CN106124550A - A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance - Google Patents
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance Download PDFInfo
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Abstract
The invention discloses a kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, the quantitative objective peak of mensuration vildagliptin sample and internal standard substance longitudinal relaxation time in deuterated reagent, by comparing the maximum longitudinal relaxation time of acquisition, according to T1maxSet pulse flip angle and the relaxation delay time of nuclear magnetic resonance chemical analyser, the mol ratio relative to internal standard substance of the pure vildagliptin in vildagliptin sample is measured again with described nuclear magnetic resonance chemical analyser, then according to the quality of internal standard substance, the quality of the pure vildagliptin in calculating vildagliptin sample, and then calculate vildagliptin sample purity, wherein, described pulse flip angle is 30 °～90 °, the described relaxation delay time is more than or equal to greatly the maximum longitudinal relaxation time of 2.3～5 times, and the chemical shift at the quantitative objective peak of described vildagliptin sample is 4.78.The vildagliptin sample purity of present invention detection is more accurate.
Description
Technical field
The invention belongs to medicine analysis technical field, be specifically related to one and quickly measure vildagliptin based on hydrogen nuclear magnetic resonance
The method of purity.
Background technology
Diabetes are the diseases of serious threat human health at present, the trouble of IDF's prediction to this disease of the year two thousand thirty
Person will have 5.52 hundred million.Dipeptidyl peptidase (DPP-4) inhibitor is the popular medicine for the treatment of diabetes at present, has dependence on the glucose
Property the effect of stimulating insulin secretion, be difficult to cause hypoglycemic generation, additionally, also have recovery pancreas during blood glucose controlling
IslandThe effect of β cell function.Vildagliptin provides with structural advantage and the application prospect treatment as type Ⅱdiabetes mellitus of its uniqueness
New selection.
As it is shown in figure 1, without conjugated structure in vildagliptin molecule, near ultraviolet band without absorbing, simultaneously in its building-up process
In often contain a small amount of near ultraviolet band without the impurity absorbed, such as 1,3-1,3-Dicyclohexylurea.This compound is not suitable for routine
HPLC-UV analyzes, because when using traditional HPLC-UV method to measure its purity, ultraviolet detection wavelength can only select end absorption,
Thus the shortcoming such as it is high to cause instrument noise, poor selectivity.Simultaneously HPLC-UV method to dissolvent residual present in sample (water,
Ethanol etc.), it is impossible to single-time measurement, still need to combine the method deduction solvent residual amounts such as gas chromatogram, could finally obtain dimension lattice
The real purity in row spit of fland.Therefore, conventional HPLC-UV method is not well positioned to meet the needs of vildagliptin purity analysis.Medicine
The research of product method for detecting purity is an important content in medicine research and development, and the purity of medicine preparation raw material finally affects patent medicine
Drug safety and curative effect.Accordingly, it would be desirable to study a kind of vildagliptin purity can be carried out simplicity, quickly, the analysis of Accurate Determining
Method.
High sensitivity that hydrogen nuclear magnetic resonance method has because of it, pinpoint accuracy, the analysis advantage such as quickly is widely used in
In the structure elucidation of organic compound and qualitative analysis, but due to the adamantyl contained in vildagliptin, pyrrolidinyl, secondary
Amido, hydroxyl, ketone group and itrile group interact and relatively greatly thus are difficult to the impact of vildagliptin proton resonance peak by proton magnetic altogether
Shake and vildagliptin is carried out quantitative analysis.
Summary of the invention
For overcoming the defect of prior art, the invention provides that a kind of quickly measure vildagliptin based on hydrogen nuclear magnetic resonance pure
The method of degree, it is possible to mensuration vildagliptin purity accurate, stable, quick.
For achieving the above object, the technical scheme is that
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, measures vildagliptin sample and internal standard substance
Quantitative objective peak longitudinal relaxation time (T in deuterated reagent1), by comparing the maximum longitudinal relaxation time (T of acquisition1max),
According to T1maxSet pulse flip angle and the relaxation delay time (d of nuclear magnetic resonance chemical analyser1), then use described NMR (Nuclear Magnetic Resonance) spectrum
Instrument measures the mol ratio relative to internal standard substance of the pure vildagliptin in vildagliptin sample, then according to the quality of internal standard substance, meter
The quality of the pure vildagliptin in calculation vildagliptin sample, and then calculate vildagliptin sample purity, wherein, described pulse is inclined
Chamfering is 30 °～90 °, the maximum longitudinal relaxation time more than or equal to 2.3～5 times of the described relaxation delay time, described Wei Gelie
Chemical shift (the δ at the quantitative objective peak of spit of fland sampleH) it is 4.78.
Pulse flip angle and relaxation delay time are to set up two important instrument ginsengs during hydrogen nuclear magnetic resonance quantitative approach
Number, directly affects the accuracy of final quantitative result, currently also has the document report studying they and testing result relation, in reality
There is a generally acknowledged determination step on border when measuring purity: internal standard substance and test substance are dissolved in solvent, carry out instrument parameter and set
Fixed measurement, is equal to the parameters such as resonant frequency when carrying out the mensuration of parameter by pulse flip angle and relaxation delay time and carries out
Set, cause method accuracy to there is blindness.The present inventor overcomes technology prejudice under study for action, and the present invention measures
The quantitative objective peak of vildagliptin sample and internal standard substance longitudinal relaxation time (T in deuterated reagent1), and determine at arteries and veins
Rushing flip angle is relaxation delay time when 30 °～90 °, and the vildagliptin sample purity making detection is more accurate.
The principle of nmr quantitative is that hydrogeneous organic compound NMR POP signal is directly directly proportional to atom number, because of
This is when experiment parameter sets, and the atomic number needing the formant on measured object and internal standard substance corresponding keeps one as far as possible
Cause, if selecting the hydrogen of improper position to carry out the mensuration of purity, can be by the shadow of the Interference Peaks such as Impurities In Solvents and solvent itself
Ringing relatively big, there is interference between tested component and impurity signal, tested component and internal standard also there will be signal overlap, cause integration
Inaccurate, testing result poor reproducibility.In vildagliptin, the proton of secondary amine and hydroxyl is active H, and its jitter is difficult to
As the proton still having many to detect on target peak, adamantyl and pyrrolidinyl, the formant of each proton can be right
Answer the parameter such as different flip angles and relaxation delay time, so selecting the hydrogen of which position to carry out purity testing is to limit at present
Utilize one of hydrogen nuclear magnetic resonance technical barrier measuring vildagliptin purity.The chemical shift of proton of adamantyl at 1-2ppm,
Its formant interference many, both sides baseline injustice, repeatability are poor, using the formant of adamantyl proton as target peak, it is difficult to
Determine the formant of adamantyl proton specifically which chemical shift corresponding, it is also difficult to be integrated concrete formant calculating,
The accuracy causing testing result is low, and detection speed slows down；Although the chemical shift of proton of pyrrolidinyl is at 2-5ppm, draw
Formant detection preferably, but owing to same position is (such as-CH2-) the chemical shift of two protons the most identical, thus
Formant corresponding to certain chemical shift all protons of a certain position of non-corresponding in hydrogen spectrum.Chemical shift in the present invention
Formant interference at 4.78ppm is little, both sides baseline is relatively flat, repeatability is preferable, and the formant at 4.78ppm can uniquely determine
For the formant of the proton on the carbon that is connected with itrile group, select chemical shift (δH) be the formant of 4.78ppm be quantitative objective
Peak, testing result accuracy is higher, it is the easiest to calculate, detect speed faster.
Preferably, the concrete steps relative to the mol ratio of internal standard substance of the pure vildagliptin in vildagliptin sample are measured
For: a certain amount of vildagliptin sample and internal standard substance are dissolved in deuterated reagent, and transfer in nuclear magnetic tube, measure Wei Gelie
In spit of fland and internal standard substance, the integral area (averaging 6 integrations of each signal) at each quantitative objective peak, draws vildagliptin phase
Mol ratio for internal standard substance.
Preferably, the detection parameter of described nuclear magnetic resonance chemical analyser is: resonant frequency is 400MHz, spectrum width 20ppm, test
Temperature 23 DEG C, relaxation delay time (d1) it is 6～100s；Sampling time (AQ) is 2.0～4.1s；Sampling accumulative frequency be 16～
32 times.Nuclear magnetic resonance analyser needs liquid nitrogen to maintain the high-intensity magnetic field of superconducting magnet generation thus ensures the properly functioning of nuclear magnetic resonance analyser,
Generally use lower temperature to reduce the consumption of liquid nitrogen during test, thus ensure the long-play of nuclear magnetic resonance analyser；Wei Gelie
Containing secondary amine and hydroxyl in spit of fland, easily produce intermolecular hydrogen bonding, the resolution of nuclear magnetic resonance map can be reduced, thus reduce
The accuracy of detection, on the premise of ensureing that less liquid nitrogen consumes, suitably rises high-temperature and can destroy hydrogen at secondary amine and hydroxyl
The formation of key so that it is proton peak spectrum moves to High-Field, reduces its chemical displacement value, thus improves resolution, selects 23 DEG C
Test, i.e. ensure that less consumption liquid nitrogen, it is ensured that the long-play of nuclear magnetic resonance analyser, improve again nuclear magnetic resonance, NMR figure
The resolution of spectrum, adds the accuracy of detection vildagliptin purity.
Preferably, the detectable concentration of vildagliptin is 13-15mg/mL.The concentration of magnetic resonance detection sample is generally
About 20mg/mL, owing to containing secondary amine and the hydroxyl that can produce hydrogen bond in vildagliptin, the detection reducing vildagliptin is dense
Degree can destroy the formation of hydrogen bond at secondary amine and hydroxyl, and the detectable concentration of vildagliptin is reduced to a certain degree, and nuclear-magnetism is common
Vibration Meter because resonance signal is more weak, thus can reduce the accuracy of detection vildagliptin purity further, selects vildagliptin
Detectable concentration is 13-15mg/mL, both ensure that nuclear magnetic resonance analyser can accurately detect resonance signal, can destroy again secondary amine and
The formation of hydrogen bond at hydroxyl, thus further increase the accuracy of detection vildagliptin purity.
It is further preferred that when described pulse flip angle is 30 °, the described relaxation delay time is more than or equal to 2.3 times
Maximum longitudinal relaxation time；When described pulse flip angle is 90 °, the maximum more than or equal to 5 times of the described relaxation delay time is indulged
To the relaxation time.The accuracy of detection vildagliptin purity can be further ensured that.
Preferably, described deuterated reagent is heavy water, deuterated methanol or deuterated dimethyl sulfoxide (DMSO-d6)。
It is further preferred that described deuterated reagent is DMSO-d6。
Preferably, under described internal standard substance is room temperature condition not with the compound of vildagliptin generation chemical reaction.
It is further preferred that the chemical shift of proton (δ of described compoundH) 16.00～6.01 or δH6.01～4.78
Or δH4.57～3.66 or δH3.44～2.51 or δH1.43～0.00 scope.Avoid vildagliptin hydrogen formant and interior target
Overlap between hydrogen formant
Further preferred, described internal standard substance is maleic acid.Be presently available for having as the material of internal standard substance benzene,
Benzyl benzoate, maleic acid, N, N-2 methylformamide, benzoyl peroxide, Phenacetin, 2,4-DNT, trifluoro second
Acid sodium, DMSO-d5, Potassium Hydrogen Phthalate, phosphoric acid etc., every kind of internal standard substance has at least one hydrogen formant, and test substance is tieed up
The proton selecting which position of Ge Lieting is also uncertain as the object detected, so selecting which kind of internal standard substance, which kind of
Hydrogen formant does not all have any foundation, and this is also to limit the technology utilizing hydrogen nuclear magnetic resonance to measure vildagliptin purity at present
One of difficult problem.
Preferably, the formula calculating vildagliptin sample purity is:
W%=(mIS×HIS×AS×MS× 100%)/(MIS×AIS×HS×mS)
The purity of W% vildagliptin；
mISThe real quality (quality × purity of internal standard substance) of internal standard substance, mg；
HISThe proton number at internal standard substance quantitative objective peak；
ASThe integrated value at vildagliptin quantitative objective peak；
MSThe molal weight of vildagliptin, g/mol；
MISThe molal weight of internal standard substance, g/mol；
AISThe integrated value at internal standard substance quantitative objective peak；
HSThe proton number at vildagliptin quantitative objective peak；
mSThe quality of vildagliptin sample, mg.
Compared with prior art, the present invention has following novelty and an advantage:
(1) present invention uses hydrogen nuclear magnetic resonance that vildagliptin has been carried out quantitative analysis first, overcomes in vildagliptin
The adamantyl, pyrrolidinyl, secondary amine, hydroxyl, ketone group and the itrile group that contain interact to vildagliptin proton resonance peak shadow
Ring relatively big thus be difficult to the difficulty by hydrogen nuclear magnetic resonance detection vildagliptin purity；
(2) present system determines the T that can be used for the quantitative echo signal of proton magnetic1Value, the most deeply begs for
The parameter impacts on assay result such as instrument pulse flip angle and relaxation delay time are discussed, it is ensured that the Wei Ge set up
The accuracy of row spit of fland method for detecting purity；
(3) present invention selects chemical shift (δH) be the formant of 4.78ppm be quantitative objective peak, testing result accuracy
Higher, calculate the easiest, detect speed faster；
(4) vildagliptin sample pre-treatments of the present invention is simple, and analysis time is short, it is not necessary to the reference substance of test vildagliptin,
Favorable reproducibility, conveniently carries out content analysis and the quality control of the new drug kind without uv absorption, solves this kind new drug and opens
The technical problem of vildagliptin purity testing in sending out；
(5) present invention selects the carrying out of 23 DEG C to test, and i.e. ensure that less consumption liquid nitrogen, it is ensured that the length of nuclear magnetic resonance analyser
Time is run, and improves again the resolution of nuclear magnetic resonance map, adds the accuracy of detection vildagliptin purity；
(6) present invention selects the detectable concentration of vildagliptin to be 13-15mg/mL, both ensure that nuclear magnetic resonance analyser can be accurate
Really detect resonance signal, the formation of hydrogen bond at secondary amine and hydroxyl can be destroyed again, thus further increase detection vildagliptin
The accuracy of purity.
Accompanying drawing explanation
Fig. 1 is vildagliptin structural formula；
Fig. 2 is hydrogen nuclear magnetic resonance spectrogram in example 1；
Fig. 3 is hydrogen nuclear magnetic resonance spectrogram in example 2；
Fig. 4 is hydrogen nuclear magnetic resonance spectrogram in example 3；
Fig. 5 is hydrogen nuclear magnetic resonance spectrogram in example 4；
Fig. 6 is hydrogen nuclear magnetic resonance spectrogram in example 5；
Fig. 7 is hydrogen nuclear magnetic resonance spectrogram in example 6；
Fig. 8 is hydrogen nuclear magnetic resonance spectrogram in example 7；
Fig. 9 is hydrogen nuclear magnetic resonance spectrogram in example 8；
Figure 10 is hydrogen nuclear magnetic resonance spectrogram in example 9；
Figure 11 is hydrogen nuclear magnetic resonance spectrogram in example 10；
Figure 12 is hydrogen nuclear magnetic resonance spectrogram in example 11；
Figure 13 is hydrogen nuclear magnetic resonance spectrogram in example 12；
Figure 14 is hydrogen nuclear magnetic resonance spectrogram in example 13；
Figure 15 is hydrogen nuclear magnetic resonance spectrogram in example 14.
Detailed description of the invention
Weigh vildagliptin 6.539mg, maleic acid 0.654mg, be respectively placed in nuclear magnetic tube, add 0.5mL
DMSO-d6Dissolve, be used for1H NMR tests.Proton is used to invert-recover T1The longitudinal direction at determination of experimental method each quantitative objective peak is relaxed
Henan time T1, and with the T of Bruker1Calculation procedure calculates.Set pulse relaxation delay time range as 1 second to 30 seconds.After measured
With DMSO-d6During for solvent, maleic acid δH6.01 signal peak T1For 2.5s, vildagliptin δHSignal T at 4.781For
1.7s。
The invention will be further described with embodiment below in conjunction with the accompanying drawings, but is not limited to the scope of the present invention.
Embodiment 1
Precision weighs vildagliptin sample 8.719mg, maleic acid 4.706mg, respectively with 600 μ L, 250 μ L DMSO-
d6Dissolving, rear precision takes 450 μ L vildagliptin solution, 50 μ L maleic acid solution are transferred in nuclear magnetic tube, carries out1H NMR surveys
Examination.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For 100s, sampling accumulative frequency is 16 times, spectrum width
20ppm, test temperature is 23 DEG C, and AQ is 4.1s.
As in figure 2 it is shown,1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.15, and the purity that can be calculated vildagliptin according to formula-1 is 85.7%, is repeated 6 times,
Standard error 0.16%, relative standard deviation 0.1%.
W%=(mIS×HIS×AS×MS× 100%)/(MIS×AIS×HS×mS) (formula-1)
Wherein: the purity of W% vildagliptin；
mISThe real quality of internal standard substance, 0.932mg；
HISThe proton number at internal standard substance quantitative objective peak, is 2；
ASThe integrated value at vildagliptin quantitative objective peak, is 1.15；
MSThe molal weight of vildagliptin, 303.40g/mol；
MISThe molal weight of internal standard substance, 116.07g/mol；
AISThe integrated value at internal standard substance quantitative objective peak, is 1；
HSThe proton number at vildagliptin quantitative objective peak, is 1；
mSThe quality of vildagliptin sample, 6.539mg.
Embodiment 2
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
80s, sampling accumulative frequency is 16 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As it is shown on figure 3,1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.15, and the purity that can be calculated vildagliptin according to formula-1 is 85.7%, is repeated 6 times,
Standard error 0.18%, relative standard deviation 0.2%.
Embodiment 3
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
50s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s, is repeated 6 times, standard error=
0.20%, relative standard deviation 0.3%.
As shown in Figure 4, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.15, and the purity that can be calculated vildagliptin according to formula-1 is 85.7%, is repeated 6 times,
Standard error 0.18%, relative standard deviation 0.1%.
Embodiment 4
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
30s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As it is shown in figure 5,1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, is repeated 6 times,
Standard error 0.22%, relative standard deviation 0.2%.
Embodiment 5
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
25s, sampling accumulative frequency is 16 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in Figure 6, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.15, and the purity that can be calculated vildagliptin according to formula-1 is 85.7%, is repeated 6 times,
Standard error 0.15%, relative standard deviation 0.1%.
Embodiment 6
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
20s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As it is shown in fig. 7,1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.17, and the purity that can be calculated vildagliptin according to formula-1 is 87.2%, is repeated 6 times,
Standard error 0.17%, relative standard deviation 0.1%.
Embodiment 7
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
15s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in Figure 8, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.17, and the purity that can be calculated vildagliptin according to formula-1 is 87.2%, is repeated 6 times,
Standard error 0.17%, relative standard deviation 0.1%.
Embodiment 8
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
13s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As it is shown in figure 9,1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin
δHAt 4.78, signal integration value is 1.17, and the purity that can be calculated vildagliptin according to formula-1 is 87.2%, is repeated 6 times,
Standard error 0.17%, relative standard deviation 0.1%.
Embodiment 9
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 90 ° of pulses, d1For
15s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 2.0s.
As shown in Figure 10, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, repeats 6
Secondary, standard error 0.22%, relative standard deviation 0.2%.
Embodiment 10
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For
30s, sampling accumulative frequency is 16 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in figure 11, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, repeats 6
Secondary, standard error 0.22%, relative standard deviation 0.2%.
Embodiment 11
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For
20s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in figure 12, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.17, and the purity that can be calculated vildagliptin according to formula-1 is 87.2%, repeats 6
Secondary, standard error 0.17%, relative standard deviation 0.1%.
Embodiment 12
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For
15s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in figure 13, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, repeats 6
Secondary, standard error 0.22%, relative standard deviation 0.2%.
Embodiment 13
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For
13s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 4.1s.
As shown in figure 14, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, repeats 6
Secondary, standard error 0.22%, relative standard deviation 0.2%.
Embodiment 14
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For
15s, sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 2.0s.
As shown in figure 15, exist1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, Wei Gelie
Spit of fland δHAt 4.78, signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, repeats 6
Secondary, standard error 0.22%, relative standard deviation 0.2%.
Embodiment 15
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For 8s,
Sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 2.0s.
?1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin δH4.78 place
Signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, is repeated 6 times, standard error
0.22%, relative standard deviation 0.2%.
Embodiment 16
1H NMR test sample is with embodiment 1.Nuclear magnetic resonance chemical analyser resonant frequency is 400MHz, 30 ° of pulses, d1For 6s,
Sampling accumulative frequency is 32 times, spectrum width 20ppm, and test temperature is 23 DEG C, and AQ is 2.0s.
?1In H H NMR spectroscopy, internal standard substance maleic acid δH6.01 signal peak integrated values are 1, vildagliptin δH4.78 place
Signal integration value is 1.16, and the purity that can be calculated vildagliptin according to formula-1 is 86.4%, is repeated 6 times, standard error
0.22%, relative standard deviation 0.2%.
Although the detailed description of the invention of the present invention is described by the above-mentioned accompanying drawing that combines, but not to invention protection domain
Restriction, one of ordinary skill in the art should be understood that, on the basis of technical scheme, those skilled in the art are not required to
Various amendments or deformation that creative work to be paid can be made are the most within the scope of the present invention.
Claims (10)
1. the method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that, measures vildagliptin sample
And the longitudinal relaxation time that the quantitative objective peak of internal standard substance is in deuterated reagent, by comparing acquisition T1max, according to T1maxSet core
The pulse flip angle of resonance spectrometer and relaxation delay time, then measure vildagliptin sample with described nuclear magnetic resonance chemical analyser
In pure vildagliptin relative to the mol ratio of internal standard substance, then according to the quality of internal standard substance, calculate in vildagliptin sample
The quality of pure vildagliptin, and then calculate vildagliptin sample purity, wherein, pulse flip angle is 30 °～90 °, described relaxation
Henan is more than or equal to the maximum longitudinal relaxation time of 2.3～5 times, the change at the quantitative objective peak of described vildagliptin sample time delay
Displacement study is 4.78.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
The detection parameter of described nuclear magnetic resonance chemical analyser is: resonant frequency is 400MHz, spectrum width 20ppm, tests temperature 23 DEG C, and relaxation is prolonged
Time is 6～100s late；Sampling time is 2.0～4.1s；Sampling accumulative frequency is 16～32 times.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
When described pulse flip angle is 30 °, the maximum longitudinal relaxation time more than or equal to 2.3 times of the described relaxation delay time；Work as institute
State pulse flip angle when being 90 °, the maximum longitudinal relaxation time more than or equal to 5 times of the described relaxation delay time.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
Described deuterated reagent is heavy water, deuterated methanol or deuterated dimethyl sulfoxide.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
Described deuterated reagent is DMSO-d6。
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
Described internal standard substance be under room temperature condition not with the compound of vildagliptin generation chemical reaction.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
The chemical shift of proton of described compound 16.00～6.01 or 6.01～4.78 or 4.57～3.66 or 3.44～2.51 or
1.43～0.00 scope.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
Described internal standard substance is maleic acid.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, is characterized in that,
The detectable concentration of vildagliptin is 13-15mg/mL.
A kind of method quickly measuring vildagliptin purity based on hydrogen nuclear magnetic resonance, its feature
It is that the formula calculating vildagliptin sample purity is:
W%=(mIS×HIS×AS×MS× 100%)/(MIS×AIS×HS×mS),
The purity of W% vildagliptin；
mISThe real quality of internal standard substance, mg；
HISThe proton number at internal standard substance quantitative objective peak；
ASThe integrated value at vildagliptin quantitative objective peak；
MSThe molal weight of vildagliptin, g/mol；
MISThe molal weight of internal standard substance, g/mol；
AISThe integrated value at internal standard substance quantitative objective peak；
HSThe proton number at vildagliptin quantitative objective peak；
mSThe quality of vildagliptin sample, mg.
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