CN108614038A - A method of measuring the related substance of shellfish cholic acid bulk pharmaceutical chemicals difficult to understand - Google Patents
A method of measuring the related substance of shellfish cholic acid bulk pharmaceutical chemicals difficult to understand Download PDFInfo
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Abstract
The present invention, which establishes, a kind of can control detection method of the shellfish cholic acid in relation to substance difficult to understand, specifically, solvent appropriate is selected, sample is detected by HPLC ELSD, known impurities use external standard method, unknown impuritie and always collecting widely to be controlled the related substance of product with 1% principal component reference substance.
Description
Technical field
The present invention relates to measurement of the bulk pharmaceutical chemicals in relation to substance, specifically, the present invention relates to the related objects of shellfish cholic acid bulk pharmaceutical chemicals difficult to understand
The measurement of matter.
Background technology
Shellfish cholic acid (OBDS) difficult to understand is the structural modification object 6- ethyl chenodeoxycholic acids of chenodeoxycholic acid, it is Intercept
A kind of method Buddhist nun ester X receptor stimulating agents of drugmaker's exploitation can inhibit cholic acid biology to close indirectly by activating farnesoid X receptor
At rate-limiting enzyme cytochromes 7A1 (CYP7A1) gene expression, and then inhibit cholic acid synthesis, can be used for treating primary biliary
Property hepatic sclerosis and non-alcohol fatty liver.
Nonalcoholic steatohepatitis is a kind of Fatty Liver Disease, is claimed according to Intercept, nonalcoholic steatohepatitis to 2020
Year is expected to the principal element as liver transplant.This disease there is no the medicine to get the Green Light at present, this has just expedited the emergence of one
The market of a potential heavy pound grade promotes biopharmaceutical company to carry out medicament research and development in this field input huge fund.
Shellfish cholic acid difficult to understand has preferable clinical value and application prospect, and research institute both domestic and external and medicine enterprise attach great importance to pair
The research and development and production of the medicine.Currently, since the bulk pharmaceutical chemicals are triterpene compound, without conjugated system, UV absorption is very weak, former
Expect that the control in relation to substance is difficult point, retrieve domestic and international pertinent literature and patent, is showed no the report of related detecting method.
Invention content
It is an object of the invention to establish it is a kind of can control detection method of the shellfish cholic acid in relation to substance difficult to understand, specifically, choosing
Solvent appropriate is selected, sample is detected by HPLC-ELSD (evaporation photodetector), it is known that impurity uses external standard method, not
Know impurity and always collect widely and the related substance of product is controlled with 1% principal component reference substance；Due to evaporation photodetector spirit
Sensitivity is poor, needs the selection by appropriate solvent, increases sample concentration and sample size, can just meet measurement and require；But
In the case of sample concentration and sample size are increased, main peak heavy overload, if using area normalization and principal component own control
There is relatively large deviation in method, according to external standard method, can accurately be measured to the content of impurity, it is ensured that the quality of drug, it should
Method has the following advantages：1, OBDS is dissolved using solvent appropriate, solubility can be made to reach 15-30mg/ml；2, can will have
Pass substance efficiently separates and being capable of quantified controlling；3, this method has general applicability, is suitable for the transfer of production company；
4, this method has enough sensitivity, can control effectively to impurity.
The present invention provide it is a kind of can control detection method of the shellfish cholic acid in relation to substance difficult to understand, step is：1) use acetonitrile and
Water mixed solvent dissolving shellfish cholic acid bulk pharmaceutical chemicals difficult to understand：2) sample is detected by HPLC-ELSD, chromatographic condition is：Use C18
Acidproof chromatographic column, mobile phase are acetonitrile and 0.1% formic acid；3) known impurities use external standard method, unknown impuritie and always collect widely with 1%
Principal component reference substance the related substance of product is controlled.
In one embodiment of the invention, the mixed solvent acetonitrile and water volume ratio are 75：25-85:15,
Preferably, volume ratio 80:20.
In one embodiment of the invention, a concentration of 15-30mg/ml of the sample, it is preferable that the sample
A concentration of 20mg/ml of product.
In one embodiment of the invention, the drift tube temperature of the ELSD is 35-40 degree.
In one embodiment of the invention, chromatographic column is C18 acidity chromatographic columns, it is preferable that chromatographic column is
ZORBAX SB-C18 chromatographic columns, parameter 4.6*250mm, 5um
In one embodiment of the invention, mobile phase is acetonitrile and 0.1% formic acid, volume ratio 50:50-
60:40, it is preferable that its volume ratio is 55:45.
In one embodiment of the invention, the flow velocity of mobile phase is 0.2-1.2ml/min, it is preferable that flowing
The flow velocity of phase is 1.0ml/min.
Description of the drawings
Fig. 1：It is acetonitrile in diluent：Water (80:20, v/v) under the conditions of, main peak tack is well-symbolized.
Fig. 2：Diluent is acetonitrile：Water (90:10, v/v) under the conditions of, main peak peak shape forward position.
Fig. 3：- 0.1% formic acid water (55 of optimal flow phase condition acetonitrile：45, v/v) shellfish cholic acid difficult to understand and each impurity point under the conditions of
From situation, the retention time at each peak as shown in each peak mark, be sequentially followed successively by from left to right D-1, SM1, D-5, D-6, D-2,
OBDS、D-4。
Specific implementation mode
Following embodiment is not limitation of the present invention for further understanding the present invention.
The preparation of shellfish cholic acid bulk pharmaceutical chemicals and its intermediate material difficult to understand refers to CN104781272A.
Embodiment 1：The selection of diluent and solution concentration
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), mobile phase：- 0.1% formic acid water (55 of acetonitrile:45, v/v), flow velocity 1ml/min, the drift of sample size 20 μ l, ELSD
Tube temperature degree is 38 degree；Quantitative manner：Known impurities use external standard method, unknown impuritie and always collect widely with 1% principal component reference substance
The related substance of product is controlled.
Table 1：
Test procedure and conclusion：
Conclusion：Diluent volume ratio ranging from 75:25-85:15, sample dissolving is good, and peak type is good.Best diluent is
Acetonitrile：Water is 80：20.As a result referring to Fig. 1 and 2.
The selection of solution concentration:
Conclusion：Between sample concentration ranging from 15mg/ml-30mg/ml, the concentration range, peak shape is preferable, and can meet sample
The bound requirements that product measure.
Embodiment 2：The selection of evaporative light scattering detector parameter
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v) drift tube temperature of, flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities are adopted
With external standard method, unknown impuritie and always collecting widely controls the related substance of product with 1% principal component reference substance
Test procedure:
Using above-mentioned chromatographic condition, different drift tube temperatures are adjusted, are to investigate to mark with the noise (6*SD) and peak shape of spectrogram
Standard optimizes.
Table 2：Test result：
| Drift tube temperature (degree) | Noise (6*SD) and peak shape |
| 30-34 | Non- appearance |
| 35-40 | 0.13, peak shape is good |
| 41-45 | Peak shape is poor |
Conclusion：Drift tube temperature is that 35-40 degree peak types are good.
Embodiment 3：The determination of mobile phase ratio
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile,
The drift tube temperature of flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities use external standard method, not
Know impurity and always collect widely and the related substance of product is controlled with 1% principal component reference substance.
Test procedure：
System suitability solution：Take OBDS and each impurity appropriate, it is accurately weighed, it sets in same volumetric flask, dilutes dilution agent
It is settled to scale, is shaken up to get (OBDS concentration 20mg/ml, each impurity concentration 0.1mg/ml).
Using above-mentioned chromatographic condition, different mobile phase ratios are adjusted, using impurity separating degree as inspection target, to mobile phase
Ratio optimizes.
Table 3：Test result：
Conclusion：- 0.1% formic acid water ratio of mobile phase acetonitrile is 50:50-60:40, v/v, each impurity can be kept completely separate
Optimal flow phase condition is that -0.1% formic acid water of acetonitrile is 55：45 (v/v), under this condition shellfish cholic acid difficult to understand and each impurity
It is (referring to attached drawing 3) as shown in the table to detach situation：
Table 4：
Conclusion：Using the elution requirement, the separating degree of each impurity meets the requirements.
Embodiment 4：The determination of chromatographic column type
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, evaporative light scattering detector (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration
For 20mg/ml, mobile phase：- 0.1% formic acid water (55 of acetonitrile:45, v/v), flow velocity 1ml/min, the drift of sample size 20 μ l, ELSD
It is 38 degree to move tube temperature degree；Quantitative manner:Known impurities use external standard method, unknown impuritie and always collect widely with 1% principal component control
Product control the related substance of product.
Test procedure：
Using above-mentioned chromatographic condition, different types of chromatographic column is adjusted, using impurity peak shape as inspection target, to chromatographic column
Type is investigated.
Table 5：Test result：
Conclusion：From the above data, optimal chromatographic column should be acid proof chromatographic column, such as Agilent zorbaxSB-
C18(4.6*250mm,5um)。
Embodiment 5：The determination of optimum flow rate
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v), the drift tube temperature of 20 μ l, ELSD of sample size are 38 degree；Quantitative manner：Known impurities use external standard method, not
Know impurity and always collect widely and the related substance of product is controlled with 1% principal component reference substance.
Test procedure：
System suitability solution：Take OBDS and each impurity appropriate, it is accurately weighed, it sets in same volumetric flask, dilutes dilution agent
It is settled to scale, is shaken up to get (OBDS concentration 20mg/ml, each impurity concentration 0.1mg/ml).
Using above-mentioned chromatographic condition, different flow velocitys is adjusted, using impurity retention time and separating degree as inspection target, convection current
It is investigated.
Table 6：Test result：
Conclusion：From the above data, the flow rates of this method are 0.8-1.2ml/min, optimum flow rate 1.0ml/
min。
Embodiment 6：The method of the present invention specificity is tested
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v) drift tube temperature of, flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities are adopted
With external standard method, unknown impuritie and always collecting widely controls the related substance of product with 1% principal component reference substance
Test procedure：
Diluent：Acetonitrile：Water (80:20, v/v)
System suitability solution：Take OBDS and each impurity appropriate, it is accurately weighed, it sets in same volumetric flask, dilutes dilution agent
It is settled to scale, is shaken up to get (OBDS concentration 20mg/ml, each impurity concentration 0.1mg/ml).
Table 7：Test result：
Conclusion：Diluent does not generate interference to sample measurement, and this method specificity is good.
Embodiment 7：The sensitivity test of this method
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v) drift tube temperature of, flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities are adopted
With external standard method, unknown impuritie and always collecting widely controls the related substance of product with 1% principal component reference substance.
Test procedure：
Take SM1, D-3, D-5, D-6, OBDS sample appropriate, it is accurately weighed, it sets in different capabilities bottle, diluent is diluted to one
Fixed concentration, with 10*S/N (S/N：Signal/noise)≤each impurity response≤20*S/N (S/N：Signal/noise) be advisable, i.e.,
For the quantitative limit concentration of each impurity.
Table 8：Test result：
| Substance code name | Quantitative limit (μ g/ml) | It is equivalent to test sample concentration (%) |
| SM1 | 5.12 | 0.02% |
| D-3 | 16.42 | 0.08% |
| D-5 | 10.57 | 0.05% |
| D-6 | 12.48 | 0.06% |
| OBDS | 15.75 | 0.08% |
Conclusion:0.1% impurity below of test sample concentration, can quantitative determine, this method sensitivity meets related request.
Embodiment 8：The linear test of this method
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v) drift tube temperature of, flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities are adopted
With external standard method, unknown impuritie and always collecting widely controls the related substance of product with 1% principal component reference substance.
Test procedure：
Take each impurity appropriate, it is accurately weighed, from quantitative limit concentration to 10 times of quantitative limit concentration, 5 concentration points are uniformly prepared,
Carry out linear determination.
Table 9：Test result：
| Impurity code | The range of linearity (μ g/ml) | Related coefficient (R2) |
| SM1 | 5.12-51.2 | 0.998 |
| D-3 | 16.42-164.2 | 0.999 |
| D-5 | 10.57-105.7 | 0.999 |
| D-6 | 12.48-124.8 | 0.999 |
| OBDS | 15.75-157.5 | 0.999 |
Conclusion：Consider that original grinds product and do not go public temporarily, the limit of impurities is unknown, therefore is increased up 10 in quantitative limit concentration
Times concentration, takes 5 points to do Linear Experiment, linear relationship is good.
Embodiment 9：The accuracy of this method is tested
Instrument and condition：
Agilent1260 liquid chromatographs, the model G1311A of pump, UV detector model G1315D, and
Chemstation processing softwares, chromatographic column：Agilent ZorbaxSB-C18 (250*4.6mm, 5 μm), Evaporative light scattering detector
Device (ELSD), solvent are acetonitrile and water (80:20, v/v), solution concentration 20mg/ml, mobile phase：- 0.1% formic acid water of acetonitrile
(55:45, v/v) drift tube temperature of, flow velocity 1ml/min, sample size 20 μ l, ELSD are 38 degree；Quantitative manner：Known impurities are adopted
With external standard method, unknown impuritie and always collecting widely controls the related substance of product with 1% principal component reference substance.
Test procedure：
Reference substance solution：Take SM1 reference substances appropriate, it is accurately weighed, it sets in volumetric flask, dilution dilution agent is settled to scale,
It shakes up up to (a concentration of 0.1mg/ml).
Test solution：Take OBDS samples appropriate, it is accurately weighed, it sets in volumetric flask, dilution dilution agent is settled to scale, shakes
It is even up to (a concentration of 20mg/ml).
The rate of recovery tests solution：SM1 reference substances are taken, it is accurately weighed, it is added in test solution, concentration difference is added in SM1
It is 50%, 100%, the 150% of limit concentration.
Table 10：Test result：
Conclusion：Determination of recovery rates, from the above data, needle are carried out to the residual impurity in shellfish cholic acid finished product step difficult to understand
To the impurity, method accuracy meets the requirements.
Claims (10)
1. a kind of detection method of Austria's shellfish cholic acid in relation to substance, step are：1) acetonitrile and water mixed solvent is used to dissolve shellfish courage difficult to understand
Acid obtains sample；2) sample is detected by HPLC-ELSD, chromatographic condition is：Use the acidproof chromatographic columns of C18, stream
Dynamic is mutually acetonitrile and 0.1% formic acid；3) known impurities in the sample use external standard method, unknown impuritie and always collect widely with 1%
Principal component product as a contrast, the related substance of shellfish cholic acid difficult to understand is controlled.
2. the detection method of claim 1, the in the mixed solvent acetonitrile and water volume ratio are 75:25-85:15, it is preferable that institute
It is 80 to state in the mixed solvent acetonitrile and water volume ratio:20.
3. the detection method of claims 1 or 2, wherein a concentration of 15-30mg/ml of the sample, it is preferable that the wherein described sample
A concentration of 20mg/ml of product.
4. the detection method of claim 3, wherein the drift tube temperature of the ELSD is 35-40 degree.
5. the detection method of claim 3, wherein the chromatographic column is ZORBAX SB-C18 chromatographic columns.
6. the detection method of claim 3, wherein the volume ratio of acetonitrile and 0.1% formic acid is 50 in the mobile phase:50-60:
40。
7. the detection method of claim 6, wherein the volume ratio of acetonitrile and 0.1% formic acid is 55 in the mobile phase:45.
8. the detection method of claim 3, wherein the flow velocity of the mobile phase is 0.2-1.2ml/min.
9. the detection method of claim 8, wherein the flow velocity of the mobile phase is 1.0ml/min.
10. the detection method of claim 3, a concentration of 20mg/ml of the in the mixed solvent sample, the drift tube of the ELSD
Temperature is 35-40 degree, and the chromatographic column is ZORBAX SB-C18 chromatographic columns, the body of acetonitrile and 0.1% formic acid in the mobile phase
Product is than being 55:45, the flow velocity of the mobile phase is 1.0ml/min.
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