648 A CN105403648 A CN 105403648A CN 201510784041 A CN201510784041 A CN 201510784041A CN 105403648 A CN105403648 A CN 105403648A
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CN
China
Prior art keywords
method
product
peak
fluoxetine
sample
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CN201510784041.9A
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Chinese (zh)
Inventor
封淑华
马春艳
段琼
冯丽
胡伟杰
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封淑华
马春艳
段琼
冯丽
胡伟杰
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Application filed by 封淑华, 马春艳, 段琼, 冯丽, 胡伟杰 filed Critical 封淑华
Priority to CN201510784041.9A priority Critical patent/CN105403648A/en
Publication of CN105403648A publication Critical patent/CN105403648A/en

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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/88Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02Column chromatography
    • G01N30/88Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/884Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
    • G01N2030/8845Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds involving halogenated organic compounds

Abstract

The invention discloses a method for detecting illegally-added fluoxetine in a product. The method comprises the following steps: carrying out primary screening and content determination by adopting a high performance liquid chromatography; and by adopting a high performance liquid chromatography-mass spectrograph, carrying out structure confirmation through comparing retention time of a sample peak and a comparison product peak, and quasimolecule ion peak and secondary mass spectrum fragment information. The method provided by the invention has strong specificity, high sensitivity and accuracy, good stability and strong practicability, and provides powerful technical supports for detection standards of the illegally-added fluoxetine in national designated products.

Description

A kind of illegal method of adding Prozac in testing product

Technical field

The present invention relates to Chinese medicine, health food and food quality detection field, be specifically related to a kind of illegal method of adding Prozac in testing product.

Background technology

In Chinese medicine and health food and food, illegal fat-reducing class chemicals situation of adding is serious in recent years, lawless person is for pursuing economic interests, reach the positive effect of quick weight-lossing, western medicine composition is added in Chinese medicine, health food and food, addition reaches or usually close to western medicine dosage, user takes when ignorant, and meeting high risks is healthy.When day-to-day supervision is checked, common detecting illegally adds sibutramine (clenbuterol hydrochloride), phenolphthalein, food Bureau of Drugs Supervision of country successively promulgates that drug inspection supplements the method for inspection and Interventions Requested approved document 2006004,2012005 and food medicine prison and does [2010] No. 114 file attachment 2 perhaps for this reason, for illegally adding the supervision and inspection of sibutramine and two kinds of derivants, phenolphthalein, caffeine, frusemide, fenfluramine, ephedrine totally 8 kinds of compositions.But lawless person is for escaping supervision, adding means and kind are constantly updated, change, carry out high-tech fraud for standard.Inventor detects recently in fat-reducing class sample and with the addition of a kind of new chemical medicine---Prozac.

Prozac, having another name called Prozac (fluoxetine, trade name is Prozac), is a kind of Oral antidepressant medicine, is used for the treatment of depression and its adjoint anxiety, and treatment obsession and disease of eating too much at one meal, thus have antiobesity action.It is antipsychotics, will produce great damage to the spirit of user.There is no at present and add Prozac qualitatively screening and method for quantitatively determining for illegal in product.Therefore set up illegal detection method of adding Prozac in product to be very important.

Summary of the invention

The present invention is intended to the deficiency overcoming existing detection method, provides a kind of illegal method of adding Prozac in testing product, can detect Prozac accurately and rapidly.

The present invention considers that high performance liquid chromatograph (outfit diode array detector) is the conventional detection apparatus of domestic testing laboratory, therefore high performance liquid chromatography preliminary screening and content assaying method is established, meet the actual conditions of domestic medicine testing agency, be conducive to effective enforcement of supervision and inspection.For primary dcreening operation positive, adopt Liquid Chromatography/Mass Spectrometry structural identification.The testing agency being equipped with LC-MS instrument also can directly use LC-MS method to screen and confirmation.

In order to achieve the above object, technical scheme provided by the invention is:

In described testing product, illegal interpolation Prozac prescreening method is extracted through methyl alcohol by sample, and gradient elution is separated and diode array detector (DAD) detects.The comparing of middle chromatographic peak and extract with fluoxetine product chromatographic peak retention time and spectrum behavior per sample, tentatively judge whether to detect Prozac.

In described testing product, illegal confirmation method of adding Prozac is extracted through methyl alcohol the positive of primary dcreening operation, and UPLC gradient elution is separated, Mass Spectrometer Method; By the retention time at comparative sample peak and reference substance peak, quasi-molecular ion peak and second order ms patch information, in confirmation sample, whether illegally add Prozac.

In described testing product, the illegal content assaying method adding Prozac is the high-efficient liquid phase chromatogram condition adopting prescreening method, calculates content by external standard method.

Specifically comprise the steps:

(1) by ultrasonic for sample methyl alcohol extraction;

(2) need testing solution after extraction is injected high performance liquid chromatograph, gradient elution is separated and diode array detector (DAD) detects; In this step, described liquid chromatograph is for wearing peace U3000 high performance liquid chromatograph;

(3) the positive need testing solution injection liquid matter combined instrument after extraction is carried out ultra high efficiency liquid phase gradient elution to be separated and Mass Spectrometer Method; In this step, described LC-MS instrument is ABSciexTripleTOF5600+ high-resolution mass spectrometer, Shimadzu NexeraUHPLCLC-30A high performance liquid chromatograph.

Chromatographic condition in step (2) is: take octadecylsilane chemically bonded silica as filling agent; With methanol-acetonitrile-0.8% triethylamine solution (with phosphoric acid adjust pH to 5.8) (5:35:60) for mobile phase; Determined wavelength is 226nm, and scanning wavelength scope is 190 ~ 400nm, flow velocity 1.0mL/min, sample size 5 μ L.

Chromatographic condition in step (3) is: with the 10mmol/L ammonium acetate solution containing 0.1% glacial acetic acid for mobile phase A, take methyl alcohol as Mobile phase B, gradient elution program 0 ~ 1min, 20%B; 1 ~ 6min, 20% ~ 80%B; 6 ~ 8min, 80%B; Determined wavelength is 226nm, flow velocity 0.3mL/min, sample size 5 μ L.

Mass Spectrometry Conditions in step (3): ESI+, mass spectrometry parameters: GS1 (55psi), GS2 (55psi), CURGAS (30psi), ion source temperature (550 DEG C), electron spray voltage (5500V), go bunch voltage to be 80V, collision energy is 24V.

Product of the present invention can be Chinese patent drug, health food and food.

In the inventive method, high performance liquid chromatography is by comparing chromatographic peak retention time and spectrum behavior, tentatively judges whether to detect Prozac; Liquid Chromatography/Mass Spectrometry is by comparing chromatographic peak retention time, quasi-molecular ion peak and secondary fragment information, and the structure of Prozac is confirmed, and check conclusion is accurate.The inventive method specificity is strong, and sensitivity, accuracy are high, and good stability is practical.The high performance liquid chromatography prescreening method set up has instrument price and the maintenance cost advantage more much lower than LC-MS instrument, is applicable to testing agency of basic unit and uses.Because the violation of law adding chemicals illegal in Chinese medicine, health food, food also will continue, and the development of analysis and detection technology lags behind the speed of development of adulterated false making generally, the present invention, just for the detection method that current food, drug safety supervision new situations and new problems are innovated, provides strong technical support for country formulates the illegal Prozac examination criteria that adds in product.

Accompanying drawing explanation

Fig. 1: the HPLC chromatogram of extract with fluoxetine product of the present invention; Fig. 2: the HPLC chromatogram of positive of the present invention; Fig. 3: the HPLC chromatogram of negative sample of the present invention; Fig. 4: the abosrption spectrogram of extract with fluoxetine product of the present invention; Fig. 5: the abosrption spectrogram of positive of the present invention; Fig. 6: the mass spectrogram of extract with fluoxetine product of the present invention; Fig. 7: the mass spectrogram of positive of the present invention; Fig. 8: Prozac cracking process figure.

The need testing solution of the positive in above-mentioned Fig. 2, Fig. 3, Fig. 5, Fig. 7 is the need testing solution that the sample containing Prozac is prepared according to the preparation method of need testing solution; The need testing solution of negative sample is not containing the need testing solution that the sample of Prozac is prepared according to the preparation method of need testing solution.

Embodiment

Below in conjunction with drawings and Examples, the present invention is further illustrated.

The present invention adopts: instrument and reagent: wear and pacify U3000 high performance liquid chromatograph, InertsilODS-SPC 18chromatographic column (4.6 × 150mm, 5 μm); ABSciexTripleTOF5600+ high-resolution mass spectrometer; Shimadzu NexeraUHPLCLC-30A; Chromatographic column: Shimadzu (Shim-packXR-ODS, 2.0mm × 100mm); Balance: MettlerAB135-S/FACT; Kunshan He Chuan ultrasonic instrument company limited KH-800KDE type high power numerical control Ultrasound Instrument; Reagent: methyl alcohol, acetonitrile are chromatographically pure (Merck company), it is pure that other reagent are analysis, and water is ultrapure water; Fluoxetine hydrochloride reference substance is provided by National Institute for Food and Drugs Control, lot number 100513-200401; Sample: sampling observation 74 batches, sample, comprises positive 3 batches.

One, high performance liquid chromatography primary dcreening operation and assay

The selection measuring wavelength gets extract with fluoxetine product solution in the interscan of 190nm-400nm wavelength coverage, and its maximum absorption wavelength is 226nm, therefore determines that determined wavelength is 226nm.

The selection of mobile phase has carried out the optimization of mobile phase with methanol-acetonitrile-50mmol/L potassium dihydrogen phosphate (5:30:65), methanol-acetonitrile-0.8% triethylamine solution (adjusting pH to 5.8 with phosphoric acid) (5:35:60) for mobile phase respectively, result with methanol-acetonitrile-0.8% triethylamine solution (with phosphoric acid adjust pH to 5.8) for mobile phase time, be separated better, Prozac peak shape is symmetrical.

The selection of Extraction solvent is dissolved in methyl alcohol due to Prozac, therefore selects methyl alcohol as Extraction solvent, and adopts ultrasonic process (power 800W, frequency 40kHz) 15 minutes, effectively to be extracted.

Chromatographic condition and system suitability: take octadecylsilane chemically bonded silica as filling agent; With methanol-acetonitrile-0.8% triethylamine solution (with phosphoric acid adjust pH to 5.8) (5:35:60) for mobile phase; Determined wavelength is 226nm, and scanning wavelength scope is 190 ~ 400nm; Flow velocity 1.0mL/min, sample size 5 μ L.

The preparation of reference substance solution: precision takes Fluoxetine hydrochloride reference substance and is about 100mg and puts in 100mL measuring bottle, adds methyl alcohol and makes dissolving in right amount and be diluted to scale, shake up, obtain reference substance storing solution (concentration 1.0mg/mL).Precision measures 1mL reference substance storing solution and puts in 10mL measuring bottle again, adds methanol dilution to scale, shakes up, obtain reference substance solution (concentration 0.1mg/mL).

The preparation of need testing solution: get test sample dose (solid dosage forms porphyrize, liquid dosage form direct sample), put in 50mL measuring bottle, add methyl alcohol appropriate, ultrasonic process (power 800W, frequency 40kHz) 15 minutes, let cool to room temperature, add methanol dilution to scale, shake up, filter, get filtrate as need testing solution.As need testing solution excessive concentration, exceed the typical curve range of linearity, in right amount desirable, dilute with methyl alcohol, make it in standard curve range.

Specificity is tested: result shows, positive presents the chromatographic peak identical with reference substance retention time, and negative sample is then without corresponding chromatographic peak.The absorption spectrum of chromatographic peak consistent with reference substance retention time in positive and the absorption spectrum of extract with fluoxetine product consistent.See Fig. 1 ~ 5.

Linear relationship is investigated: respectively accurate draw reference substance stock solution stepwise dilution make concentration be 0.005,0.01,0.05,0.1,0.2,0.4, the reference substance solution of 0.8mg/mL, injection liquid chromatography, record peak area.With sample introduction concentration (mg/mL) for horizontal ordinate, take peak area as ordinate, drawing standard working curve, carries out regretional analysis, and obtaining regression equation is y=145.2x+0.081, r=0.9999, and the range of linearity is 0.005mg/mL ~ 0.8mg/mL.

Accuracy (recovery) and replica test: precision takes negative sample 0.3g (being equivalent to a dose), put in 50mL volumetric flask, prepare 18 parts altogether, precision adds concentration is respectively 1.0mg/mL reference substance solution 0.25mL, 0.5mL, 2.5mL, each 6 parts of three concentration, add methyl alcohol more appropriate, recovery need testing solution is prepared by need testing solution preparation method, accurate absorption 5 μ L, measure as stated above, result average recovery rate is respectively 98.7%, 101.7%, 102.6% (three each n=6 of concentration), shows that method accuracy is high; The RSD of replica test is respectively 1.9%, 2.0%, 1.1% (three each n=6 of concentration), shows that method has good repeatability.

Stability test: get reference substance solution and need testing solution, in 0h, 1h, 2h, 4h, 8h, 24h sample introduction respectively under above-mentioned chromatographic condition, measure integrating peak areas value, the RSD of result reference substance solution and sample solution integrated value is respectively 0.40%, 0.32%, and result shows that reference substance solution and need testing solution are stable in 24h.

Detection limit is investigated: precision takes negative sample 0.3g (being equivalent to a dose), put in 50mL measuring bottle, adding concentration is 1.0mg/mL reference substance solution 0.05mL, adds methyl alcohol appropriate, ultrasonic 15 minutes, let cool to room temperature, add methanol dilution to scale, shake up, filter, get subsequent filtrate, measure, result detects and is limited to 0.17mg/g.

Two, Liquid Chromatography/Mass Spectrometry structural identification

Chromatographic condition is: with the 10mmol/L ammonium acetate solution containing 0.1% glacial acetic acid for mobile phase A, take methyl alcohol as Mobile phase B, gradient elution program 0 ~ 1min, 20%B; 1 ~ 6min, 20% ~ 80%B; 6 ~ 8min, 80%B; Determined wavelength is 226nm, flow velocity 0.3mL/min, sample size 5 μ L.

Mass Spectrometry Conditions: ESI+, mass spectrometry parameters: GS1 (55psi), GS2 (55psi), CURGAS (30psi), ion source temperature (550 DEG C), electron spray voltage (5500V), go bunch voltage to be 80V, collision energy is 24V.

The preparation precision of reference substance solution takes Fluoxetine hydrochloride reference substance in right amount, adds methyl alcohol and dissolves, make the solution of about hydrochloric Prozac 1 μ g in every 1mL.

The preparation of need testing solution: need testing solution under same, high performance liquid chromatography primary dcreening operation and assay item.As need testing solution excessive concentration, available methyl alcohol suitably dilutes.

Specificity is tested: each 5 μ L of accurate absorption reference substance solution, positive need testing solution and negative need testing solution respectively, injection liquid matter combined instrument.Result: adopt ESI positive ion scan pattern, Prozac formed quasi-molecular ion peak [M+H] peak be 310 and the stronger fragment ion peak m/e of two abundance be 44,148; In positive chromatogram, there is the corresponding chromatographic peak with extract with fluoxetine product with identical retention time and mass spectral characteristic; In negative sample chromatogram, there is not the corresponding chromatographic peak with extract with fluoxetine product with identical retention time and mass spectral characteristic.Extract with fluoxetine product mass spectrogram is shown in Fig. 6, and positive mass spectrogram is shown in Fig. 7, and Prozac cracking process is shown in Fig. 8.

Detectability gets negative sample 0.3g (being equivalent to a dose), put in 50mL measuring bottle, precision adds the Fluoxetine hydrochloride solution 0.15mL that concentration is 0.1 μ g/mL, adds methyl alcohol appropriate, ultrasonic 15 minutes, let cool to room temperature, add methanol dilution to scale, shake up, filter, get subsequent filtrate, measure, result detects and is limited to 0.05 μ g/g.

Three, the application of method

By above-mentioned condition, 74 batches of fat-reducing class Chinese patent drugs, health food and the food that market surveillance is inspected by random samples are detected, result wherein 3 batches detect Prozac, the illegal additive detected is dense (content is respectively 116.7mg/g, 110.9mg/g, 8.9mg/g), causes serious harm to the healthy meeting of consumer.

More than experiment show, the detection method that the present invention sets up can effectively screen with quantitative measurement product in illegally add Prozac, avoid vacation " positive " problem.The foundation of the method, by effectively hitting the illegal use adding Prozac in fat-reducing series products to a great extent, ensures the safety of broad masses' food and medicine.

Claims (6)

1. an illegal method of adding Prozac in testing product, is characterized in that comprising the following steps:
(1) by ultrasonic for sample methyl alcohol extraction;
(2) need testing solution after extraction is injected high performance liquid chromatograph, gradient elution is separated and diode array detector (DAD) detects, the comparing of middle chromatographic peak and extract with fluoxetine product chromatographic peak retention time and spectrum behavior per sample, preliminary screening and assay;
(3) the positive need testing solution injection liquid matter combined instrument after primary dcreening operation is carried out ultra high efficiency liquid phase gradient elution to be separated and Mass Spectrometer Method, carry out structural identification by the retention time at comparative sample peak and extract with fluoxetine product peak, quasi-molecular ion peak and second order ms patch information.
2. the method for claim 1, is characterized in that the condition of step (1) ultrasonic process is 15 minutes, power 800W, frequency 40kHz.
3. the method for claim 1, is characterized in that the chromatographic condition of step (2) is: take octadecylsilane chemically bonded silica as filling agent; With methanol-acetonitrile-0.8% triethylamine solution (with phosphoric acid adjust pH to 5.8) (5:35:60) for mobile phase; Determined wavelength is 226nm, and scanning wavelength scope is 190 ~ 400nm, flow velocity 1.0mL/min, sample size 5 μ L.
4. the method for claim 1, is characterized in that the chromatographic condition of step (3) is: with the 10mmol/L ammonium acetate solution containing 0.1% glacial acetic acid for mobile phase A, take methyl alcohol as Mobile phase B, gradient elution program 0 ~ 1min, 20%B; 1 ~ 6min, 20% ~ 80%B; 6 ~ 8min, 80%B; Determined wavelength is 226nm, flow velocity 0.3mL/min, sample size 5 μ L.
5. the method for claim 1, it is characterized in that the Mass Spectrometry Conditions in step (3): LC-MS instrument is ABSciexTripleTOF5600+ high-resolution mass spectrometer, ESI+, mass spectrometry parameters: GS1(55psi), GS2(55psi), CURGAS(30psi), ion source temperature (550 DEG C), electron spray voltage (5500V), go bunch voltage to be 80V, collision energy is 24V.
6. the method for claim 1, is characterized in that described product is Chinese patent drug, health food and food.
CN201510784041.9A 2015-11-16 2015-11-16 Method for detecting illegally-added fluoxetine in product CN105403648A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN102175778A (en) * 2010-12-03 2011-09-07 杭州谷歌科技有限公司 Method for synchronously measuring blood drug concentrations of multiple antidepressants
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Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101398414A (en) * 2008-10-15 2009-04-01 上海市公安局刑事侦查总队 Method for qualitatively screening 242 kinds of compounds by liquid phase chromatography-mass spectra at the same times
US20120205532A1 (en) * 2010-08-31 2012-08-16 Waters Technologies Corporation Techniques For Sample Analysis
CN102175778A (en) * 2010-12-03 2011-09-07 杭州谷歌科技有限公司 Method for synchronously measuring blood drug concentrations of multiple antidepressants
CN104535702A (en) * 2014-12-30 2015-04-22 天津大学 Method used for detecting multiple trace drug pollutants in drinking water simultaneously

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