CN117849243A - Impurity Z in mometasone furoate cream 3r And impurity Z 3q Method for separation and measurement of (2) - Google Patents
Impurity Z in mometasone furoate cream 3r And impurity Z 3q Method for separation and measurement of (2) Download PDFInfo
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- CN117849243A CN117849243A CN202311812452.5A CN202311812452A CN117849243A CN 117849243 A CN117849243 A CN 117849243A CN 202311812452 A CN202311812452 A CN 202311812452A CN 117849243 A CN117849243 A CN 117849243A
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- 239000012535 impurity Substances 0.000 title claims abstract description 183
- 229960002744 mometasone furoate Drugs 0.000 title claims abstract description 54
- WOFMFGQZHJDGCX-ZULDAHANSA-N mometasone furoate Chemical compound O([C@]1([C@@]2(C)C[C@H](O)[C@]3(Cl)[C@@]4(C)C=CC(=O)C=C4CC[C@H]3[C@@H]2C[C@H]1C)C(=O)CCl)C(=O)C1=CC=CO1 WOFMFGQZHJDGCX-ZULDAHANSA-N 0.000 title claims abstract description 54
- 239000006071 cream Substances 0.000 title claims abstract description 18
- 238000000926 separation method Methods 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 35
- 238000005259 measurement Methods 0.000 title description 6
- 238000001514 detection method Methods 0.000 claims abstract description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- WXYIONYJZVWSIJ-UHFFFAOYSA-N acetonitrile;methanol;hydrate Chemical compound O.OC.CC#N WXYIONYJZVWSIJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 5
- 239000000945 filler Substances 0.000 claims abstract description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 4
- 239000012488 sample solution Substances 0.000 claims description 26
- 238000012360 testing method Methods 0.000 claims description 21
- 239000000523 sample Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- 230000014759 maintenance of location Effects 0.000 claims description 8
- 238000007865 diluting Methods 0.000 claims description 6
- 238000012937 correction Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- 239000000243 solution Substances 0.000 description 54
- 239000002904 solvent Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000011550 stock solution Substances 0.000 description 10
- 238000005303 weighing Methods 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000009210 therapy by ultrasound Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000011159 matrix material Substances 0.000 description 6
- 239000013558 reference substance Substances 0.000 description 6
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 5
- 239000012086 standard solution Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- 229960001664 mometasone Drugs 0.000 description 4
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 4
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000002075 main ingredient Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012088 reference solution Substances 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- KUVIULQEHSCUHY-XYWKZLDCSA-N Beclometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O KUVIULQEHSCUHY-XYWKZLDCSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229950000210 beclometasone dipropionate Drugs 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- -1 octenyl aluminum succinate Chemical compound 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Abstract
The invention discloses an impurity Z in mometasone furoate emulsifiable paste 3r And impurity Z 3q During separation, octadecylsilane chemically bonded silica is used as chromatographic column filler, methanol-acetonitrile-water is used as mobile phase, detection wavelength is 334nm, and impurity Z is separated from mometasone furoate cream by high performance liquid chromatography 3r And impurity Z 3q . The invention can be used for preparing the impurity Z 3r And impurity Z 3q Detecting Z 3r And impurity Z 3q Has a warning structure, and the control of the warning structure is beneficial to the quality control of the mometasone furoate emulsifiable paste, and the impurity Z in the mometasone furoate emulsifiable paste 3r And impurity Z 3q Has important significance for improving the quality of mometasone furoate cream.
Description
Technical Field
The invention relates to the technical field of chemical analysis, in particular to an impurity Z in mometasone furoate emulsifiable paste 3r And impurity Z 3q Is a method for separation and measurement of (a).
Background
The auxiliary materials of the mometasone furoate emulsifiable paste comprise hexanediol, hydrogenated soybean phosphatidylcholine, titanium dioxide, octenyl aluminum succinate starch, white beeswax, white vaseline, purified water and phosphoric acid, and the main degradation impurities are mometasone furoate impurity H, mometasone furoate impurity Q, mometasone furoate impurity G and mometasone furoate impurity D. Mometasone furoate impurity Z under strong acid and strong alkali conditions 3r And mometasone furoate impurity Z 3q Degradation occurs.
At present, the mometasone furoate emulsifiable paste has a load in USP2023, BP2023 and national drug standards, and the mometasone furoate impurity Z is not contained in all the standards 3r And mometasone furoate impurity Z 3q And controlling. The main component and the impurity Z are determined by adopting a related substance determination method in USP2023 3r Impurity D and impurity Z 3r Baseline separation cannot be achieved (see fig. 18), so an alternative approach is proposed for impurity Z 3r And impurity Z 3q And (5) detecting.
In the prior art, CN113203807A discloses a detection method of mometasone furoate related substances, which comprises the following steps: mometasone furoate and beclomethasone dipropionate degrade impurity B, C, D, G, H (formula not disclosed). The chromatographic conditions are as follows: chromatographic column: octadecylsilane chemically bonded silica packed chromatographic column; detection wavelength: 245-265nm; column temperature: 20-40 ℃; flow rate: 0.8-1.2mL/min; sample injection amount: 15-25 mu L; mobile phase: acetonitrile-water, mobile phase ratio 41-51:46-59.
The publication fails to achieve a reduction in impurity Z 3r And impurity Z 3q Is detected. Thus, how to realize impurity Z in mometasone furoate cream 3r And impurity Z 3q The detection of the mometasone furoate is used for improving the quality control of the mometasone furoate emulsifiable paste, and the technical problem to be solved is needed to be solved.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a method for separating impurity Z from mometasone furoate 3r And/or impurity Z 3q Selecting proper chromatographic column, mobile phase and detection wavelength, and adding impurity Z in mometasone furoate emulsifiable paste 3r And/or impurity Z 3q And (3) carrying out effective separation.
In order to achieve the above purpose, the invention adopts the following technical scheme:
separation of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q The structural formula of the impurity Z3r is shown as formula I, and the impurity Z 3q The structural formula is shown as a formula II; the method comprises the following steps: octadecylsilane chemically bonded silica is used as a chromatographic column filling agent, methanol-acetonitrile-water is used as a mobile phase, and an impurity Z is separated from mometasone furoate cream by a high performance liquid chromatography 3r And/or impurity Z 3q 。
Further, the volume ratio of the mobile phase methanol-acetonitrile-water is 17-19:46-48:34-36.
Further, the specification of the column was 4.6mm×250mm,5 μm.
Further, when the separation is performed by high performance liquid chromatography, the flow rate is 0.9-1.1ml per minute; the column temperature is 24-26 ℃; the sample volume was 50. Mu.l.
The second purpose of the invention is to provide a qualitative identification method for the impurity Z in mometasone furoate emulsifiable paste 3r And/or impurity Z 3q The method can realize the impurity Z at ultra-low concentration 3r And impurity Z 3q Is provided.
In order to achieve the above purpose, the invention adopts the following technical scheme:
qualitative identification of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q The method provided by the invention is used for detecting mometasone furoate and impurity Z in a substance 3r And impurity Z 3q And (3) separating, detecting by using a detector with detection wavelength of 334nm, and obtaining a chromatogram.
Further, according to the retention time, the three components are mometasone furoate and impurity Z sequentially from short to long 3r And/or impurity Z 3q 。
As a preferable technical scheme, the volume ratio of the mobile phase methanol-acetonitrile-water is 18:47:35; the flow rate is 1.0ml per minute; the column temperature is 25 ℃; detection wavelengths are 334nm and 254nm; the sample volume was 50. Mu.l.
Further, mometasone furoate with retention time of 12.7+ -0.5 min and impurity Z with retention time of 13.8+ -0.5 min 3r The retention time is 15.5+ -0.5 min and is impurity Z 3q 。
The third object of the invention is to provide a method for measuring the impurity Z in mometasone furoate cream 3r And/or impurity Z 3q Content method, which can realize impurity Z 3r And/or impurity Z 3q And (3) content detection and recovery.
In order to achieve the above purpose, the invention adopts the following technical scheme:
determination of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q The content method comprises the following steps:
(1) Preparing a reference substance solution, a test substance solution and a test substance labeling solution: dissolving a sample to be detected in a diluent to obtain a sample solution; taking out the impurity Z 3r And/or impurity Z 3q Respectively dissolving with diluent to obtain reference solution;
(2) Separating: the method provided by the purpose of the invention is adopted to separate the impurity Z in the mometasone furoate emulsifiable paste 3r And/or impurity Z 3q ；
(3) And (3) identification: after separation, the method provided by the second object of the invention is adopted to separate the impurity Z 3r And/or impurity Z 3q Performing identification;
(4) And (3) content calculation: calculating the impurity Z according to the chromatogram 3r And/or impurity Z 3q Is contained in the composition.
Further, according to the chromatograms, the impurity Z is calculated according to a self-contrast method added with correction factors 3r And impurity Z 3q Is contained in the composition.
Further, the self-contrast method for adding the correction factors comprises the following steps:
wherein A is s : peak area of impurity (334 nm) in the sample solution; a is that z : peak area of principal component in control solution (254 nm); f: an impurity correction factor; n: dilution factors of the control solution were formulated.
Compared with the prior art, the invention has the beneficial effects that:
1. the invention can be used for preparing the impurity Z 3r And impurity Z 3q Detecting Z 3r And impurity Z 3q Has a warning structure, and the control of the warning structure is beneficial to the quality control of the mometasone furoate emulsifiable paste, and the impurity Z in the mometasone furoate emulsifiable paste 3r And impurity Z 3q Has important significance for improving the quality of mometasone furoate cream.
2. The invention aims at impurity Z 3r And impurity Z 3q In the measurement, impurity Z was detected at a detection wavelength of 334nm 3r And impurity Z 3q The absorption is strong, the absorption of other impurities is weak, no peak appears when the concentration level is about 0.5 percent (higher than the limit of the impurities), the interference of other impurities on the measurement result can be effectively avoided, and the detection time is shortened.
Drawings
FIG. 1 shows a specificity map (at 334nm, peaks from left to right are in turn mometasone 1-furoate, 2-impurity Z 3r And 3-impurity Z 3q The method comprises the steps of carrying out a first treatment on the surface of the At 254nm, the peaks from left to right are 1-furoic acid, 2-impurity H, 3-impurity G, 4-impurity Q, 5-impurity C, 6-furoic acid mometasone, 7-impurity Z 3r 8-impurity D and 9-impurity Z 3q )。
FIG. 2 shows an accuracy representative spectrum (peaks from left to right at 334nm are in turn mometasone 1-furoate, 2-impurity Z) 3r And 3-impurity Z 3q The method comprises the steps of carrying out a first treatment on the surface of the At 254nm, the peaks from left to right are in turn mometasone 1-furoate, 2-impurity Z 3r And 3-impurity Z 3q )。
Fig. 3 shows the durability-normal condition (334 nm) according to an embodiment of the present invention.
FIG. 4 shows durability-column flow rate 0.9ml/min (334 nm) according to an embodiment of the present invention.
FIG. 5 shows durability-column flow rate 1.1ml/min (334 nm) according to an embodiment of the present invention.
Fig. 6 shows durability-column temperature 24 ℃ (334 nm) according to an embodiment of the present invention.
Fig. 7 shows durability-column temperature 26 ℃ (334 nm) according to an embodiment of the present invention.
Fig. 8 shows the durability-mobile phase ratio (methanol: acetonitrile: water=17:48:35) according to an embodiment of the invention.
Fig. 9 shows the durability-mobile phase ratio (methanol: acetonitrile: water=19:46:35) according to an embodiment of the invention.
Fig. 10 shows the durability-mobile phase ratio (methanol: acetonitrile: water=18:48:34) according to an embodiment of the invention.
Fig. 11 shows the durability-mobile phase ratio (methanol: acetonitrile: water=17:47:36) according to an embodiment of the invention.
Fig. 12 shows the durability-mobile phase ratio (methanol: acetonitrile: water=18:46:36) according to an embodiment of the invention.
Fig. 13 shows the durability-mobile phase ratio (methanol: acetonitrile: water=19:47:34) according to an embodiment of the invention.
FIG. 14 shows the solution stability-test sample solution (upper 0h test sample solution, lower 27h test sample solution at 334 nm) according to an embodiment of the present invention.
FIG. 15 shows a solution stability-control solution (upper 0h control solution, lower 27h control solution at 254 nm) according to an embodiment of the invention.
Fig. 16 shows an impurity solution stability-system solution (upper 0h system solution, lower 24h system solution at 334 nm) according to an embodiment of the present invention.
FIG. 17 shows solution stability-test labeling solution (upper 0h test labeling solution, lower 24h test labeling solution at 334 nm) according to an embodiment of the invention.
FIG. 18 shows the content of USP2023 chromatographic conditions, impurity Z 3r Impurity Z 3q Separated from the main component and other impurities.
Detailed Description
The following examples are given for the purpose of better illustration only, but the invention is not limited to the examples. Those skilled in the art will appreciate from the foregoing disclosure that various modifications and adaptations of the embodiments described herein can be made to other examples without departing from the scope of the invention.
The invention will now be further described with reference to the accompanying drawings.
The chemical names and structural descriptions are shown in Table 1:
table 1. List of names and structural formulas:
example 1:
the embodiment of the invention provides an impurity Z in mometasone furoate emulsifiable paste 3r And impurity Z 3q According to the separation and measurement method, the target impurity, the main component and other known impurities are not easy to be well separated by adjusting the proportion of the mobile phase, and then the impurity Z is obtained by adopting ultraviolet spectrum scanning 3r And impurity Z 3q The maximum absorption wavelength of (a) is about 334nm, and other known impurities (including impurity D) are weak in absorption at the wavelength, and no peak is generated at the concentration level of about 0.5% (higher than the limit of the impurity) (FIG. 2), so that under the detection condition of 334nm, the main component and other known impurities do not interfere with the impurity Z 3q And impurity Z 3r The detection is carried out, and the method has good specificity.
Preparing impurity mixed solution (each impurity concentration is about 0.5 μg/ml, and is equivalent to 0.5% of main component concentration), and measuring under 254nm and 334nm conditions, respectively, and measuring furoic acid and impurity under 254nmThe substances H, Q, G, C and D all have peaks, but no peak at 334nm, and only the impurity Z is detected at 334nm 3r Impurity Z 3q And the main component, and the peak-to-peak separation degree is good.
Sample preparation:
solvent acetonitrile-water-glacial acetic acid (50:50:0.1).
Taking 2g of sample solution (about 2mg of mometasone furoate), placing in a 50ml beaker, adding 10ml of acetonitrile, placing in a 60 ℃ water bath, strongly stirring for 20min, then performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking uniformly, placing in an ice water bath for more than 30min, filtering, and taking the subsequent filtrate.
Precisely measuring 1ml of the sample solution in the control solution, placing the sample solution in a 100ml measuring flask, diluting the sample solution to a scale with a solvent, shaking the sample solution uniformly, precisely measuring 5ml of the sample solution, placing the sample solution in a 50ml measuring flask, diluting the sample solution to the scale with the solvent, and shaking the sample solution uniformly.
System applicability solution taking mometasone furoate cream system applicability reference (containing mometasone furoate and impurity Z) 3q Impurity Z 3r ) After a proper amount of acetonitrile is added for ultrasonic dissolution, the solution is diluted by a solvent to prepare a solution containing about 0.1mg of acetonitrile per 1 ml.
Chromatographic conditions:
octadecyl bonded silica gel as filler (Symmetry C18,4.6 mm. Times.250 mm,5 μm or column with equivalent potency); methanol-acetonitrile-water (18:47:35) as mobile phase; the flow rate is 1.0ml per minute; the column temperature is 25 ℃; detection wavelengths are 334nm and 254nm; the sample volume was 50. Mu.l.
Example 2: specificity experiments
Blank solvent acetonitrile-water-glacial acetic acid (50:50:0.1)
Weighing 2g of the sample solution, placing in a 50ml beaker, adding 10ml of acetonitrile, placing in a 60 ℃ water bath, strongly stirring for 20min, performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking uniformly, placing in an ice water bath for more than 30min, taking the solution, filtering, and taking the subsequent filtrate as the sample solution.
The blank matrix solution is prepared by weighing 2g of blank matrix, placing in a 50ml beaker, adding 10ml acetonitrile, placing in a water bath at 60 ℃, strongly stirring for 20min, performing ultrasonic treatment for 5min, adding 10ml solvent, shaking uniformly, placing in an ice water bath for more than 30min, filtering the solution, and taking the subsequent filtrate as the blank matrix solution.
And weighing a proper amount of mometasone furoate reference substances, and respectively preparing a main ingredient stock solution with the concentration of 1mg/ml and a main ingredient positioning solution with the concentration of 0.1 mg/ml.
Weighing impurity Z 3r And impurity Z 3q An impurity stock solution having a concentration of 0.1mg/ml and an impurity locating solution having a concentration of 0.1. Mu.g/ml were prepared, respectively.
Weighing impurity H, impurity Q, impurity G, impurity C, impurity D and proper amount of furoic acid, and respectively preparing into impurity stock solution with concentration of 0.1mg/ml and impurity positioning solution with concentration of 0.5 mug/ml.
And precisely transferring the mixed positioning solution, placing the impurity stock solution and the main component stock solution in a same 100ml measuring flask, diluting to a scale with a solvent, and shaking uniformly.
50 μl of the blank solvent, the blank matrix solution, the sample solution, each positioning solution and the mixed positioning solution were respectively taken, injected into a liquid chromatograph, and the chromatograms were recorded, and the test results are shown in table 2, table 3 and fig. 1.
TABLE 2 specificity test results 1
TABLE 3 specificity test results 2
Conclusion: the blank solvent and the blank matrix do not interfere with the detection of the sample; impurity D, impurity C, impurity H, impurity Q, impurity G, and furoic acid at 0.5% sample concentration level, peak at 254nm, but no peak at 334 nm. At 334nm, impurity Z 3r The separation degree from the adjacent peaks is 2.14, and the impurity Z 3q The separation degree from the adjacent peak is 3.61, which shows that the method has no interference to the measurement of the target impurity at 334nm, and shows that the method measures the impurity Z 3r And impurity Z 3q The specificity is good.
Example 3: accuracy experiment
Weighing impurity Z 3r About 5mg of reference substance is put into a 50ml measuring flask, dissolved and diluted to the scale with acetonitrile, and shaken uniformly to be used as impurity Z 3r A stock solution;
weighing impurity Z 3q About 5mg of reference substance is put into a 50ml measuring flask, dissolved and diluted to the scale with acetonitrile, and shaken uniformly to be used as impurity Z 3q A stock solution;
respectively and precisely removing the Z 3r Stock solution and Z 3q Stock solution 2ml was diluted to scale with acetonitrile in the same 100ml volumetric flask and shaken well as impurity mixed solution.
Precisely transferring 2.5ml of the impurity mixed solution, placing the mixed solution into a 50ml measuring flask, and diluting the mixed solution to a scale with a solvent to serve as a reference substance solution;
weighing 2g of the sample solution, placing in a 50ml beaker, adding 10ml of acetonitrile, placing in a 60 ℃ water bath, strongly stirring for 20min, performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking uniformly, placing in an ice water bath for more than 30min, taking the solution, filtering, and taking the subsequent filtrate as the sample solution.
2g of the sample is weighed by adding the nominal solution into 2 parts in parallel, placing the sample into a 50ml beaker, adding 1ml of the impurity mixed solution, uniformly stirring, adding 9ml of acetonitrile, placing the sample into a water bath at 60 ℃, strongly stirring for 20min, performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking uniformly, placing the sample into an ice water bath for more than 30min, taking the solution, filtering, and taking the subsequent filtrate as the sample adding standard solution.
Taking 50 μl of each of the reference solution, the test solution and the test standard solution, respectively injecting into chromatograph, and recording chromatogram at 334 nm. Recovery results were calculated by external standard method and self-contrast method, respectively, and test results are shown in tables 4, 5 and fig. 2.
TABLE 4 Standard addition assay-external Standard results
TABLE 5 Standard addition assay-self-control results
Conclusion: calculating impurity Z by adopting external standard method 3r And impurity Z 3q The accuracy of (2) is 110.7% and 109.9%, respectively; calculating impurity Z by self-contrast method 3r And impurity Z 3q The accuracy of (2) is 108.5% and 101.6%, respectively; the sample matrix does not interfere with the detection of the impurity.
Example 3: solution stability experiment
Taking 2g of the product, placing the product in a 50ml beaker, adding 10ml of acetonitrile, placing the mixture in a water bath at 60 ℃, strongly stirring the mixture for 20min, performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking the mixture uniformly, placing the mixture in an ice water bath for more than 30min, filtering the mixture, and taking a subsequent filtrate, namely the sample solution. Taking 1ml to 100ml of sample solution from a volumetric flask, adding solvent to dilute to a scale, and shaking uniformly. Then precisely transferring 1ml to 10ml volumetric flask, diluting with solvent to scale, shaking, and taking as self control solution.
Weighing 2g of the product, placing in a 50ml beaker, adding 1ml of impurity mixed solution (under the special term), adding 9ml of acetonitrile, placing in a 60 ℃ water bath, strongly stirring for 20min, performing ultrasonic treatment for 5min, adding 10ml of solvent, shaking uniformly, placing in an ice water bath for more than 30min, taking the solution, filtering, and taking the subsequent filtrate as a sample and adding a standard solution.
5ml of the main component stock solution (under the special item) and 2.5ml of the impurity mixed solution (under the special item) are precisely removed, placed in the same 50ml measuring flask, and diluted to the scale with a solvent to obtain a system applicability solution.
At different time points, 50 μl of each of the test sample solution, the self-control solution, the system applicability solution and the test sample addition standard solution was injected into a chromatograph, the chromatogram was recorded, and the peak area RSD was calculated and compared with each peak area for 0 hour. The test results are shown in Table 6, FIGS. 14 to 17.
TABLE 6 solution stability results
Conclusion: the main peak areas of the sample solution and the control solution at 12 hours, 18 hours, 24 hours and 27 hours respectively have no obvious change compared with 0 hour, and the RSD of the peak areas is respectively 0.4 percent and 3.2 percent and is less than 5.0 percent; the test solution and the control solution were stable for 27 hours. System applicability solution impurity Z at 8, 12, 18, 24 hours respectively 3r Impurity Z 3q The peak area of the main component has no obvious change compared with 0 hour, and the RSD of the peak area is respectively 3.9%, 3.9% and 0.4% and less than 5.0%; impurity Z of sample adding standard solution in 8, 12, 18 and 24 hours respectively 3r Impurity Z 3q The peak area of the main component was not significantly changed from 0 hours, and the RSD of the peak area was 3.5%, 2.3%, 0.7%, and less than 5.0%, respectively. The test sample addition and system solutions were stable over 24 hours.
Example 4: chromatographic durability test
System applicability solution: taking mometasone furoate cream system applicability reference substance (containing mometasone furoate and impurity Z) 3r Impurity Z 3q ) 3ml of acetonitrile was added in an appropriate amount, and the mixture was dissolved by ultrasonic treatment, and diluted with a solvent to prepare a solution containing about 0.1mg per 1 ml.
The system applicability solution was measured precisely, and the system applicability solution was tested by performing minute changes in flow rate, column temperature and mobile phase ratio, and the degree of separation between the target impurity and the adjacent peak in the system applicability solution was recorded at a wavelength of 334nm, and the test results are shown in tables 7, 8 and fig. 3 to 13.
TABLE 7 impurity Z 3r Chromatographic durability test results
TABLE 8 impurity Z 3q Chromatographic durability test results
Conclusion: when the proportion of the mobile phase, the flow rate of the column and the temperature of the column slightly fluctuate, the impurity Z 3r And impurity Z 3q The separation degree from the adjacent peaks is more than 1.5, and the durability of the chromatographic condition is good.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention, and are intended to be included within the scope of the appended claims and description.
Claims (10)
1. Separation of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q Is characterized in that the impurity Z 3r The structural formula is shown as formula I, the impurity Z 3q The structural formula is shown as a formula II; the method comprises the following steps: octadecylsilane chemically bonded silica is used as a chromatographic column filling agent, methanol-acetonitrile-water is used as a mobile phase, and an impurity Z is separated from mometasone furoate cream by a high performance liquid chromatography 3r And/or impurity Z 3q ；
2. The method according to claim 1, wherein the mobile phase methanol-acetonitrile-water volume ratio is 17-19:46-48:34-36.
3. The method of claim 1, wherein the chromatographic column has a specification of 4.6mm x 250mm,5 μm.
4. The method according to claim 1, wherein the flow rate is 0.9-1.1ml per minute when the separation is performed by high performance liquid chromatography; the column temperature is 24-26 ℃; the sample volume was 50. Mu.l.
5. Qualitative identification of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q Characterized in that mometasone furoate and impurity Z in the test substance are reacted by the method according to any one of claims 1 to 4 3r And/or impurity Z 3q And (3) separating, detecting by using a detector with detection wavelength of 334nm, and obtaining a chromatogram.
6. The method according to claim 5, wherein the three components are mometasone furoate, impurity Z in order from short to long according to the retention time 3r And/or impurity Z 3q 。
7. The method according to claim 5, wherein the mobile phase methanol-acetonitrile-water volume ratio is 18:47:35; the flow rate is 1.0ml per minute; the column temperature is 25 ℃; detection wavelengths are 334nm and 254nm; the sample volume was 50. Mu.l.
8. The method according to claim 7, wherein mometasone furoate is used as the mometasone furoate with a retention time of 12.7+ -0.5 min and impurity Z is used as the impurity Z with a retention time of 13.8+ -0.5 min 3r The retention time is 15.5+ -0.5 min and is impurity Z 3q 。
9. Determination of impurity Z in mometasone furoate cream 3r And/or impurity Z 3q The content method is characterized by comprising the following steps:
(1) Preparing a control solution and a test sample solution: dissolving a detection product in a diluent to obtain a sample solution; diluting a sample solution with a diluent to prepare a control solution;
(2) Separating: separating impurity Z in mometasone furoate cream by the method as claimed in any one of claims 1 to 4 3r And/or impurity Z 3q ；
(3) And (3) identification: after separation, the separated impurity Z is subjected to the method as claimed in any one of claims 5 to 8 3r And/or impurity Z 3q Performing identification;
(4) And (3) content calculation: calculating the impurity Z according to the chromatogram 3r And/or impurity Z 3q Is contained in the composition.
10. The method according to claim 9, wherein the impurity Z is calculated from the chromatogram by self-contrast with added correction factors 3r And/or impurity Z 3q Is contained in the composition.
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