CN104198611A - Oxiracetam sample impurity detection device - Google Patents
Oxiracetam sample impurity detection device Download PDFInfo
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- CN104198611A CN104198611A CN201410471020.7A CN201410471020A CN104198611A CN 104198611 A CN104198611 A CN 104198611A CN 201410471020 A CN201410471020 A CN 201410471020A CN 104198611 A CN104198611 A CN 104198611A
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Abstract
The invention discloses an oxiracetam sample impurity detection device which comprises a liquid chromatograph, a weighing feeding machine, a mixed quantitative conveying bottle, simple component quantitative conveying bottle, a gas chromatograph and an oxiracetam sample container. The weighing is all performed in a quantitative manner, the weighing accuracy is improved, the errors are reduced, the measurement accuracy is improved, measurement errors caused by artificial factors are avoided, qualitative and quantitative analysis is achieved, and the repeatability is good. The oxiracetam sample impurity detection device further has the advantages that the structure is simple and compact, the manufacturing cost is low, and the use is simple and convenient.
Description
Technical field
The present invention relates to a kind of impurity detection device, is exactly a kind of Oxiracetam sample impurity detection device.
Background technology
In Oxiracetam, the detection of related substance is the whether qualified important process of inspection medicine.At present, method of inspection impurity method is very single, needs each impurity to check separately, and process complexity is easily omitted.Because various reagent need to now be allocated, various allotments are manual operation, and the amount of taking error is larger, cause final detection result confidence level lower.
Summary of the invention
For overcoming above-mentioned deficiency of the prior art, the present invention is to provide a kind of Oxiracetam sample impurity detection device, can qualitative and quantitative analysis, and result degree of accuracy is high.
The present invention for achieving the above object, is achieved through the following technical solutions: Oxiracetam sample impurity detection device, comprises liquid chromatograph, the dispenser of weighing, mix quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph and Oxiracetam sample holder, the dispenser of weighing is by the 4-chloroacetyl acetacetic ester dispenser of weighing, the 4-chloro-3-hydroxyl ethyl butyrate dispenser of weighing, the first Oxiracetam samples weighing dispenser, the second Oxiracetam samples weighing dispenser, the glycyl amide hydrochloride dispenser of weighing, the glycine anhydride dispenser of weighing, the Oxiracetam acid dispenser of weighing, the dehydroxylation Oxiracetam dispenser of weighing, , mix quantitative transfusion bottle by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle, the first Oxiracetam sample mix quantitative transfusion bottle, the second Oxiracetam sample mix quantitative transfusion bottle, the second Oxiracetam sample secondary mixing quantitative transfusion bottle, the second Oxiracetam sample three times mixes quantitative transfusion bottle, glycyl amide hydrochloride mixing quantitative transfusion bottle, glycine anhydride mixing quantitative transfusion bottle, Oxiracetam acid mixes quantitative transfusion bottle, dehydroxylation Oxiracetam mixing quantitative transfusion bottle, impurity reference substance secondary mixing quantitative transfusion bottle, impurity reference substance mixed once quantitative transfusion bottle, the second Oxiracetam sample component mixing quantitative transfusion bottle, according to product mixing quantitative transfusion bottle composition, one-component quantitative transfusion bottle is by blank solvent one-component quantitative transfusion bottle, potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, ethoxy Oxiracetam one-component quantitative transfusion bottle, acetonitrile-water mobile phase one-component quantitative transfusion bottle composition, liquid chromatograph connects respectively the discharging opening of the second Oxiracetam sample component mixing quantitative transfusion bottle, discharging opening, the second Oxiracetam sample of ethoxy Oxiracetam one-component quantitative transfusion bottle mixes the discharging opening of quantitative transfusion bottle, the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle three times, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle connects respectively the discharging opening of the second Oxiracetam sample mix quantitative transfusion bottle and the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle, the charging aperture of ethoxy Oxiracetam one-component quantitative transfusion bottle connects the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle, the charging aperture that the second Oxiracetam sample three times mixes quantitative transfusion bottle connects respectively the discharging opening of the second Oxiracetam sample secondary mixing quantitative transfusion bottle, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle connects respectively the discharging opening of impurity reference substance mixed once quantitative transfusion bottle, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the charging aperture of the second Oxiracetam sample mix quantitative transfusion bottle connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the charging aperture of the second Oxiracetam sample secondary mixing quantitative transfusion bottle connects respectively the discharging opening of the 3rd Oxiracetam samples weighing dispenser, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the discharging opening of the second Oxiracetam samples weighing dispenser, the charging aperture of the 3rd Oxiracetam samples weighing dispenser connects the discharging opening of Oxiracetam sample holder, and the charging aperture of the second Oxiracetam samples weighing dispenser connects Oxiracetam sample holder, discharging opening, the discharging opening of glycyl amide hydrochloride mixing quantitative transfusion bottle, the discharging opening of glycine anhydride mixing quantitative transfusion bottle, Oxiracetam acid that the charging aperture of impurity reference substance mixed once quantitative transfusion bottle connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle mix the discharging opening of quantitative transfusion bottle, the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle, the weigh discharging opening of dispenser of discharging opening, the glycyl amide hydrochloride that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the weigh discharging opening of dispenser of discharging opening, the glycine anhydride that the charging aperture of glycine anhydride mixing quantitative transfusion bottle connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the weigh discharging opening of dispenser of discharging opening, the Oxiracetam acid that the charging aperture that Oxiracetam acid mixes quantitative transfusion bottle connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the weigh discharging opening of dispenser of discharging opening, the dehydroxylation Oxiracetam that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, gas chromatograph connects respectively the discharging opening of impurity reference substance mixing quantitative transfusion bottle, the discharging opening of the first Oxiracetam sample mix quantitative transfusion bottle, the charging aperture of impurity reference substance mixing quantitative transfusion bottle connects respectively the discharging opening of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle, the discharging opening of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle, the discharging opening of blank solvent one-component quantitative transfusion bottle, the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle connects respectively 4-chloroacetyl acetacetic ester the weigh discharging opening of dispenser, the discharging opening of blank solvent one-component quantitative transfusion bottle, the charging aperture of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle connects respectively 4-chloro-3-hydroxyl ethyl butyrate the weigh discharging opening of dispenser, the discharging opening of blank solvent one-component quantitative transfusion bottle, the discharging opening of the first Oxiracetam samples weighing dispenser of the first Oxiracetam sample mix quantitative transfusion bottle, the discharging opening of blank solvent one-component quantitative transfusion bottle, the charging aperture of the first Oxiracetam samples weighing dispenser connects Oxiracetam sample holder.
In order further to realize object of the present invention, can also be by the following technical solutions: the described dispenser of weighing comprises support, oblique delivery chute and weighing instrument are installed respectively on support, bracing frame is installed on weighing instrument, on bracing frame, fixedly mount discharging barrel, Open Side Down for discharging barrel, and solenoid valve is set on discharging barrel, the lower end of discharging barrel is positioned at the upper end of oblique delivery chute, and tiltedly the lower end of delivery chute is discharging opening.Described mixing quantitative transfusion bottle comprises mixing capacity bottle, installs and mix constant-delivery pump on mixing capacity bottle, and stirrer is installed in mixing capacity bottle bottom, and the bottleneck of mixing capacity bottle is charging aperture, and mixing constant-delivery pump output terminal is discharging opening.Described one-component quantitative transfusion bottle comprises one-component volumetric flask, and one-component constant-delivery pump is installed on one-component volumetric flask, and the bottleneck of one-component volumetric flask is charging aperture, and the output terminal of one-component constant-delivery pump is discharging opening.
Advantage of the present invention is: all taking all adopts quantitative manner to carry out, and weighs accuracy and improves, and error reduces, and improves the accuracy of measuring, and avoids the measurement error that human factor causes, can qualitative and quantitative analysis, and reproducible.The present invention also has advantages of compactness simple for structure, cheap for manufacturing cost and easy to use.
Brief description of the drawings
Fig. 1 is structural representation of the present invention; Fig. 2 is in Fig. 1, weigh dispenser and the structural representation that mixes quantitative transfusion bottle; Fig. 3 is one-component quantitative transfusion bottle structure schematic diagram in Fig. 1.
Reference numeral: 1 liquid chromatograph, 21, the 4-chloroacetyl acetacetic ester dispenser of weighing, 22, the 4-chloro-3-hydroxyl ethyl butyrate dispenser of weighing, 23 first Oxiracetam samples weighing dispensers, 24 second Oxiracetam samples weighing dispensers, the 25 glycyl amide hydrochlorides dispenser of weighing, the 26 glycine anhydrides dispenser of weighing, the 27 Oxiracetam acid dispenser of weighing, the 28 dehydroxylation Oxiracetams dispenser of weighing, 29 the 3rd Oxiracetam samples weighing dispensers, 201 supports, 202 weighing instruments, 203 solenoid valves, 204 discharging barrels, 205 bracing frames, 206 oblique delivery chutes, 3A4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle, 3B, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle, 3C the first Oxiracetam sample mix quantitative transfusion bottle, 3D the second Oxiracetam sample mix quantitative transfusion bottle, 3E the second Oxiracetam sample secondary mixing quantitative transfusion bottle, 3F the second Oxiracetam sample mixes quantitative transfusion bottle three times, 3G glycyl amide hydrochloride mixing quantitative transfusion bottle, 3H glycine anhydride mixing quantitative transfusion bottle, the acid of 3I Oxiracetam mixes quantitative transfusion bottle, 3J dehydroxylation Oxiracetam mixing quantitative transfusion bottle, 3K impurity reference substance secondary mixing quantitative transfusion bottle, 3L impurity reference substance mixed once quantitative transfusion bottle, 3M the second Oxiracetam sample component mixing quantitative transfusion bottle, 3N impurity reference substance mixing quantitative transfusion bottle, 301 mixing capacity bottles, 302 stirrers, 303 mix constant-delivery pump, 41 blank solvent one-component quantitative transfusion bottles, 42 potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottles, 43 ethoxy Oxiracetam one-component quantitative transfusion bottles, 44 acetonitrile-water mobile phase one-component quantitative transfusion bottles, 401 simple substance volumetric flasks, 402 simple substance constant-delivery pumps, 5 gas chromatographs, 6 Oxiracetam sample holders.
Embodiment
Oxiracetam sample impurity detection device, as shown in Figure 1, comprises liquid chromatograph 1, the dispenser of weighing, mix quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph 5 and Oxiracetam sample holder 6, the dispenser of weighing is by the 4-chloroacetyl acetacetic ester dispenser 21 of weighing, the 4-chloro-3-hydroxyl ethyl butyrate dispenser 22 of weighing, the first Oxiracetam samples weighing dispenser 23, the second Oxiracetam samples weighing dispenser 24, the glycyl amide hydrochloride dispenser 25 of weighing, the glycine anhydride dispenser 26 of weighing, the Oxiracetam acid dispenser 27 of weighing, the dehydroxylation Oxiracetam dispenser 28 of weighing, , mix quantitative transfusion bottle by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B, the first Oxiracetam sample mix quantitative transfusion bottle 3C, the second Oxiracetam sample mix quantitative transfusion bottle 3D, the second Oxiracetam sample secondary mixing quantitative transfusion bottle 3E, the second Oxiracetam sample three times mixes quantitative transfusion bottle 3F, glycyl amide hydrochloride mixing quantitative transfusion bottle 3G, glycine anhydride mixing quantitative transfusion bottle 3H, Oxiracetam acid mixes quantitative transfusion bottle 3I, dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J, impurity reference substance secondary mixing quantitative transfusion bottle 3K, impurity reference substance mixed once quantitative transfusion bottle 3L, the second Oxiracetam sample component mixing quantitative transfusion bottle 3M, according to product mixing quantitative transfusion bottle 3N composition, one-component quantitative transfusion bottle is by blank solvent one-component quantitative transfusion bottle 41, potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, ethoxy Oxiracetam one-component quantitative transfusion bottle 43, acetonitrile-water mobile phase one-component quantitative transfusion bottle 44 forms, liquid chromatograph 1 connects respectively the discharging opening of the second Oxiracetam sample component mixing quantitative transfusion bottle 3M, discharging opening, the second Oxiracetam sample of ethoxy Oxiracetam one-component quantitative transfusion bottle 43 mixes the discharging opening of quantitative transfusion bottle 3F, the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle 3K three times, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle 3M connects respectively the discharging opening of the second Oxiracetam sample mix quantitative transfusion bottle 3D and the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle 44, the charging aperture of ethoxy Oxiracetam one-component quantitative transfusion bottle 43 connects the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle 44, the charging aperture that the second Oxiracetam sample three times mixes quantitative transfusion bottle 3F connects respectively the discharging opening of the second Oxiracetam sample secondary mixing quantitative transfusion bottle 3E, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle 3K connects respectively the discharging opening of impurity reference substance mixed once quantitative transfusion bottle 3L, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the charging aperture of the second Oxiracetam sample mix quantitative transfusion bottle 3D connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the charging aperture of the second Oxiracetam sample secondary mixing quantitative transfusion bottle 3E connects respectively the discharging opening of the 3rd Oxiracetam samples weighing dispenser 29, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the discharging opening of the second Oxiracetam samples weighing dispenser 24, the charging aperture of the 3rd Oxiracetam samples weighing dispenser 29 connects the discharging opening of Oxiracetam sample holder 6, and the charging aperture of the second Oxiracetam samples weighing dispenser 24 connects Oxiracetam sample holder 6, discharging opening, the discharging opening of glycyl amide hydrochloride mixing quantitative transfusion bottle 3G, the discharging opening of glycine anhydride mixing quantitative transfusion bottle 3H, Oxiracetam acid that the charging aperture of impurity reference substance mixed once quantitative transfusion bottle 3L connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42 mix the discharging opening of quantitative transfusion bottle 3I, the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J, the weigh discharging opening of dispenser 25 of discharging opening, the glycyl amide hydrochloride that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle 3G connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the weigh discharging opening of dispenser 26 of discharging opening, the glycine anhydride that the charging aperture of glycine anhydride mixing quantitative transfusion bottle 3H connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the weigh discharging opening of dispenser 27 of discharging opening, the Oxiracetam acid that the charging aperture that Oxiracetam acid mixes quantitative transfusion bottle 3I connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the weigh discharging opening of dispenser 28 of discharging opening, the dehydroxylation Oxiracetam that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, gas chromatograph 5 connects respectively the discharging opening of impurity reference substance mixing quantitative transfusion bottle 3N, the discharging opening of the first Oxiracetam sample mix quantitative transfusion bottle 3C, the charging aperture of impurity reference substance mixing quantitative transfusion bottle 3N connects respectively the discharging opening of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A, the discharging opening of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B, the discharging opening of blank solvent one-component quantitative transfusion bottle 41, the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A connects respectively 4-chloroacetyl acetacetic ester the weigh discharging opening of dispenser 21, the discharging opening of blank solvent one-component quantitative transfusion bottle 41, the charging aperture of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B connects respectively 4-chloro-3-hydroxyl ethyl butyrate the weigh discharging opening of dispenser 22, the discharging opening of blank solvent one-component quantitative transfusion bottle 41, the discharging opening of the first Oxiracetam samples weighing dispenser 23 of the first Oxiracetam sample mix quantitative transfusion bottle 3C, the discharging opening of blank solvent one-component quantitative transfusion bottle 41, the charging aperture of the first Oxiracetam samples weighing dispenser 23 connects Oxiracetam sample holder 6.
Specific operation process is:
The content that checks glycyl amide hydrochloride (impurity C), glycine anhydride (impurity A), Oxiracetam acid (impurity B), dehydroxylation Oxiracetam (impurity E) in Oxiracetam sample, concrete operations are as follows:
With octadecylsilane chemically bonded silica be filling agent, with 0.05mol/L potassium dihydrogen phosphate mobile phase (adjusting pH=3.0 with phosphoric acid), be placed in potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42; Flow velocity is 0.5ml/min; Detection wavelength is 200nm; Column temperature is: room temperature.Precision measures mixes reference substance solution 20 μ l, and injection liquid chromatography, records chromatogram, and theoretical cam curve is not less than 5000 by Oxiracetam, and the degree of separation between Oxiracetam peak and each impurity peaks should meet the requirements.
Assay method:
Get Oxiracetam sample in the second Oxiracetam samples weighing dispenser 24 accurately weighed, add mobile phase and be mixed with at the second Oxiracetam sample mix quantitative transfusion bottle 3D the need testing solution that concentration is 1mg/ml.Precision measures need testing solution 1ml, be placed in the second Oxiracetam sample secondary mixing quantitative transfusion bottle 3E, be diluted to 100ml with mobile phase, shake up, precision measures 5ml again, puts the second Oxiracetam sample three times and mixes in quantitative transfusion bottle 3F, is diluted to 100ml with mobile phase, shake up, in contrast solution.
Take impurity C, impurity A, impurity B, the each about 10mg of impurity E at glycyl amide hydrochloride dispenser 25, glycine anhydride dispenser 26, Oxiracetam acid dispenser 27, the dehydroxylation Oxiracetam dispenser 28 of weighing of weighing of weighing of weighing respectively, put respectively in glycyl amide hydrochloride mixing quantitative transfusion bottle 3G, glycine anhydride mixing quantitative transfusion bottle 3H, Oxiracetam acid mixing quantitative transfusion bottle 3I, dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J, add mobile phase appropriate, jolting makes to dissolve, and be diluted to 100ml, shake up, as impurity reference substance stock solution.Precision measures above-mentioned each impurity reference substance stock solution 5ml, 5ml, 5ml, 5ml and puts in impurity reference substance mixed once quantitative transfusion bottle 3L respectively, adds mobile phase and is diluted to 100ml, shakes up.Precision measures 1 ml and puts in impurity reference substance secondary mixing quantitative transfusion bottle 3K again, is diluted to 10ml with mobile phase, shakes up and obtain mixing reference substance solution.
Get contrast solution 20 μ l injection liquid chromatographies 1, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10%～25% of full scale.Precision measures need testing solution, contrast solution and mixes the each 20 μ l of reference substance solution, and injection liquid chromatography, records 3 times to major component peak retention time of chromatogram respectively.In the chromatogram of need testing solution, if any impurity peaks, wherein impurity A, impurity C, impurity E with calculated by peak area, all must not cross 0.05% by external standard method; Impurity B with calculated by peak area, must not cross 0.30% by external standard method; Other single impurity peak area must not be greater than contrast solution main peak area (0.05%); It's 1.0% (comprising impurity D, impurity F and impurity G) must not past for total impurities.
The content that checks Oxiracetam ethyl ester (impurity D) in Oxiracetam sample, concrete operations are as follows:
Chromatographic column: C18 post Hydro-RP 250 × 4.6mm, 4 μ m
Mobile phase: acetonitrile-water (20:80) flow velocity: 0.6ml/min wavelength: 200nm
Sample size: 20 μ l
Get this product by the 3rd Oxiracetam samples weighing dispenser 29 appropriate, accurately weighed, add to the second Oxiracetam sample component mixing quantitative transfusion bottle 3M, add mobile phase and dissolve and be quantitatively diluted in every 1ml the approximately solution containing 1mg, as need testing solution; Separately get ethoxy Oxiracetam (impurity D) appropriate, accurately weighed, make impure D 0.5 μ g in every 1ml with mobile phase dissolving quantitative dilution and insert ethoxy Oxiracetam one-component quantitative transfusion bottle 43, product solution in contrast.With octadecylsilane chemically bonded silica be filling agent; Taking acetonitrile-water (20:80) as mobile phase, detection wavelength is 200nm, flow velocity 0.6ml/min; Measure reference substance solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10%～25% of full scale.Measure reference substance solution, the each 20 μ l of need testing solution, injection liquid chromatography 1, records 3 times to major component peak retention time of chromatogram respectively again.In the chromatogram of need testing solution, if any impurity D peak, with calculated by peak area, must not cross 0.05% by external standard method.
The content of 4-chloroacetyl acetacetic ester (impurity F) and 4-chloro-3-hydroxyl ethyl butyrate (impurity G) in inspection Oxiracetam sample, concrete operations are as follows:
Instrument: Shimadzu GC-2014C gas chromatograph
Detecting device: FID detecting device
Chromatographic column: HP-5 quartz capillary column (5% diphenyl-95% dimethyl polysiloxane)
Analysis condition:
Column temperature: 80 DEG C, keep 8 min, 10 DEG C/min is warming up to 230 DEG C, keeps 3min;
Injector temperature: 180 DEG C;
Detector temperature: 230 DEG C;
Carrier gas: high pure nitrogen;
Sample size: 0.2 μ l;
Blank solvent: DMF: water=90:10
Eliminate matrix effect test concrete operations as follows:
Solution preparation:
Impurity stock solution: take impurity F, the each 25mg of impurity G by 4-chloroacetyl acetacetic ester dispenser 21, the 4-chloro-3-hydroxyl ethyl butyrate dispenser 22 of weighing of weighing, be added to respectively in 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B, be diluted to 100ml by the blank solvent in blank solvent one-component quantitative transfusion bottle 41, shake up, to obtain final product.（0.25?mg/ml）
Impurity reference substance solution: accurately measure the each 1.0ml of impurity stock solution to matter reference substance mixing quantitative transfusion bottle 3N, be diluted to 10ml by blank solvent, shake up, to obtain final product.（25μg/ml?）
Need testing solution: take crowd Oxiracetam sample 0.5g by the first Oxiracetam samples weighing dispenser 23 and insert in the first Oxiracetam sample mix quantitative transfusion bottle 3C, dissolve and dilute 10ml by blank solvent, shake up, to obtain final product.（50?mg/ml）
Chromatographic condition is according to the rules sample introduction respectively, and impurity reference substance solution 2 pins, need testing solution respectively enter 2 pins, record chromatographic process.
The described dispenser of weighing is the equipment that can measure amount and the injected volume function of solid matter, as shown in Figure 2, comprise support 201, oblique delivery chute 206 and weighing instrument 202 are installed respectively on support 201, bracing frame 205 is installed on weighing instrument 202, on bracing frame 205, fixedly mount discharging barrel 204, Open Side Down for discharging barrel 204, solenoid valve 203 is set on discharging barrel 204, and the lower end of discharging barrel 204 is positioned at the upper end of oblique delivery chute 206, and tiltedly the lower end of delivery chute 206 is discharging opening.Discharging barrel 204 is emitted material by solenoid valve 203, and material drops on oblique delivery chute 206, and inventory is that weighing instrument 202 records weight reduction.This equipment directly takes compared with inventory with existing, avoids the impact to weighing device in inventory dropping process, causes weighing device to quit work in advance, and actual inventory is less than theoretical inventory, makes testing result inaccurate.
Described mixing quantitative transfusion bottle is to have the device stirring with quantitative conveying function, as shown in Figure 2, comprise mixing capacity bottle 301, on mixing capacity bottle 301, install and mix constant-delivery pump 303, stirrer 302 is installed in mixing capacity bottle 301 bottoms, the bottleneck of mixing capacity bottle 301 is charging aperture, and mixing constant-delivery pump 303 output terminals is discharging opening.
Described simple substance quantitative transfusion bottle is the device with quantitative conveying function, as shown in Figure 3, comprise simple substance volumetric flask 401, simple substance constant-delivery pump 402 is installed on simple substance volumetric flask 401, the bottleneck of simple substance volumetric flask 401 is charging aperture, and the output terminal of simple substance constant-delivery pump 402 is discharging opening.
The using method that this equipment is corresponding, also can adopt conventional test equipment to carry out, but degree of accuracy is far smaller than employing equipment of the present invention, is specially:
The content that checks glycyl amide hydrochloride (impurity C), glycine anhydride (impurity A), Oxiracetam acid (impurity B), dehydroxylation Oxiracetam (impurity E) in Oxiracetam sample, concrete operations are as follows:
Chromatographic condition and system suitability:
With octadecylsilane chemically bonded silica be filling agent, with 0.05mol/L potassium dihydrogen phosphate mobile phase (adjusting pH=3.0 with phosphoric acid); Flow velocity is 0.5ml/min; Detection wavelength is 200nm; Column temperature is: room temperature.Precision measures mixes reference substance solution 20 μ l, and injection liquid chromatography, records chromatogram, and theoretical cam curve is not less than 5000 by Oxiracetam, and the degree of separation between Oxiracetam peak and each impurity peaks should meet the requirements.
Assay method: get this product, accurately weighed, add mobile phase and be mixed with the need testing solution that concentration is 1mg/ml.Precision measures need testing solution 1ml, puts in 100ml measuring bottle, is diluted to scale with mobile phase, shake up, then precision measures 5ml, puts in 100ml measuring bottle, is diluted to scale with mobile phase, shakes up, in contrast solution.
Take respectively glycyl amide hydrochloride (impurity C), glycine anhydride (impurity A), Oxiracetam acid (impurity B), the each about 10mg of dehydroxylation Oxiracetam (impurity E), accurately weighed, put respectively in 100ml measuring bottle, add mobile phase appropriate, jolting makes to dissolve, and be diluted to scale, shake up, as impurity reference substance stock solution.Precision measures above-mentioned each impurity reference substance stock solution 5ml, 5ml, 5ml, 5ml and puts in same 100ml measuring bottle respectively, adds mobile phase and is diluted to scale, shakes up.Precision measures 1 ml and puts in 10 ml volumetric flasks again, is diluted to scale with mobile phase, shakes up and obtain mixing reference substance solution.
Get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10%～25% of full scale.Precision measures need testing solution, contrast solution and mixes the each 20 μ l of reference substance solution, and injection liquid chromatography, records 3 times to major component peak retention time of chromatogram respectively.In the chromatogram of need testing solution, if any impurity peaks, wherein impurity A, impurity C, impurity E with calculated by peak area, all must not cross 0.05% by external standard method; Impurity B with calculated by peak area, must not cross 0.30% by external standard method; Other single impurity peak area must not be greater than contrast solution main peak area (0.05%); It's 1.0% (comprising impurity D, impurity F and impurity G) must not past for total impurities.
The contrast of method shown in table 1-4 independent development method and documents and materials
Table 1-5 related substance methodology the result
Check impurity D(Oxiracetam ethyl ester in Oxiracetam) content, concrete operations are as follows:
Chromatographic condition and test method
Chromatographic column: C18 post Hydro-RP 250 × 4.6mm, 4 μ m
Mobile phase: acetonitrile-water (20:80) flow velocity: 0.6ml/min wavelength: 200nm
Sample size: 20 μ l
Get this product appropriate, accurately weighed, add mobile phase and dissolve and be quantitatively diluted to the solution that approximately contains 1mg in every 1ml, as need testing solution; Separately get ethoxy Oxiracetam (impurity D) appropriate, accurately weighed, dissolve also quantitatively dilution with mobile phase and make impure D 0.5 μ g in every 1ml, product solution in contrast.With octadecylsilane chemically bonded silica be filling agent; Taking acetonitrile-water (20:80) as mobile phase, detection wavelength is 200nm, flow velocity 0.6ml/min; Measure reference substance solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10%～25% of full scale.Measure reference substance solution, the each 20 μ l of need testing solution, injection liquid chromatography, records 3 times to major component peak retention time of chromatogram respectively again.In the chromatogram of need testing solution, if any impurity D peak, with calculated by peak area, must not cross 0.05% by external standard method.
Checking content comprises: specificity, system suitability, linearity and scope, precision, accuracy and method durability.See the following form.
Table 2-2 impurity D inspection method the result summary
The content of 4-chloroacetyl acetacetic ester (impurity F) and 4-chloro-3-hydroxyl ethyl butyrate (impurity G) in inspection Oxiracetam sample, concrete operations are as follows:
Chromatographic condition and experimental technique
Instrument: Shimadzu GC-2014C gas chromatograph
Detecting device: FID detecting device
Chromatographic column: HP-5 quartz capillary column (5% diphenyl-95% dimethyl polysiloxane)
Analysis condition:
Column temperature: 80 DEG C, keep 8 min, 10 DEG C/min is warming up to 230 DEG C, keeps 3min;
Injector temperature: 180 DEG C;
Detector temperature: 230 DEG C;
Carrier gas: high pure nitrogen;
Sample size: 0.2 μ l;
Blank solvent: DMF: water=90:10
General introduction: find in impurity F, G method research process, Oxiracetam sample has obvious interference to the analytical test of impurity F, has matrix effect, and we adopt standard addition method to eliminate matrix effect, carries out the methodology checking of system.
Eliminate matrix effect test concrete operations as follows:
Solution preparation:
Impurity stock solution: take impurity F, the each 25mg of impurity G, accurately weighed in 100ml volumetric flask respectively, be diluted to scale by blank solvent, shake up, to obtain final product.（0.25?mg/ml）
Impurity reference substance solution: accurately measure the each 1.0ml of impurity stock solution in same 10ml volumetric flask, be diluted to scale by blank solvent, shake up, to obtain final product.（25μg/ml?）
Need testing solution: take 120601 crowdes of Oxiracetam sample 0.5g, accurately weighed in 10ml volumetric flask, with blank solvent ultrasonic dissolution and be diluted to scale, shake up, to obtain final product.（50?mg/ml）
Chromatographic condition is according to the rules sample introduction respectively, and impurity reference substance solution 2 pins, need testing solution respectively enter 2 pins, record chromatographic process.
Crucial initiation material 4-chloroacetyl acetacetic ester (impurity F) and intermediate 4-chloro-3-hydroxyl ethyl butyrate (impurity G) are all liquid materials, with reference to the relevant character of material and the detection method of 4-chloroacetyl acetacetic ester, we adopt vapor-phase chromatography research, according to Oxiracetam related substance analytical approach proof scheme, our company verifies the detection method of impurity F, impurity G, the content of checking comprises: specificity, system suitability, quantitative limit and detectability, linearity, accuracy and method durability.Methodology the result summary sees the following form:
Table 3.2.S.4.3.4-1 related substance (impurity F, impurity G) methodology the result summary
Technical scheme of the present invention is not restricted in the scope of embodiment of the present invention.The present invention not technology contents of detailed description is known technology.
Claims (4)
1. Oxiracetam sample impurity detection device, is characterized in that: comprise liquid chromatograph (1), the dispenser of weighing, mix quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph (5) and Oxiracetam sample holder (6), the dispenser of weighing is by the 4-chloroacetyl acetacetic ester dispenser (21) of weighing, the 4-chloro-3-hydroxyl ethyl butyrate dispenser (22) of weighing, the first Oxiracetam samples weighing dispenser (23), the second Oxiracetam samples weighing dispenser (24), the glycyl amide hydrochloride dispenser (25) of weighing, the glycine anhydride dispenser (26) of weighing, the Oxiracetam acid dispenser (27) of weighing, the dehydroxylation Oxiracetam dispenser (28) of weighing, , mix quantitative transfusion bottle by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A), 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle (3B), the first Oxiracetam sample mix quantitative transfusion bottle (3C), the second Oxiracetam sample mix quantitative transfusion bottle (3D), the second Oxiracetam sample secondary mixing quantitative transfusion bottle (3E), the second Oxiracetam sample three times mixes quantitative transfusion bottle (3F), glycyl amide hydrochloride mixing quantitative transfusion bottle (3G), glycine anhydride mixing quantitative transfusion bottle (3H), Oxiracetam acid mixes quantitative transfusion bottle (3I), dehydroxylation Oxiracetam mixing quantitative transfusion bottle (3J), impurity reference substance secondary mixing quantitative transfusion bottle (3K), impurity reference substance mixed once quantitative transfusion bottle (3L), the second Oxiracetam sample component mixing quantitative transfusion bottle (3M), according to product mixing quantitative transfusion bottle (3N) composition, one-component quantitative transfusion bottle is by blank solvent one-component quantitative transfusion bottle (41), potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), ethoxy Oxiracetam one-component quantitative transfusion bottle (43), acetonitrile-water mobile phase one-component quantitative transfusion bottle (44) composition, discharging opening, the discharging opening of ethoxy Oxiracetam one-component quantitative transfusion bottle (43), the second Oxiracetam sample that liquid chromatograph (1) connects respectively the second Oxiracetam sample component mixing quantitative transfusion bottle (3M) mix the discharging opening of quantitative transfusion bottle (3F), the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle (3K) three times, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle (3M) connects respectively the discharging opening of the second Oxiracetam sample mix quantitative transfusion bottle (3D) and the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle (44), the charging aperture of ethoxy Oxiracetam one-component quantitative transfusion bottle (43) connects the discharging opening of acetonitrile-water mobile phase one-component quantitative transfusion bottle (44), the charging aperture that the second Oxiracetam sample three times mixes quantitative transfusion bottle (3F) connects respectively the discharging opening of the second Oxiracetam sample secondary mixing quantitative transfusion bottle (3E), the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle (3K) connects respectively the discharging opening of impurity reference substance mixed once quantitative transfusion bottle (3L), the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the charging aperture of the second Oxiracetam sample mix quantitative transfusion bottle (3D) connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the charging aperture of the second Oxiracetam sample secondary mixing quantitative transfusion bottle (3E) connects respectively the discharging opening of the 3rd Oxiracetam samples weighing dispenser (29), the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the discharging opening of the second Oxiracetam samples weighing dispenser (24), the charging aperture of the 3rd Oxiracetam samples weighing dispenser (29) connects the discharging opening of Oxiracetam sample holder (6), and the charging aperture of the second Oxiracetam samples weighing dispenser (24) connects Oxiracetam sample holder (6), discharging opening, the discharging opening of glycyl amide hydrochloride mixing quantitative transfusion bottle (3G), the discharging opening of glycine anhydride mixing quantitative transfusion bottle (3H), Oxiracetam acid that the charging aperture of impurity reference substance mixed once quantitative transfusion bottle (3L) connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) mix the discharging opening of quantitative transfusion bottle (3I), the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle (3J), the weigh discharging opening of dispenser (25) of discharging opening, the glycyl amide hydrochloride that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle (3G) connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the weigh discharging opening of dispenser (26) of discharging opening, the glycine anhydride that the charging aperture of glycine anhydride mixing quantitative transfusion bottle (3H) connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the weigh discharging opening of dispenser (27) of discharging opening, the Oxiracetam acid that the charging aperture that Oxiracetam acid mixes quantitative transfusion bottle (3I) connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), the weigh discharging opening of dispenser (28) of discharging opening, the dehydroxylation Oxiracetam that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle (3J) connects respectively potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42), gas chromatograph (5) connects respectively the discharging opening of impurity reference substance mixing quantitative transfusion bottle (3N), the discharging opening of the first Oxiracetam sample mix quantitative transfusion bottle (3C), the charging aperture of impurity reference substance mixing quantitative transfusion bottle (3N) connects respectively the discharging opening of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A), the discharging opening of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle (3B), the discharging opening of blank solvent one-component quantitative transfusion bottle (41), the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A) connects respectively 4-chloroacetyl acetacetic ester the weigh discharging opening of dispenser (21), the discharging opening of blank solvent one-component quantitative transfusion bottle (41), the charging aperture of 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle (3B) connects respectively 4-chloro-3-hydroxyl ethyl butyrate the weigh discharging opening of dispenser (22), the discharging opening of blank solvent one-component quantitative transfusion bottle (41), the discharging opening of the first Oxiracetam samples weighing dispenser (23) of the first Oxiracetam sample mix quantitative transfusion bottle (3C), the discharging opening of blank solvent one-component quantitative transfusion bottle (41), the charging aperture of the first Oxiracetam samples weighing dispenser (23) connects Oxiracetam sample holder (6).
2. aminomethylbenzoic acid sample impurity detection device according to claim 1, it is characterized in that: the described dispenser of weighing comprises support (201), oblique delivery chute (206) and weighing instrument (202) are installed respectively on support (201), the upper bracing frame (205) of installing of weighing instrument (202), bracing frame (205) upper fixed installation discharging barrel (204), Open Side Down for discharging barrel (204), solenoid valve (203) is set on discharging barrel (204), the lower end of discharging barrel (204) is positioned at the upper end of oblique delivery chute (206), tiltedly the lower end of delivery chute (206) is discharging opening.
3. aminomethylbenzoic acid sample impurity detection device according to claim 1, it is characterized in that: described mixing quantitative transfusion bottle comprises mixing capacity bottle (301), the upper installation of mixing capacity bottle (301) mixed constant-delivery pump (303), stirrer (302) is installed in mixing capacity bottle (301) bottom, the bottleneck of mixing capacity bottle (301) is charging aperture, and mixing constant-delivery pump (303) output terminal is discharging opening.
4. aminomethylbenzoic acid sample impurity detection device according to claim 1, it is characterized in that: described one-component quantitative transfusion bottle comprises one-component volumetric flask (401), the upper one-component constant-delivery pump (402) of installing of one-component volumetric flask (401), the bottleneck of one-component volumetric flask (401) is charging aperture, and the output terminal of one-component constant-delivery pump (402) is discharging opening.
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| CN115267003A (en) * | 2022-08-09 | 2022-11-01 | 宣城菁科生物科技有限公司 | Method for detecting content of S (-) -4-chloro-3-hydroxybutyric acid ethyl ester isomer |
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Cited By (4)
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| CN105486770A (en) * | 2015-12-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Method for separating measurement of chemical purity of oxiracetam intermediate through gas chromatographic method |
| CN112147261A (en) * | 2020-10-27 | 2020-12-29 | 精晶药业股份有限公司 | High performance liquid detection method for R-4-chloro-3-hydroxy ethyl butyrate in L-carnitine reaction solution |
| CN115267003A (en) * | 2022-08-09 | 2022-11-01 | 宣城菁科生物科技有限公司 | Method for detecting content of S (-) -4-chloro-3-hydroxybutyric acid ethyl ester isomer |
| CN115267003B (en) * | 2022-08-09 | 2023-08-08 | 宣城菁科生物科技有限公司 | Method for detecting isomer content of S (-) -4-chloro-3-hydroxybutyric acid ethyl ester |
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Denomination of invention: Olaxitam sample impurity detection device Effective date of registration: 20230814 Granted publication date: 20160420 Pledgee: Dezhou Lingcheng Rural Commercial Bank Co.,Ltd. Pledgor: DEZHOU BOCHENG PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980051998 |
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