CN108120784A - A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity - Google Patents
A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity Download PDFInfo
- Publication number
- CN108120784A CN108120784A CN201711479032.4A CN201711479032A CN108120784A CN 108120784 A CN108120784 A CN 108120784A CN 201711479032 A CN201711479032 A CN 201711479032A CN 108120784 A CN108120784 A CN 108120784A
- Authority
- CN
- China
- Prior art keywords
- impurity
- mobile phase
- fosaprepitant
- double
- detection method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
Abstract
The invention discloses a kind of double meglumine raw materials of Fosaprepitant or the detection methods of preparation and its impurity, it is detected analysis using high performance liquid chromatography to the double meglumine raw materials of Fosaprepitant or formulation samples solution, the stationary phase of chromatographic column used in detection is octadecylsilane chemically bonded silica, mobile phase includes mobile phase A and Mobile phase B, wherein mobile phase A includes phosphate buffer, Mobile phase B includes acetonitrile, and gradient elution is carried out to the double meglumine raw materials of Fosaprepitant or formulation samples solution in 0 ~ 50min by mobile phase A and Mobile phase B.The present invention is easy to operate, is easy to control, and testing cost is low, the content of impurity and Accurate Determining impurity in the double meglumine drugs of energy effective monitoring Fosaprepitant.
Description
Technical field
The invention belongs to drug and its technical fields of the chemical detection of impurity.
Background technology
Double meglumine (the fosaprepitantdimeglumine trade names of Fosaprepitant：EMEND), the entitled 2-S- of chemistry
(1-R-3,5- trifluoromethyls ethyl) -3-S-4- fluorophenyls -4-（Three nitrogen of 1- benzyl phosphoryl -3- oxygen -4- hydrogen -1,2,4-
Azoles）The double meglumine salts of-methyl morpholine（Molecular formula：C23H22F7N4O6P•2C7H17NO5）, it is by Merck Pharmaceuticals Co., Ltd
One kind of (Merck KGaA) exploitation is referred to as people's Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2/neurokinin 1 (NK-1) high selectivity affinity receptor blocking agent, main
It will be by the way that the novel mechanism of action of brain nausea and vomiting signal be blocked to play a role.Aprepitant to serotonin (5-HT3),
Dopamine and glucocorticoid receptor are atomic weak or without compatibility, for treating the nausea and vomiting and postoperative nausea of chemotherapy induction
And vomiting.
Due to being limited by production technology and controlled level, in the double meglumine products of Fosaprepitant for producing gained, often
There are plurality of impurities, for example, [3- [[(2R, 3S) -2- [(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3-
(4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphate dibenzyl ester, [3-
[[(2R, 3S) -2- [(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- first
Base] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphoric acid-mono- benzyl ester, 5- [[(2R, 3S) -2- [(1R) -1- [3,5- bis-
(trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -4- morpholines] methyl] -1,2- dihydro -3H-1,2,4- triazoles -3-
Ketone etc. seriously affects the double product qualities of meglumine of Fosaprepitant and the drug safety of patient.
However, there is not the detection method for the double meglumines of Fosaprepitant and above-mentioned plurality of impurities in the prior art.
The content of the invention
It is an object of the invention to provide a kind of double meglumine raw materials of Fosaprepitant or the detection methods of preparation and its impurity.
Technical scheme is as follows：A kind of double meglumine raw materials of Fosaprepitant or the detection side of preparation and its impurity
Method is detected the double meglumine raw material of Fosaprepitant or formulation samples solution analysis, used in detection using high performance liquid chromatography
The stationary phase of chromatographic column is octadecylsilane chemically bonded silica, and mobile phase includes mobile phase A and Mobile phase B, wherein mobile phase A bag
Phosphate buffer is included, Mobile phase B includes acetonitrile, interior to the double meglumines of Fosaprepitant in 0 ~ 50min by mobile phase A and Mobile phase B
Raw material or formulation samples solution carry out gradient elution；Detection wavelength 200-300nm；According to high performance liquid chromatography result to object
Matter carries out qualitative or quantitative；The target substance includes the double meglumines of Fosaprepitant；Reference substance is corresponding with target substance.
Using the technical solution, the double meglumines of Fosaprepitant with 7 kinds of impurity such as its impurity A ~ G can be efficiently separated, arranged
Except the influence that above-mentioned impurity qualitatively or quantitatively detects the double meglumines of Fosaprepitant in HPLC detection process, for more accurately
Ground realization provides new method to the detection of main ingredient ingredient.
The structure of impurity A ~ G is as follows：
The entitled phosphate dibenzyl ester of impurity A；
The entitled dibenzyl ester ammonium phosphate of impurity B；
The entitled triphen oxygen phosphorus of impurity C；
Entitled [the 3- [[(2 of impurity DR,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4-
Fluorophenyl)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphate dibenzyl ester；
Entitled [the 3- [[(2 of impurity ER,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4-
Fluorophenyl)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphoric acid-mono- benzyl ester；
The entitled 5- [[(2 of impurity FR,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorine
Phenyl) -4- morpholines] methyl] -1,2- dihydro -3H-1,2,4- triazole -3- ketone；
Four benzyl ester of entitled pyrophosphoric acid of impurity G.
Certainly, based on above-mentioned chromatographic isolation effect, except that can realize to the qualitative of main ingredient ingredient in above-mentioned detection method
Or quantitative control, while can also realize the qualitative or quantitative detection to above-mentioned each impurity.Therefore, further, the target
Substance further includes the one or more in following impurity：Phosphate dibenzyl ester, dibenzyl ammonium phosphate, triphen oxygen phosphorus, [3- [[(2R,3S)-
2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,
5- dihydros-[1,2,4] triazol-1-yl]-phosphate dibenzyl ester, [3- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl)
Phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphorus
Acid-mono- benzyl ester, 5- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -
4- morpholines] methyl] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, four benzyl ester of pyrophosphoric acid.
Heretofore described " reference substance is corresponding with target substance " refers to choose the compound according to target substance opposite
The reference substance answered, if target substance is the double meglumines of Fosaprepitant, then corresponding is exactly the double meglumine reference substances of Fosaprepitant；If
Target substance is phosphate dibenzyl ester, then corresponding is exactly phosphate dibenzyl ester reference substance.
Heretofore described reference substance is satisfied by chromatographic grade purity requirement.
In addition, the present invention also provides the detection methods of impurity in a kind of double meglumine raw materials of Fosaprepitant or preparation, make
Analysis, chromatographic column used in detection are detected to the double meglumine raw materials of Fosaprepitant or formulation samples solution with high performance liquid chromatography
Stationary phase for octadecylsilane chemically bonded silica, mobile phase includes mobile phase A and Mobile phase B, and wherein mobile phase A includes phosphoric acid
Buffer solution, Mobile phase B include acetonitrile, gradient elution；Detection wavelength 200-300nm；According to high performance liquid chromatography result to impurity
It carries out qualitative or quantitative.
The impurity includes phosphate dibenzyl ester, dibenzyl ammonium phosphate, triphen oxygen phosphorus, [3- [[(2R,3S)-2-[(1R)-1-[3,
5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydro-[1,2,4]
Triazol-1-yl]-phosphate dibenzyl ester, [3- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -
3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphoric acid-mono- benzyl ester, 5-
[[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -4- morpholines] first
Base] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, the one or more in four benzyl ester of pyrophosphoric acid；Reference substance and impurity phase pair
It should.
Using the technical solution, the one or more in the above-mentioned impurity A ~ G of the double meglumines of Fosaprepitant can be effectively detected.
It, can be separately or concurrently to the double meglumine raw materials of Fosaprepitant or preparation sample in a specific embodiment of the invention
One or more in product solution in impurity A ~ G are qualitatively or quantitatively detected, and the separating degree of each impurity peaks is good.
Qualitative detection in the present invention can be carried out using conventional method, such as reference substance is selected to be carried out pair by external standard method
After should analyzing or each ingredient being separated by HPLC, carry out qualitative analysis, such as mass spectrum, thin by general survey means
Layer, ultraviolet etc..
It is quantitatively detected in the present invention, the conventional methods such as external standard method, area normalization method can be used to carry out content calculation.
In quantitative analysis, if using external standard method, make standard curve using conventional means and calculated；But fixed
Property analysis when, then need not make standard curve, can be judged by retention time.
In a specific embodiment of the invention, the condition of the gradient elution of above-mentioned each detection method is：
Wherein, in the phosphate buffer containing dihydrogen phosphate ions and phosphate anion, pH for 2 ~ 3 further,
The phosphate buffer is ammonium dihydrogen phosphate-phosphate buffer.
In a specific embodiment of the invention, biphosphate ammonium concentration is 20 ~ 50mM, preferably 50 mM.
In a specific embodiment of the invention, pH of buffer 2.2.
Contain acetonitrile in Mobile phase B, can be pure acetonitrile or the mixing containing acetonitrile He other auxiliary agents simultaneously
Liquid, these auxiliary agents perhaps can help acetonitrile to improve appearance effect, and in a specific embodiment of the invention, Mobile phase B is selected from
Acetonitrile.
In a specific embodiment of the invention, the chromatogram column length is 250nm, internal diameter 4.6mm, and packing material size is
5μm。
Selection can be adjusted by conventional means in foregoing scope of disclosure in Detection wavelength of the present invention.It is finding
During best detection wavelength, the modes such as the matching used all band scanning of ultraviolet spectrophotometry, HPLC can be used to carry out, then matched somebody with somebody
Close the detection result of HPLC detectors（Solvent is such as avoided to disturb）, suitable Detection wavelength is found using routine techniques mandate.
In a specific embodiment of the invention, Detection wavelength is selected from 210-220nm, such as in 215nm.
In the present invention, the parameters such as column temperature, flow velocity, sample size can select in Typical ranges.
The column temperature of the chromatographic column can be selected from 20 DEG C~40 DEG C, such as 20,25,30,35,40 DEG C etc..
The flow velocity of the mobile phase be 0.8ml/min~1.2ml/min, such as 1.0ml/min etc..
The sampling volume is the μ l of 10 μ l~50, such as sampling volume is 10,20 μ l etc..
In the present invention, the double meglumine raw materials of Fosaprepitant or formulation samples solution are by Fosaprepitant raw material or formulation samples
It is dissolved in acetonitrile or acetonitrile-water mixed liquor is prepared；Further, in acetonitrile-water mixed liquor, acetonitrile volume ratio more than 40%,
It can be further selected from 50%.
In the present invention, reference substance is prepared into reference substance solution using acetonitrile or acetonitrile-water mixed liquor as solvent；Acetonitrile-water mixes
It closes in liquid, acetonitrile volume ratio can be further selected from 50% more than 40%.The double meglumine of Fosaprepitant and its impurity A in the present invention ~
Separating degree between each chromatographic peaks of G is high, noiseless between each other, can realize simultaneously to Fosaprepitant double meglumine, impurity As ~ G
Accurate detection, such as tested in one embodiment of the invention through control, the separating degree of impurity A and impurity B is 27.567；It is miscellaneous
Matter B and the separating degree of the double meglumines of Fosaprepitant are 4.544；The double meglumines of Fosaprepitant and the separating degree of impurity C are 4.08；It is miscellaneous
The separating degree of matter C and impurity E is 26.961；The separating degree of impurity E and impurity F is 16.455；The separating degree of impurity F and impurity G
For 33.266；The separating degree of impurity G and impurity D is 19.741.
Further with standard control solution by external standard method, with calculated by peak area or according to peak area and concentration it
Between standard curve calculate, the impurity content in the double meglumine samples of accurate Fosaprepitant can be obtained, as of the invention
It detects and obtains in standard curve and range of linearity embodiment：Impurity A is in the range of the μ g/ml of 0.0409 μ g/ml~2.0437, linearly
Equation is y=43803.6818x+716.2411 (R=0.9996), and peak area is in good linear relationship with measured concentration；It is miscellaneous
Matter B in the range of the μ g/ml of 0.0410 μ g/ml~2.0486, linear equation for y=48310.1758x-97.6981 (R=
1.0000), peak area and measured concentration are in good linear relationship；Impurity C is in the μ g/ml models of 0.0418 μ g/ml~2.0889
In enclosing, linear equation is y=120408.1584x+1266.6445 (R=0.9998), and peak area is with measured concentration in good
Linear relationship；For impurity D in the range of the μ g/ml of 0.0402 μ g/ml~2.0114, linear equation is y=35128.1845x+
184.4510 (R=1.0000), peak area are in good linear relationship with measured concentration；Impurity E 0.0398 μ g/ml~
In the range of 1.9891 μ g/ml, linear equation is y=30822.6781x-422.0519 (R=0.9996), and peak area is dense with measuring
Degree is in good linear relationship；For impurity F in the range of the μ g/ml of 0.21 μ g/ml~10.5, linear equation is y=34192.4773x-
1277.1516 (R=1.0000), peak area are in good linear relationship with measured concentration；Prove containing for the impurity of the present invention
The detection method method range of linearity of amount is wide, and accuracy is high.
In addition, the specificity of the double meglumines of the Fosaprepitant of the present invention and its method for detecting impurities is strong, as in the present invention
Shown in embodiment 1, other impurity in the double meglumine sample of Fosaprepitant and the double meglumine samples of Fosaprepitant to impurity A,
B, the measure of C, D, E, F, G are noiseless.
In addition, the precision of the double meglumines of the Fosaprepitant of the present invention and its method for detecting impurities is high, as in the present invention
It shows in precision embodiment, is tested and analyzed using HPLC, the RSD of impurity A peak area is：1.78%, the RSD of impurity B peak area
For：0.21%, the RSD of impurity C peak areas are：0.11%, the RSD of impurity D peak areas are：1.09%, the RSD of impurity E peak area
For：0.45%, the RSD of impurity F peak area are：0.06%, it was demonstrated that detection method precision of the invention is excellent.
In addition, the high sensitivity of the present invention, such as shows, impurity A, impurity B, impurity in the sensitivity embodiment of the present invention
C, the peak height of impurity D, impurity E and impurity F is each about 10 times of baseline noise, based on signal-to-noise ratio S/N=10, can obtain determining for impurity A
Amount is limited to 0.4087ng, and quantifying for impurity B is limited to 0.4097ng, and quantifying for impurity C is limited to 0.1253ng, obtains quantifying for impurity D
0.4023ng is limited to, quantifying for impurity E is limited to 0.3978ng, and quantifying for impurity F is limited to 0.6300ng, it was demonstrated that the method for the present invention
Detection sensitivity is high, can fully meet the requirement of impurity quantitative determination.
In addition, the repeatability of the present invention is good, such as shown in the repeated embodiment of the present invention, in repeated detection
In, the double meglumine impurity of Fosaprepitant are consistent substantially containing numerical quantity.
In addition, the sample recovery rate of the present invention is high, testing result is accurate, reliable, is such as shown in rate of recovery embodiment, miscellaneous
The rate of recovery of matter A is between 93.37%~102.60%, relative standard deviation 2.65%；The rate of recovery of impurity B 99.17%~
Between 100.18%, relative standard deviation 0.32%；For the rate of recovery of impurity C between 99.85%~100.99%, relative standard is inclined
Difference is 0.59%；The rate of recovery of impurity D is between 101.31%~104.47%, relative standard deviation 1.00%；The recycling of impurity E
Rate is between 98.96%~103.41%, relative standard deviation 1.31%；The rate of recovery of impurity F 101.68%~114.16% it
Between, relative standard deviation 4.05%；The rate of recovery of impurity G is between 95.34%~99.86%, relative standard deviation 1.74%；
It is each in relation to substance basic, normal, high three concentration levels the rate of recovery between 80% ~ 120%, the rate of recovery is high, and accuracy is good.
In addition, the present invention is easy to operate, it is easy to control, testing cost is low.The good linear relationship that has with reference to it, specially
Attribute, precision, stability, sensitivity and repeatability, high sample recovery rate, testing result is accurate, reliability, for monitoring
Main ingredient or/and impurity provide effective detection method in the double meglumine drugs of Fosaprepitant, into ensure that Fosaprepitant
The product quality of double meglumines and the drug safety of patient.
Description of the drawings
Fig. 1 is the HPLC figures of the standard control solution of impurity A in embodiment 1；
Fig. 2 is the HPLC figures of the standard control solution of impurity B in embodiment 1；
Fig. 3 is the HPLC figures of the standard control solution of impurity C in embodiment 1；
Fig. 4 is the HPLC figures of the standard control solution of impurity D in embodiment 1；
Fig. 5 is the HPLC figures of the standard control solution of impurity E in embodiment 1；
Fig. 6 is the HPLC figures of the standard control solution of impurity F in embodiment 1；
Fig. 7 is the HPLC figures of the standard control solution of impurity G in embodiment 1；
Fig. 8 is the HPLC figures of the double meglumine sample solutions of Fosaprepitant in embodiment 1；
Fig. 9 is the HPLC figures that sample solution is compared described in embodiment 1；
Figure 10 is the HPLC figures that the double meglumines of Fosaprepitant described in embodiment 2 prepare sample solution；
Figure 11 is the HPLC figures that the double meglumines of Fosaprepitant described in comparative example 1 prepare impurity C in sample solution；
Figure 12 is the ultraviolet spectrogram of the double meglumine sample solutions of Fosaprepitant in embodiment 3- wavelength selection examples；
Figure 13 is concentration-peak area canonical plotting of impurity A in embodiment 4- standard curves and range of linearity embodiment；
Figure 14 is concentration-peak area canonical plotting of impurity B in embodiment 4；
Figure 15 is concentration-peak area canonical plotting of impurity C in embodiment 4；
Figure 16 is concentration-peak area canonical plotting of impurity D in embodiment 4；
Figure 17 is concentration-peak area canonical plotting of impurity E in embodiment 4；
Figure 18 is concentration-peak area canonical plotting of impurity F in embodiment 4.
Specific embodiment
The specific embodiment of form by the following examples remakes further specifically the above of the present invention
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
The impurity A used in the present invention ~ G reference substances can obtain or pass through the prior art by buying commercial product
It is prepared.
The reference substance of impurity A ~ G used is obtained by Chengdu Baiyu Pharmaceutical Technology Co., Ltd. in following whole embodiments
, wherein the reference substance purity of impurity A is more than 99.79%, and the reference substance purity of impurity B is more than 98.68%, pair of impurity C
It is more than 99.0%% according to product purity, the reference substance purity of impurity D is more than 97.45%, and the reference substance purity of impurity E is 99.06%
More than, the reference substance purity of impurity F is 99.85 more than %, and the reference substance purity of impurity G is more than 99.70%.
Embodiment 1
It is detected using following steps：
（1）The reference substance of impurity A, B, C, D, E, F, G are taken respectively, are 50 by volume ratio:As molten after 50 acetonitrile and water mixing
These reference substances are dissolved in agent, are configured to the standard control solution of the impure each 5 μ g of every 1mL；
（2）The double meglumine samples of Fosaprepitant are taken, are 50 by volume ratio:After 50 acetonitrile and water mixing the sample is dissolved as solvent
Product are configured to sample solutions of every 1mL containing about the 1.0mg samples；
（3）Part is taken by step（2）Obtained sample solution and part are prepared by step（1）Prepare obtain impurity A, B, C,
The two is obtained comparison sample solution by D, the standard control solution of E, F, G after mixing；
（4）The standard control solution of gained, sample solution and comparison sample solution are subjected to HPLC detections, record by the following conditions
Chromatogram：
Chromatographic column：ACE C18, 4.6mm × 250mm, 5 μm；
Column temperature：30℃；Detection wavelength：215nm；
Sampling volume：20μL.
Mobile phase：Mobile phase A is made with the 50mM ammonium dihydrogen phosphate buffer solutions of phosphorus acid for adjusting pH to 2.2, acetonitrile is mobile phase
B, flow velocity：1.0ml/min；
According to the form below carries out gradient elution：
Gradient elution program
Gained chromatogram is as shown in attached drawing 1 ~ 9.
Wherein attached drawing 1 ~ 7 is the HPLC figures of the standard control solution of impurity A ~ G in embodiment, and impurity is understood from HPLC figures
The retention time of A is 3.942min；The retention time of impurity B is 10.639min, and the retention time of impurity C is 14.993min,
The retention time of impurity D is 40.034min, and the retention time of impurity E is 23.590min, and the retention time of impurity F is
The retention time of 27.164min, impurity G are 34.540min.
Attached drawing 8 is the HPLC figures of the double meglumine sample solutions of Fosaprepitant in embodiment；The wherein double meglumines of Fosaprepitant
The retention time of main peak is 12.613min.
Attached drawing 9 is the HPLC figures that sample solution is compared in embodiment, it is seen that husky of good fortune in comparison sample solution
The retention time of smooth double meglumines is 13.246min, and the retention time of impurity A is 3.885min, and the retention time of impurity B is
The retention time of 11.139min, impurity C are 15.358min, and the retention time of impurity D is 40.800min, during the reservation of impurity E
Between for 24.000min, the retention time of impurity F is 27.651min, and the retention time of impurity G is 35.207min.
It further calculates and understands, the separating degree of impurity A and impurity B is 27.567；Impurity B and the double meglumines of Fosaprepitant
Separating degree is 4.544；The double meglumines of Fosaprepitant and the separating degree of impurity C are 4.08；The separating degree of impurity C and impurity E is
26.961；The separating degree of impurity E and impurity F is 16.455；The separating degree of impurity F and impurity G are 33.266；Impurity G and impurity D
Separating degree be 19.741.
From above-mentioned testing result, under the testing conditions of the present embodiment, Fosaprepitant is double between meglumine and impurity
Separating degree it is high, can realize to being detected while the double meglumines of Fosaprepitant and plurality of impurities content.
Attached drawing 1 ~ 9 is also shown under the testing conditions of the present embodiment simultaneously, and the double meglumine samples of Fosaprepitant and good fortune are husky
Remaining impurity is noiseless to the measure of impurity A, B, C, D, E, F, G in smooth double meglumines, it was demonstrated that the specificity of the detection method
By force.
Embodiment 2
It is detected using following steps：
（1）The double meglumine samples of impurity A, the reference substance of B, C, D, E, F, G and Fosaprepitant are taken, are 50 by volume ratio:50 second
It is dissolved after nitrile and water mixing as solvent, is configured to every 1mL containing about impurity A, B, C, D, E, F, G 0.5mg, the double Portugals of Fosaprepitant
The double meglumines of the Fosaprepitant of methylamine sample 1.0mg prepare sample solution；
（2）The double meglumines of gained Fosaprepitant are prepared into sample solution and carry out HPLC detections by the following conditions, record chromatogram：
Chromatographic column：ACE C18, 4.6mm × 250mm, 5 μm；
Column temperature：30℃；Detection wavelength：215nm；
Sampling volume：20μL.
Mobile phase：Mobile phase A is made with the 20mM ammonium dihydrogen phosphate buffer solutions of phosphorus acid for adjusting pH to 2.2, acetonitrile is mobile phase
B, flow velocity：1.0ml/min；
According to the form below carries out gradient elution：
Gradient elution program
Gained chromatogram is as shown in Figure 10.
Attached drawing 10 shows, the retention times of the wherein double meglumines of Fosaprepitant is 13.964min, the retention time of impurity A
For 7.313min, the retention time of impurity B is 10.341min, and the retention time of impurity C is 20.753min.The reservation of impurity D
Time is 40.041min.The retention time of impurity E is 27.409min.The retention time of impurity F is 30.667min.Impurity G's
Retention time is 34.505min.
It further calculates and understands the separating degree of impurity A and impurity B for 3.155；Point of impurity B and the double meglumines of Fosaprepitant
It is 7.477 from degree；The double meglumines of Fosaprepitant and the separating degree of impurity C are 10.137；The separating degree of impurity C and impurity E is
12.464；The separating degree of impurity E and impurity F is 7.176；The separating degree of impurity F and impurity G are 8.480；Impurity G and impurity D's
Separating degree is 13.246.
Comparative example 1
It is detected using following steps：
（1）The double meglumine samples of impurity A, the reference substance of B, C, D, E, F, G and Fosaprepitant are taken, are 50 by volume ratio:50 second
It is dissolved after nitrile and water mixing as solvent, is configured to every 1mL containing about impurity A, B, C, D, E, F, G 0.5mg, the double Portugals of Fosaprepitant
The double meglumines of the Fosaprepitant of methylamine sample 1.0mg prepare sample solution；
（2）The double meglumines of gained Fosaprepitant are prepared into sample solution and carry out HPLC detections by the following conditions, record chromatogram：
Chromatographic column：ACE C18, 4.6mm × 250mm, 5 μm；
Column temperature：30℃；Detection wavelength：215nm；
Sampling volume：20μL.
Mobile phase：Using volume ratio as 80:20 buffer salt solution-acetonitrile makees mobile phase A, wherein buffer salt solution by
1.96g phosphoric acid, 0.34g 4-butyl ammonium hydrogen sulfates, 1.0g potassium dihydrogen phosphates add water 1000ml dissolvings to be made；With same but body
Product is than being 20:80 buffer salt solutions-acetonitrile be Mobile phase B, flow velocity：1.0ml/min；
According to the form below carries out gradient elution：
Gradient elution program
Attached drawing 11 prepares the HPLC spectrograms of impurity C in sample solution for the double meglumines of the Fosaprepitant, it can be seen that impurity C
Retention time for 15.565min, the hangover of impurity C peak shapes is serious.
Further combined with the comparison of embodiment 1,2, it can be seen that impurity separating degree is real slightly poorer to embodiment 1 in embodiment 2
The chromatographic condition of example 1 is applied more preferably to select.
3 wavelength selection example of embodiment
The double meglumine samples of Fosaprepitant are taken, is dissolved with solvent and dilutes the solution that suitable concentration is made, according to ultraviolet-visible point
Light photometry（Two annex IVA of Chinese Pharmacopoeia version in 2010）Spectral scan is carried out in the range of 200~400nm, is obtained as attached
Ultraviolet spectrogram shown in Figure 12, it is known that each impurity has larger absorption in 264 ± 3nm and end region, under 264 ± 3nm
Each Impurity Absorption is smaller, therefore is tested compared in end region 210nm being selected to be carried out further with 215nm, and selects 215nm works
It is used for most optimum wavelengths.
Take following testing conditions in example 4 below ~ 9（Hereinafter referred to as unified testing conditions）：
Column temperature：30℃；Detection wavelength：215nm；
Sampling volume：20μL.
Mobile phase：Mobile phase A is made with the 50mM ammonium dihydrogen phosphate buffer solutions of phosphorus acid for adjusting pH to 2.2, acetonitrile is mobile phase
B, flow velocity：1.0ml/min；
According to the form below carries out gradient elution：
Gradient elution program
4 standard curve of embodiment and range of linearity embodiment
The reference substance of impurity A, B, C, D, E, F, G are taken, is 50 by volume ratio:It is dissolved after 50 acetonitrile and water mixing as solvent,
And mix, the hybrid standard reference substance solution of various concentration is configured to, HPLC detections is carried out by unified testing conditions, records chromatography
Figure, and peak area is measured, obtain testing result as shown in Table 1：
Table 1
Using the concentration of hybrid standard contrast solution as abscissa X, using its peak area as ordinate Y, draw standard curve, obtain as
Concentration-peak area standard curve shown in attached drawing 13 ~ 18, difference equation of linear regression and correlation coefficient r, it is known that：The embodiment
Middle impurity A in the range of the μ g/ml of 0.0409 μ g/ml~2.0437, linear equation for y=43803.6818x+716.2411 (R=
0.9996), peak area and measured concentration are in good linear relationship；Impurity B is in the μ g/ml models of 0.0410 μ g/ml~2.0486
In enclosing, linear equation is y=48310.1758x-97.6981 (R=1.0000), and peak area is in good line with measured concentration
Sexual intercourse；For impurity C in the range of the μ g/ml of 0.0418 μ g/ml~2.0889, linear equation is y=120408.1584x+
1266.6445 (R=0.9998), peak area are in good linear relationship with measured concentration；Impurity D 0.0402 μ g/ml~
In the range of 2.0114 μ g/ml, linear equation is y=35128.1845x+184.4510 (R=1.0000), and peak area is with measuring
Concentration is in good linear relationship；Impurity E in the range of the μ g/ml of 0.0398 μ g/ml~1.9891, linear equation for y=
(30822.6781x-422.0519 R=0.9996), peak area is in good linear relationship with measured concentration；Impurity F is 0.21
In the range of the μ g/ml of μ g/ml~10.5, linear equation is y=34192.4773x-1277.1516 (R=1.0000), peak area
It is in good linear relationship with measured concentration.
Above to prove that the detection method range of linearity of the invention is wide, accuracy is high.
In addition, as can be seen that each slope of curve is far longer than intercept from the calibration curve equation of attached drawing, endpoint curve connects
Nearly origin illustrates that the assay of each impurity is suitable for the one point external standard method of the present invention.
5 precision embodiment of embodiment
Reference substance solution is taken, is injected in high performance liquid chromatograph, continuous sample introduction 6 times, every time 20 μ L, is examined by unified testing conditions
It surveys, and measures peak area respectively, obtain detection data as shown in Table 2：
Table 2
The RSD that impurity A peak area is further calculated is：1.78%, the RSD of impurity B peak area are：0.21%, impurity C peaks face
Long-pending RSD is：0.11%, the RSD of impurity D peak areas are：1.09%, the RSD of impurity E peak area are：0.45%, impurity F peak area
RSD be：0.06%, it was demonstrated that the detection method precision is excellent.
6 quantitative limit embodiment of embodiment
Reference substance solution is taken, mobile phase is added in and is diluted, precision is measured in 20 μ L injection high performance liquid chromatographs, is examined by unified
Survey condition detects, and measures peak area and baseline noise, obtains detection data as shown in table 3：
Table 3
The repeated embodiment of embodiment 7
（1）The reference substance of impurity A, B, C, D, E, F, G are taken respectively, are 50 by volume ratio:As molten after 50 acetonitrile and water mixing
These reference substances are dissolved in agent, are configured to the standard control solution of the impure each 5 μ g of every 1mL；
（2）Precision weighs double 6 parts of the meglumine samples of Fosaprepitant, and respectively about 10mg, puts respectively in 10mL measuring bottles, is by volume ratio
50:It dissolves as solvent, solubilizer after 50 acetonitrile and water mixing and is diluted to scale, obtain sample solution；
（3）Precision measures above-mentioned 6 parts of sample solutions, each 20 μ L of standard control solution, is detected by unified testing conditions, records chromatography
Figure, and measure peak area；
（4）According to standard curve, using external standard method with calculated by peak area impurity A, impurity B, impurity C, impurity D, impurity E and impurity
The content of F, testing result are as shown in table 4：
Table 4
From the above results, the repeatability of the detection method is good.
8 rate of recovery embodiment of embodiment
Parallel to weigh double 9 parts of the meglumine samples of Fosaprepitant, every 3 parts add respectively according to 80%, 100%, 120% mass percent
Enter the contrast solution of poly-doped impurity A ~ G, test sample solution is made, the contrast solution is dissolved in volume by impurity A ~ G reference substances
Than for 50:50 acetonitrile and water mixed liquid is made, and the test sample solution is pressed unified testing conditions and is detected, records chromatography
Figure, according to standard curve, using external standard method with calculated by peak area impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, miscellaneous
The measured amount of matter G, and the rate of recovery is calculated according to the following formula：
Wherein：A is the amount of impurities in the double meglumine samples of Fosaprepitant（mg）；
B is the addition of impurity reference substance（mg）；
C is the measured amount of impurity（mg）；
Obtain the testing result as shown in table 5 ~ 11：
Table 5
The rate of recovery of impurity A in the double meglumines of Fosaprepitant that this detection method of the results show measures 93.37%~
Between 102.60%, relative standard deviation 2.65%, the rate of recovery is good, and accuracy is high.
Table 6
The rate of recovery of impurity B in the double meglumines of Fosaprepitant that this detection method of the results show measures 99.17%~
Between 100.18%, relative standard deviation 0.32%, the rate of recovery is good, and accuracy is high.
Table 7
The rate of recovery of impurity C in the double meglumines of Fosaprepitant that this detection method of the results show measures 99.85%~
Between 100.99%, relative standard deviation 0.59%, the rate of recovery is good, and accuracy is high.
Table 8
The rate of recovery of impurity D in the double meglumines of Fosaprepitant that this detection method of the results show measures 101.31%~
Between 104.47%, relative standard deviation 1.00%, the rate of recovery is good, and accuracy is high.
Table 9
The rate of recovery of impurity E in the double meglumines of Fosaprepitant that this detection method of the results show measures 98.96%~
Between 103.41%, relative standard deviation 1.31%, the rate of recovery is good, and accuracy is high.
Table 10
The rate of recovery of impurity F in the double meglumines of Fosaprepitant that this detection method of the results show measures 101.68%~
Between 114.16%, relative standard deviation 4.05%, the rate of recovery is good, and accuracy is high.
Table 11
The rate of recovery of impurity G in the double meglumines of Fosaprepitant that this detection method of the results show measures 95.34%~
Between 99.86%, relative standard deviation 1.74%, the rate of recovery is good, and accuracy is high.
The above results show each rate of recovery in relation to basic, normal, high three concentration levels of substance between 80% ~ 120%,
Method accuracy is good.
9 stability of solution embodiment of embodiment
Precision weighs the double meglumine sample 10.0mg of Fosaprepitant, is placed in 10mL measuring bottles, and solubilizer dissolves and is diluted to scale,
Solvent is that volume ratio is 50:50 acetonitrile and water mixed liquid, obtains sample solution, after preparation 0h, 1h, 2h, 4h, 6h,
20 μ L of 8h, 10h and 12h sample introduction are detected by unified testing conditions, and are recorded chromatogram, investigate the impurity A measured, impurity B, miscellaneous
Matter C, impurity D, the steadiness of impurity E and impurity F, by taking wherein impurity F as an example, as a result as shown in table 12：
Table 12
It was found from above-mentioned data, it was found from data above, when 12 is small, impurity F increases as time went in interior test solution
Add, single impurity and total impurities it is almost unchanged, impurity number does not increase, it is known that test solution is interior when 12 is small after preparation
It is unstable, it is proposed that face with newly matching somebody with somebody.
In conclusion the present invention provides a kind of double meglumine raw materials of Fosaprepitant or the detection sides of preparation and its impurity
Method, it is easy to operate, it is easy to control, testing cost is low, the good linear relationship that has, specificity, precision, stability, spirit
Sensitivity and repeatability, high sample recovery rate, testing result are accurate, reliable.
Claims (10)
1. the detection method of a kind of double meglumine raw materials of Fosaprepitant or preparation, it is characterised in that：Use high performance liquid chromatography pair
The double meglumine raw materials of Fosaprepitant or formulation samples solution are detected analysis, and the stationary phase of chromatographic column used in detection is octadecane
Base silane bonded silica gel, mobile phase include mobile phase A and Mobile phase B, and wherein mobile phase A includes phosphate buffer, Mobile phase B bag
Acetonitrile is included, is further selected from acetonitrile, it is interior to the double meglumine raw materials of Fosaprepitant or system in 0 ~ 50min by mobile phase A and Mobile phase B
Agent sample solution carries out gradient elution；Detection wavelength 200-300nm, is further selected from 210-220nm；According to high performance liquid chromatography
As a result target substance is carried out qualitative or quantitative；The target substance includes the double meglumines of Fosaprepitant, reference substance and mesh
It is corresponding to mark substance.
2. detection method according to claim 1, it is characterised in that:Eluent gradient elution requirement is as follows：
。
3. detection method according to claim 1 or 2, it is characterised in that:Contain biphosphate in the phosphate buffer
Radical ion and phosphate anion, for 2 ~ 3 further, the phosphate buffer is ammonium dihydrogen phosphate-phosphate buffer to pH；More into
One step, pH 2.2；Further, biphosphate ammonium concentration is 20 ~ 50mM.
4. detection method according to claim 1 or 2, it is characterised in that：The chromatogram column length is 250nm, and internal diameter is
4.6mm, packing material size are 5 μm.
5. detection method according to claim 1 or 2, it is characterised in that：The column temperature of the chromatographic column is 20 DEG C~40 DEG C,
It is further 30 DEG C.
6. detection method according to claim 1 or 2, it is characterised in that：The flow velocity of the mobile phase for 0.8ml/min~
1.2ml/min；Further, the flow velocity of the mobile phase is 1.0ml/min.
7. detection method according to claim 1 or 2, it is characterised in that：The double meglumine raw materials of Fosaprepitant or preparation sample
Product solution or the solvent of reference substance solution are selected from acetonitrile or acetonitrile-water mixed liquor；Further, in acetonitrile-water mixed liquor, second
The volume ratio of nitrile is more than 40%.
8. according to the detection method described in claim 1 ~ 7 any one, it is characterised in that：The target substance further includes as follows
One or more in impurity：Phosphate dibenzyl ester, dibenzyl ammonium phosphate, triphen oxygen phosphorus, [3- [[(2R,3S)-2-[(1R)-1-[3,
5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydro-[1,2,4]
Triazol-1-yl]-phosphate dibenzyl ester, [3- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -
3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphoric acid-mono- benzyl ester, 5-
[[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls) -4- morpholines] first
Base] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, four benzyl of pyrophosphoric acid.
9. the detection method of impurity in a kind of double meglumine raw materials of Fosaprepitant or preparation, it is characterised in that：Use efficient liquid phase
Chromatography is detected analysis to the double meglumine raw materials of Fosaprepitant or formulation samples solution, and the stationary phase of chromatographic column is used in detection
Octadecylsilane chemically bonded silica, mobile phase include mobile phase A and Mobile phase B, and wherein mobile phase A includes phosphate buffer, stream
Dynamic phase B includes acetonitrile, gradient elution；Detection wavelength 200-300nm；According to high performance liquid chromatography result to impurity carry out it is qualitative or
It is quantitative；Wherein, eluent gradient elution requirement is as follows：
。
10. detection method according to claim 9, it is characterised in that：The impurity includes phosphate dibenzyl ester, dibenzyl phosphoric acid
Ammonium, triphen oxygen phosphorus, [3- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorobenzene
Base)-morpholine -4- methyl] -5- oxygen -4,5- dihydros-[1,2,4] triazol-1-yl]-phosphate dibenzyl ester, [3- [[(2R,3S)-2-
[(1R) -1- [3,5- bis- (trifluoromethyl) phenyl] ethyoxyl] -3- (4- fluorophenyls)-morpholine -4- methyl] -5- oxygen -4,5-
Dihydro-[1,2,4] triazol-1-yl]-phosphoric acid-mono- benzyl ester, 5- [[(2R,3S)-2-[(1R) -1- [3,5- bis- (trifluoromethyl) benzene
Base] ethyoxyl] -3- (4- fluorophenyls) -4- morpholines] methyl] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, pyrophosphoric acid four
One or more in benzyl ester, reference substance are corresponding with impurity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711479032.4A CN108120784A (en) | 2017-12-29 | 2017-12-29 | A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711479032.4A CN108120784A (en) | 2017-12-29 | 2017-12-29 | A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108120784A true CN108120784A (en) | 2018-06-05 |
Family
ID=62232343
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711479032.4A Pending CN108120784A (en) | 2017-12-29 | 2017-12-29 | A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108120784A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116429920A (en) * | 2023-02-20 | 2023-07-14 | 浙江亚瑟医药有限公司 | Detection method for resolving isomer in fosaprepitant starting material |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104042572A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Composition for injection containing fosaprepitant dimeglumine and preparation method thereof |
| CN104650142A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Preparation method of fosaprepitant dimeglumine |
| EP3100735A1 (en) * | 2015-06-03 | 2016-12-07 | Navinta, llc. | Crystalline fosaprepitant dicyclohexylamine salt and its preparation |
| CN106588989A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Novel crystal form of fosaprepitant dual-meglumine compound and preparing method thereof |
-
2017
- 2017-12-29 CN CN201711479032.4A patent/CN108120784A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104042572A (en) * | 2013-03-12 | 2014-09-17 | 江苏奥赛康药业股份有限公司 | Composition for injection containing fosaprepitant dimeglumine and preparation method thereof |
| CN104650142A (en) * | 2013-11-25 | 2015-05-27 | 山东新时代药业有限公司 | Preparation method of fosaprepitant dimeglumine |
| EP3100735A1 (en) * | 2015-06-03 | 2016-12-07 | Navinta, llc. | Crystalline fosaprepitant dicyclohexylamine salt and its preparation |
| CN106588989A (en) * | 2016-11-08 | 2017-04-26 | 山东裕欣药业有限公司 | Novel crystal form of fosaprepitant dual-meglumine compound and preparing method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116429920A (en) * | 2023-02-20 | 2023-07-14 | 浙江亚瑟医药有限公司 | Detection method for resolving isomer in fosaprepitant starting material |
| CN116429920B (en) * | 2023-02-20 | 2023-09-19 | 浙江亚瑟医药有限公司 | Detection method for resolving isomer in fosaprepitant starting material |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105699524B (en) | The detection method of isomer impurities content in a kind of ticagrelor | |
| CN105424822B (en) | The method for detecting (1R, 2S) 2 (3,4 difluorophenyl) cyclopropylamine in ticagrelor | |
| CN109633063B (en) | Method for detecting concentration of ticagrelor and active metabolite thereof in human plasma | |
| CN105510482B (en) | The detection method of isomer impurities content in a kind of ticagrelor raw material | |
| CN109060973A (en) | A method of ethylenediamine in detection lipoic acid injection | |
| CN108152418A (en) | The HPLC detection methods of ketorolac tromethamine or/and impurity in ketorolac tromethamine or its preparation | |
| CN108120784A (en) | A kind of double meglumine raw materials of Fosaprepitant or the detection method of preparation and its impurity | |
| CN114994213A (en) | Kit and method for determining blood concentration of anti-tumor drug tyrosine kinase inhibition in human plasma | |
| Gu et al. | Development and validation of a stability-indicating HPLC method for determination of voriconazole and its related substances | |
| Khattab et al. | Simultaneous determination of metronidazole and spiramycin in bulk powder and in tablets using different spectrophotometric techniques | |
| Basu et al. | Development and Validation of High Performance Liquid Chromatographic Method for Simultaneous Estimation of Potassium Clavulanate and CefiximeTrihydrate in Tablet Dosage Form | |
| Shah et al. | Difference spectroscopic and reverse phase HPLC methods for the estimation of cefdinir in pharmaceutical dosage forms | |
| CN115248260A (en) | HPLC analysis detection method for related substances in cisatracurium besilate bulk drug | |
| KR101718697B1 (en) | Rapid and simultaneous analysis for hydroxyphermine, phentermine and mephentermine | |
| Rashed et al. | Validated stability-indicating high performance liquid chromatographic and spectroscopic methods for determination of Agomelatine | |
| CN105628807B (en) | A kind of quality determining method of the amino piperidines of 1 Boc 4 | |
| CN111257441B (en) | Method for detecting impurities in parecoxib sodium synthesis process | |
| CN115144500B (en) | Method for detecting ifosfamide, impurity E and impurity G in ifosfamide bulk drug | |
| CN112083106B (en) | Method for detecting 3-chloro-2, 2-dimethyl-1-propanol in ibuprofen | |
| CN113917043B (en) | Detection method of afatinib maleate genotoxic impurities | |
| Taha et al. | Enantioseparation of cetirizine by chromatographic methods and discrimination by 1H‐NMR | |
| CN114324663B (en) | Method for detecting lornoxicam-related substances | |
| CN111060629B (en) | Method for detecting related substances of lifusy | |
| Rao et al. | Development and validation of a reversed-phase HPLC method for separation and simultaneous determination of process-related substances of mirtazapine in bulk drugs and formulations | |
| Athish | Development of Newer Validated Analytical Methods for the Determination of Riociguat in Tablet Dosage Form |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180605 |