CN106370718A - Rapid measurement method of drug dissolution rate - Google Patents
Rapid measurement method of drug dissolution rate Download PDFInfo
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- CN106370718A CN106370718A CN201611119528.6A CN201611119528A CN106370718A CN 106370718 A CN106370718 A CN 106370718A CN 201611119528 A CN201611119528 A CN 201611119528A CN 106370718 A CN106370718 A CN 106370718A
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- G—PHYSICS
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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
- G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
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Abstract
The invention discloses a rapid measurement method of a drug dissolution rate. A paper spray mass spectrometry MRM mode is used as a quantitative mode, and is used for measurement of the drug dissolution rate. Measurement of the dissolution rate comprises the steps of: firstly, shearing qualitative filter paper into a triangle; mixing dissolution liquid with corresponding internal standard solution according to a volume ratio of 1 to (0.1 to 10); dropping the obtained mixed solution on the triangle paper piece; carrying out air-drying; applying an external voltage of 3 to 5kv to the sample paper piece; dropping a spray solvent acetonitrile onto the paper piece to carry out spray detection. The invention provides mass spectrometry, so that for tolerance of involatile buffer salt, dissolution liquid of a drug can be directly analyzed without suffering from the pre-treatment process, and thus, a new method is provided for rapid measurement of the drug dissolution rate.
Description
Technical field
The present invention relates to a kind of drug detection method, particularly to a kind of rapid assay methods of drug dissolution.
Background technology
Mass spectral analyses (mass spectrometry, ms) technology has that analyze speed is fast, specificity is strong and sensitivity is high
Feature.In recent years, constantly bringing forth new ideas and improving with ionization techniques and mass analyzer, mass spectrum becomes development and the most rapidly divides
One of analysis technology.The innovation of ionization techniques promotes " great-leap-forward " of mass spectral analyses to develop always, new open type ionizing
The development forward position becoming mass spectrometry art of (ambient ionization, ai) technology and the research direction receiving much concern,
The aspects such as the direct analysis of sample, the quick analysis of body surface achieve important breakthrough, have greatly promoted mass-spectrometric technique to exist
In real time, surface, in situ, the development of high throughput analysis aspect.
2004, cooks etc. developed desorption electrospray technology (desorption electrospray on the basis of esi
Ionization, desi), cody in 2005 etc. develops the dart technology of real-time direct detection on the basis of apci, thus
Open the development of normal pressure open type ionization techniques, and the normal pressure open type ion source that has been born (ambient ionization,
Ai) technology and normal pressure open type mass spectrum (ambient ms) field.The distinguishing feature of ai technology is not only can be in atmospheric conditions
Ionizing, more meaningfully ionogenic open design are implemented to testing sample, is very easy to realize the straight of body surface
Connect ionizing and mass spectral analyses.This kind of ion source operation is convenient, fast, sample pre-treatments that need not be complicated, achievable organ group
The quick analysis of key substance in matrix, the real-time analysis of trace constituent and the mass spectroscopy molecular imaging on different objects surface such as knit
Analysis etc..
Drug dissolution (dissolution rate) refer to regulation solvent and under the conditions of, medicine is from tablet, capsule
The speed of dissolution and degree in the solid preparation such as agent or granule.The dissolution in vitro inspection of medicine is for evaluating drug quality
With the effective means of technological level, the development of novel form can be instructed, active constituents of medicine life in vivo can be predicted simultaneously
Thing availability situation and the evaluation preparation uniformity.The conventional detection method of drug dissolution is high performance liquid chromatography and ultraviolet
Method, both approaches detection time is long, is easily disturbed by impurity.
Mass spectrography is as the detection method that a kind of sensitivity being widely used is high, selectivity is good but not in drug-eluting
Degree is used widely in measuring, and its main cause is that usually the buffering containing fixedness salt is molten for the dissolution medium of tablet medicine
Liquid, such as phosphate buffer, sodium-acetate buffer etc..These fixedness salt are because can produce ion suppression and mass spectrum in mass spectrum
Detect not compatible it is impossible to be used for the direct analysis of solution, and mass spectrometry method is subject in the detection application of drug dissolution
Arrive restriction, be used for, currently without mass spectrography, the report that drug dissolution measures.
Paper spraying ionizes (paper spray ionization psi) mass spectrum as a kind of atmospheric pressure ion source mass-spectrometric technique,
The method produce electron spray and transport solution place be the scraps of paper, do not exist blocking capillary tube the drawbacks of, need not be extra pneumatic
Auxiliary equipment.Importantly, the scraps of paper inherently have the detached process to sample, can effective exclusive PCR, can be to sample
Carry out direct detection, current the method has successfully been applied to the quickly direct qualitative and quantitative analysis of medicine in blood sample,
But do not have paper spraying ionization to measure fixed report for drug-eluting.
Content of the invention
It is an object of the invention to provide a kind of rapid assay methods of drug dissolution.
A kind of rapid assay methods of drug dissolution, are carried out in accordance with the following steps:
(1) prepare drug-eluting liquid to be measured；
(2) dissolution fluid obtaining step (1) and inner mark solution are by 1:(0.1-10) mix, stand 8-12 minute；
(3) the mixing drop obtaining step (2), in triangular multi-hole substrate, dries 10-14 minute；
(4) porous matrix obtaining step (3) adds 3-5kv external voltage；
(5) Deca organic solvent carries out spraying detection on porous matrix；
(6) adopt inner mark solution, configure pharmaceutical standards substance solution to be measured, operate by the method for step (3)-(5),
Measure mass spectral intensities, standard substance content corresponding with interior target mass spectral intensities ratio carries out quantitative analyses as calibration trace；
(7) it is calculated the stripping quantity of drug sample to be measured according to the calibration trace that step (6) obtains.
The preparation method of described drug-eluting liquid to be measured is: 900ml phosphate buffer is used as dissolving medium, 50
Rpm mixing speed and 37 DEG C of bath temperature under carry out dissolution experiment, after 30 minutes with injection from dissolving medium
Device extracts sample.
Described inner mark solution is deuterated reagent or structure analogue compounds；Described analogue compounds are and drug molecule to be measured
One hydroxyl of difference or the compound of a methyl.
Described organic solvent is acetonitrile.
Described porous matrix adopts qualitative filter paper or the close scraps of paper of property, is cut into the triangle that tip angle is 30 °,
Careful pruning makes its tip not have prominent fiber, and the bottom of the triangle scraps of paper is 5mm, a height of 10mm.
Compared with prior art, the invention has the following beneficial effects: the sample dissolution that obtains of dissolution determination of the present invention
Liquid is not required to the pre-treatments such as filtration operation, and direct point sample is analyzed.Efficiently solve in dissolution fluid fixedness salt and mass spectrum not
Compatible problem, achieves the detection that mass-spectrometric technique is applied to drug dissolution first.The dissolution testing of this method
Method shorten to 1/10 with respect to prior art (high performance liquid chromatography) time, and sensitivity improves 300 times, and operates simpler
Single it is adaptable to the quick analysis of a large amount of samples.
Brief description
Fig. 1 is drug dissolution assay general flow chart of the present invention.
Fig. 2 be inventive samples solution point sample after porous matrix the different point sample times to determination influences, drying in 12 minutes
The interference of buffer salt in solution can be avoided completely.
Fig. 3 is that enalapril of the present invention measures linear relationship chart.
Specific embodiment
Below in conjunction with the accompanying drawings, the specific embodiment of the present invention is described in detail, it is to be understood that the guarantor of the present invention
Shield scope is not limited by specific embodiment.
Embodiment 1
A kind of rapid assay methods of drug dissolution, carry out that (drug dissolution assay always flows in accordance with the following steps
Journey figure is as shown in Figure 1):
The preparation of standard solution: unless otherwise stated, phosphate buffer contain 0.05m potassium phosphate and with phosphoric acid adjust to
ph 6.8.Prepared by phosphate buffer all stock solutions (enalapril maleate, quinapril hydrochloride, hydrochloric acid shellfish that
Puli).By diluting corresponding stock solution with phosphate buffer, a series of caliberators prepared for calibration curve are molten
Liquid, concentration is 0.01 μ g/ml to 160 μ g/ml.Be marked in deuterated internal standard or structure analogue compounds in phosphate buffer with
The concentration preparation of 100 μ g/ml.
Prepared by sample solution: 900ml phosphate buffer (ph=6.8) is used as dissolving medium, at 50 rpms
Mixing speed and 37 DEG C of bath temperature under carry out dissolution experiment.Extract sample with syringe from dissolving medium after 30 minutes
Product.100ul sample solution and the deuterated inner mark solution of same volume are added same plastic tube, vortex oscillation mixes for 2 minutes, stands 10
Minute is standby.
Prepared by porous matrix: using qualitative filter paper and the close scraps of paper of property, be cut into the triangle that tip angle is 30 °
Shape, careful pruning makes its tip not have prominent fiber.The bottom of the triangle scraps of paper is 5mm, a height of 10mm.
Voltage: the alligator clamp of high-voltage DC power supply is clipped in triangle scraps of paper base centre position, forward extends out 1-2mm and protect
The card scraps of paper are parallel to ground.Scraps of paper distance between two tips mass spectrum injection port about 6mm, maintains the power off, beats after Deca organic solvent
Switch power supply.
Point sample: 5 μ l sample solutions are dripped in the triangle scraps of paper near the tip of mass spectrum injection port, in the air dries 12 naturally
Minute.Deca 10ul organic solvent (acetonitrile) and 4kv voltage on paper, the drift angle of triangular plate will produce electron spray, enters matter
Spectrum is detected.(Fig. 2 needs at least to dry 12 minutes to eliminate the interference of inorganic salt in solution)
Mass spectroscopy () taking enalapril maleate as a example:
Carry out all experiments using triple quadrupole mass spectrometer, collect data and with masslynx 4.0 software processes.Make
Ms parameter is as follows: m/z scope 50-600, lm resolution 15v, hm resolution 15v, with argon as collision gas collision
Energy 20v.Subtracting background from mass spectrum.By using m/z377.2 → 234.1, m/z 439.2 → 234.1 and m/z 425.2
→ 351.1 parent ion monitors (mrm) pattern to the multiple reaction of product ion, and the quantitation realizing enalapril maleate is divided
Analysis.Build calibration song by drawing the signal intensity of analyte with the ratio of the signal intensity of its internal standard substance and its theoretical concentration
Line (Fig. 3).
Establishing criteria curve and said method calculate 6 enalapril maleate sample dissolutions, and result is as shown in table 1,
Record result consistent with traditional high performance liquid chromatography result.
Table 1 porous matrix electron spray triple level Four bar mass spectrometric analysis method and traditional high effective liquid chromatography for measuring medicine
Dissolution results
The present invention detects the mass spectrometry method of drug dissolution, and, detection is limited to 0.117ng/ taking enalapril maleate as a example
Ml is linearly good in the range of 0.1 μ g/ml-80 μ g/ml.Record the dissolution of ENALAPRIL MALEATE TABLETS agent, the result of mensure
Basically identical with existing chromatography.But the time shorten to the 1/10 of traditional method, detection sensitivity improves 300 times.If point
During sample, Deca 10ul organic solvent is selected from two chloroacetonitriles, Tritox, dimethylformamide, dehydrocostuslactone, richness
In acid or oxolane；Then detection sensitivity is respectively increased 400 times, 450 times, 600 times, 340 times, 600 times, 600 times.
The specific embodiment being only the present invention disclosed above, but, the present invention is not limited to this, any this area
What technical staff can think change all should fall into protection scope of the present invention.
Claims (5)
1. a kind of rapid assay methods of drug dissolution are it is characterised in that carry out in accordance with the following steps:
(1) prepare drug-eluting liquid to be measured；
(2) dissolution fluid obtaining step (1) and inner mark solution are by 1:(0.1-10) mix, stand 8-12 minute；
(3) the mixing drop obtaining step (2), in triangular multi-hole substrate, dries 10-14 minute；
(4) porous matrix obtaining step (3) adds 3-5kv external voltage；
(5) Deca organic solvent carries out spraying detection on porous matrix；
(6) adopt inner mark solution, configure pharmaceutical standards substance solution to be measured, by the method operation of step (3)-(5), measure
Mass spectral intensities, standard substance content corresponding with interior target mass spectral intensities ratio carries out quantitative analyses as calibration trace；
(7) it is calculated the stripping quantity of drug sample to be measured according to the calibration trace that step (6) obtains.
2. the rapid assay methods of drug dissolution according to claim 1 are it is characterised in that described drug-eluting to be measured
The preparation method of liquid is: 900ml phosphate buffer is used as dissolving medium, in 50 rpms of mixing speeds and 37 DEG C
Bath temperature under carry out dissolution experiment, extract sample with syringe from dissolving medium after 30 minutes.
3. the rapid assay methods of drug dissolution according to claim 1 are it is characterised in that described inner mark solution is deuterium
For reagent or structure analogue compounds；Described analogue compounds are to differ a hydroxyl or a methyl with drug molecule to be measured
Compound.
4. the rapid assay methods of drug dissolution according to claim 1 are it is characterised in that described organic solvent is second
Nitrile.
5. according to claim 1 drug dissolution assay method it is characterised in that described porous matrix adopt qualitative filter
Paper or the close scraps of paper of property, are cut into the triangle that tip angle is 30 °, and careful pruning makes its tip not have prominent fibre
Dimension, the bottom of the triangle scraps of paper is 5mm, a height of 10mm.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611119528.6A CN106370718A (en) | 2016-12-08 | 2016-12-08 | Rapid measurement method of drug dissolution rate |
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| CN201611119528.6A CN106370718A (en) | 2016-12-08 | 2016-12-08 | Rapid measurement method of drug dissolution rate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107024436A (en) * | 2017-05-27 | 2017-08-08 | 北京环境特性研究所 | A kind of method for analyzing medicine to cytosis point |
| CN108037174A (en) * | 2017-12-06 | 2018-05-15 | 上海应用技术大学 | A kind of sharp slide ionization apparatus and its application based on tip electron spray |
| CN111413393A (en) * | 2019-12-20 | 2020-07-14 | 杭州师范大学 | Method for rapidly detecting formaldehyde content in food by high-throughput reaction paper spray mass spectrometry |
| CN114078687A (en) * | 2020-08-20 | 2022-02-22 | 中国科学院化学研究所 | Capillary paper spray ion source device and ion generation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010127059A1 (en) * | 2009-04-30 | 2010-11-04 | Purdue Research Foundation | Ion generation using wetted porous material |
| CN103499632A (en) * | 2013-09-17 | 2014-01-08 | 中国广州分析测试中心 | Paper-based electrospray ionization mass spectrometry fingerprint technology and construction method thereof |
| US20140183351A1 (en) * | 2011-06-03 | 2014-07-03 | Purdue Research Foundation | Ion generation using modified wetted porous materials |
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2016
- 2016-12-08 CN CN201611119528.6A patent/CN106370718A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010127059A1 (en) * | 2009-04-30 | 2010-11-04 | Purdue Research Foundation | Ion generation using wetted porous material |
| US20140183351A1 (en) * | 2011-06-03 | 2014-07-03 | Purdue Research Foundation | Ion generation using modified wetted porous materials |
| CN103499632A (en) * | 2013-09-17 | 2014-01-08 | 中国广州分析测试中心 | Paper-based electrospray ionization mass spectrometry fingerprint technology and construction method thereof |
Non-Patent Citations (1)
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| 刘晓宁: "纸喷雾技术在诊断性药物分析中的研究", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107024436A (en) * | 2017-05-27 | 2017-08-08 | 北京环境特性研究所 | A kind of method for analyzing medicine to cytosis point |
| CN108037174A (en) * | 2017-12-06 | 2018-05-15 | 上海应用技术大学 | A kind of sharp slide ionization apparatus and its application based on tip electron spray |
| CN111413393A (en) * | 2019-12-20 | 2020-07-14 | 杭州师范大学 | Method for rapidly detecting formaldehyde content in food by high-throughput reaction paper spray mass spectrometry |
| CN114078687A (en) * | 2020-08-20 | 2022-02-22 | 中国科学院化学研究所 | Capillary paper spray ion source device and ion generation method |
| CN114078687B (en) * | 2020-08-20 | 2023-03-21 | 中国科学院化学研究所 | Capillary paper spray ion source device and ion generation method |
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