CN110927262A - Method for detecting initial material impurities in posaconazole - Google Patents
Method for detecting initial material impurities in posaconazole Download PDFInfo
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- 229960001589 posaconazole Drugs 0.000 title abstract description 27
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title abstract description 27
- 238000000034 method Methods 0.000 title abstract description 15
- 239000012535 impurity Substances 0.000 title description 7
- 239000000463 material Substances 0.000 title description 2
- 238000001514 detection method Methods 0.000 abstract description 11
- 239000007858 starting material Substances 0.000 abstract description 8
- 239000007788 liquid Substances 0.000 abstract description 6
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 abstract description 4
- 238000010812 external standard method Methods 0.000 abstract description 4
- 238000011084 recovery Methods 0.000 abstract description 4
- PEUPUKDBCPLDIH-UHFFFAOYSA-N 1,2,4-triazole Chemical group C1=NC=N[N]1 PEUPUKDBCPLDIH-UHFFFAOYSA-N 0.000 abstract description 3
- 238000004811 liquid chromatography Methods 0.000 abstract description 2
- 230000035945 sensitivity Effects 0.000 abstract description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 abstract 1
- 239000012488 sample solution Substances 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 14
- 239000011550 stock solution Substances 0.000 description 12
- 238000005303 weighing Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000012088 reference solution Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000007865 diluting Methods 0.000 description 7
- 239000013558 reference substance Substances 0.000 description 7
- 239000012085 test solution Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010050346 Oropharyngeal candidiasis Diseases 0.000 description 2
- DFWVLCJRFGIRAK-UHFFFAOYSA-N [5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CC(CN2N=CN=C2)(C=2C(=CC(F)=CC=2)F)OC1 DFWVLCJRFGIRAK-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 201000002909 Aspergillosis Diseases 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 208000036641 Aspergillus infections Diseases 0.000 description 1
- 206010007134 Candida infections Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000003984 candidiasis Diseases 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
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- 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
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Abstract
The invention discloses a detection method for determining a starting material BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyl tetrahydrofuran-3-methyl ester) in posaconazole, which adopts liquid chromatography, wherein the chromatographic column is an Agilent ZORBAX-Phenyl chromatographic column (150mm multiplied by 4.6 mm, 3.5um), and acetonitrile-water (50: 50) is used as a mobile phase; the flow rate was 1.0ml per minute; the column temperature was 40 ℃; the detection wavelength was 225 nm. Precisely measuring 20 mu L of sample solution, injecting into a liquid chromatograph, recording chromatogram, and calculating by adopting an external standard method. As a result, the concentration was 0.0699 to 1.9960. mu.g/ml‑1In the range of (a), the peak area and the concentration showed a good linear relationship with a correlation coefficient of 0.9998, a recovery of 96.21% -99.2%, and an RSD of 1.14% (n = 9). The conclusion is that the method has strong specificity, good repeatability and high sensitivity, and can be used for measuring BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-methyl ester) in posaconazole.
Description
Technical Field
The invention belongs to the technical field of medical analysis, and particularly relates to a detection method of a starting material BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in a posaconazole synthesis process.
Background
Posaconazole is a broad-spectrum triazole antifungal agent useful for the prevention of invasive Aspergillus and Candida infections and for the treatment of oropharyngeal candidiasis, including itraconazole and/or fluconazole refractory oropharyngeal candidiasis. The chemical name of the starting material of posaconazole is: ((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazol-1-yl) methyltetrahydrofuran-3-ylmethyl ester) formula: C21H21F2N3O4S, molecular weight: 449.47, the structural formula is as follows:
((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazol-1-yl) methyltetrahydrofuran-3-ylmethyl ester) is a starting material for synthesizing posaconazole, and impurities of the starting material are inevitably carried into a posaconazole product in a synthesis reaction. Therefore, it would be advantageous to prepare posaconazole if the impurities in the posaconazole starting material could be detected or controlled.
Disclosure of Invention
The invention provides a detection method of a starting material BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-methyl ester) in a posaconazole synthesis process. The method is simple, exclusive and accurate, and is suitable for detecting the starting material BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in posaconazole.
In order to achieve the purpose, the invention adopts the technical scheme that:
a detection method for determining BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in posaconazole is hereinafter referred to as BSKZ-1. The method comprises the following steps:
(1) chromatographic conditions
A chromatographic column: agilent ZORBAX-Phenyl chromatographic column (150 mm. times.4.6 mm, 3.5 um);
a detector: an ultraviolet absorption detector (UVD);
detection wavelength: 225 nm;
flow rate: 1.0ml/min-1；
Column temperature: min at 40 ℃;
a solvent; acetonitrile: water (50: 50);
sample introduction volume: 20 ul.
(2) Preparing test solution and reference solution: the reference solution is prepared by precisely weighing about 10mg of BSKZ-1, placing the BSKZ-1 in a 100ml measuring flask, adding a solvent to dissolve and quantitatively dilute the BSKZ-1, and shaking up the BSKZ-1 to serve as a reference stock solution. Precisely measuring 1ml of the stock solution, placing in a 100ml measuring flask, adding solvent to dilute to scale, and shaking up to obtain a reference solution. Taking 10mg of posaconazole, precisely weighing, adding absolute ethyl alcohol for dissolving, and quantitatively diluting to prepare a solution containing 1mg of posaconazole in each lml.
(3) The determination method comprises the following steps: precisely measuring 20ul of sample, injecting into a liquid chromatograph, recording chromatogram, and calculating according to an external standard method; the retention time of the main peak of the test solution is consistent with that of the main peak of the reference solution; if BSKZ-1 exists in the chromatogram of the test solution, the BSKZ-1 can not exceed 0.1 percent according to the external standard method.
(5) From the above, the mobile phase control be acetonitrile: water (50: 50). The flow rate is controlled as follows: 1.0ml/min-1(ii) a The column temperature was controlled to 40 ℃. The detector is an ultraviolet absorption detector (UVD), and the detection wavelength is as follows: 225 nm.
The invention adopts liquid chromatography to establish a detection method for an initiator BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in the posaconazole synthesis process. The detection method can accurately determine the content of BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-methyl ester); the method has high sensitivity and strong specificity, and the limit of quantification can reach 0.0699 ug/ml; the content of the impurities can be effectively detected, and the quality of BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) is controlled, so that the posaconazole with qualified quality is synthesized.
Detailed Description
The present invention will be described in further detail by way of examples, but the following examples are merely illustrative of the present invention and do not represent the scope of the present invention as defined in the claims.
Example 1
Establishment of methodology
1.1 specificity
The specificity test needs to verify the influence of the sample solvent and potential other impurities of posaconazole on the determination of BSKZ-1. Precisely weighing 10mg of posaconazole, placing in a 10ml volumetric flask, precisely weighing 0.1ml of BSKZ-1 reference substance stock solution, adding the BSKZ-1 reference substance stock solution, dissolving with solvent, quantitatively diluting, and mixing to obtain mixed solution. Precisely measure 20. mu.l of the solution, inject the solution into a liquid chromatograph, and record a chromatogram, which is shown in FIG. 1. The test result shows that the blank solvent has no interference peak, and unknown impurities have no interference on the measurement of BSKZ-1, which indicates that the method has strong specificity.
1.2 Linear Range
Precisely measuring 2ml of reference stock solution, placing in 20ml, adding solvent, and diluting to scale to obtain linear mother liquor; precisely taking linear mother liquor, 0.3, 0.5, 0.8, 1, 1.5 and 2ml, respectively placing into 10ml measuring flasks, adding solvent to dilute to scale, shaking up, respectively measuring 20 μ l, injecting into a liquid chromatograph, and recording chromatogram. And drawing a standard curve by taking the BSKZ-1 peak area as the ordinate and the concentration as the abscissa. The results show that the linear relation of the concentration (C) of BSKZ-1 and the peak area (A) in the range of 0.0699-1.9960 [ mu ] g-ml-1 is good, the linear regression equation is A = 0.5411C-0.0081, and R = 0.9998. The correlation coefficient was 0.9999.
1.3 recovery rate
Precisely measuring 2ml of a reference substance stock solution under the item of '1.2', placing the reference substance stock solution into a 20ml measuring flask, adding a solvent to dilute the solution to a scale, and shaking up the solution to be used as an accuracy mother solution; taking 9 parts of posaconazole, each part of posaconazole is 10mg, placing the posaconazole in a 10ml measuring flask, precisely weighing, respectively taking 3 parts, respectively weighing 0.5 ml, 1ml and 1.5ml of reference substances, dissolving and diluting to a scale, shaking up, measuring by a method, and calculating the BSKZ-1 recovery rate. The results show that the recovery of BSKZ-1 is between 96.21% and 99.2%, RSD =1.14% (n = 9).
1.4 BSKZ-1 solution stability Studies
Taking 10mg of posaconazole, precisely weighing, placing in a 10ml measuring flask, adding a solvent for dissolving, adding 0.1ml of BSKZ-1 stock solution, diluting to scale, shaking up, precisely weighing 20ul at regular intervals, injecting into a liquid chromatograph, and recording the chromatogram. Within 24h, the peak area RSD of BSKZ-124 h is 1.99% < 2%, which indicates that BSKZ-1 is stable within at least 24 h.
1.5 quantitative Limit determination
Taking BSKZ-1 reference substance stock solution under the item of '1.2', gradually diluting the stock solution into reference substance solutions with different concentrations, measuring according to a method, and recording the signal-to-noise ratio of a BSKZ-1 peak. The quantitative limit is set at S/N = 10, and the corresponding concentration is 0.0699 ug/ml－ 1S/N = 3, the detection limit is 0.0210 ug/ml－ 1. As shown in fig. 2.
Example 2
BSKZ-1 content in posaconazole
Chromatographic conditions are as follows:
(1) a chromatographic column: agilent ZORBAX-Phenyl chromatographic column (150 mm. times.4.6 mm, 3.5 um);
a detector: an ultraviolet absorption detector (UVD);
detection wavelength: 225 nm;
flow rate: 1.0ml/min-1；
Column temperature: min at 40 ℃;
a solvent; acetonitrile: water (50: 50);
sample introduction volume: 20 ul.
(2) Preparing test solution and reference solution: the reference solution is prepared by precisely weighing about 10mg of BSKZ-1, placing the BSKZ-1 in a 100ml measuring flask, adding a solvent to dissolve and quantitatively dilute the BSKZ-1, and shaking up the BSKZ-1 to serve as a reference stock solution. Precisely measuring 1ml of the stock solution, placing in a 100ml measuring flask, adding solvent to dilute to scale, and shaking up to obtain a reference solution. Taking 10mg of posaconazole, precisely weighing, adding a solvent for dissolving, and quantitatively diluting to prepare a solution containing 1mg of posaconazole in each l of ml.
(3) The determination method comprises the following steps: precisely measuring 20ul of sample, injecting into a liquid chromatograph, recording chromatogram, and calculating according to an area normalization method; the retention time of the main peak of the test solution is consistent with that of the main peak of the reference solution; if an isomer peak exists in the chromatogram of the test solution, the BSKZ-1 can not exceed 0.1 percent calculated by an external standard method.
(4) Calculation results
The retention time of the BSKZ-1 peak of the control product is t =7.833min, and no BSKZ-1 is detected in the sample, as shown in FIG. 3.
Description of the drawings:
FIG. 1 System adaptive chromatogram;
FIG. 2 is a quantitative limit diagram;
FIG. 3 is a graph showing the measurement results of the sample.
Claims (6)
1. A detection method for determining BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in posaconazole is characterized in that a posaconazole sample is prepared into a solution, then a liquid chromatograph is used for detecting BSKZ-1((5R-cis) -toluene-4-sulfonic acid 5- (2, 4-difluorophenyl) -5- (1H-1,2, 4-triazole-1-yl) methyltetrahydrofuran-3-ylmethyl ester) in posaconazole according to a reference substance, and the BSKZ-1 is called as BSKZ-1 for short, the method specifically comprises the following steps:
(1) chromatographic conditions
A chromatographic column: agilent ZORBAX-Phenyl chromatographic column (150 mm. times.4.6 mm, 3.5 um);
a detector: an ultraviolet absorption detector (UVD);
detection wavelength: 225 nm;
flow rate: 1.0ml/min-1；
Column temperature: min at 40 ℃;
a solvent; acetonitrile: water (50: 50);
sample introduction volume: 20 ul;
(2) sample preparation:
precisely weighing about 10mg of BSKZ-1 in a reference solution, placing the reference solution in a 100ml measuring flask, adding a solvent for dissolving, quantitatively diluting, shaking up to obtain a reference stock solution, precisely weighing 1ml of the stock solution, placing the stock solution in a 100ml measuring flask, adding the solvent for diluting to a scale, shaking up to obtain the reference solution;
precisely weighing 10mg of posaconazole in the sample solution, placing the posaconazole in a 10ml measuring flask, precisely weighing, adding a solvent for dissolving, and quantitatively diluting to prepare a solution containing 1.0mg in each ml;
(3) the determination method comprises the following steps: precisely measuring 20ul of sample, injecting into a liquid chromatograph, recording chromatogram, and calculating according to an external standard method; the retention time of the main peak of the test solution is consistent with that of the main peak of the reference solution; if an impurity BSKZ-1 peak exists in a chromatogram of a test solution, the BSKZ-1 is not more than 0.1 percent calculated by an external standard method.
2. The detection method according to claim 1, wherein the column temperature is controlled to 40 ℃.
3. The detection method for liquid chromatography as claimed in claim 1, wherein the detection wavelength is 225 nm.
4. The detection method according to claim 1, wherein the flow rate is 1.0 ml/min.
5. The detection method according to claim 1, wherein the mobile phase is acetonitrile-water (50: 50).
6. The method according to claim 1, wherein the column is an AgilentZORBAX-Phenyl column (150mm x 4.6 mm, 3.5 um).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112697937A (en) * | 2020-12-18 | 2021-04-23 | 卓和药业集团有限公司 | Method for analyzing dissolution rate of posaconazole enteric-coated tablets |
| CN114184721A (en) * | 2021-12-14 | 2022-03-15 | 江苏恒盛药业有限公司 | Method for detecting residual posaconazole solvent |
| CN114478438A (en) * | 2020-11-13 | 2022-05-13 | 江苏恒盛药业有限公司 | Semicarbazide analogue compound, preparation method and application |
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2018
- 2018-09-20 CN CN201811098699.4A patent/CN110927262A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478438A (en) * | 2020-11-13 | 2022-05-13 | 江苏恒盛药业有限公司 | Semicarbazide analogue compound, preparation method and application |
| CN112697937A (en) * | 2020-12-18 | 2021-04-23 | 卓和药业集团有限公司 | Method for analyzing dissolution rate of posaconazole enteric-coated tablets |
| CN114184721A (en) * | 2021-12-14 | 2022-03-15 | 江苏恒盛药业有限公司 | Method for detecting residual posaconazole solvent |
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