CN107576734A - A kind of detection method of faropenem impurity - Google Patents
A kind of detection method of faropenem impurity Download PDFInfo
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- CN107576734A CN107576734A CN201710584245.7A CN201710584245A CN107576734A CN 107576734 A CN107576734 A CN 107576734A CN 201710584245 A CN201710584245 A CN 201710584245A CN 107576734 A CN107576734 A CN 107576734A
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Abstract
The invention discloses a kind of detection method of faropenem impurity, it comprises the following steps：The stationary phase of high performance liquid chromatograph is 100% porous graphite, mobile phase 10mmol/l formic acid aqueous ammoniums methanol=45:55~55:45, column temperature is 30 DEG C~40 DEG C, and Detection wavelength is 218nm~222nm.Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, records chromatogram.The value for calculating reference substance solution concentration is X and corresponding peak area value is Y, carries out linear fit, draws equation of linear regression, the intermediate C range of linearity is 0.38 ~ 5.25 μ g/ml, and the range of linearity of faropenem is 0.38 ~ 28.92 μ g/ml.For the present invention using the intermediate C of back in high performance liquid chromatography separation faropenem, separative efficiency is high, analyze speed is fast, detection sensitivity is high, by detecting the content of intermediate C in faropenem, can more preferably control the quality of faropenem.
Description
Technical field
The present invention relates to high-efficient liquid phase chromatogram technology field, and in particular to a kind of high effective liquid chromatography for measuring faropenem
Impurities intermediate C method.
Background technology
Faropenem sodium is developed by Japanese Suntory companies, in a kind of penems antibiotics of listing in 1997, tool
There are has a broad antifungal spectrum, antibacterial activity strong.It is stable to beta-lactamase, to extended spectrumβ-lactamase producing strains, citrobacter, intestines
Coccus has the characteristics of good action, and faropenem is handled by faropenem through SODIUM PERCARBONATE, sodium acid carbonate or 2 ethyl hexanoic acid sodium
Obtain.Therefore faropenem is the key intermediate of Faropenem sodium production, and faropenem life passes through hydrogenation reaction by intermediate C
Be made, due to had in faropenem when hydrogenation reaction is not thorough moiety intermediate C residual, not only influence yield, can also into
The quality of product Faropenem sodium impacts.Detected for this by rational means and control the amount of intermediate C in faropenem
Have important practical significance.
The content of the invention
The purpose of the present invention is to establish a kind of detection method of faropenem impurity, can preferably control faropenem
Quality, preferably intermediate C that may be present in faropenem is detected.
The technical scheme is that：Intermediate C method in high performance liquid chromatography Luo Peinan, it includes as follows
Step：
The preparation of system testing liquid：Weigh intermediate C reference substances to put in measuring bottle, intermediate C molecular structures are shown in Fig. 1, separately weigh
Faropenem reference substance is appropriate, and faropenem molecular structure is shown in Fig. 2, add flowing phased soln and dilute be made in every 1ml containing about
μ g of intermediate C 3.75, the μ g of faropenem 25 mixed solution solution, as system testing liquid；
It is prepared by reference substance solution：It is appropriate that precision weighs faropenem reference substance, accurately weighed, with flowing phased soln and uses dilution
Dilution is made every 1mL and produced containing about 25 μ g solution；
It is prepared by need testing solution：Precision weighs that this product is put in volumetric flask in right amount plus flowing phased soln and diluting is made in every 1ml about
The solution of the 2.5mg containing faropenem, as need testing solution；
The preparation of blank solution：Mobile phase；
Measure：The stationary phase of high performance liquid chromatograph is 100% porous graphite,
Mobile phase is 0.1mol/l Ammonium formate buffers, 10mmol/l formic acid aqueous ammonium-methanol=50:50, column temperature is 35 DEG C,
Detection wavelength is 220nm.Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, records color
Spectrogram, read data；
Calculate the equation of linear regression of value and the corresponding peak area value of reference substance solution concentration, coefficient correlation and should be not less than
0.99, reference substance solution peak shape is symmetrical, and theoretical cam curve is with faropenem more than 2000；In every gram of faropenem intermediate, in
Mesosome C total amounts must not exceed 50mg.
Brief description of the drawings：Fig. 1 is intermediate C molecular structural formulas；
Fig. 2 is faropenem molecular structural formula；
Fig. 3 is faropenem system testing liquid chromatography figure；
Fig. 4 intermediate C peak areas and concentration curve graph of a relation；
Fig. 5 faropenems peak area and concentration curve graph of a relation.
Form is described in further details to present disclosure again by the following examples, but not the present invention should not be interpreted as with regard to this
Following examples are only limitted in above-mentioned subject area.Under the premise of the above-mentioned technology of the present invention is not departed from, according to the common skill in this area
The modification of corresponding replacement or change that art knowledge and customary means are made, is included in the present invention.
The determination of the chromatographic column of embodiment 1 and mobile phase
The preparation of system testing liquid：Weigh intermediate C reference substances to put in measuring bottle, intermediate C molecular structures are shown in figure, separately weigh method
Luo Peinan reference substances are appropriate, and faropenem molecular structure is shown in Fig. 2, add flowing phased soln and dilution is made in every 1ml containing about in
μ g of mesosome C 3.75, the μ g of faropenem 25 mixed solution solution, as system testing liquid；
Chromatographic column：Waters Xterra RP, 150mm × 4.6mm × 3.50 μm；Wavelength：220nm；Flow velocity：1.0ml/min；Enter
Sample amount：20μl；Column temperature：35℃；Mobile phase：5mg/l ammonium acetate buffers：Acetonitrile=90:10；
Take system testing liquid to inject liquid chromatograph, as a result show one chromatographic peak of appearance in chromatogram.
Conclusion：This method retention time faropenem and intermediate C can not be separated
The determination of the chromatographic column of embodiment 2 and mobile phase
The preparation of system testing liquid, with embodiment 1.
Chromatographic column：Waters Xterra RP, 150mm × 4.6mm × 3.50 μm；Wavelength：220nm；Flow velocity：1.0ml/
min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffer 5mg/l ammonium acetate buffers：Acetonitrile=
50:50；
Take system testing liquid to inject liquid chromatograph, as a result show that one chromatographic peak of appearance, retention time are in chromatogram
3.53min。
Conclusion：Faropenem retention time is too short, and number of theoretical plate does not reach requirement.
The determination of the chromatographic column of embodiment 3 and mobile phase
The preparation of system testing liquid, with embodiment 1.
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Ripple
It is long：220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=80:20；
Take system testing liquid to inject liquid chromatograph, two chromatographic peaks of appearance in chromatogram are as a result shown, when faropenem retains
Between be 2.64min, intermediate C retention times are 2.51min.
Conclusion：Faropenem and intermediate C are not completely separated, and separating degree does not reach requirement.
The system suitability of experimental example 4 is tested
The preparation of system testing liquid, with embodiment 1
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Wavelength：
220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=50:50.
Take system testing liquid to inject liquid chromatograph, as a result show two chromatographic peaks of appearance in chromatogram, faropenem is protected
It is 4.72min to stay the time, and intermediate C retention times are 3.79min, as a result see Fig. 3.
Conclusion：Faropenem and intermediate C can be kept completely separate, and separating degree reaches and met the requirements.
Experimental example 5 is linear and scope
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Wavelength：
220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=50:50；
Take the intermediate C of various concentrations and faropenem solution injecting chromatograph result is shown in Fig. 4,5 and table 1,2.
The intermediate C peak areas of table 1 and concentration curve relation table
| Concentration ug/ml | Average peak area | Peak area RSD |
| 5.3 | 61224 | 0.47% |
| 4.7 | 52041 | 0.86% |
| 3.8 | 42662 | 1.86% |
| 1.9 | 21635 | 2.38% |
| 0.9 | 12405 | 2.95% |
| 0.4 | 4590 | 0.03% |
The faropenem peak area of table 2 and concentration curve relation table
| Concentration ug/ml | Average peak area | Peak area RSD |
| 28.9 | 367156 | 0.78% |
| 24.1 | 303646 | 0.22% |
| 9.6 | 123123 | 2.01% |
| 5.6 | 64920 | 1.28% |
| 4.7 | 56917 | 0.89% |
| 3.8 | 45603 | 1.99% |
| 1.9 | 22596 | 2.13% |
| 0.9 | 13280 | 1.45% |
| 0.38 | 5657 | 0.42% |
Conclusion：Intermediate C y=R=0.999 of 13147.8 x+885.5, faropenem 0.4 in the range of 0.4 ~ 5.3 μ g/ml
X -1252.0 R=0.9998 of y in the range of ~ 28.92 μ g/ml=12692.8, each peak peak area is with concentration in good linear pass
System.
The test limit of experimental example 6 and quantitative limit
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Wavelength：
220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=50:50；
Test limit and quantitative limit determine that the signal and the signal of blank space measured are compared according to by signal to noise ratio method
Compared with calculating the least concentration or percentage that can be reliably detected.
It is test limit as S/N ≈ 3, is quantitative limit as S/N ≈ 10.
Conclusion：Intermediate C detections are limited to 0.0814 μ g/ml, and faropenem detection is limited to 0.2088 μ g/ml.
The precision test of experimental example 7
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Wavelength：
220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=50:50；
Precision claim faropenem reference substance it is appropriate, it is accurately weighed, with flowing phased soln and with diluted be made every 1mL containing about
25 μ g solution, continuously enter the pin of reference substance solution 6；Record chromatogram.The RSD of average peak area is 1.7%
Conclusion：The sample introduction precision of this method is good.
The replica test of experimental example 8
Chromatographic column：Thermo Hypercarb, 150mm × 4.6mm × 3.00 μm, 100% porous graphite packing；Wavelength：
220nm；Flow velocity：1.0 ml/min；Sample size：20μl；Column temperature：35℃；Mobile phase：0.1mol/l Ammonium formate buffers,
10mmol/l formic acid aqueous ammonium-methanol=50:50；
Repeatability is that each pin of solution sample introduction 1 the results are shown in Table 3 come what is verified by preparing 6 sample solutions and being tested.
The faropenem reperformance test result table of table 3
| Sequence number | Concentration | Intermediate C | Unknown impuritie | Total impurities |
| 1 | 2.597 | 0.13% | Do not detect | 0.13% |
| 2 | 2.547 | 0.13% | Do not detect | 0.13% |
| 3 | 2.438 | 0.12% | Do not detect | 0.12% |
| 4 | 2.502 | 0.12% | Do not detect | 0.12% |
| 5 | 2.51 | 0.13% | Do not detect | 0.13% |
| 6 | 2.512 | 0.13% | Do not detect | 0.13% |
| RSD | N/A | 2.97% | N/A | 2.97% |
Conclusion：Each impurity peak number of the content of 6 measurement results more than test limit is consistent, and the absolute deviation of impurity sum must not
More than the 50% of quality standard, upper table result shows that the repeatability of this method is good.
The liquid phase chromatogram condition durability of experimental example 9, mobile phase ratio change the influence to separating degree.
Flow phase change 1：0.1mol/l Ammonium formate buffers, 10mmol/l formic acid aqueous ammonium-methanol=45:55；Flowing
Phase change 2：0.1mol/l Ammonium formate buffers, 10mmol/l formic acid aqueous ammonium-methanol=55:45；Original mobile phase ratio：
0.1mol/l Ammonium formate buffers, 10mmol/l formic acid aqueous ammonium-methanol=50:50, test result is shown in Table 4.
The mobile phase ratio of table 4 changes test result contrast table
| Flow phase change | Flow phase change 1 | Flow phase change 2 | Original mobile phase ratio |
| Separating degree | 4.38 | 3.97 | 4.17 |
Conclusion：By being determined under above-mentioned chromatographic condition, it can reach required separating effect, it is seen that mobile phase ratio is in conditions permit
In the range of change on impurity separation do not influence.
The liquid phase chromatogram condition durability of experimental example 10, column temperature change the influence to separating degree
Column temperature is become and turned to：Change 1：30 DEG C, change:2：40 DEG C, column temperature：35 DEG C, test result is shown in Table 5.
The column temperature of table 5 changes test result contrast table
| Column temperature | 30℃ | 40℃ | 35℃ |
| Separating degree | 4.10 | 4.27 | 4.17 |
Conclusion：By being determined under above-mentioned chromatographic condition, it can reach required separating effect, it is seen that column temperature is in 30 DEG C~40 DEG C scopes
The change of interior chromatographic condition does not influence on impurity separation.
The liquid phase chromatogram condition durability of experimental example 11, influence of the change in flow to separating degree
It is by change in flow：Change in flow 1：Flow velocity 0.9ml/min, change in flow 2：Flow velocity 1.1ml/min, original flow velocity：Stream
Fast 1.0ml/min, test result are shown in Table 6.
The change in flow test result contrast table of table 6
| Flow velocity | 0.9ml/min | 1.1ml/min | 1.0ml/min（Original flow velocity） |
| Separating degree | 4.15 | 4.20 | 4.17 |
Conclusion：By being determined under above-mentioned chromatographic condition, can reach required separating effect, it is seen that flow velocity 0.9ml/min~
The change of chromatographic condition does not influence on impurity separation in the range of 1.1ml/min.
The liquid phase chromatogram condition durability of experimental example 17, Detection wavelength change the influence to separating degree
Detection wavelength is become and turned to：Detection wavelength 1：218nm, Detection wavelength 2:222nm, original wavelength：220nm, test result
It is shown in Table 7.
The Detection wavelength of table 7 changes test result contrast table
| Wavelength | 218nm | 222nm | 220nm |
| Separating degree | 4.17 | 4.18 | 4.17 |
Conclusion：By being determined under above-mentioned chromatographic condition, it can reach required separating effect, it is seen that wavelength is in 218nm~220nm models
Enclose the change of interior chromatographic condition does not influence on impurity separation.
Claims (4)
1. intermediate C method in high performance liquid chromatography Luo Peinan, it is characterised in that it comprises the following steps：
The preparation of system testing liquid：Weigh intermediate C reference substances, put in measuring bottle, it is appropriate separately to weigh faropenem reference substance, adds stream
Dynamic phased soln and diluting is made in every 1ml containing about μ g of intermediate C 3.75, the μ g of faropenem 25 mixed solution solution, as being
Unified test test solution；
It is prepared by reference substance solution：It is appropriate that precision weighs faropenem reference substance, accurately weighed, with flowing phased soln and uses dilution
Dilution is made every 1mL and produced containing about 25 μ g solution；
It is prepared by need testing solution：Precision weighs that this product is put in volumetric flask in right amount plus flowing phased soln and diluting is made in every 1ml about
The solution of the 2.5mg containing faropenem, as need testing solution；
The preparation of blank solution：Mobile phase；
Measure：The stationary phase of high performance liquid chromatograph is 100% porous graphite, and mobile phase buffers for 0.1mol/l ammonium formates
Liquid, 10mmol/l formic acid aqueous ammonium-methanol=45:55~55:45, column temperature be 30 DEG C~40 DEG C, Detection wavelength be 218nm~
222nm；
Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, chromatogram is recorded, reads number
According to；Calculate the equation of linear regression of value and the corresponding peak area value of reference substance solution concentration, coefficient correlation and 0.99 should be not less than,
Reference substance solution peak shape is symmetrical, and theoretical cam curve is with faropenem more than 2000；In every gram of faropenem intermediate, intermediate C
Total amount must not exceed 50mg.
2. intermediate C method in the high performance liquid chromatography Luo Peinan described in claim 1, it is characterised in that it is wrapped
Include following steps：
The preparation of system testing liquid：Weigh intermediate C reference substances, put in measuring bottle, it is appropriate separately to weigh faropenem reference substance, adds stream
Dynamic phased soln and diluting is made in every 1ml containing about μ g of intermediate C 3.75, the μ g of faropenem 25 mixed solution solution, as being
Unified test test solution；
It is prepared by reference substance solution：It is appropriate that precision weighs faropenem reference substance, accurately weighed, with flowing phased soln and uses dilution
Dilution is made every 1mL and produced containing about 25 μ g solution；
It is prepared by need testing solution：Precision weighs that this product is put in volumetric flask in right amount plus flowing phased soln and diluting is made in every 1ml about
The solution of the 2.5mg containing faropenem, as need testing solution；
The preparation of blank solution：Mobile phase；
Measure：The stationary phase of high performance liquid chromatograph is 100% porous graphite, and mobile phase buffers for 0.1mol/l ammonium formates
Liquid, 10mmol/l formic acid aqueous ammonium-methanol=50:50, column temperature is 35 DEG C, Detection wavelength 220nm；
Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, chromatogram is recorded, reads number
According to；Calculate the equation of linear regression of value and the corresponding peak area value of reference substance solution concentration, coefficient correlation and 0.99 should be not less than,
Reference substance solution peak shape is symmetrical, and theoretical cam curve is with faropenem more than 2000；In every gram of faropenem intermediate, intermediate C
Total amount must not exceed 50mg.
3. intermediate C method in the high performance liquid chromatography Luo Peinan described in claim 1, it is characterised in that it is wrapped
Include following steps：
The preparation of system testing liquid：Weigh intermediate C reference substances, put in measuring bottle, it is appropriate separately to weigh faropenem reference substance, adds stream
Dynamic phased soln and diluting is made in every 1ml containing about μ g of intermediate C 3.75, the μ g of faropenem 25 mixed solution solution, as being
Unified test test solution；
It is prepared by reference substance solution：It is appropriate that precision weighs faropenem reference substance, accurately weighed, with flowing phased soln and uses dilution
Dilution is made every 1mL and produced containing about 25 μ g solution；
It is prepared by need testing solution：Precision weighs that this product is put in volumetric flask in right amount plus flowing phased soln and diluting is made in every 1ml about
The solution of the 2.5mg containing faropenem, as need testing solution；
The preparation of blank solution：Mobile phase；
Measure：The stationary phase of high performance liquid chromatograph is 100% porous graphite, and mobile phase buffers for 0.1mol/l ammonium formates
Liquid, 10mmol/l formic acid aqueous ammonium-methanol=45:55, column temperature is 30 DEG C, Detection wavelength 218nm；
Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, chromatogram is recorded, reads number
According to；Calculate the equation of linear regression of value and the corresponding peak area value of reference substance solution concentration, coefficient correlation and 0.99 should be not less than,
Reference substance solution peak shape is symmetrical, and theoretical cam curve is with faropenem more than 2000；In every gram of faropenem intermediate, intermediate C
Total amount must not exceed 50mg.
4. intermediate C method in the high performance liquid chromatography Luo Peinan described in claim 1, it is characterised in that it is wrapped
Include following steps：
The preparation of system testing liquid：Weigh intermediate C reference substances, put in measuring bottle, it is appropriate separately to weigh faropenem reference substance, adds stream
Dynamic phased soln and diluting is made in every 1ml containing about μ g of intermediate C 3.75, the μ g of faropenem 25 mixed solution solution, as being
Unified test test solution；
It is prepared by reference substance solution：It is appropriate that precision weighs faropenem reference substance, accurately weighed, with flowing phased soln and uses dilution
Dilution is made every 1mL and produced containing about 25 μ g solution；
It is prepared by need testing solution：Precision weighs that this product is put in volumetric flask in right amount plus flowing phased soln and diluting is made in every 1ml about
The solution of the 2.5mg containing faropenem, as need testing solution；
The preparation of blank solution：Mobile phase；
Measure：The stationary phase of high performance liquid chromatograph is 100% porous graphite, and mobile phase buffers for 0.1mol/l ammonium formates
Liquid, 10mmol/l formic acid aqueous ammonium-methanol=55:45, column temperature is 40 DEG C, Detection wavelength 222nm；
Each 20 μ l injections liquid chromatograph of reference substance solution, need testing solution, blank solution is drawn, chromatogram is recorded, reads number
According to；Calculate the equation of linear regression of value and the corresponding peak area value of reference substance solution concentration, coefficient correlation and 0.99 should be not less than,
Reference substance solution peak shape is symmetrical, and theoretical cam curve is with faropenem more than 2000；In every gram of faropenem intermediate, intermediate C
Total amount must not exceed 50mg.
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