CN106908531B - A kind of Gradient High Performance Liquid Chromatography measures Nabumetone simultaneously for Buddhist nun's Photodegradation Products and other methods in relation to substance - Google Patents
A kind of Gradient High Performance Liquid Chromatography measures Nabumetone simultaneously for Buddhist nun's Photodegradation Products and other methods in relation to substance Download PDFInfo
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- CN106908531B CN106908531B CN201710096465.5A CN201710096465A CN106908531B CN 106908531 B CN106908531 B CN 106908531B CN 201710096465 A CN201710096465 A CN 201710096465A CN 106908531 B CN106908531 B CN 106908531B
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- nabumetone
- buddhist nun
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- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 title claims abstract description 126
- 229960004270 nabumetone Drugs 0.000 title claims abstract description 126
- 239000000126 substance Substances 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000001782 photodegradation Methods 0.000 title claims abstract description 10
- 238000004128 high performance liquid chromatography Methods 0.000 title claims description 12
- 239000000243 solution Substances 0.000 claims abstract description 44
- 239000012535 impurity Substances 0.000 claims abstract description 35
- 238000001514 detection method Methods 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 238000010828 elution Methods 0.000 claims abstract description 26
- 239000013558 reference substance Substances 0.000 claims abstract description 26
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 25
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 25
- 239000010452 phosphate Substances 0.000 claims abstract description 25
- 239000012085 test solution Substances 0.000 claims abstract description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000035945 sensitivity Effects 0.000 claims abstract description 10
- 238000010812 external standard method Methods 0.000 claims abstract description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims description 24
- 239000002994 raw material Substances 0.000 claims description 23
- 239000007788 liquid Substances 0.000 claims description 19
- 238000005259 measurement Methods 0.000 claims description 17
- 239000002775 capsule Substances 0.000 claims description 16
- 239000000523 sample Substances 0.000 claims description 14
- 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 claims description 11
- 239000012043 crude product Substances 0.000 claims description 9
- 230000014759 maintenance of location Effects 0.000 claims description 8
- 239000003643 water by type Substances 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 7
- 239000012086 standard solution Substances 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 5
- 238000012360 testing method Methods 0.000 claims description 5
- 238000010829 isocratic elution Methods 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 4
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000012488 sample solution Substances 0.000 claims description 3
- 239000008363 phosphate buffer Substances 0.000 claims description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 238000007689 inspection Methods 0.000 claims 1
- 239000012071 phase Substances 0.000 abstract description 63
- 238000004587 chromatography analysis Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000007791 liquid phase Substances 0.000 abstract description 2
- 238000005457 optimization Methods 0.000 abstract 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 239000008096 xylene Substances 0.000 description 15
- -1 chloro- 4- fluorophenyl Chemical group 0.000 description 12
- 238000005286 illumination Methods 0.000 description 8
- 230000005484 gravity Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 5
- 239000004258 Ethoxyquin Substances 0.000 description 5
- 229940093500 ethoxyquin Drugs 0.000 description 5
- 235000019285 ethoxyquin Nutrition 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229960001686 afatinib Drugs 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003139 buffering effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000004262 preparative liquid chromatography Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- DKPBWQKQXNICDH-UHFFFAOYSA-N aniline;quinazoline Chemical class NC1=CC=CC=C1.N1=CN=CC2=CC=CC=C21 DKPBWQKQXNICDH-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses the high efficiency liquid phase chromatographic analysis methods that a kind of Nabumetone replaces Buddhist nun, specifically chromatographic column is octadecylsilane chemically bonded silica column (100 × 4.6mm, 3.5 μm), with phosphate buffer-methanol (82: 18) for mobile phase A, with phosphate buffer-methanol (40:60) for Mobile phase B, gradient elution, column temperature is 30 DEG C, flow velocity is 1.0ml/min, Detection wavelength 247nm；Nabumetone is taken, for Buddhist nun's preparation, to add mobile phase A that the solution that concentration is 0.5mg/ml is made, as test solution for Buddhist nun or Nabumetone；It takes Nabumetone for Buddhist nun's reference substance, adds mobile phase A that the solution that concentration is 0.005mg/ml is made, as reference substance solution.Sample introduction respectively, by external standard method with calculated by peak area, the sum of each impurity peak area must not exceed 1.0% in the chromatogram of test solution.First Determination of the present invention Nabumetone replaces Buddhist nun's Photodegradation Products and other contents in relation to substance, has no pertinent literature report.It can fast and accurately detect that Nabumetone replaces the Photodegradation Products and other impurity of Buddhist nun, easy to operate, favorable reproducibility, high sensitivity can control Nabumetone preferably for Buddhist nun's product quality, provide guarantee for synthesis and preparation process optimization.
Description
Technical field
The present invention relates to Nabumetones for the analysis method of Buddhist nun's raw material and its related preparations, and in particular to a kind of to use high-efficient liquid phase color
The method that the method for spectral gradient is measured belongs to Pharmaceutical Analysis detection field.
Background technique
Nabumetone is a kind of aniline quinazoline class anti-cancer drugs for Buddhist nun, and clinic is envisaged for the treatment of advanced Non-small cell lung.
Its chemical name is (E)-N- [4- (the chloro- 4- fluorophenyl of 3-) amino) -7- ethoxyquin oxazoline -6- base] -4- (dimethylamino)
But-2-enamides xylenesulfonate crystalline hydrate, molecular formula C22H23ClFN5O2·(C7H8O3S)2, chemical structural formula
It is as follows:
Nabumetone is easy to produce cis-isomer in 2 double bonds in synthesis and storage for Buddhist nun, separately simultaneously may also
There are each intermediate, by-product and catabolite, it is different for Buddhist nun and its optics to be difficult to separate Nabumetone using general analysis method
Structure body, herein by adjusting different flowing phase composition, ratio, different types of elution, different pH value and different inorganic
Salinity realizes for the first time while measuring Nabumetone for Buddhist nun's Photodegradation Products and other related purposes in relation to substance, guarantees well
Nabumetone is quality controllable for Buddhist nun raw material, has realistic meaning.
Summary of the invention
The object of the present invention is to provide a kind of Gradient High Performance Liquid Chromatography measure simultaneously Nabumetone for Buddhist nun's Photodegradation Products and
Other methods in relation to substance can be used for Nabumetone for Buddhist nun's preparation process and the control of the quality of final products.
The technical solution of the present invention is as follows:
A kind of Gradient High Performance Liquid Chromatography measures Nabumetone simultaneously for Buddhist nun's Photodegradation Products and other related related substances
Method, which is characterized in that detection method includes the following steps for this:
(1) standard solution is prepared
System suitability is carried out under following chromatographic conditions with the standard solution, edits detection system:
Chromatographic condition: chromatographic column is octadecylsilane chemically bonded silica column, is with phosphate buffer-methanol (82: 18)
Mobile phase A, with phosphate buffer-methanol (40: 60) for Mobile phase B, gradient elution, the concentration of phosphate buffer is 0.04
~0.1mol/L, pH value are 7.0~7.8, and column temperature is 25~35 DEG C, and flow velocity is 0.9~1.1ml/min, and Detection wavelength is
247nm；
Standard solution preparation: starting material, intermediate 1, intermediate 2, intermediate 3, impurity A, illumination product are taken respectively
(impurity B) and Nabumetone add mobile phase A that the mixed solution in every 1ml containing about 0.0025~0.5mg is made for Buddhist nun's reference substance；
Precision measures mixed solution described in 10 μ l and injects liquid chromatograph, records chromatogram, edits detection system to Nabumetone
It should be greater than 1.5 for the separating degree of Buddhist nun's main peak and the peak of other impurities B, number of theoretical plate and tailing factor are calculated by Nabumetone for Buddhist nun's main peak
It should be not less than 10000 and no more than 1.5；
(2) test solution and control solution are prepared
It takes Nabumetone for Buddhist nun's sample to be tested, adds mobile phase A that the solution that concentration is 0.5mg/ml is made, as test solution；
It takes Nabumetone for Buddhist nun's reference substance, adds mobile phase A that the solution that concentration is 0.005mg/ml is made, as reference substance solution.
(3) impurity B and the related content in relation to substance in sample to be tested are measured by high performance liquid chromatography
Liquid chromatograph after above-mentioned steps (1) edit is injected with reference substance solution, adjusts detection sensitivity, then will be for
Test sample solution injects liquid chromatograph, carries out high performance liquid chromatography measurement under the chromatographic condition described in step (1), records chromatography
Figure replaces 3~4 times of Buddhist nun's main peak retention time to Nabumetone.
(4) content of each impurity in sample to be tested is calculated
By external standard method with calculated by peak area, the sum of each impurity peak area must not cross 1.0%.
Wherein, in above-mentioned gradient elution, the variation range of mobile phase A ratio is in 0~10 minute, and linear gradient is washed
De-, the ratio of mobile phase A is 55% from 75% variation, and it is 45% that the ratio of Mobile phase B changes from 25%；In 10~20 minutes,
The ratio holding 55% of isocratic elution, mobile phase A is constant, and the ratio holding 45% of Mobile phase B is constant；In 20~30 minutes, line
Property gradient elution, the ratio of mobile phase A from 55% variation be 0%, the ratio of Mobile phase B from 45% variation be 100%；In 30~
40 minutes, the ratio holding 0% of isocratic elution, mobile phase A was constant, and the ratio holding 100% of Mobile phase B is constant, in 40~45
Minute, mobile phase A and B return to initial proportion, and chromatographic column rebalances.
It is highly preferred that above-mentioned phosphate is selected from sodium dihydrogen phosphate, concentration 0.05mol/L, pH value 7.5.
Above-mentioned chromatographic condition are as follows: chromatographic column is octadecylsilane chemically bonded silica column (100 × 4.6mm, 3.5 μm), with body
Product is mobile phase A than the phosphate buffer-methanol for being 82: 18, is for phosphate buffer-methanol of 40:60 with volume ratio
Mobile phase B, gradient elution, column temperature are 30 DEG C, flow velocity 1.0ml/min, Detection wavelength 247nm.
It is highly preferred that above-mentioned chromatographic column is Waters XBridge C18Chromatographic column.
Above-mentioned Nabumetone includes that Nabumetone replaces Buddhist nun for Buddhist nun's intermediate, Nabumetone for Buddhist nun's raw material, Nabumetone for Buddhist nun's piece and Nabumetone for Buddhist nun's sample
Capsule.
By the present invention in that measuring Nabumetone simultaneously with Gradient High Performance Liquid Chromatography for the Photodegradation Products of Buddhist nun and other having
Substance is closed, the exploration to chromatographic condition is passed through, it is determined that Nabumetone can be efficiently separated for Buddhist nun and the chromatographic condition in relation to substance, originally
Method specificity is good, separating degree is good, high sensitivity, favorable reproducibility, to superiority and inferiority, the finished product quality of evaluation synthesis and preparation process
Control and stability sample detection have great importance, and First Determination of the present invention Nabumetone is for Buddhist nun Photodegradation Products and other has
The content for closing substance has no that pertinent literature is reported.
It is described to refer in medicine preparation and storage process " in relation to substance " in the present invention, it may generate and degradation generates
Impurity (including the organic impurities such as intermediate, by-product).Wherein, Nabumetone for Buddhist nun related substance include: impurity A, impurity B,
Intermediate 1, intermediate 2, intermediate 3, starting material.
The method of the present invention is suitable for the related preparations that Nabumetone replaces Buddhist nun for Buddhist nun's intermediate, Nabumetone for Buddhist nun's raw material and containing Nabumetone, such as
Solid pharmaceutical preparation includes tablet and capsule etc..Detection method is accurate, easy to operate, and the time is rapid, can sufficiently meet
The requirement of Related substances separation and decomposition product measurement, the preferably specific impurities in control sample and nonspecific impurity, guarantee
Product quality, it is practical in actual mass control work.
Detailed description of the invention
Fig. 1 is system suitability typical case's HPLC map, and 1 is impurity A, and 2 be illumination product (impurity B), and 3 be Nabumetone for Buddhist nun, 4
It is intermediate 2,5 be intermediate 3,6 is starting material, 7 be intermediate 1；
Fig. 2 is the chromatogram (lot number: 20141201) that Nabumetone replaces Buddhist nun's raw material test solution；
Fig. 3 is the chromatogram (lot number: 20141201) that Nabumetone replaces Buddhist nun's crude product test solution；
Fig. 4 is the chromatogram (lot number: 20150204) that Nabumetone replaces Buddhist nun's tablet test solution；
Fig. 5 is the chromatogram (lot number: 20150301) that Nabumetone replaces Buddhist nun's capsule test solution；
Specific embodiment
Instrument: 1260 series of high efficiency liquid chromatograph of Agilent；
Reagent: sodium dihydrogen phosphate (analysis is pure), sodium hydroxide (analysis is pure), methanol (chromatographically pure, Merk company)；
Chromatographic column: Waters XBridge C18Chromatographic column (100 × 4.6mm, 3.5 μm)；
Chemical name, structural formula and the source of standard items:
Nabumetone replaces Buddhist nun: self-control, purity: 97.6%, lot number: 20141001；Nabumetone is taken to tie again for Buddhist nun's raw material through methanol-water
Crystalline substance, it is dry to get；
Impurity A:
Chemical name: 1- [4- (the chloro- 4- Fluorophenylamino of 3-) -7- ethoxyquin oxazoline -6- base] -5- hydroxyl pyrrolidine -2-
Ketone
Structural formula:
Source: self-control, purity: 98.6%, lot number: 20141105, take Nabumetone to be dissolved in methanol-water, 60 DEG C of drops for Buddhist nun's raw material
Solution 2 hours, is collected through preparative liquid chromatography, is concentrated, is freeze-dried to obtain the final product；
Impurity B:
Chemical name: (Z)-N- [4- (the chloro- 4- fluorophenyl of 3-) amino) -7- ethoxyquin oxazoline -6- base] -4- (diformazan ammonia
Base) but-2-enamides
Structural formula:
Source: self-control, purity: 98.2%, lot number: 20141117, it takes Nabumetone to be dissolved in methanol-water for Buddhist nun's raw material, sets illumination
It is placed 5 days under the conditions of (5000 ± 500lx), takes out, collected through preparative liquid chromatography, be concentrated, be freeze-dried to obtain the final product；
Starting material: chemical name: the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7-, lot number: BM-
20140410, it is commercially available；
Intermediate 1:
Chemical name: N- (the chloro- 4- fluorophenyl of 3-) -7- ethyoxyl -6- nitro -4- quinazoline amine
Structural formula:
Source: self-control, purity: 95.0%, lot number: 20140501, referring to Publication No. CN 103755688A, entitled
A kind of method in " preparation method of afatinib compound " is made；
Intermediate 2:
Chemical name: N- (the chloro- 4- fluorophenyl of 3-) -7- ethyoxyl -4,6- quinazoline diamines
Structural formula:
Source: self-control, purity: 95.4%, lot number: 20140501, referring to Publication No. CN 103755688A, entitled
A kind of method in " preparation method of afatinib compound " is made；
Intermediate 3:
Chemical name: diethyl-[4- (the chloro- 4- Fluorophenylamino of 3-) -7- ethoxyquin oxazoline -6- amino] -2- oxygen ethyl
Phosphate
Structural formula:
Source: self-control, purity: 97.7%, lot number: 20140501, referring to Publication No. CN 103755688A, entitled
A kind of method in " preparation method of afatinib compound " is made；
Nabumetone replaces Buddhist nun's raw material and crude product: referring to Patent No. ZL201410822395.3, entitled " Nabumetone is for Buddhist nun to toluene
The alpha-crystal form and preparation method of sulfonate and pharmaceutical composition containing it " in method be made；
CN105777655A discloses Nabumetone for Buddhist nun with the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7-
For starting material, prepared by referenced patent WO2007085638 similar method, salification process referenced patent WO2012121764
Preparation method.
Nabumetone replaces Buddhist nun's tablet and capsule: referring to a kind of our company's patent " (4- ((the chloro- 4- fluorophenyl of 3-) ammonia containing (E)-N-
Base) -7- ethoxyquin oxazoline -6- base) -4- (dimethylamino) but-2-enamides or its salt preparation compositions and its impurity control
Method processed " in method be made.
Nabumetone for Buddhist nun's tablet and capsule the preparation method is as follows:
1, the capsule that xylene monosulfonic acid Nabumetone replaces Buddhist nun is prepared
Table 1 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the capsule of Buddhist nun
Preparation method: according to component shown in table 1 and amount, active constituent xylene monosulfonic acid Nabumetone is crossed into 60-100 mesh for Buddhist nun
Sieve processing, then crosses the primary simultaneously total mix of 40-60 mesh with mannitol, colloidal silicon dioxide, Compritol 888 ATO, and total mix is completed
Afterwards, be placed directly in capsule automatic filling machine, according to content weight be filled in No. 4, No. 3, in No. 2 gelatin hollow capsules i.e.
It can.
2, the tablet that xylene monosulfonic acid Nabumetone replaces Buddhist nun is prepared
2.1
Table 2 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: according to component shown in table 2 and amount, active constituent xylene monosulfonic acid Nabumetone is crossed into 60-100 mesh for Buddhist nun
Sieve processing, other auxiliary materials cross 40-60 mesh, it is another rise carry out total mix after carry out tabletting, according to specification 1~4 be respectively adopted 6mm,
6mm, 7mm and 9mm circle shallow concave punch are pressed into plain piece.Coating material (HPMC, glyceryl triacetate or dioxy are sprayed to plain piece
Change titanium), control sheet surface heating temperature is between 40-55 DEG C when coating.
2.2
Table 3 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: identical as 2.1.
2.3
Table 4 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: identical as 2.1.
2.4
Table 5 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: identical as 2.1.
2.5 xylene monosulfonic acid Nabumetones of the preparation containing stabilizer replace the tablet of Buddhist nun
Table 6 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: active constituent xylene monosulfonic acid Nabumetone is crossed into the processing of 60-100 mesh for Buddhist nun, tartaric acid smashes it through
Xylene monosulfonic acid Nabumetone after screening is pre-mixed by the processing of 80-120 mesh for Buddhist nun, tartaric acid and colloidal silicon dioxide, then
With other auxiliary material total mix, tabletting is then carried out, 6mm, 6mm, 7mm and 9mm circle scrobicula are respectively adopted respectively according to specification 1~4
Punch die is pressed into plain piece.Coating material (HPMC, glyceryl triacetate or titanium dioxide) is sprayed to plain piece, control sheet table when coating
Face heating temperature is between 40-55 DEG C.
2.6 xylene monosulfonic acid Nabumetones of the preparation containing stabilizer replace the tablet of Buddhist nun
Table 7 prepares xylene monosulfonic acid Nabumetone for the raw material and specific gravity of the tablet of Buddhist nun
Preparation method: identical as 2.5.
The conditional filtering of [embodiment 1] Gradient High Performance Liquid Chromatography
1 chromatographic condition and system suitability
The selection of 1.1 mobile phases
The separating degree of Buddhist nun and impurity B (illumination product), main peak number of theoretical plate and symmetrical factor is replaced to refer to as evaluation with Nabumetone
Mark carries out gradient elution according to the following table 8, screens best phosphate buffering liquid concentration, and the pH value of optimal flow phase finally determines phosphoric acid
Sodium dihydrogen buffer optium concentration is 0.05mol/L, and the optimal pH of mobile phase is 7.5 or so.Phosphate buffering liquid concentration and
PH value selection result see the table below 9~10.
8. mobile phase of table and elution time
9. phosphate concn selection result of table
Table 10.pH value selection result
The selection of 1.2 chromatographic columns
The separating degree of Buddhist nun and impurity B (illumination product), main peak number of theoretical plate and symmetrical factor is replaced to refer to as evaluation with Nabumetone
Mark attempts the chromatographic column with different brands, different model, finally determines and uses Waters XBridge C18Column (100 ×
4.6mm, 3.5 μm), chromatographic column selection result is shown in Table 11.
11. chromatographic column selection result of table
The selection of 1.3 column temperatures
The separating degree of Buddhist nun and impurity B (illumination product), main peak number of theoretical plate and symmetrical factor is replaced to refer to as evaluation with Nabumetone
Mark, selects column temperature to be investigated for 25 DEG C, 28 DEG C, 30 DEG C, 32 DEG C and 35 DEG C, finally determines that column temperature is 30 DEG C, column temperature selection knot
Fruit is shown in Table 12.
12. column temperature selection result of table
1.4 instruments and flow velocity
1260 series of Agilent, DAD detector；Flow velocity is 1.0ml/min.
Under above-mentioned chromatographic condition, Nabumetone is moderate for Buddhist nun's main peak retention time, and number of theoretical plate is high, and peak shape is symmetrical, main peak with
The separating degree of adjacent miscellaneous peak meets the requirements.
The measurement of 1.5 sensitivity
It takes appropriate Nabumetone for Buddhist nun's reference substance, the solution that every 1ml Nabumetone containing 0.5mg replaces Buddhist nun is configured to mobile phase A, as confession
Test sample solution.It is diluted to a series of solution of various concentrations with mobile phase A respectively again, 10 μ l of sample introduction, is allowed to generate main peak respectively
For the signal of baseline noise three times.Through testing, detectability 0.6ng, (S/N >=3), if dense when with Related substances separation
It spends 0.5mg/ml to calculate, limit of detection 0.01%.
1.6 stability of solution
It takes with a test solution, is measured respectively at 0,0.5,1,2,4,6,8,10,12 hour difference sample introduction, main peak
Area and related substance-measuring result are basicly stable in 12 hours.
The experimental results showed that, the method simple and sensitive, favorable reproducibility can carry out Nabumetone in sample for the quality of Buddhist nun above
Preferable control.
The determination of chromatographic condition: through above-mentioned Selection experiment, determining chromatographic condition are as follows: with octadecylsilane chemically bonded silica
(100 × 4.6mm, 3.5 μm) is filler, with phosphate buffer-methanol (82: 18) for mobile phase A, with phosphate-buffered
Liquid-methanol (40:60) is Mobile phase B, and gradient elution, column temperature is 30 DEG C, flow velocity 1.0ml/min, Detection wavelength 247nm；
Wherein in the gradient elution, the variation range of mobile phase A ratio is the linear gradient elution in 0~10 minute, mobile phase A
Ratio from 75% variation be 55%, the ratio of Mobile phase B from 25% variation be 45%；In 10~20 minutes, isocratic elution flowed
The ratio holding 55% of dynamic phase A is constant, and the ratio holding 45% of Mobile phase B is constant；In 20~30 minutes, linear gradient elution,
The ratio of mobile phase A is 0% from 55% variation, and it is 100% that the ratio of Mobile phase B changes from 45%；It is isocratic in 30~40 minutes
Elution, the ratio of mobile phase A keep 0% constant, and the ratio of Mobile phase B keeps 100% constant, in 40~45 minutes, mobile phase A
Initial proportion is returned to B, chromatographic column rebalances.
1.7 system suitabilities:
Starting material, intermediate 1, intermediate 2, intermediate 3, impurity A, illumination product (impurity B) and Nabumetone is taken to replace respectively
Buddhist nun's reference substance adds mobile phase A that the mixed solution in every 1ml containing about 0.0025~0.5mg is made；Precision is measured and is mixed described in 10 μ l
Solution injects liquid chromatograph, records chromatogram, edits separation of the detection system to Nabumetone for Buddhist nun's main peak and the peak of other impurities B
It spends and should be greater than 1.5, number of theoretical plate and tailing factor are calculated by Nabumetone for Buddhist nun's main peak should be not less than 10000 and no more than 1.5；Map
As shown in Fig. 1, Nabumetone is 2.84 for the separating degree of Buddhist nun and illumination product, and Nabumetone replaces the number of theoretical plate and tailing factor of Buddhist nun's main peak
Respectively 26395 and 1.00, separating degree, theoretical cam curve, tailing factor meet above-mentioned requirements, accordingly, it is determined that chromatographic condition
It can be used for Nabumetone and replace measurement of Buddhist nun's capsule in relation to substance for Buddhist nun's crude product, Nabumetone for Buddhist nun's raw material, Nabumetone for Buddhist nun's tablet, Nabumetone.
The preparation of 2 test solutions
It takes Nabumetone for Buddhist nun's sample to be tested, adds mobile phase A that the solution that concentration is 0.5mg/ml is made, as test solution；
The preparation of 3 reference substance solutions
It takes Nabumetone for Buddhist nun's reference substance, adds mobile phase A that the solution that concentration is 0.005mg/ml is made, as reference substance solution.
4 measuring methods
Precision measures 10 μ l of reference substance solution and injects liquid chromatograph, adjusts detection sensitivity, makes principal component chromatography peak height
About the 10~20% of full scale, then the accurate 10 μ l of test solution that measures inject liquid chromatograph, record chromatogram to Nabumetone
For 3~4 times of Buddhist nun's main peak retention time, if any impurity peaks in test solution chromatogram, the sum of each impurity peak area is measured, is pressed
External standard method must not cross 1.0% with calculated by peak area, the sum of each impurity peak area.
[embodiment 2] Nabumetone replaces measurement of Buddhist nun's raw material in relation to substance
Take Nabumetone appropriate for Buddhist nun's raw material, it is accurately weighed, add mobile phase A that the solution of concentration 0.5mg/ml is made, as examination
Product solution.It separately takes Nabumetone for Buddhist nun's reference substance, mobile phase A is added to dilute and the solution that concentration is 0.005mg/ml is made, as control
Product solution.Under following selected chromatographic condition: Waters XbridgeC18Column (100 × 4.6mm, 3.5 μm), it is slow with phosphate
Fliud flushing-methanol (82: 18) is mobile phase A, with phosphate buffer-methanol (40: 60) for Mobile phase B, carries out ladder according to the following table 13
Degree elution, column temperature are 30 DEG C, flow velocity 1.0ml/min, Detection wavelength 247nm；Number of theoretical plate is by Nabumetone for the calculating of Buddhist nun's main peak
10000 should be not less than, the separating degree of main peak and other impurities peak should be greater than 1.5.Precision measures 10 μ l of reference substance solution and injects liquid
Chromatography adjusts detection sensitivity, and making principal component chromatography peak height is about the 10~20% of full scale, then accurate measurement test sample
10 μ l of solution injects liquid chromatograph, and record chromatogram to Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time, test solution color
If any impurity peaks in spectrogram, the sum of each impurity peak area is calculated, must not calculate 1.0%) by external standard method.Respectively to three batches
The Nabumetone of (20141001,20141101,20141201) is measured for Buddhist nun's raw material, wherein Nabumetone replaces the related substance of Buddhist nun's raw material
Measurement result it is as shown in table 15 below, map is as shown in Fig. 2.
13. mobile phase of table and elution time
14. Nabumetone of table replaces the related substance-measuring result of Buddhist nun's raw material
[embodiment 3] Nabumetone replaces measurement of Buddhist nun's crude product in relation to substance
Take Nabumetone appropriate for Buddhist nun's crude product, it is accurately weighed, add mobile phase A that the solution of concentration 0.5mg/ml is made, as examination
Product solution.It separately takes Nabumetone for Buddhist nun's reference substance, mobile phase A is added to dilute and the solution that concentration is 0.005mg/ml is made, as control
Product solution.Under following selected chromatographic condition: Waters Xbridge C18Column (100 × 4.6mm, 3.5 μm), with phosphate
Buffer-methanol (82: 18) is mobile phase A, with phosphate buffer-methanol (40: 60) for Mobile phase B, is carried out according to the following table 15
Gradient elution, column temperature are 30 DEG C, flow velocity 1.0ml/min, Detection wavelength 247nm；Number of theoretical plate is by Nabumetone for based on Buddhist nun's main peak
10000 should be not less than by calculating, and the separating degree of main peak and other impurities peak should be greater than 1.5.Precision measures 10 μ l of reference substance solution injection
Liquid chromatograph adjusts detection sensitivity, and making principal component chromatography peak height is about the 10~20% of full scale, then accurate measurement is for examination
10 μ l of product solution injects liquid chromatograph, and record chromatogram to Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time, test solution
If any impurity peaks in chromatogram, the sum of each impurity peak area is calculated, must not calculate 1.0%) by external standard method.Respectively to three batches
The Nabumetone of secondary (20141001,20141101,20141201) is measured for Buddhist nun's crude product, wherein Nabumetone replaces the related object of Buddhist nun's crude product
The measurement result of matter is as shown in table 16 below.Map is as shown in Fig. 3.
15. mobile phase of table and elution time
16. Nabumetone of table replaces the related substance-measuring result of Buddhist nun's crude product
[embodiment 4] Nabumetone replaces measurement of Buddhist nun's tablet in relation to substance
Take Nabumetone appropriate for Buddhist nun's piece fine powder, precision weighs appropriate (be approximately equivalent to Nabumetone and replace Buddhist nun 25mg), and mobile phase A is added to be made
The solution of concentration 0.5mg/ml, as test solution.It separately takes Nabumetone for Buddhist nun's reference substance, adds mobile phase A to dilute and concentration is made
For the solution of 0.005mg/ml, as reference substance solution.Under following selected chromatographic condition: Waters Xbridge C18Column
(100 × 4.6mm, 3.5 μm), with phosphate buffer-methanol (82: 18) for mobile phase A, with phosphate buffer-methanol (40
: 60) it is Mobile phase B, carries out gradient elution according to the following table 17, column temperature is 30 DEG C, flow velocity 1.0ml/min, and Detection wavelength is
247nm；Number of theoretical plate, which is calculated by Nabumetone for Buddhist nun's main peak, should be not less than 10000, and the separating degree of main peak and other impurities peak should be greater than
1.5.Precision measures 10 μ l of reference substance solution and injects liquid chromatograph, adjusts detection sensitivity, makes the principal component chromatography peak height be about
The 10~20% of full scale, then the accurate 10 μ l of test solution that measures inject liquid chromatograph, and record chromatogram to Nabumetone replaces Buddhist nun
3~4 times of main peak retention time measure the sum of each impurity peak area, by external standard if any impurity peaks in test solution chromatogram
Method must not calculate 1.0%.Respectively to the Nabumetone of three batches (20150202,20150203,20150204) for Buddhist nun's tablet into
Row measurement, wherein Nabumetone is as shown in table 18 below for measurement result of Buddhist nun's piece in relation to substance.Map is as shown in Fig. 4.
17. mobile phase of table and elution time
18 Nabumetone of table replaces the related substance-measuring result of Buddhist nun's piece
[embodiment 5] Nabumetone replaces measurement of Buddhist nun's capsule in relation to substance
Take Nabumetone for the mixing of Buddhist nun's capsule powders, precision weighs appropriate (be approximately equivalent to Nabumetone and replace Buddhist nun 25mg), adds mobile phase A system
At the solution of concentration 0.5mg/ml, as test solution.It separately takes Nabumetone for Buddhist nun's reference substance, adds mobile phase A to dilute and be made dense
Degree is the solution of 0.005mg/ml, as reference substance solution.Under following selected chromatographic condition: Waters Xbridge C18
Column (100 × 4.6mm, 3.5 μm), with phosphate buffer-methanol (82: 18) for mobile phase A, with phosphate buffer-methanol
(40: 60) it is Mobile phase B, carries out gradient elution according to the following table 19, column temperature is 30 DEG C, flow velocity 1.0ml/min, and Detection wavelength is
247nm；Number of theoretical plate, which is calculated by Nabumetone for Buddhist nun's main peak, should be not less than 10000, and the separating degree of main peak and other impurities peak should be greater than
1.5.Precision measures 10 μ l of reference substance solution and injects liquid chromatograph, adjusts detection sensitivity, makes the principal component chromatography peak height be about
The 10~20% of full scale, then the accurate 10 μ l of test solution that measures inject liquid chromatograph, and record chromatogram to Nabumetone replaces Buddhist nun
3~4 times of main peak retention time measure the sum of each impurity peak area, by external standard if any impurity peaks in test solution chromatogram
Method must not calculate 1.0%.Respectively to the Nabumetone of three batches (20150301,20150302,20150303) for Buddhist nun's capsule into
Row measurement, wherein Nabumetone is as shown in table 20 below for measurement result of Buddhist nun's capsule in relation to substance.Map is as shown in Fig. 5.
19. mobile phase of table and elution time
20. Nabumetone of table replaces the related substance-measuring result of Buddhist nun's capsule
Claims (6)
1. a kind of Gradient High Performance Liquid Chromatography measures Nabumetone simultaneously and replaces Buddhist nun's Photodegradation Products and other methods in relation to substance,
It is characterized in that, detection method includes the following steps for this:
(1) standard solution is prepared, system suitability is carried out under following chromatographic conditions with the standard solution, is edited
Detection system；
Chromatographic condition: chromatographic column is octadecylsilane chemically bonded silica column, is phosphate buffer-first of 82:18 with volume ratio
Alcohol is mobile phase A, using volume ratio for 40:60 phosphate buffer-methanol as Mobile phase B, gradient elution, phosphate buffer
Concentration be 0.04~0.1mol/L, pH value be 7.0~7.8, column temperature be 25~35 DEG C, flow velocity be 0.9~1.1ml/min, inspection
Survey wavelength is 247nm；
Standard solution preparation: starting material, intermediate 1, intermediate 2, intermediate 3, impurity A, impurity B and Nabumetone is taken to replace respectively
Buddhist nun's reference substance adds mobile phase A that the mixed solution for containing 0.0025~0.5mg in every 1ml is made；
Precision measures mixed solution described in 10 μ l and injects liquid chromatograph, records chromatogram, edits detection system to Nabumetone for Buddhist nun
The separating degree at the peak of main peak and other impurities B is greater than 1.5, and Nabumetone is not less than 10000 for the number of theoretical plate of Buddhist nun's main peak, tailing factor
No more than 1.5；
(2) test solution and control solution are prepared；
It takes Nabumetone for Buddhist nun's sample to be tested, adds mobile phase A that the solution that concentration is 0.5mg/ml is made, as test solution；Take naphthalene
It is general to replace Buddhist nun's reference substance, add mobile phase A that the solution that concentration is 0.005mg/ml is made, as reference substance solution；
(3) impurity B and the related content in relation to substance in sample to be tested are measured by high performance liquid chromatography；
Liquid chromatograph after above-mentioned steps (1) edit is injected with reference substance solution, adjusts detection sensitivity, then by test sample
Solution injects liquid chromatograph, high performance liquid chromatography measurement is carried out under the chromatographic condition described in step (1), record chromatogram is extremely
Nabumetone replaces 3~4 times of Buddhist nun's main peak retention time；
(4) content of each impurity in sample to be tested is calculated；
By external standard method with calculated by peak area, the sum of each impurity peak area must not exceed 1.0%；
Wherein in the gradient elution, the variation range of mobile phase A ratio are as follows: in 0~10 minute, linear gradient elution flowed
The ratio of dynamic phase A is 55% from 75% variation, and it is 45% that the ratio of Mobile phase B changes from 25%；It is isocratic to wash in 10~20 minutes
De-, the ratio holding 55% of mobile phase A is constant, and the ratio holding 45% of Mobile phase B is constant；In 20~30 minutes, linear gradient
Elution, the ratio of mobile phase A are 0% from 55% variation, and it is 100% that the ratio of Mobile phase B changes from 45%；In 30~40 points
The ratio holding 0% of clock, isocratic elution, mobile phase A is constant, and the ratio holding 100% of Mobile phase B is constant, in 40~45 minutes,
Mobile phase A and B return to initial proportion, and chromatographic column rebalances.
2. the method as described in claim 1, wherein the phosphate is sodium dihydrogen phosphate.
3. method according to claim 2, wherein the concentration of the sodium dihydrogen phosphate is 0.05mol/L, pH value 7.5.
4. the method as described in claim 1, chromatographic condition are as follows: chromatographic column is that octadecylsilane is bonded column, with volume ratio
Be mobile phase A for phosphate buffer-methanol of 82:18, using volume ratio for 40:60 phosphate buffer-methanol as flowing
Phase B, gradient elution, column temperature are 30 DEG C, flow velocity 1.0ml/min, Detection wavelength 247nm.
5. method as claimed in claim 4, the chromatographic column is Waters XBridge C18Chromatographic column.
6. the method according to claim 1 to 5, which is characterized in that the Nabumetone includes that Nabumetone replaces for Buddhist nun's sample to be tested
Buddhist nun's raw material, Nabumetone replace Buddhist nun's capsule for Buddhist nun's crude product, Nabumetone for Buddhist nun's tablet and Nabumetone.
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