CN1271401C - Optical fiber in situ tester for dissolution and release of medicine - Google Patents
Optical fiber in situ tester for dissolution and release of medicine Download PDFInfo
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- CN1271401C CN1271401C CN 200410001179 CN200410001179A CN1271401C CN 1271401 C CN1271401 C CN 1271401C CN 200410001179 CN200410001179 CN 200410001179 CN 200410001179 A CN200410001179 A CN 200410001179A CN 1271401 C CN1271401 C CN 1271401C
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- optical fiber
- chemical sensor
- light source
- drug dissolution
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- 239000013307 optical fiber Substances 0.000 title claims abstract description 104
- 238000004090 dissolution Methods 0.000 title claims abstract description 45
- 239000003814 drug Substances 0.000 title claims abstract description 42
- 238000011065 in-situ storage Methods 0.000 title abstract 4
- 239000000126 substance Substances 0.000 claims abstract description 57
- 239000000523 sample Substances 0.000 claims abstract description 55
- 229940079593 drug Drugs 0.000 claims abstract description 37
- 238000012360 testing method Methods 0.000 claims description 49
- 239000000835 fiber Substances 0.000 claims description 29
- 239000012528 membrane Substances 0.000 claims description 19
- 230000029087 digestion Effects 0.000 claims description 11
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 6
- 229910052753 mercury Inorganic materials 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 229910052724 xenon Inorganic materials 0.000 claims description 6
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- 229910052805 deuterium Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 24
- 239000007787 solid Substances 0.000 abstract description 11
- 239000007788 liquid Substances 0.000 abstract description 9
- 238000012544 monitoring process Methods 0.000 abstract description 8
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- 238000001228 spectrum Methods 0.000 abstract description 5
- 230000003287 optical effect Effects 0.000 abstract description 3
- 238000005070 sampling Methods 0.000 abstract description 3
- 238000010586 diagram Methods 0.000 description 10
- 239000000825 pharmaceutical preparation Substances 0.000 description 10
- 238000010521 absorption reaction Methods 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000013558 reference substance Substances 0.000 description 6
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 5
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 5
- 229930003471 Vitamin B2 Natural products 0.000 description 5
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 5
- 229960002702 piroxicam Drugs 0.000 description 5
- 229960002477 riboflavin Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000011716 vitamin B2 Substances 0.000 description 5
- 235000019164 vitamin B2 Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012491 analyte Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical class C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
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- 230000000171 quenching effect Effects 0.000 description 4
- 230000005855 radiation Effects 0.000 description 4
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- 238000001069 Raman spectroscopy Methods 0.000 description 3
- 238000001237 Raman spectrum Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960004170 clozapine Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000002189 fluorescence spectrum Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000013523 data management Methods 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000013178 mathematical model Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001296 phosphorescence spectrum Methods 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000000985 reflectance spectrum Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000002165 resonance energy transfer Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000003980 solgel method Methods 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Investigating Or Analysing Materials By Optical Means (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
Abstract
The present invention relates to a tester for the dissolution degree/the releasing degree of optical fiber in-situ drugs, which comprises a light source, at least one Y-shaped probe of an optical fiber chemical sensor, a dissolution instrument and a detector, wherein the input end of the light source of the Y-shaped probe of the optical fiber chemical sensor is connected to the light source, the detecting end of the Y-shaped probe of the optical fiber chemical sensor is arranged in the dissolution instrument, and the output end of the light source of the Y-shaped probe of the optical fiber chemical sensor is connected to the input end of the detector. The present invention can be used for the in-situ and real-time monitoring of liquid, the dissolution degree or the releasing degree of a solid drug preparation can be detected by the tester for the dissolution degree / the releasing degree of optical fiber in-situ drugs so as to obtain data which accords with an official method and data that occurs when the solid drug preparation just starts to enter liquid, wherein the data that occurs when the solid drug preparation just starts to enter the liquid can not be obtained by the hand sampling in the past; the detecting data of total optical spectrums is realized; accordingly, the present invention has the advantages of reduced operational errors, more detected data, labor saving and time saving.
Description
One, technical field:
The present invention relates to utilize fibre optic chemical sensor to carry out the test instrument that characteristics of liquids is measured, is a kind of optical fiber in site online drug dissolution/release test instrument, is used in particular for the inspection of solid pharmaceutical preparation (tablet, capsule etc.) dissolution rate or release.
Two, background technology:
" solid pharmaceutical preparation (tablet, capsule etc.) dissolution rate or release inspection " is that whole world medicine is identified essential project.Drug dissolution is determined at quality and the new aspects such as dosage form research of development that improves pharmaceutical preparation, and is essential.The application of dissolution rate method at first is conventional drug quality control; Secondly, the quality examination after process reform or preparation pilot scale are amplified; The 3rd, new spec exempts to do the foundation of bioequivalence test; In addition,, calculate dosage and on the course of treatment, exploring new dosage, study aspects such as efficient, quick-acting, slowly-releasing sustained action dosage form, all play important effect for design of control pharmaceutical preparation quality prescription and screening.Pharmaceutical factory, medicine inspecting institute, clinical hospital, drug research and pharmacologic education unit all need to carry out this work.But China overwhelming majority units remain manual sample analysis operation so far, and not only trivial operations and the data that obtain are imperfect.
Because importance and the hard work amount of dissolution determination in Pharmaceutical Analysis.Abroad begin the seventies, and ' dissolution rate automatic analyzer ' becomes one of emphasis of big instrument company of many families research and development, if any the product of companies such as U.S. Beckman, Hanson, Vandeikamp.
Present widely used automatic analysis of dissolution instrument, it comprises self-actuated sampler or multiple tracks peristaltic pump, dissolving device, detecting instrument (visible-ultraviolet spectrophotometer, electrochemical detector or high performance liquid chromatograph) and computing machine etc.For example: Precision Instrument Factory, Tianjin Univ. " the automatic analyzing and testing of ADUV8 medicine stripping system ", it has realized constant temperature water bath control, controllable rotation speed, software can be pointed out sample stripping, release test, can also calculate, print stripping curve and test parameters automatically.The automatic dissolution rate monitor of the first generation by " multitube peristaltic pump " test solution in the test glass is pumped into the UV-Vis spectrophotometer respectively or HPLC detects, and has reduced the miscellaneous work amount of hand sampling and the error that operation brings.But, its real-time monitoring on the throne of being unrealized, and have that filter easily stops up, trace drug absorption and measure problems such as cleaning amount in back is big.
Two, summary of the invention:
The invention provides a kind of optical fiber in site online drug dissolution/release test instrument, the on the throne real-time monitoring that it has solved liquid has solved the on the throne real-time monitoring to solid pharmaceutical preparation (tablet, capsule etc.) dissolution rate or release especially.
Technical scheme of the present invention realizes by following measure: a kind of optical fiber in site online drug dissolution/release test instrument, it comprises light source, is no less than one y-type optical fiber chemical sensor probe, digestion instrument and detecting device, the light source input end of y-type optical fiber chemical sensor probe is connected on the light source, the test side of y-type optical fiber chemical sensor probe places in the digestion instrument, and the light source output terminal of y-type optical fiber chemical sensor probe is connected on the input end of detecting device.
Above-mentioned light source can adopt deuterium lamp or xenon lamp or mercury lamp or xenon/mercury lamp or laser instrument.
Above-mentioned detecting device can adopt charge-coupled detector(CCD) CCD, cmos image sensor CMOS, electric charge injector CID or diode array DAD detecting device.
Above-mentioned y-type optical fiber chemical sensor probe can adopt one of following three type optical fiber chemical sensors probe:
One of them is: this y-type optical fiber chemical sensor probe comprises jacket layer, optical fiber and sensitive membrane, and the test side of optical fiber is equipped with sensitive membrane.The length of above-mentioned optical fiber is that 25cm to 250cm, diameter are 10.0 μ m to 2500 μ m.
Wherein two be: this y-type optical fiber chemical sensor probe comprises sleeve pipe, optical fiber and reflective mirror, and the test side of optical fiber is installed in the inner end of sleeve pipe, in the outer end of sleeve pipe reflective mirror is installed, and has at the middle part of sleeve pipe to be no less than one injection port.The length of above-mentioned optical fiber is that 25cm to 250cm, diameter are 0.1cm to 2.50cm.
Wherein three be: this y-type optical fiber chemical sensor probe comprises sleeve pipe, optical fiber and reflective mirror, the test side of optical fiber is installed in the inner end of sleeve pipe, outer end at sleeve pipe is equipped with adjusting light path bar by engage thread or inserted mode, at the inner end of regulating the light path bar reflective mirror is installed, has at the middle part of sleeve pipe to be no less than one injection port.The length of above-mentioned optical fiber is that 25cm to 250cm, diameter are 0.1cm to 2.50cm.
Inboard at above-mentioned reflective mirror can be equipped with sensitive membrane.
The above-mentioned reflective mirror outside can be coated with the ultraviolet reflectance film.
The test side of above-mentioned optical fiber can be equipped with the optical fiber focus lamp.
Above-mentioned optical fiber can adopt the single-mode fiber or the multimode optical fiber of Y type.
The present invention can be used for the on the throne real-time monitoring of liquid, utilize this optical fiber in site online drug dissolution/release test instrument that solid pharmaceutical preparation (tablet, capsule etc.) dissolution rate or release are detected, except that can obtain with the corresponding to data of official method, also can obtain the data (this hand sampling in the past can't obtain) that solid pharmaceutical preparation has just begun to enter liquid, also can realize the detection data of full spectrum, therefore, not only reduce operate miss and detected more data, gone back saving of work and time.
Four, description of drawings:
Accompanying drawing 1 is looked the sectional structure synoptic diagram for the master of one of fibre optic chemical sensor probe among the present invention;
Accompanying drawing 2 is looked the sectional structure synoptic diagram for two master of fibre optic chemical sensor probe among the present invention;
Accompanying drawing 3 is looked the sectional structure synoptic diagram for three master of fibre optic chemical sensor probe among the present invention;
Accompanying drawing 4 is four main TV structure synoptic diagram of fibre optic chemical sensor probe among the present invention, and accompanying drawing 5 is the side-looking sectional structure synoptic diagram of accompanying drawing 4;
Accompanying drawing 6 is five main TV structure synoptic diagram of fibre optic chemical sensor probe among the present invention.
Accompanying drawing 7 is single bosom enlarged diagram of digestion instrument in the accompanying drawing 8, and accompanying drawing 8 is a structural representation of the present invention;
Accompanying drawing 9 detects the ultra-violet absorption spectrum (quite labelled amount 23.8%, 43.6%, 63.4%, 79.3%, 99.1%) that obtains for utilizing the present invention to Clozapine series solution,
Accompanying drawing 10 is for utilizing the present invention and Chinese Pharmacopoeia method (square point) comparison diagram to Clozapine sheet stripping curve;
Accompanying drawing 12 is for utilizing the present invention and Chinese Pharmacopoeia method (square point) comparison diagram to piroxicam reference substance stripping curve;
Accompanying drawing 13 detects the ultra-violet absorption spectrum (quite labelled amount 20.0%, 40.0%, 60.0%, 81.0%, 100%) that obtains for utilizing the present invention to the vitamin B2 reference substance,
Accompanying drawing 14 is for utilizing the present invention and Chinese Pharmacopoeia method (square point) comparison diagram to vitamin B2 reference substance stripping curve;
Coding in the accompanying drawing is respectively: 1 is jacket layer, and 2 is optical fiber, and 3 is sensitive membrane, 4 is the test side of optical fiber, and 5 is sleeve pipe, and 6 is reflective mirror, 7 is the inner end of sleeve pipe, and 8 is the outer end of sleeve pipe, and 9 is the inboard of reflective mirror, 10 is the middle part of sleeve pipe, 11 is injection port, and 12 for regulating the light path bar, and 13 for regulating the inner end of light path bar, 14 are the ultraviolet reflectance film, and 15 is the optical fiber focus lamp; 16 is single glass of digestion instrument, and 17 is stirring arm, and 18 is digestion instrument, and 19 is light source, and 20 are the fibre optic chemical sensor probe, and 21 is detecting device, and 22 is computing machine.
Five, embodiment:
The present invention is not subjected to the restriction of following embodiment, can determine concrete embodiment according to technical scheme of the present invention and actual conditions.
Below in conjunction with embodiment and accompanying drawing the present invention is further described:
Embodiment, shown in accompanying drawing 7 and 8, this optical fiber in site online drug dissolution/release test instrument comprises light source 19, is no less than one y-type optical fiber chemical sensor probe 20, digestion instrument 18 and detecting device 21, the light source input end of y-type optical fiber chemical sensor probe 20 is connected on the light source 19, the test side of y-type optical fiber chemical sensor probe 20 places in the digestion instrument 18, and the light source output terminal of y-type optical fiber chemical sensor probe 20 is connected on the input end of detecting device 21.
Wherein: light source can adopt deuterium lamp or xenon lamp or mercury lamp or xenon/mercury lamp or laser instrument, detecting device can adopt charge-coupled detector(CCD) CCD, cmos image sensor CMOS, electric charge injector CID or diode array DAD detecting device, and concrete selection comes to determine as required.As shown in Figure 8, detecting device can adopt single channel or multichannel detector, and y-type optical fiber chemical sensor probe can adopt single or many y-type optical fiber chemical sensor probes.
Fibre optic chemical sensor probe among the present invention can adopt one of following fibre optic chemical sensor probe:
As shown in Figure 1, one of this fibre optic chemical sensor probe comprises jacket layer 1, optical fiber 2 and sensitive membrane 3, the test side 4 of optical fiber is equipped with sensitive membrane 3, the length of its optical fiber 2 is that 25cm to 250cm, diameter are 10.0 μ m to 2500 μ m, can determine concrete length and diameter according to actual needs, it is applicable to makes mini optical fibre original position drug dissolution/release test instrument.
As shown in Figure 2, two of this fibre optic chemical sensor probe comprises sleeve pipe 5, optical fiber 2 and reflective mirror 6, the test side 4 of optical fiber is installed in the inner end 7 of sleeve pipe 5, outer end 8 at sleeve pipe 5 is equipped with reflective mirror 6, one injection port 11 is arranged at the middle part 10 of sleeve pipe 5, the length of its optical fiber 2 is that 25cm to 250cm, diameter are 0.1cm to 2.50cm, determines concrete length and diameter too according to actual needs; As shown in Figure 2, according to the mensuration of different solid pharmaceutical preparations being carried out dissolution rate or release, produce the fibre optic chemical sensor probe of different light paths, be specially adapted to mensuration, be applicable to the fibre optic chemical sensor probe of making ad hoc type particular solid pharmaceutical preparation (tablet, capsule etc.) dissolution rate or release.
Shown in accompanying drawing 2 and 3, three of this fibre optic chemical sensor probe is with two difference of above-mentioned fibre optic chemical sensor probe: two injection port 11 is arranged at the middle part 10 of sleeve pipe 5.
Shown in accompanying drawing 2,3,4 and 5, four of this fibre optic chemical sensor probe is with two difference of above-mentioned fibre optic chemical sensor probe: the injection port 11 that a big lateral opening is arranged at the middle part 10 of sleeve pipe 5.
Shown in accompanying drawing 5 and 6, five of this fibre optic chemical sensor probe is with four difference of above-mentioned fibre optic chemical sensor probe: the outer end 8 at sleeve pipe 5 is equipped with adjusting light path bar 12 by engage thread or inserted mode, at the inner end 13 of regulating light path bar 12 reflective mirror 6 is installed, the injection port 11 of a big side opening is arranged at the middle part 10 of sleeve pipe 5.By regulating light path bar its light paths of 12 scalable (being the distance between reflective mirror and the optical fiber test side), thereby be applicable to mensuration to different solid pharmaceutical preparations (tablet, capsule etc.) dissolution rate or release, thereby it can be used as universal fibre optic chemical sensor probe, can adopt ultraviolet/visible/near infrared absorption, reflection and phosphorescence/fluorescence/light sources such as Raman spectrum radiation.
To detect performance in order further improving, as shown in Figure 6, sensitive membrane 3 can be installed in the inboard of reflective mirror 6; In order to be applicable to the detection of ultraviolet light, can be coated with ultraviolet reflectance film 14 in reflective mirror 6 outsides; In order to be applicable to more weak light source, optical fiber focus lamp 15 can be installed in the test side 4 of optical fiber.In order to increase adaptability, optical fiber can adopt y-type optical fiber or branch type optical fiber or not branch type optical fiber or single-mode fiber or multimode optical fiber.
The most preferred embodiment of the present invention that above technical characterictic has constituted, it has stronger adaptability and best implementation result, can increase and decrease non-essential technical characterictic according to actual needs.
Sensitive membrane among the present invention can adopt following three class disclosed methods to obtain respectively.
1. " molecular probe+polymkeric substance+plastifier " solvent evaporation method is made even sensitive membrane; Its disclosed document is:
[1] Seitz, WR., etc. based on the fibre optic chemical sensor of immobilizing indicator.Analytical chemistry, CRC Crit Rev, 1988; 19:135-139. (Seitz, WR., et al, Chemical Sensors based on immobilizedindicators and fiber optic, Anal.Chem., CRC Crit Rev, 1988; 19:135-139.)
[2] W.Rudolt Seitz. fibre optic chemical sensor polymkeric substance indicator substrate.Biosensor technology. (W.Rudolt Seitz.Polymeric Indicator Substrates for Fiber Optic Chemical Sensors.Biosensor Technology.)
[3] Kuit Seiler, Kemin Wang, Matthias Kuratli and Wilhelm Simon; A kind of ethanol selectivity optical fiber sensing membrane based on the reversible chemical identifying.The analytical chemistry journal, 1991; 244:151-1601. (KuitSeiler, Kemin Wang, Matthias Kuratli and Wilhelm Simon; Development of anethanol-selective optode membrane based on a reversible chemical recognitionprocess.Anal.Chim.Acta, 1991; 244:151-1601.)
[4] Otto S.Wolfbeis. chemical sensitisation indicator dye.Fibre optic chemical sensor, 1997,4:53-107. (Otto S.Wolfbeis.Chemical sensing using indicator dyes.Optical fiber sensor.1997,4:53-107.)
2. " sol-gel " legal system sensitive membrane (mesh is arranged, get rid of solid content disturb) in the sensitive membrane surface distributed, its disclosed document is:
[5] Rainer Klein, the ammoniacal sensor that Edgar Voges. optics is integrated. Dutch analytical chemistry magazine, (1994) 349:394-398. (Rainer Klein, Edgar Voges.Integrated-optic ammonia sensor.Fresenius J Anal.Chem. (1994) 349:394-398.)
[6] David J.Blyth, Sarah J.Poynter and David A.Russell is with the fixing calcium biology sensor of photosensitive protein of sol-gal process.The analyst, 1996,12, vol.121 (1975-1978). (David J.Blyth, Sarah J.Poynter and David A.Russell, Calcium Biosensing with a Sol-gelImmobilized Photo protein.Analyst, December 1996, vol.121 (1975-1978) .)
[7] R.C.Hughes, S.V.Patel, M.W.Jenkins, T.J.Boyle, T.J.Gardner and C.J.Brinker is based on collosol and gel porous membrane chemical catalysis sensor.(R.C.Hughes，S.V.Patel，M.W.Jenkins，T.J.Boyle，T.J.Gardner?and?C.J.Brinker，Thin?film?Porous?MembranesBased?on?Sol-gel?Chemistry?for?Catalytic?Sensors.)
[8] the collosol and gel membrane technology prepares sulfate anion chemistry microsensor (Sulfate Anion-SensingChemical Microsensors Prepared by the Sol-gel Membrane Technology.)
[9] O.Lev, M.Tsionsky, L.Rabinovich, the collosol and gel sensor of et al. organic decoration.Analytical chemistry, 1995, Vol.67 (1): 22A-30A. (O.Lev, M.Tsionsky, L.Rabinovich, et al.Organically modified Sol-Gel Sensors.Analytical Chemistry, 1995, Vol.67 (1): 22A-30A.)
[10] Dave B.C., Dunn B., Valentine J.S.et al. sol-gel embedding legal system is equipped with biology sensor.Analytical chemistry, 1994,66 (22): 1120A-1127A. (Dave B.C., Dunn B., Valentine J.S.et al.Sol-Gel encapsulation methods for biosensors.Anal.Chem.[J], 1994,66 (22): 1120A-1127A.)
[11] Kwang E.Chung, Esther H.Lan, Michael S.Davidson. glass embedding myoglobin is measured oxygen in water.Analytical chemistry, 1995 (67): 1505-1509. (Kwang E.Chung, Esther H.Lan, MichaelS.Davidson.Measurement of dissolved oxygen in water using glass-encapsulatedMyoglobin.Anal.Chem.1995 (67): 1505-1509.)
[12] Upvan Narang, Paras n.Prasad, and Frank V.Bright. is based on the glucose biological sensor of collosol and gel derivatization.Analytical chemistry, 1994 (66): 3139-3144. (Upvan Narang, Paras n.Prasad, and Frank V.Bright.Glucose biosensor based on Sol-Gel-derived platform.Anal.Chem.1994 (66): 3139-3144.)
[13] Faida A.El-Essi, Ali Z.Abu Zuhri, Suleiman I.Al-Khalil, et al. is with the fixing hydrogen peroxide that produces of horseradish peroxidase spectrographic determination enzymatic of collosol and gel.Talanta，1997(44)2051-2058.(Faida?A.El-Essi，Ali?Z.Abu?Zuhri，Suleiman?I.Al-Khalil，et?al.Spectrophometric?determination?of?enzymatically?generated?hydrogen?peroxideusing?Sol-gel?immobilized?horseradish?peroxidase.Talanta，1997(44)2051-2058.)
[14] L.M.Ellerby, C.R.Nishida, S.A.Yamanka, the transparent porous silica glass of et.al. Prepared by Sol Gel Method embedding albumen.Science [J], 1992,225:1113-1115. (L.M.Ellerby, C.R.Nishida, S.A.Yamanka, et.al.Encapsulation of protein in transparent porous silicate glassesprepared by the sol-gel method.Science[J], 1992,225:1113-1115.)
3. the covalent bonding legal system is equipped with sensitive membrane, and its disclosed document is:
[15] the optical fiber fluorescence sensing method of evaluation antibody technique for fixing.The analytical chemistry journal, 229 (1990) 169-176. (Evaluation of antibody immobilization techniques for fiber optic-basedfluoroimmunosensing.Analytica Chimica Acta, 229 (1990) 169-176.)
[16] optical fiber biosensor of immobilized enzyme.Biosensor technique.(Fiber?Optic-Based?BiosensorsUtilizing?Immobilized?Enzyms.Biosensor?Technology.)
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[18] Julia Cordek, Xinwen Wang and Weihong Tan; Fibre-optical probe directly fixedly the glutamate dehydrogenasa be used for hypersensitive and measure glutamate.Analytical chemistry, 1999,71,1529-1533. (Julia Cordek, XinwenWang and Weihong Tan; Direct immobilization of Glutamate dehydrogenase on opticalfiber probes for ultrasensitive glutamate detection.Anal.Chem.1999,71,1529-1533.)
[19] Zhongping Chen, D.L.Kaplan and H.Gao; Molecule integrated multi-layer enzyme: be used to develop a kind of based on chemiluminescent optical fiber biosensor.Materials Science and Engineering, C 4 (1996) 155-159. (Zhongping Chen, D.L.Kaplan and H.Gao; Molecular assembly of multiplayer enzyme:toward thedevelopment of a chemiluminescence-based fiber optic biosensor.Material Scienceand Engineering.C 4 (1996) 155-159.)
[20] Frank Kleinjung, Krank F.Bier and Axel Warsinke; The optical fibre bio gas sensor is used for selectivity and measures nanomole DNA oligomer.The analytical chemistry journal, 350 (1997) 51-58. (Frank Kleinjung, Krank F.Bier and Axel Warsinke; Fibre-optic genosensor for specific determinationof femtomolar DNA oligomer.Analytical Chimica Acta 350 (1997) 51-58.)
[21] M.A.Karymov, A.A.Kruchinin and Yu.A.Tarantov; The direct fixed dna in fibre-optic waveguide surface is used to measure the biology sensor of molecule.Sensor and actuator B 29 (1995) 324-327. (M.A.Karymov, A.A.Kruchinin and Yu.A.Tarantov; Fixation of DNA directly on optical waveguidesurfaces for molecular probe biosensor development.Sensors and actuators B 29 (1995) 324-327.)
More than the sensitive membrane of three kinds of methods preparation be applicable to the monitoring of various chemical constitutions in liquid or the gas respectively.
The principle of work of fibre optic chemical sensor probe among the present invention:, be applicable to the process monitoring on the throne of mensuration " ultraviolet/visible/near infrared absorption, reflection and phosphorescence/fluorescence/raman radiation spectrum " respectively according to different analytic targets.
One, the measurement of ultraviolet/visible/near infrared absorption or reflectance spectrum radiation: optical signals optical fiber feeds back to detecting device or spectrophotometer, and output signal meets following mathematic(al) representation:
a?or?K：E
1％、E
1‰?or?ε/λ
max、1cm。C：g/100ml、g/L?or?mol/L
Two, the actinometry of fluorescent/phosphorescent and Raman spectrum: spectral signal feeds back to ultraviolet/visible/near infrared spectrometer or fluorospectrophotometer or detecting device by optical fiber, and signal output meets following mathematic(al) representation:
I(F、P?or?R)＝Φ
0×I
0×ε×L×C
I (F): fluorescence intensity, I (P): phosphorescence intensity, I (R): Raman light intensity, Φ: constant term, I
0: incident intensity, ε: absorptivity, L: light path, C: analyte concentration.
Spectral signal feeds back to detecting device or fluorescent/phosphorescent/Raman spectrometer by optical fiber, obtains fluorescence, phosphorescence or Raman spectrum.
Three, the measurement of the polynary quencher spectral radiance of fluorescence: in optical fiber end device sensitive membrane, accurate adjustable distance is arranged, form microcuvette.Analyte absorbs radiation (the first inner filtration IFE from light source in this space
1), weaken the exciting light that arrives sensitive membrane (reagent phase), the film emitted fluorescence is weakened.When the fluorescence spectrum of the ultraviolet-visible UV-VIS spectrum of analyte and sensitive membrane overlaps, also will absorb fluorescence (second inner filtration, the IFE of sensitive membrane
2), resonance energy takes place simultaneously shift (FTE) or dynamics quencher.Mathematic(al) representation:
First is the dynamics quencher; Second is static quenching; The 3rd is the resonance energy transfer; The 4th is first inner filtration; The 5th is second inner filtration; F
0Be respectively quencher Q with F and add fluorescence intensity preceding and that the adding back is measured, [Q] is broad sense quencher concentration, τ
0Be fluorescence decay life-span, K
QBe dynamics quenching constant, K
SThe static quenching constant, E
ExQuencher is to the molar absorptivity of exciting light, E
EmQuencher is to radiative molar absorptivity, and b is the effective light path of light by the agent of slightly going out.Following formula calculates through multivariate linear model, obtains two and simplifies mathematic(al) representation:
F
0/ F=K
Pq[Q]+C or log (F
0/ F)=K
Pq[Q]+C
F
0Fluorescence intensity when/F exists for blank and analyte, K
PqClaim apparent quenching constant, characterize the sensitivity of response.C is an intercept.Because multifactorial compatible and addition has improved mensuration sensitivity.Chemical reaction does not take place based on the physical optics principle in response in the mensuration process, therefore have good reversibility and long-life.
The present invention is when using, preferably by the detected data of computer acquisition detecting device, by to the spectral characteristic in object 200～1100nm to be measured interval in real time, original position, on-line analysis, by multiple mathematical model, set up the corresponding relation of drug concentration and spectrum.Realization just can be finished drug dissolution/release test overall process easily to the on-line automaticization operation of analytic target real-time data acquisition and processing, spectrum demonstration, stripping curve Real time dynamic display, data storage, data management, parameter extraction and reporting printing.
Application example of the present invention is as follows:
Application examples 1: the drug dissolution test of fast release formulation Clozapine sheet.Adopt Self-control method with dissolution rate test solvent preparation Clozapine series standard solution, instrument of the present invention shows acquisition serial absorption spectrum (accompanying drawing 9).With 285nm is to measure wavelength.Select No. 5 probes of №, 900ml is a solvent with hydrochloric acid solution (9 → 1000), changes blue laws, 50 rev/mins, measure 30 minutes stripping curves (accompanying drawing 10), and do control experiment by official method simultaneously.Obtain data consistent.But rapid delivery of pharmaceuticals drug concentration variation in the very short time of beginning is very fast as can be seen from real-time monitoring curve, and sample analysis can't obtain preceding 2 minutes more information.
Application examples 2: disintegrating tablet piroxicam tablet drug dissolution test.The piroxicam reference substance is with dissolution rate test solvent configuration series standard solution, and instrument of the present invention shows acquisition serial absorption spectrum (accompanying drawing 11).Piroxicam has absorption maximum at the 332nm place, as measuring wavelength.Select No. 2 probes of №, 900ml is a solvent with hydrochloric acid solution (9 → 1000), changes blue laws, 50 rev/mins, measure 40 minutes stripping curves (accompanying drawing 12), and do control experiment by official method simultaneously.Obtain data consistent.But this law is compared with official method, not only reduces operate miss and the more information amount is provided.
Applicating example 3: not disintegrating tablet vitamin B2 sheet drug dissolution test.The vitamin B2 reference substance is with dissolution rate test solvent configuration series standard solution, and instrument of the present invention shows the serial absorption spectrum of acquisition, at the 264nm place absorption maximum is arranged, and good linear is arranged, as measuring wavelength (accompanying drawing 13).Select No. 2 probes of №, the oar method is measured 25 minutes.Obtain the real-time stripping curve of vitamin B2 (accompanying drawing 14), do control experiment by official method simultaneously.This law and official method obtain data consistent.
Claims (15)
1. optical fiber in site online drug dissolution/release test instrument, it is characterized in that comprising light source, be no less than one y-type optical fiber chemical sensor probe, digestion instrument and detecting device, the light source input end of y-type optical fiber chemical sensor probe is connected on the light source, the test side of y-type optical fiber chemical sensor probe places in the digestion instrument, and the light source output terminal of y-type optical fiber chemical sensor probe is connected on the input end of detecting device; Wherein, y-type optical fiber chemical sensor probe comprises sleeve pipe, optical fiber and reflective mirror, and the test side of optical fiber is installed in the inner end of sleeve pipe, in the outer end of sleeve pipe reflective mirror is installed, and has at the middle part of sleeve pipe to be no less than one injection port.
2. optical fiber in site online drug dissolution/release test instrument, it is characterized in that comprising light source, be no less than one y-type optical fiber chemical sensor probe, digestion instrument and detecting device, the light source input end of y-type optical fiber chemical sensor probe is connected on the light source, the test side of y-type optical fiber chemical sensor probe places in the digestion instrument, and the light source output terminal of y-type optical fiber chemical sensor probe is connected on the input end of detecting device; Wherein, y-type optical fiber chemical sensor probe comprises sleeve pipe, optical fiber and reflective mirror, the test side of optical fiber is installed in the inner end of sleeve pipe, outer end at sleeve pipe is equipped with adjusting light path bar by engage thread or inserted mode, at the inner end of regulating the light path bar reflective mirror is installed, has at the middle part of sleeve pipe to be no less than one injection port.
3. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument, the length that it is characterized in that optical fiber are that 25cm to 250cm, diameter are 0.1cm to 2.50cm.
4. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that the installed inside of reflective mirror has sensitive membrane.
5. optical fiber in site online drug dissolution according to claim 3/release test instrument is characterized in that the installed inside of reflective mirror has sensitive membrane.
6. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that the reflective mirror outside is coated with the ultraviolet reflectance film.
7. optical fiber in site online drug dissolution according to claim 5/release test instrument is characterized in that the reflective mirror outside is coated with the ultraviolet reflectance film.
8. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that the test side of optical fiber is equipped with the optical fiber focus lamp.
9. optical fiber in site online drug dissolution according to claim 7/release test instrument is characterized in that the test side of optical fiber is equipped with the optical fiber focus lamp.
10. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that optical fiber adopts the single-mode fiber or the multimode optical fiber of Y type.
11. optical fiber in site online drug dissolution according to claim 9/release test instrument is characterized in that optical fiber adopts the single-mode fiber or the multimode optical fiber of Y type.
12. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that light source adopts deuterium lamp or xenon lamp or mercury lamp or laser instrument.
13. optical fiber in site online drug dissolution according to claim 11/release test instrument is characterized in that light source adopts deuterium lamp or xenon lamp or mercury lamp or laser instrument.
14. optical fiber in site online drug dissolution according to claim 1 and 2/release test instrument is characterized in that detecting device adopts charge-coupled detector(CCD) CCD, cmos image sensor CMOS, electric charge injector CID or diode array DAD detecting device.
15. optical fiber in site online drug dissolution according to claim 13/release test instrument is characterized in that detecting device adopts charge-coupled detector(CCD) CCD, cmos image sensor CMOS, electric charge injector CID or diode array DAD detecting device.
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| CN 200410001179 CN1271401C (en) | 2004-01-23 | 2004-01-23 | Optical fiber in situ tester for dissolution and release of medicine |
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| CN1271401C true CN1271401C (en) | 2006-08-23 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102192480A (en) * | 2010-03-08 | 2011-09-21 | 上海富科思分析仪器有限公司 | Fiber light-splitting multipath ultraviolet light source |
| CN102192889B (en) * | 2010-03-08 | 2012-11-21 | 上海富科思分析仪器有限公司 | Correction method for UV-visible absorption spectrum of fiber in-situ medicine leaching degree/releasing degree tester |
| CN104089879A (en) * | 2013-04-01 | 2014-10-08 | 上海富科思分析仪器有限公司 | Optical fiber-based drug dissolution rate and release rate process analyzer |
| CN107576635B (en) * | 2017-08-30 | 2024-04-12 | 南京航空航天大学 | Transparent liquid concentration measuring method and system based on reflection type optical fiber system |
| CN109030398B (en) * | 2018-08-28 | 2024-05-17 | 中国烟草总公司郑州烟草研究院 | Method for detecting nicotine release behavior of buccal cigarettes and special test instrument thereof |
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