CN104198611B - Oxiracetam sample impurity detection device - Google Patents
Oxiracetam sample impurity detection device Download PDFInfo
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- CN104198611B CN104198611B CN201410471020.7A CN201410471020A CN104198611B CN 104198611 B CN104198611 B CN 104198611B CN 201410471020 A CN201410471020 A CN 201410471020A CN 104198611 B CN104198611 B CN 104198611B
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Abstract
Oxiracetam sample impurity detection device, comprises liquid chromatograph, dispenser of weighing, mixing quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph and Oxiracetam sample holder.All taking all adopts quantitative manner to carry out, and weigh accuracy and improve, error reduces, and improves the accuracy measured, and the measurement avoiding human factor to cause is slipped up, can qualitative and quantitative analysis, reproducible.The present invention also has advantage compact, cheap for manufacturing cost and easy to use simple for structure.
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 important process whether inspection medicine is qualified.At present, method of inspection impurity method is very single, needs each impurity to check separately, and process is complicated, easily omits.Because various reagent needs existing allotment, various allotment is manual operation, and the amount of taking error is comparatively large, causes 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, to weigh dispenser, mixing quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph and Oxiracetam sample holder, dispenser of weighing to be weighed dispenser by 4-chloroacetyl acetacetic ester, 4-chloro-3-hydroxyl ethyl butyrate is weighed dispenser, first Oxiracetam samples weighing dispenser, second Oxiracetam samples weighing dispenser, glycyl amide hydrochloride is weighed dispenser, glycine anhydride is weighed dispenser, Oxiracetam acid is weighed dispenser, dehydroxylation Oxiracetam is weighed dispenser composition, and mixing quantitative transfusion bottle is by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle, first Oxiracetam sample mix quantitative transfusion bottle, second Oxiracetam sample mix quantitative transfusion bottle, second Oxiracetam sample secondary mixing quantitative transfusion bottle, second Oxiracetam sample three times mixing quantitative transfusion bottle, glycyl amide hydrochloride mixing quantitative transfusion bottle, glycine anhydride mixing quantitative transfusion bottle, Oxiracetam acid mixing 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, second Oxiracetam sample component mixing quantitative transfusion bottle, impurity reference substance mixing quantitative transfusion bottle forms, and 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 forms, liquid chromatograph connects discharging opening, the discharging opening of ethoxy Oxiracetam one-component quantitative transfusion bottle, the discharging opening of the second Oxiracetam sample three mixing quantitative transfusion bottles, the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle of the second Oxiracetam sample component mixing quantitative transfusion bottle respectively, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle connects 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 respectively, 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 of the second Oxiracetam sample three times mixing quantitative transfusion bottle connects 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 respectively, the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle connects 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 respectively, 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 discharging opening, the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the discharging opening of the second Oxiracetam samples weighing dispenser of the 3rd Oxiracetam samples weighing dispenser respectively, 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, the charging aperture of impurity reference substance mixed once quantitative transfusion bottle connects discharging opening, the discharging opening of glycyl amide hydrochloride mixing quantitative transfusion bottle, the discharging opening of glycine anhydride mixing quantitative transfusion bottle, the discharging opening of Oxiracetam acid mixing quantitative transfusion bottle, the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle respectively, the discharging opening that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle respectively, glycyl amide hydrochloride weighs dispenser, the discharging opening that the charging aperture of glycine anhydride mixing quantitative transfusion bottle connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle respectively, glycine anhydride weighs dispenser, the charging aperture of Oxiracetam acid mixing quantitative transfusion bottle connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle, the discharging opening of the sour dispenser of weighing of Oxiracetam respectively, the discharging opening that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle respectively, dehydroxylation Oxiracetam weighs dispenser, gas chromatograph connects the discharging opening of impurity reference substance mixing quantitative transfusion bottle, the discharging opening of the first Oxiracetam sample mix quantitative transfusion bottle respectively, the charging aperture of impurity reference substance mixing quantitative transfusion bottle connects discharging opening, 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 of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle respectively, the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle connects 4-chloroacetyl acetacetic ester respectively and to weigh the 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 4-chloro-3-hydroxyl ethyl butyrate respectively and to weigh the 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 to realize object of the present invention further, can also by the following technical solutions: described dispenser of weighing comprises support, support installs oblique delivery chute and weighing instrument respectively, bracing frame installed by weighing instrument, bracing frame fixedly mounts discharging barrel, and Open Side Down for discharging barrel, and discharging barrel arranges solenoid valve, the lower end of discharging barrel is positioned at the upper end of oblique delivery chute, and the lower end of oblique delivery chute is discharging opening.Described mixing quantitative transfusion bottle comprises mixing capacity bottle, and mixing capacity bottle is installed mixing constant-delivery pump, install stirrer bottom mixing capacity bottle, 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, one-component volumetric flask is installed one-component constant-delivery pump, 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 weigh accuracy and improve, error reduces, and improves the accuracy measured, and the measurement avoiding human factor to cause is slipped up, can qualitative and quantitative analysis, reproducible.The present invention also has advantage compact, cheap for manufacturing cost and easy to use simple for structure.
Accompanying drawing explanation
Fig. 1 is structural representation of the present invention; Fig. 2 is weigh in Fig. 1 dispenser and the structural representation mixing quantitative transfusion bottle; Fig. 3 is one-component quantitative transfusion bottle structure schematic diagram in Fig. 1.
Reference: 1 liquid chromatograph 214 - chlorine ethyl acetoacetate weighing machine 224 - chlorine - 3 - hydroxy ethyl butyrate weighing on the machine 23 first olathe temple sample weighing on the machine 24 second olathe temple sample weighing on the machine 25 f ammonia amide hydrochloride weighing on the machine 26 glycine anhydride weighing on 27 olathe jotham acid weighing on the machine and dehydroxylation olathe admitted heavy on the machine and the third olathe temple sample weighing 201 bracket 202 weighing device of machine 203 solenoid valve 204 feeding barrel 205 racks oblique conveying groove 3 a4-206 chloride mixed ethyl acetoacetate quantitative infusion bottle 3 b4 - chlorine - 3 - hydroxy ethyl butyrate combine quantitative infusion bottle 3 c first olathe temple samples mixed quantitative infusion bottle 3 d second olathe samples mixed quantitative infusion bottle 3 e firstTwo olathe temple samples two times combine quantitative infusion bottle 3 f the second olathe temple samples three quantitative infusion bottle 3 g f ammonia amide hydrochloride mix quantitative infusion bottle 3 h aminoacetic acid anhydride mixed infusion bottle 3 I olathe temple mixed acid quantitative infusion bottle 3 j dehydroxylation olathe temple combine quantitative infusion bottle 3 k impurity reference substance mixed secondary quantitative impurity reference substance a transfusion bottle 3 l combine quantitative infusion bottle of 3 m's second olathe temple sample components mix quantitative infusion bottle 3 n impurity reference substance mixed infusion bottle 301 volumetric flask 302 mixer 303 mix quantitative pump 41 blank solvent one-component infusion bottle of potassium dihydrogen phosphate as 42 mobile phase one-component quantitative infusion bottle 43 ethoxy olathe temple one-component quantitative infusion bottle 44 acetonitrile - water flow phase one-component quantitative infusion bottle 401 elemental volumetric flask elemental quantitative pump 5 402 gas chromatograph 6 olathe cheng fang temple samples.
Embodiment
Oxiracetam sample impurity detection device, as shown in Figure 1, comprises liquid chromatograph 1, to weigh dispenser, mixing quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph 5 and Oxiracetam sample holder 6, dispenser of weighing to be weighed dispenser 21 by 4-chloroacetyl acetacetic ester, 4-chloro-3-hydroxyl ethyl butyrate is weighed dispenser 22, first Oxiracetam samples weighing dispenser 23, second Oxiracetam samples weighing dispenser 24, glycyl amide hydrochloride is weighed dispenser 25, glycine anhydride is weighed dispenser 26, Oxiracetam acid is weighed dispenser 27, dehydroxylation Oxiracetam dispenser 28 of weighing forms, and mixing quantitative transfusion bottle is by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B, first Oxiracetam sample mix quantitative transfusion bottle 3C, second Oxiracetam sample mix quantitative transfusion bottle 3D, second Oxiracetam sample secondary mixing quantitative transfusion bottle 3E, second Oxiracetam sample three times mixing quantitative transfusion bottle 3F, 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, impurity reference substance secondary mixing quantitative transfusion bottle 3K, impurity reference substance mixed once quantitative transfusion bottle 3L, second Oxiracetam sample component mixing quantitative transfusion bottle 3M, impurity reference substance mixing quantitative transfusion bottle 3N forms, and 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 discharging opening, the discharging opening of ethoxy Oxiracetam one-component quantitative transfusion bottle 43, the discharging opening of the second Oxiracetam sample three mixing quantitative transfusion bottle 3F, the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle 3K of the second Oxiracetam sample component mixing quantitative transfusion bottle 3M respectively, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle 3M connects 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 respectively, 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 of the second Oxiracetam sample three times mixing quantitative transfusion bottle 3F connects 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 respectively, the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle 3K connects 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 respectively, 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 discharging opening, 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 of the 3rd Oxiracetam samples weighing dispenser 29 respectively, 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, the charging aperture of impurity reference substance mixed once quantitative transfusion bottle 3L connects 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, the discharging opening of Oxiracetam acid mixing quantitative transfusion bottle 3I, the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42 respectively, the discharging opening that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle 3G connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42 respectively, glycyl amide hydrochloride weighs dispenser 25, the discharging opening that the charging aperture of glycine anhydride mixing quantitative transfusion bottle 3H connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42 respectively, glycine anhydride weighs dispenser 26, the charging aperture of Oxiracetam acid mixing quantitative transfusion bottle 3I connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42, the discharging opening of the sour dispenser 27 of weighing of Oxiracetam respectively, the discharging opening that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle 3J connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle 42 respectively, dehydroxylation Oxiracetam weighs dispenser 28, gas chromatograph 5 connects 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 respectively, the charging aperture of impurity reference substance mixing quantitative transfusion bottle 3N connects discharging opening, 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 of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A respectively, the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A connects 4-chloroacetyl acetacetic ester respectively and to weigh the 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 4-chloro-3-hydroxyl ethyl butyrate respectively and to weigh the 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:
Check the content of 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:
Be filling agent with octadecylsilane chemically bonded silica, 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; Determined wavelength is 200nm; Column temperature is: room temperature.Precision measures mixing reference substance solution 20 μ l, and injection liquid chromatography, record chromatogram, 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:
The Oxiracetam sample got in the second Oxiracetam samples weighing dispenser 24 is accurately weighed, adds mobile phase and is 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, 100ml is diluted to mobile phase, shake up, precision measures 5ml again, puts in the second Oxiracetam sample three mixing quantitative transfusion bottle 3F, is diluted to 100ml with mobile phase, shake up, in contrast solution.
Impurity C, impurity A, impurity B, impurity E respectively about 10mg is taken respectively at glycyl amide hydrochloride dispenser 25, glycine anhydride dispenser 26, Oxiracetam acid dispenser 27, dehydroxylation Oxiracetam dispenser 28 of weighing of weighing of weighing of weighing, put 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 respectively, add mobile phase appropriate, jolting makes dissolving, 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, shake up.Precision measures 1ml and puts in impurity reference substance secondary mixing quantitative transfusion bottle 3K again, is diluted to 10ml, shakes up and obtain mixing reference substance solution with mobile phase.
Get contrast solution 20 μ l injection liquid chromatography 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 each 20 μ l of reference substance solution, respectively injection liquid chromatography, and record chromatogram is to 3 times of major component peak retention time.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.
Check the content of Oxiracetam ethyl ester (impurity D) in Oxiracetam sample, concrete operations are as follows:
Chromatographic column: C18 post Hydro-RP250 × 4.6mm, 4 μm
Mobile phase: acetonitrile-water (20:80) flow velocity: 0.6ml/min wavelength: 200nm
Sample size: 20 μ l
This product is got in right amount by the 3rd Oxiracetam samples weighing dispenser 29, accurately weighed, add to the second Oxiracetam sample component mixing quantitative transfusion bottle 3M, add mobile phase and dissolve and be quantitatively diluted to the solution about containing 1mg in every 1ml, as need testing solution; Separately get ethoxy Oxiracetam (impurity D) appropriate, accurately weighed, to dissolve with mobile phase and quantitatively dilution is made impure D0.5 μ g in every 1ml and inserted ethoxy Oxiracetam one-component quantitative transfusion bottle 43, product solution in contrast.Be filling agent with octadecylsilane chemically bonded silica; With acetonitrile-water (20:80) for mobile phase, determined wavelength is 200nm, flow velocity 0.6ml/min; Measure reference substance solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10% ~ 25% of full scale.Measure reference substance solution, each 20 μ l of need testing solution again, respectively injection liquid chromatography 1, record chromatogram is to 3 times of major component peak retention time.If any impurity D peak in the chromatogram of need testing solution, by external standard method with calculated by peak area, must not 0.05% be crossed.
Check the content of 4-chloroacetyl acetacetic ester (impurity F) and 4-chloro-3-hydroxyl ethyl butyrate (impurity G) in Oxiracetam sample, concrete operations are as follows:
Eliminate matrix effect test concrete operations as follows:
Solution preparation:
Impurity stock solution: take impurity F, each 25mg of impurity G by 4-chloroacetyl acetacetic ester dispenser 21,4-chloro-3-hydroxyl ethyl butyrate dispenser 22 of weighing of weighing, be added in 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle 3A, 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle 3B respectively, 100ml is diluted to by the blank solvent in blank solvent one-component quantitative transfusion bottle 41, shake up, to obtain final product.(0.25mg/ml)
Impurity reference substance solution: accurately measure each 1.0ml of impurity stock solution in 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 by blank solvent and dilute 10ml, shaking up, to obtain final product.(50mg/ml)
According to the chromatographic condition sample introduction respectively of regulation, impurity reference substance solution 2 pin, need testing solution respectively enter 2 pins, record chromatographic process.
Described dispenser of weighing is to measure the amount of solid matter and the equipment of injected volume function, as shown in Figure 2, comprise support 201, support 201 is installed respectively oblique delivery chute 206 and weighing instrument 202, weighing instrument 202 is installed bracing frame 205, bracing frame 205 fixedly mounts discharging barrel 204, Open Side Down for discharging barrel 204, discharging barrel 204 is arranged solenoid valve 203, the lower end of discharging barrel 204 is positioned at the upper end of oblique delivery chute 206, and the lower end of oblique delivery chute 206 is discharging opening.Discharging barrel 204 releases 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, and avoid the impact of weighing instrument in inventory dropping process, cause weighing device to quit work in advance, actual inventory is less than theoretical inventory, makes testing result inaccurate.
Described mixing quantitative transfusion bottle is for having the device of stirring and quantitative conveying function, as shown in Figure 2, comprise mixing capacity bottle 301, mixing capacity bottle 301 is installed mixing constant-delivery pump 303, stirrer 302 is installed bottom mixing capacity bottle 301, the bottleneck of mixing capacity bottle 301 is charging aperture, and mixing constant-delivery pump 303 output terminal is discharging opening.
Described simple substance quantitative transfusion bottle is for having the device of quantitative conveying function, as shown in Figure 3, comprise simple substance volumetric flask 401, simple substance volumetric flask 401 is installed simple substance constant-delivery pump 402, 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:
Check the content of 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:
Be filling agent with octadecylsilane chemically bonded silica, with 0.05mol/L potassium dihydrogen phosphate mobile phase (adjusting pH=3.0 with phosphoric acid); Flow velocity is 0.5ml/min; Determined wavelength is 200nm; Column temperature is: room temperature.Precision measures mixing reference substance solution 20 μ l, and injection liquid chromatography, record chromatogram, 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, put in 100ml measuring bottle, be diluted to scale with mobile phase, shake up, then precision measures 5ml, puts in 100ml measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution.
Take glycyl amide hydrochloride (impurity C), glycine anhydride (impurity A), Oxiracetam acid (impurity B), each about 10mg of dehydroxylation Oxiracetam (impurity E) respectively, accurately weighed, put in 100ml measuring bottle respectively, add mobile phase appropriate, jolting makes dissolving, 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, shake up.Precision measures 1ml and puts in 10ml volumetric flask again, is diluted to scale, shakes up and obtain mixing reference substance solution with mobile phase.
Get contrast solution 20 μ l injection liquid chromatography, 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 each 20 μ l of reference substance solution, respectively injection liquid chromatography, and record chromatogram is to 3 times of major component peak retention time.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 Method validation result
Check the content of impurity D (Oxiracetam ethyl ester) in Oxiracetam, concrete operations are as follows:
Chromatographic condition and test method
Chromatographic column: C18 post Hydro-RP250 × 4.6mm, 4 μm
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 about containing 1mg in every 1ml, as need testing solution; Separately get ethoxy Oxiracetam (impurity D) appropriate, accurately weighed, dissolve with mobile phase and quantitatively dilute and make impure D0.5 μ g in every 1ml, product solution in contrast.Be filling agent with octadecylsilane chemically bonded silica; With acetonitrile-water (20:80) for mobile phase, determined wavelength is 200nm, flow velocity 0.6ml/min; Measure reference substance solution 20 μ l injection liquid chromatography, regulate detection sensitivity, make the peak height of major component chromatographic peak be about 10% ~ 25% of full scale.Measure reference substance solution, each 20 μ l of need testing solution again, respectively injection liquid chromatography, record chromatogram is to 3 times of major component peak retention time.If any impurity D peak in the chromatogram of need testing solution, by external standard method with calculated by peak area, must not 0.05% be crossed.
Checking content comprises: specificity, system suitability, linear and scope, precision, accuracy and method durability.See the following form.
Table 2-2 impurity D inspection method the result summary
Check the content of 4-chloroacetyl acetacetic ester (impurity F) and 4-chloro-3-hydroxyl ethyl butyrate (impurity G) in Oxiracetam sample, concrete operations are as follows:
Chromatographic condition and experimental technique
General introduction: find in impurity F, G technique study process, the analytical test of Oxiracetam sample to impurity F has obvious interference, namely there is matrix effect, and we adopt standard addition method to eliminate matrix effect, carry out the Method validation of system.
Eliminate matrix effect test concrete operations as follows:
Solution preparation:
Impurity stock solution: take impurity F, each 25mg of impurity G, is accurately weighedly respectively diluted to scale by blank solvent in 100ml volumetric flask, shakes up, to obtain final product.(0.25mg/ml)
Impurity reference substance solution: accurately measure in each 1.0ml of impurity stock solution to 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, be diluted to scale with blank solvent ultrasonic dissolution, shake up, to obtain final product.(50mg/ml)
According to the chromatographic condition sample introduction respectively of regulation, impurity reference substance solution 2 pin, need testing solution respectively enter 2 pins, record chromatographic process.
Key starting 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 method validation scheme, we verify the detection method of company to impurity F, impurity G, the content of checking comprises: specificity, system suitability, quantitative limit and detectability, linearly, accuracy and method durability.Method validation result summary sees the following form:
Table 3.2.S.4.3.4-1 related substance (impurity F, impurity G) Method validation result summary
Technical scheme of the present invention is not restricted in the scope of embodiment of the present invention.The technology contents of the not detailed description of the present invention is known technology.
Claims (4)
1. Oxiracetam sample impurity detection device, is characterized in that: comprise liquid chromatograph (1), to weigh dispenser, mixing quantitative transfusion bottle, one-component quantitative transfusion bottle, gas chromatograph (5) and Oxiracetam sample holder (6), dispenser of weighing to be weighed dispenser (21) by 4-chloroacetyl acetacetic ester, 4-chloro-3-hydroxyl ethyl butyrate is weighed dispenser (22), first Oxiracetam samples weighing dispenser (23), second Oxiracetam samples weighing dispenser (24), glycyl amide hydrochloride is weighed dispenser (25), glycine anhydride is weighed dispenser (26), Oxiracetam acid is weighed dispenser (27), dehydroxylation Oxiracetam is weighed dispenser (28) composition, and mixing quantitative transfusion bottle is by 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A), 4-chloro-3-hydroxyl ethyl butyrate mixing quantitative transfusion bottle (3B), first Oxiracetam sample mix quantitative transfusion bottle (3C), second Oxiracetam sample mix quantitative transfusion bottle (3D), second Oxiracetam sample secondary mixing quantitative transfusion bottle (3E), second Oxiracetam sample three times mixing quantitative transfusion bottle (3F), 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), impurity reference substance secondary mixing quantitative transfusion bottle (3K), impurity reference substance mixed once quantitative transfusion bottle (3L), second Oxiracetam sample component mixing quantitative transfusion bottle (3M), impurity reference substance mixing quantitative transfusion bottle (3N) forms, and 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 discharging opening, the discharging opening of ethoxy Oxiracetam one-component quantitative transfusion bottle (43), the discharging opening of the second Oxiracetam sample three mixing quantitative transfusion bottle (3F), the discharging opening of impurity reference substance secondary mixing quantitative transfusion bottle (3K) of the second Oxiracetam sample component mixing quantitative transfusion bottle (3M) respectively, the charging aperture of the second Oxiracetam sample component mixing quantitative transfusion bottle (3M) connects 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) respectively, 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 of the second Oxiracetam sample three times mixing quantitative transfusion bottle (3F) connects 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) respectively, the charging aperture of impurity reference substance secondary mixing quantitative transfusion bottle (3K) connects 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) respectively, 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 discharging opening, 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) of the 3rd Oxiracetam samples weighing dispenser (29) respectively, 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), the charging aperture of impurity reference substance mixed once quantitative transfusion bottle (3L) connects 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), the discharging opening of Oxiracetam acid mixing quantitative transfusion bottle (3I), the discharging opening of dehydroxylation Oxiracetam mixing quantitative transfusion bottle (3J) of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) respectively, the discharging opening that the charging aperture of glycyl amide hydrochloride mixing quantitative transfusion bottle (3G) connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) respectively, glycyl amide hydrochloride weighs dispenser (25), the discharging opening that the charging aperture of glycine anhydride mixing quantitative transfusion bottle (3H) connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) respectively, glycine anhydride weighs dispenser (26), the discharging opening that charging aperture connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) respectively, weighed in dispenser (27) in Oxiracetam acid of Oxiracetam acid mixing quantitative transfusion bottle (3I), the discharging opening that the charging aperture of dehydroxylation Oxiracetam mixing quantitative transfusion bottle (3J) connects the discharging opening of potassium dihydrogen phosphate mobile phase one-component quantitative transfusion bottle (42) respectively, dehydroxylation Oxiracetam weighs dispenser (28), gas chromatograph (5) connects 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) respectively, the charging aperture of impurity reference substance mixing quantitative transfusion bottle (3N) connects discharging opening, 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) of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A) respectively, the charging aperture of 4-chloroacetyl acetacetic ester mixing quantitative transfusion bottle (3A) connects 4-chloroacetyl acetacetic ester respectively and to weigh the 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 4-chloro-3-hydroxyl ethyl butyrate respectively and to weigh the 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. Oxiracetam sample impurity detection device according to claim 1, it is characterized in that: described dispenser of weighing comprises support (201), support (201) is installed respectively oblique delivery chute (206) and weighing instrument (202), weighing instrument (202) is installed bracing frame (205), bracing frame (205) fixedly mounts discharging barrel (204), Open Side Down for discharging barrel (204), discharging barrel (204) is arranged solenoid valve (203), the lower end of discharging barrel (204) is positioned at the upper end of oblique delivery chute (206), the lower end of oblique delivery chute (206) is discharging opening.
3. Oxiracetam sample impurity detection device according to claim 1, it is characterized in that: described mixing quantitative transfusion bottle comprises mixing capacity bottle (301), mixing capacity bottle (301) is upper installs mixing 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. Oxiracetam 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), one-component volumetric flask (401) is upper installs one-component constant-delivery pump (402), 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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| 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 |
| 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 |