CN108362792A - A kind of detection method of flupentixol and melitracen compound medicine impurity, new recognizable impurity and safer compound medicine - Google Patents
A kind of detection method of flupentixol and melitracen compound medicine impurity, new recognizable impurity and safer compound medicine Download PDFInfo
- Publication number
- CN108362792A CN108362792A CN201810092630.4A CN201810092630A CN108362792A CN 108362792 A CN108362792 A CN 108362792A CN 201810092630 A CN201810092630 A CN 201810092630A CN 108362792 A CN108362792 A CN 108362792A
- Authority
- CN
- China
- Prior art keywords
- flupentixol
- impurity
- melitracen
- solution
- compound medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000012535 impurity Substances 0.000 title claims abstract description 275
- NJMYODHXAKYRHW-DVZOWYKESA-N cis-flupenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C2/1 NJMYODHXAKYRHW-DVZOWYKESA-N 0.000 title claims abstract description 190
- 229960002419 flupentixol Drugs 0.000 title claims abstract description 190
- 229960004794 melitracen Drugs 0.000 title claims abstract description 104
- 238000001514 detection method Methods 0.000 title claims abstract description 63
- 239000003814 drug Substances 0.000 title claims abstract description 52
- -1 melitracen compound Chemical class 0.000 title claims abstract description 39
- 150000001875 compounds Chemical class 0.000 title claims abstract description 8
- 238000010525 oxidative degradation reaction Methods 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 14
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 8
- 238000010828 elution Methods 0.000 claims abstract description 5
- 238000004458 analytical method Methods 0.000 claims abstract 2
- 238000001228 spectrum Methods 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 88
- GWWLWDURRGNSRS-UHFFFAOYSA-N melitracen Chemical compound C1=CC=C2C(=CCCN(C)C)C3=CC=CC=C3C(C)(C)C2=C1 GWWLWDURRGNSRS-UHFFFAOYSA-N 0.000 claims description 71
- 230000003647 oxidation Effects 0.000 claims description 62
- 238000007254 oxidation reaction Methods 0.000 claims description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 54
- 239000013558 reference substance Substances 0.000 claims description 34
- 239000012085 test solution Substances 0.000 claims description 34
- 238000010790 dilution Methods 0.000 claims description 31
- 239000012895 dilution Substances 0.000 claims description 31
- 239000012925 reference material Substances 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003085 diluting agent Substances 0.000 claims description 23
- 238000012360 testing method Methods 0.000 claims description 22
- 230000014759 maintenance of location Effects 0.000 claims description 20
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 15
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 15
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 15
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- 230000015556 catabolic process Effects 0.000 claims description 11
- 238000006731 degradation reaction Methods 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 11
- 238000004587 chromatography analysis Methods 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 150000003839 salts Chemical group 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 229960002163 hydrogen peroxide Drugs 0.000 claims description 7
- 239000008363 phosphate buffer Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 238000010606 normalization Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910001868 water Inorganic materials 0.000 claims description 6
- 238000010812 external standard method Methods 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- MCGSCYPIQDUAQD-UHFFFAOYSA-N C1=CC=CC=2SC3=CC=CC=C3CC12.N1CCNCC1 Chemical compound C1=CC=CC=2SC3=CC=CC=C3CC12.N1CCNCC1 MCGSCYPIQDUAQD-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical class OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims description 2
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 claims description 2
- 239000000908 ammonium hydroxide Substances 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 235000019837 monoammonium phosphate Nutrition 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- IGLKELDWPZFFKF-UHFFFAOYSA-N OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.P.P Chemical compound OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.OC(C1=CC=CC=C1C(O)=O)=O.P.P IGLKELDWPZFFKF-UHFFFAOYSA-N 0.000 claims 2
- 239000000872 buffer Substances 0.000 claims 2
- 239000002019 doping agent Substances 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- GDXWHFPKFUYWBE-UHFFFAOYSA-N [F].Cl Chemical compound [F].Cl GDXWHFPKFUYWBE-UHFFFAOYSA-N 0.000 claims 1
- 238000007689 inspection Methods 0.000 claims 1
- AUZMDLDJTGPIEA-UHFFFAOYSA-N litracen Chemical compound C1=CC=C2C(=CCCNC)C3=CC=CC=C3C(C)(C)C2=C1 AUZMDLDJTGPIEA-UHFFFAOYSA-N 0.000 claims 1
- 229950008498 litracen Drugs 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 11
- 239000012071 phase Substances 0.000 description 51
- 239000000523 sample Substances 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- 239000007791 liquid phase Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 238000010200 validation analysis Methods 0.000 description 7
- 238000004364 calculation method Methods 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 230000006652 catabolic pathway Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- PQJUJGAVDBINPI-UHFFFAOYSA-N 9H-thioxanthene Chemical compound C1=CC=C2CC3=CC=CC=C3SC2=C1 PQJUJGAVDBINPI-UHFFFAOYSA-N 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000012489 system suitability test solution Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- BCOMNMYMUMEKIW-UHFFFAOYSA-N N1CCNCC1.S1C=CC=C1.[F] Chemical compound N1CCNCC1.S1C=CC=C1.[F] BCOMNMYMUMEKIW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000012494 forced degradation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000010561 standard procedure Methods 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of detection methods of flupentixol and melitracen compound medicine impurity, new recognizable impurity and safer compound medicine, the wherein described detection method includes in 0~60min, gradient elution is carried out in the performance liquid chromatographic column containing octadecylsilane chemically bonded silica filler, and the process of further analysis of spectra, the detection method may recognize that the plurality of impurities and its exact level of flupentixol and melitracen compound medicine, it is especially separable, identify 6 kinds of new oxidative degradation impurity, and safer flupentixol and melitracen compound medicine control standard can be obtained accordingly.
Description
Technical field
The present invention relates to the technical fields of flupentixol and melitracen compound medicine.
Background technology
The U.S. profit of flupentixol and melitracen compound medicine common dosage forms such as Flupentixol and Melitracen Tablets, Flupentixol is bent
Pungent capsule etc. contains two kinds of drugs of Flupentixol and melitracen, and the labelled amount difference of the two is huge, such as every fluorine piperazine thiophene
Contain Flupentixol 0.5mg and melitracen 10mg in ton melitracen capsule, the two labelled amount difference reaches 20 times, therefore miscellaneous
For reasonable science, strictly Quality Control drug quality is particularly important matter source ownership.
For the impurity of flupentixol and melitracen compound medicine other than process contaminants F, main includes coming in existing standard
Degradation impurity Lu-28-159, impurity G from Flupentixol come from the degradation impurity impurity A (Lu 23-120) of melitracen,
The source of its difference and degradation pathway are as shown in Figure 1 and Figure 2：
Source and the degradation pathway of Fig. 1 impurity G and impurity Lu-28-159
The source of Fig. 2 impurity As and degradation pathway
Find in addition to above-mentioned impurity exist in flupentixol and melitracen compound medicine in the further research of inventor
The source ownership of other unknown impurities exist and do not know place, and the controlled quentity controlled variable for consequently leading to these unknown impurities is asked
Topic.
Invention content
It is an object of the invention to propose a kind of detection method of flupentixol and melitracen compound medicine, via the detection
Method can accurately tell flupentixol and melitracen compound medicine and its impurity, and include this in the impurity that can be differentiated
6 kinds of unknown impurities that invention newly identifies, in addition, the present invention is further according to the detection method to the impurity of the compound medicine
Controlled quentity controlled variable is corrected, to obtain a kind of more accurate tightened up safer compound medicine of Control of Impurities.
Technical scheme is as follows：
A kind of detection method of flupentixol and melitracen compound medicine comprising the following contents：Use high-efficient liquid phase color
Spectral analysis method, the performance liquid chromatographic column used in the process is interior to be filled with octadecylsilane chemically bonded silica, to raw material
Drug and/or reference substance solution carry out gradient elution.
Reference substance solution described in said program refers to the correspondence standard items for needing selection according to test target object.On
The scheme of stating can also be served only for being detected the impurity in drug.If object is impurity A in material medicine, then reference substance pair
The standard sample of impurity A, object are the impurity G in material medicine, then reference substance is the standard sample of impurity G, and object is
Plurality of impurities in material medicine, then reference substance is the standard sample of plurality of impurities.The standard sample is satisfied by purity requirement.
Chromatographic column particulate filler diameter is 2.7~3 μm in the present invention.Dimensions length can be 100 × 4.6mm~150 ×
4.6mm。
In a kind of specific implementation mode of the detection method, including following testing conditions：
Mobile phase A：Phosphate buffer；
Mobile phase B：Including acetonitrile；
Mobile phase C：Including methanol；
Mobile phase elution requirement is：
In the present invention, the parameters such as column temperature, flow velocity, sample size can select in Typical ranges.
In a kind of specific implementation mode of the detection method, phosphate buffer is by biphosphate described in mobile phase A
Salt, alkali and water composition, or be made of phosphoric acid hydrogen disalt, acid and water.As long as guarantee can meet pH requirements of the present invention.
For example, the dihydric phosphate includes but not limited to one in potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate
Kind is a variety of, and the alkali includes but not limited to one or more in sodium hydroxide, potassium hydroxide, ammonium hydroxide, the phosphoric acid hydrogen two
Salt includes but not limited to one or more in dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate, and the acid includes but unlimited
It is one or more in phosphoric acid, hydrochloric acid, acetic acid.
In a preferred embodiment, the phosphate buffer is made of dihydric phosphate, sodium hydroxide and water,
Wherein a concentration of 0.01~0.05mol/L of potassium dihydrogen phosphate, preferably 0.01mol/L.
The Mobile phase B described in a kind of specific embodiment is acetonitrile；The mobile phase C is methanol；The mobile phase
Flow velocity -0.95~1.05mL/min, preferably 0.98~1.02mL/min, more preferably 1.0mL/min.
Selection can be adjusted by conventional means in aforementioned scope of disclosure in Detection wavelength of the present invention.It is finding
When best detection wavelength, the modes such as the matching used all band scanning of ultraviolet spectrophotometry, HPLC can be used to carry out, then match
The detection result (solvent is such as avoided to interfere) for closing HPLC detectors, suitable Detection wavelength is found using routine techniques.
In a kind of specific implementation mode of the detection method, including following testing conditions：Detection wavelength be 254~
280nm, preferably 270nm.Chromatographic column column temperature of the present invention is 35~45 DEG C, preferably 40 DEG C.
In a kind of specific implementation mode of the detection method, the material medicine and/or reference substance solution are by bulk pharmaceutical chemicals
Object and/reference substance are dissolved in solvent and obtaining, and the solvent includes phosphate buffer and methanol；Wherein phosphate buffer is preferred
The potassium dihydrogen phosphate of 0.01mol/L, the volume ratio with methanol are 40:60~35:65, preferably 35:65.
In a kind of specific implementation mode of the detection method, include the following steps：
(1) standard reference material of impurity A and impurity G is taken, the impurity storing solution of impure A, impurity G are made after dissolving；
(2) Flupenthixol Hydrochloride standard reference material, melitracen hydrochloride standard reference material, impurity Lu-28-159 standards are taken
The second storing solution is made in reference substance after being dissolved using diluent；
(3) the impurity storing solution is measured, is added in second storing solution, it is miscellaneous with impure A is made after dilution dilution agent
The system suitability solution of matter G, impurity Lu-28-159, Flupentixol and melitracen；
(4) Flupenthixol Hydrochloride bulk pharmaceutical chemicals are weighed, after being dissolved with diluent, the hydrogen peroxide of addition 30% is molten thereto
Liquid is stood, to through chromatography test simultaneously usable floor area normalization method be calculated wherein Flupentixol degradation rate reach 5%~
Until when 10%, as Flupenthixol Hydrochloride oxidative degradation solution；
(5) after taking the flupentixol and melitracen compound medicine for examination to add diluent dissolving, filtering, it is molten to obtain test sample
Liquid；
(6) each 20 μ L of the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution are measured and inject liquid chromatogram
Instrument, record gained spectrogram；
(7) 20 μ L of the test solution are measured and inject liquid chromatograph, record gained spectrogram；
(8) system solvent peak and auxiliary material peak, impurity Lu-28-159, impurity will be deducted in obtained test solution spectrogram
G, impurity A, compared with the chromatographic peak of corresponding position in system suitability solution spectrogram, unknown oxidative degradation impurity 1~6 and salt
The Flupentixol oxidation impurities 1~6 of corresponding position compare in sour Flupentixol oxidative degradation solution spectrogram, other unknown impurities
Compared with other impurity peaks of melitracen corresponding position, each impurity content is gone out i.e. with calculated by peak area by external standard method respectively
It can.
In a kind of specific implementation mode of the detection method, include the following steps：
(1) it takes the standard reference material of impurity A and impurity G, with methanol dilution dissolves constant volume after accurately weighed, every 1mL is made
Containing about 0.2mg impurity As, the impurity storing solution of 0.1mg impurity G in mixed liquor；
(2) Flupenthixol Hydrochloride standard reference material, melitracen hydrochloride standard reference material, impurity Lu-28-159 standards are taken
The second storing solution is made in reference substance after being dissolved using diluent；
(3) the impurity storing solution is measured, is added in second storing solution, with every 1mL is made after the dilution dilution agent
Containing 2 μ g impurity As, the system of 0.4 μ g impurity G, 0.85 μ g impurity Lu-28-159,5 μ g Flupentixols and 20 μ g melitracens are applicable in
Property solution；
(4) Flupenthixol Hydrochloride bulk pharmaceutical chemicals are weighed, after being dissolved with the diluent, is made in every 1mL and contains Flupentixol 500
The solution of μ g takes the 1mL solution, and 30% hydrogenperoxide steam generator 0.3mL is added thereto, the diluent is added to be diluted to
25mL shakes up, and stands, until the degradation rate that wherein Flupentixol is calculated through chromatography test and usable floor area normalization method reaches
Until when 5%~10%, as Flupenthixol Hydrochloride oxidative degradation solution；
(5) the flupentixol and melitracen compound medicine 1 for examination is taken, wherein 0.5mg containing Flupentixol, melitracen
10mg is placed in 25mL measuring bottles, and the diluent is added to dissolve, and constant volume shakes up, and is filtered, using filtrate as test solution；
(6) accurate respectively to measure each 20 μ L injections of the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution
Liquid chromatograph, record gained spectrogram；
(7) the accurate 20 μ L of the test solution that measure inject liquid chromatograph, record gained spectrogram；
(8) system solvent peak and auxiliary material peak, impurity Lu-28-159, impurity will be deducted in obtained test solution spectrogram
G, impurity A, compared with the chromatographic peak of corresponding position in system suitability solution spectrogram, unknown oxidative degradation impurity 1~6 and salt
The Flupentixol oxidation impurities 1~6 of corresponding position compare in sour Flupentixol oxidative degradation solution spectrogram, other unknown impurities
Compared with other impurity peaks of melitracen corresponding position, each impurity content is gone out i.e. with calculated by peak area by external standard method respectively
It can；
The diluent is the mixed solution of methanol and the mobile phase A solution of 0.01mol/L；Wherein potassium dihydrogen phosphate
Volume ratio with methanol is 35:65.
In a kind of specific implementation mode of the detection method, the impurity Lu-28-159 standard reference materials use impurity
The salt form of Lu-28-159.
The present invention also provides the detection methods of oxidation impurities in flupentixol and melitracen compound medicine, using aforementioned side
Method is detected flupentixol and melitracen compound medicine to be checked；The oxidation impurities are in Flupentixol oxidation impurities 1-6
It is one or more, the relative retention time of Flupentixol oxidation impurities 1-6 is as follows：It is reference peak with Flupentixol chromatographic peak,
The corresponding Flupentixol oxidation impurities 1 of two chromatographic peaks, the Flupentixol oxidation impurities of relative retention time about 0.42~0.43
2；The corresponding Flupentixol oxidation impurities of 1 chromatographic peak of relative retention time about 0.46 3；The 1 of relative retention time about 0.50
The corresponding Flupentixol oxidation impurities of a chromatographic peak 4；The corresponding fluorine of two chromatographic peaks of relative retention time about 0.67~0.70
Piperazine thioxanthene oxidation impurities 5, Flupentixol oxidation impurities 6.
When being detected using this method, it is only necessary to loading correlation test solution, by retaining the opposite of chromatographic peak
The judgement of time, you can corresponding impurity, realization qualitatively or quantitatively determine.
In quantitative determination, the conventional means such as external standard method, internal standard method, normalization method can be selected.
Meanwhile based on the aforementioned discovery for the first time to each oxidation impurities peak, present invention provides flupentixol and melitracens
The new recognizable impurity of compound medicine, the impurity is one or more in Flupentixol oxidation impurities 1-6, and use is aforementioned
Method be detected, the relative retention time of Flupentixol oxidation impurities 1-6 is as follows in gained chromatogram：With Flupentixol color
Spectral peak is with reference to peak, the corresponding Flupentixol oxidation impurities 1 of two chromatographic peaks of relative retention time about 0.42~0.43, fluorine piperazine
Thioxanthene oxidation impurities 2；The corresponding Flupentixol oxidation impurities of 1 chromatographic peak of relative retention time about 0.46 3；When opposite reservation
Between about 0.50 the corresponding Flupentixol oxidation impurities of 1 chromatographic peak 4；Two chromatographies of relative retention time about 0.67~0.70
The corresponding Flupentixol oxidation impurities 5 in peak, Flupentixol oxidation impurities 6.
Present invention further proposes a kind of new Control of Impurities standards, and the U.S. profit of safer Flupentixol can be obtained accordingly
Bent pungent compound medicine, the Control of Impurities standard are as follows：
The wherein described Flupentixol oxidation impurities are above-mentioned new recognizable impurity, i.e., Flupentixol oxidation impurities 1~
6, opposite Flupentixol labelled amount≤0.5%, each Flupentixol oxidation impurities for referring to are ≤0.5%.
The present invention has following advantageous effect：
(1) detection method of the invention may recognize that the oxidation in 6 kinds of new flupentixol and melitracen compound medicines is miscellaneous
Matter, 6 kinds of impurity are considered as the unknown impuritie from melitracen, the nothing in existing detection method in import registered standard
Method is efficiently separated, and the detection method through the present invention can cleanly separate 6 kinds of impurity on HPLC spectrograms, and
Further by being compared with the spectrogram of Flupentixol oxidative degradation object, it is the oxidation from Flupentixol that can specify 6 kinds of impurity
Degradation impurity；
(2) detection method of the invention can be efficiently separated and accurately be tested out each in flupentixol and melitracen compound medicine
Impurity and its content, including described 6 kinds new recognizable impurity；
(3) detection method of the invention has good system suitability and specificity good；
(4) detection method of the invention has high sensitivity, as can be seen that master in the method validation embodiment of the present invention
Ingredient and known impurities quantitative limit and detection limit S/N meet the requirements, it is known that 50% of impurity quantitative limit no more than its limit,
The peak area RSD of six needle quantitative limits is respectively less than 10.0%；
(5) detection method of the invention is linearly good, can be seen that in the method validation embodiment of the present invention, it is known that miscellaneous
Matter presents good linear in the limit concentration range of quantitative limit~150%, and Flupenthixol Hydrochloride is supplied in quantitative limit~37.5%
Present in test product concentration range good linear, melitracen hydrochloride is presented within the scope of the test sample concentration of quantitative limit~7.5%
Good linear, linear regression coeffficient R is all higher than 0.99；
(6) the sample introduction precision of detection method of the invention, repeatability, Intermediate precision are good, in the method for the present invention
It verifies in embodiment as can be seen that 6 needle sample introduction of system suitability, retention time RSD is less than 2.0%, the RSD of main peak peak area
Less than 2.0%；In repeated experiment and Intermediate precision 12 parts of test samples detection impurity phases with and respectively to measure impurity content RSD small
In 15.0%；
(7) accuracy of detection method of the invention is good, as can be seen that supplying in the method validation embodiment of the present invention
For the recovery of standard addition of each known impurities of test product between 85%~110%, the sample recovery rate RSD of each concentration level is small
In 10.0%；
(8) in certain specific embodiments of the invention, good tolerance is such as implemented in the method validation of the present invention
As can be seen that by column flow rate, column temperature and the buffer salt pH value in minor alteration chromatographic condition in example, impurity Detection capability is without change
Change, good tolerance..
Description of the drawings
Fig. 1 is the superposition chromatogram described in the embodiment of the present invention 1；
Fig. 2 is the system suitability solution obtained in the embodiment of the present invention 2, Flupenthixol Hydrochloride oxidative degradation solution, supplies
The HPLC spectrograms of test sample solution；
Fig. 3 be the embodiment of the present invention 3 in obtain system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution,
The HPLC spectrograms of melitracen hydrochloride oxidative degradation solution, test solution；
Fig. 4 is obtained HPLC spectrograms in the embodiment of the present invention 4, be respectively test sample oxidation solution from top to bottom with
The superposition chromatogram that system suitability solution is 5.5 in flowing phase pH value；Test sample aoxidizes solution and exists with system suitability solution
The superposition chromatogram that flowing phase pH value is 7.5；Flupentixol oxidative degradation solution is with system suitability solution in mobile phase and first
Alcohol volume ratio is 40:Superposition chromatogram under conditions of 60；
Fig. 5 is the HPLC spectrograms of the system suitability solution and test solution that are obtained in the embodiment of the present invention 5；
Fig. 6 is the HPLC spectrograms of the system suitability solution and test solution that are obtained in the embodiment of the present invention 6；
Fig. 7 is the HPLC spectrograms of the system suitability solution and test solution that are obtained in the embodiment of the present invention 7；
Fig. 8 is system suitability solution, test solution, the Flupentixol oxidation obtained in the embodiment of the present invention 8
The HPLC spectrograms of degraded solutions；
Specific implementation mode
The reagent used in following embodiment includes：
The standard reference material of impurity A (Lu 23-120), purity of 50 percent .998；
The standard reference material of impurity G (Lu 14-119), purity of 50 percent .98；
The standard reference material of process contaminants F, purity of 50 percent .809；
Lu 28-159-HCl, purity of 50 percent .968；
Flupenthixol Hydrochloride standard reference material is obtained by Chengdu Bei Te medicine companies；
Melitracen hydrochloride standard reference material is obtained by Chengdu Bei Te medicine companies.
Embodiment 1
The verification of impurity：
Blank auxiliary, Flupenthixol Hydrochloride, melitracen hydrochloride, Flupenthixol Hydrochloride is taken to add blank auxiliary, hydrochloric acid respectively
Melitracen adds blank auxiliary, Flupenthixol Hydrochloride that melitracen hydrochloride, flupentixol and melitracen capsule is added (hereinafter referred to as to supply
Test product) carry out drug forced degradation experiment；And the sample after degradation is analyzed using high performance liquid chromatography, record its color
Spectrogram；By other chart addings in addition to test sample, and the spectrogram measured with test sample is compared, and as shown in Fig. 1, is passed through
Compare identical retention time chromatographic peak in different solutions chromatogram and its full spectrogram it is found that impurity is originated from fluorine in test sample
Piperazine thioxanthene in addition to known impurities G, impurity Lu-28-159, there is also 6 unknown impurities, 6 unknown impurities and Flupentixol
The substance generated in Oxidative Degradation Process is consistent, such as Flupentixol oxidation impurities 1,2,3,4 in attached drawing 1, shown in 5,6 positions,
There is no other impurity from Flupentixol, these impurity are all attributed in the unknown impuritie of melitracen in primary standard,
This 6 kinds of impurity are actually the oxidative degradation impurity from Flupentixol it can be seen from the present embodiment.
Therefore after grinding import registered standard with reference to original, the new understanding of the present invention is：In flupentixol and melitracen compound medicine
The degradation impurity for coming from Flupentixol in object includes known impurities Lu-28-159, impurity G, and the Flupentixol newly identified
Oxidative degradation impurity 1~6；The degradation impurity for coming from melitracen includes known impurities A and remaining unknown impuritie.
Embodiment 2
It is detected according to following procedure and calculates impurity and its content in flupentixol and melitracen compound medicine：
(1) it takes the standard reference material of impurity A and impurity G, with methanol dilution dissolves constant volume after accurately weighed, every 1mL is made
Containing about 0.2mg impurity As, the impurity storing solution of 0.1mg impurity G in mixed liquor；
(2) Flupenthixol Hydrochloride standard reference material, melitracen hydrochloride standard reference material, impurity Lu-28-159 standards are taken
Reference substance (when practical operation with the salt Lu 28-159-HCl of impurity Lu-28-159 be to launch object), it is accurately weighed after with appropriate
Diluent dissolves, which includes the mobile phase A solution and methanol of a concentration of 0.01mol/L, and the volume ratio of the two is 35:
65, obtain the second storing solution；
(3) the impurity storing solution is measured, is added in second storing solution, dissolves constant volume, system with the dilution dilution agent
At containing about 2 μ g impurity As, 0.4 μ g impurity G, 0.85 μ g impurity Lu-28-159 (are changed with Lu 28-159-HCl in every 1mL mixed liquors
After calculation), (after being converted with Flupenthixol Hydrochloride, the conversion factor of Flupentixol and Flupenthixol Hydrochloride is 5 μ g Flupentixols
0.8562) (after being converted with melitracen hydrochloride, the conversion factor of melitracen and melitracen hydrochloride is with 20 μ g melitracens
0.8887) system suitability solution；
(4) Flupenthixol Hydrochloride bulk pharmaceutical chemicals are weighed, is dissolved and is diluted with the diluent, about fluorine-containing piperazine in every 1mL is made
The solution of 500 μ g of thioxanthene, takes the 1mL solution, and 30% hydrogenperoxide steam generator 0.3mL is added thereto, adds the dilution dilution agent
It to 25mL, shakes up, places about 4 hours, make Flupentixol degradation rate (based on area normalization method) between 5%~10%, make
For Flupenthixol Hydrochloride oxidative degradation solution；
(5) flupentixol and melitracen capsule 1 is taken, containing Flupentixol 0.5mg, melitracen 10mg, is placed in
In 25ml measuring bottles, the diluent is added to dissolve, constant volume shakes up, and filters, using filtrate as test solution；
(6) accurate respectively to measure each 20 μ L injections of the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution
Liquid chromatograph, record gained spectrogram；
(7) the accurate 20 μ L of the test solution that measure inject liquid chromatograph, record gained spectrogram；
(8) the auxiliary material peak before system solvent peak and 4min will be deducted in obtained test solution spectrogram, known to remaining
Impurity, such as impurity Lu-28-159, impurity G, impurity A, compared with the chromatographic peak of corresponding position in system suitability solution spectrogram,
The oxidative degradation impurity 1~6 newly identified and the Flupentixol oxidation impurities 1 in Flupenthixol Hydrochloride oxidative degradation solution spectrogram
~6 compare, other unknown impurities go out content i.e. by external standard method with calculated by peak area respectively compared with the other impurity peaks of melitracen
It can；
Step (6) and step (7) use following liquid phase chromatogram condition in the present embodiment：
Chromatographic column：YMC-Pack Pro C18 RS chromatographic columns, filler are octadecylsilane chemically bonded silica, chromatography
Column 150 × 4.6mm of specification, 3 μm of filler grain size；
Mobile phase A：The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted using potassium hydroxide solution；
Mobile phase B：Acetonitrile；
Mobile phase C：Methanol；
Column temperature is 40 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
According to the form below is eluted：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
| 0.0 | 67 | 22 | 11 |
| 10.0 | 49 | 34 | 17 |
| 27.5 | 38 | 43 | 19 |
| 29.0 | 27 | 57 | 16 |
| 49.0 | 27 | 57 | 16 |
| 51.0 | 67 | 22 | 11 |
| 60.0 | 67 | 22 | 11 |
The chromatogram for the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution that the present embodiment records and its
Typical chromatogram is consistent.
Flupentixol oxidation impurities 1, Flupentixol oxidation impurities 2, Flupentixol oxidation on test solution chromatogram
Impurity 3, Flupentixol oxidation impurities 4, Lu-28-159, Flupentixol oxidation impurities 5, Flupentixol oxidation impurities 6, impurity A,
Flupentixol, impurity G, melitracen appearance successively.
Lu-28-159, impurity A, Flupentixol, impurity G, melitracen and phase in the chromatogram of system suitability solution
The separating degree of adjacent impurity peaks is more than 1.5.
Flupentixol oxidation impurities 5 and Flupentixol oxidation impurities in the spectrogram of Flupenthixol Hydrochloride oxidative degradation solution
The height of higher peak peak height to baseline is more than peak valley to 1.5 times of baseline height between 6.
Show that the content meter formula of impurity is：
(1) calculation formula of known impurities G and impurity Lu-28-159：
Wherein：
AsplFor the peak area of known impurities G or Lu-28-159 in test solution；
AstdTo correspond to known impurities G or Lu-28-159 peak area in system suitability solution；
WstdTo correspond to the weight mg of known impurities G or Lu-28-159 in system suitability solution；
WsplFor the weight mg of test solution Flupentixol, (i.e. Flupentixol labelled amount is multiplied by test sample Flupentixol and contains
Amount)；
VstdTo correspond to the dilution volume ml of known impurities G or Lu-28-159 in system suitability solution；
VsplVolume ml is diluted for test solution；
(2) calculation formula of known impurities A：
Wherein：
AsplFor the peak area of known impurities A in test solution；
AstdTo correspond to known impurities A peak areas in system suitability solution；
WstdTo correspond to the weight mg of known impurities A in system suitability solution；
WsplFor the weight mg of test solution melitracen, (i.e. melitracen labelled amount is multiplied by test sample melitracen and contains
Amount)；
VstdTo correspond to the dilution volume ml of known impurities A in system suitability solution；
VsplVolume ml is diluted for test solution；
(3) calculation formula any in Flupentixol oxidation impurities 1~6：
Wherein：
0.8562 is the conversion factor of Flupentixol and Flupenthixol Hydrochloride
AsplFor the peak area of Flupentixol oxidation impurities in test solution；
AstdFor Flupentixol peak area in system suitability solution；
WstdFor the weight mg of Flupenthixol Hydrochloride in system suitability solution；
WsplFor the weight mg of test solution Flupentixol, (i.e. Flupentixol labelled amount is multiplied by test sample Flupentixol and contains
Amount)；
VstdFor the dilution volume ml of Flupenthixol Hydrochloride in system suitability solution；
VsplVolume ml is diluted for test solution；
(4) unknown impuritie calculation formula：
Wherein：
0.8887 is the conversion factor of melitracen and melitracen hydrochloride；
AsplFor the peak area of unknown impuritie in test solution；
AstdFor melitracen peak area in system suitability solution；
WstdFor the weight mg of melitracen hydrochloride in system suitability solution；
WsplFor the weight mg of test solution melitracen, (i.e. melitracen labelled amount is multiplied by test sample melitracen and contains
Amount)；
VstdFor the dilution volume ml of melitracen hydrochloride in system suitability solution；
VsplVolume ml is diluted for test solution.
Embodiment 3, comparative example
It is detected according to following procedure and calculates impurity and its content in flupentixol and melitracen compound medicine：
(1) it takes the standard reference material of impurity A and impurity G, with methanol dilution dissolves constant volume after accurately weighed, every 1mL is made
Containing about 0.2mg impurity As, the impurity storing solution of 0.1mg impurity G in mixed liquor；
(2) Flupenthixol Hydrochloride standard reference material, melitracen hydrochloride standard reference material, impurity Lu-28-159 standards are taken
Reference substance (when practical operation with the salt Lu 28-159-HCl of impurity Lu-28-159 be to launch object), it is accurately weighed after with appropriate
Diluent dissolves, which includes the mobile phase A solution and methanol of a concentration of 0.01mol/L, and the volume ratio of the two is 35:
65, obtain the second storing solution；
(3) the impurity storing solution is measured, is added in second storing solution, dissolves constant volume, system with the dilution dilution agent
At containing about 2 μ g impurity As, 0.4 μ g impurity G, 0.85 μ g impurity Lu-28-159 (are changed with Lu 28-159-HCl in every 1mL mixed liquors
After calculation), (after being converted with Flupenthixol Hydrochloride, the conversion factor of Flupentixol and Flupenthixol Hydrochloride is 5 μ g Flupentixols
0.8562) (after being converted with melitracen hydrochloride, the conversion factor of melitracen and melitracen hydrochloride is with 20 μ g melitracens
0.8887) system suitability solution；
(4) Flupenthixol Hydrochloride bulk pharmaceutical chemicals are weighed, is dissolved and is diluted with the diluent, about fluorine-containing piperazine in every 1mL is made
The solution of 500 μ g of thioxanthene, takes the 1mL solution, and 30% hydrogenperoxide steam generator 0.3mL is added thereto, adds the dilution dilution agent
It to 25mL, shakes up, places about 4 hours, make Flupentixol degradation rate (based on area normalization method) between 5%~10%, make
For Flupenthixol Hydrochloride oxidative degradation solution；
(5) flupentixol and melitracen capsule 1 is taken, containing Flupentixol 0.5mg, melitracen 10mg, is placed in
In 25ml measuring bottles, the diluent is added to dissolve, constant volume shakes up, and filters, using filtrate as test solution；
(6) accurate respectively to measure each 20 μ L injections of the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution
Liquid chromatograph, record gained spectrogram；
(7) the accurate 20 μ L of the test solution that measure inject liquid chromatograph, record gained spectrogram；
Step (6)~(7) use following liquid phase chromatogram condition in the present embodiment：
Chromatographic column：X-BridgeTM Phenyl chromatographic columns, chromatographic column 250 × 4.6mm of specification, 5 μm of filler grain size；
Mobile phase：The potassium dihydrogen phosphate and methanol of the 0.01mol/L of pH value to 6.5 are adjusted using potassium hydroxide solution
Mixed solution, the volume ratio of the two is 35:65；
Column temperature is 30,40,45 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
Carry out isocratic elution.
If attached drawing 3 is the results show that under the detection method of the present embodiment, each ingredient separating degree in system suitability solution
Well, but Flupentixol oxidative degradation impurity and known impurities Lu-28-159 and oxidative degradation impurity and melitracen main peak
It cannot efficiently separate, melitracen oxidative degradation impurity cannot be efficiently separated with known impurities A, flupentixol and melitracen capsule
Oxidative degradation impurity with known impurities Lu-28-159, impurity A separating degree is not good enough.
Embodiment 4, comparative example
It is detected three times using preparation process and detection process same as Example 3, institute is the difference is that this reality
It applies example and has selected different liquid phase chromatogram conditions, it is as follows：
Chromatographic column：X-BridgeTM Phenyl chromatographic columns, chromatographic column 250 × 4.6mm of specification, 5 μm of filler grain size；
Mobile phase：The phosphoric acid of the 0.01mol/L of pH value to 5.5 is adjusted using potassium hydroxide solution in wherein one-time detection
The mixed solution of dihydro potassium solution and methanol is detected as mobile phase, wherein the volume of potassium dihydrogen phosphate and methanol
Than being 35：65；The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted in detecting twice using potassium hydroxide solution
The mixed solution of solution and methanol is detected as mobile phase, and the wherein volume ratio of potassium dihydrogen phosphate and methanol is
40:60；
Column temperature is respectively 30,40,45 DEG C in detecting three times, and Detection wavelength is 270nm, and flow velocity is 1.0ml/min；
Carry out different gradient elutions.
If attached drawing 4 is the results show that under the detection method of the present embodiment, exist known impurities be defined as with original it is unknown
The case where oxidative degradation impurity of impurity cannot efficiently separate.
Embodiment 5
It is detected using preparation process and detection process same as Example 3, institute is the difference is that the present embodiment
Different liquid phase chromatogram conditions has been selected, it is as follows：
Chromatographic column：Poroshell HPH-C18 chromatographic columns, filler are octadecylsilane chemically bonded silica, chromatographic column
100 × 4.6mm of specification, 2.7 μm of filler grain size；
Mobile phase A：The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted using potassium hydroxide solution；
Mobile phase B：Acetonitrile；
Mobile phase C：Methanol；
Column temperature is 40 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
According to the form below is eluted：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
| 0.0 | 67 | 22 | 11 |
| 10.0 | 49 | 34 | 17 |
| 27.5 | 38 | 43 | 19 |
| 29.0 | 27 | 57 | 16 |
| 49.0 | 27 | 57 | 16 |
| 51.0 | 67 | 22 | 11 |
| 60.0 | 67 | 22 | 11 |
If attached drawing 5 is the results show that under the detection method of the present embodiment, each known impurities of system suitability solution and its
Separating degree between main peak is preferable, Flupentixol oxidative degradation impurity and melitracen oxidative degradation impurity and known impurities
It can efficiently separate, but find that chromatographic column column effect declines comparatively fast in verification process repeatedly, there may be not for chromatographic column durability
Foot.
Embodiment 6, comparative example
It is detected using preparation process and detection process same as Example 3, institute is the difference is that the present embodiment
Different liquid phase chromatogram conditions has been selected, it is as follows：
Chromatographic column：YMC-Pack Pro C18 RS chromatographic columns, filler are octadecylsilane chemically bonded silica, chromatography
Column 150 × 4.6mm of specification, 3.0 μm of filler grain size；
Mobile phase A：The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted using potassium hydroxide solution；
Mobile phase B：Acetonitrile；
Mobile phase C：Methanol；
Column temperature is 30 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
According to the form below is eluted：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
| 0.0 | 67 | 22 | 11 |
| 10.0 | 49 | 34 | 17 |
| 20.0 | 46 | 36 | 18 |
| 25.0 | 43 | 38 | 19 |
| 35.0 | 24 | 57 | 19 |
| 50.0 | 24 | 57 | 19 |
| 52.0 | 67 | 22 | 11 |
| 60.0 | 67 | 22 | 11 |
If attached drawing 6 is the results show that under the detection method of the present embodiment, each known impurities of system suitability solution and its
Separating degree between main peak is preferable, Flupentixol oxidative degradation impurity and melitracen oxidative degradation impurity and known impurities
It can efficiently separate, but the separating degree between known impurities A and unknown impuritie is not ideal enough.
Embodiment 7, comparative example
It is detected using preparation process and detection process same as Example 3, institute is the difference is that the present embodiment
Different liquid phase chromatogram conditions has been selected, it is as follows：
Chromatographic column：YMC-Pack Pro C18 RS chromatographic columns, filler are octadecylsilane chemically bonded silica, chromatography
Column 150 × 4.6mm of specification, 3.0 μm of filler grain size；
Mobile phase A：The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted using potassium hydroxide solution；
Mobile phase B：Acetonitrile；
Mobile phase C：Methanol；
Column temperature is 40 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
According to the form below is eluted：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
| 0.0 | 67 | 22 | 11 |
| 10.0 | 49 | 34 | 17 |
| 33.0 | 37 | 42 | 21 |
| 36.0 | 24 | 57 | 19 |
| 51.0 | 24 | 57 | 19 |
| 53.0 | 67 | 22 | 11 |
| 62.0 | 67 | 22 | 11 |
If attached drawing 7 is the results show that under the detection method of the present embodiment, each known impurities of system suitability solution and its
Separating degree between main peak is preferable, Flupentixol oxidative degradation impurity and melitracen oxidative degradation impurity and known impurities
It can efficiently separate, but the separating degree between known impurities A and unknown impuritie is still not ideal enough.
Embodiment 8
It is detected using preparation process and detection process same as Example 3, institute is the difference is that the present embodiment
Different liquid phase chromatogram conditions has been selected, it is as follows：
Chromatographic column：YMC-Pack Pro C18 RS chromatographic columns, filler are octadecylsilane chemically bonded silica, chromatography
Column 150 × 4.6mm of specification, 3.0 μm of filler grain size；
Mobile phase A：The potassium dihydrogen phosphate of the 0.01mol/L of pH value to 7.5 is adjusted using potassium hydroxide solution；
Mobile phase B：Acetonitrile；
Mobile phase C：Methanol；
Column temperature is 40 DEG C, Detection wavelength 270nm, flow velocity 1.0ml/min；
According to the form below is eluted：
| Time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
| 0.0 | 67 | 22 | 11 |
| 10.0 | 49 | 34 | 17 |
| 27.5 | 38 | 43 | 19 |
| 29.0 | 27 | 57 | 16 |
| 49.0 | 27 | 57 | 16 |
| 51.0 | 67 | 22 | 11 |
| 60.0 | 67 | 22 | 11 |
If attached drawing 8 is the results show that under the detection method of the present embodiment, each known impurities of system suitability solution and its
Separating degree between main peak is preferable, Flupentixol oxidative degradation impurity and melitracen oxidative degradation impurity and known impurities
It can efficiently separate, impurity A peak shape is good, is detached with unknown impuritie well, Flupentixol oxidative degradation impurity 5 and 6 separating degrees
Well.
9 methodology validation of embodiment
Following solution is prepared, and methodology validation is carried out according to States Pharmacopoeia specifications by the chromatographic condition of embodiment 2：
A. storing solution：
S1：Blank solution：That is diluent is 35 by v/v ratios:65 mobile phase A and the mixed liquor of methanol form；
S2：Flupenthixol Hydrochloride reference substance storing solution：Precision weighs Flupenthixol Hydrochloride standard reference material 29.24mg, adds
Enter methanol constant volume to 10mL；
S3：Melitracen hydrochloride reference substance storing solution：Precision weighs melitracen hydrochloride standard reference material 31.02mg, adds
Enter methanol constant volume to 10mL；
S4：Lu-28-159-HCl reference substance storing solutions：Precision weighs Lu-28-159-HCl standard reference material 12.68mg,
Methanol constant volume is added to 50mL；
S5：Impurity A reference substance storing solution：Precision weighs impurity A standard reference material 26.18mg, and methanol constant volume is added extremely
100mL；
S6：Impurity G reference substance storing solutions：Precision weighs impurity G standard reference material 12.95mg, and methanol constant volume is added extremely
100mL；
S7：Impurity F reference substance storing solution：Precision weighs impurity F standard reference material 3.251mg, and methanol constant volume is added extremely
50mL；
B. system suitability test solution：
It is accurate respectively to measure Flupenthixol Hydrochloride reference substance storing solution 0.1mL, melitracen hydrochloride reference substance storing solution
0.4mL, Lu-28-159-HCl reference substance storing solution 0.2mL, impurity A reference substance storing solution 0.4mL, impurity G reference substance storing solutions
0.2mL is placed in 50mL measuring bottles, and the dilution dilution agent constant volume is added up to system suitability test solution；
C. system suitability+impurity F test solution：
It is accurate respectively to measure Flupenthixol Hydrochloride reference substance storing solution 0.1mL, melitracen hydrochloride reference substance storing solution
0.4mL, Lu 28 159-HCl reference substance storing solution 0.2mL, impurity A reference substance storing solution 0.4mL, impurity G reference substance storing solutions
0.2mL, impurity F reference substance storing solution 1mL, is placed in 50ml measuring bottles, adds the dilution dilution agent constant volume to obtain the final product；
D. impurity positions solution：
Take 28 159-HCl reference substance storing solutions of Lu respectively, impurity A reference substance storing solution, impurity G reference substance storing solutions,
Each 0.5mL of impurity F reference substance storing solution, respectively sets in 25mL measuring bottles, adds the dilution dilution agent constant volume to obtain the final product；
E. Flupenthixol Hydrochloride mother liquor：
Flupenthixol Hydrochloride 20.88mg is weighed, the diluent dissolving is added and is settled to 100mL；
F. Flupenthixol Hydrochloride does not destroy solution (Flupenthixol Hydrochloride positioning solution)：
The Flupenthixol Hydrochloride mother liquor 2.5mL is weighed, the diluent is added and is settled to 25mL；
G. melitracen hydrochloride mother liquor：
Melitracen hydrochloride 200.24mg is weighed, the diluent is added and is settled to 50mL；
H. melitracen hydrochloride does not destroy solution (melitracen hydrochloride positioning solution)：
The melitracen hydrochloride mother liquor 2.5mL is weighed, the diluent is added and is settled to 25mL；
I. Flupenthixol Hydrochloride Oxidative demage solution：
The Flupenthixol Hydrochloride mother liquor 2.5mL is weighed, 30% hydrogen peroxide 0.3mL is added, with the dilution dilution agent constant volume
To 25mL；
J. melitracen hydrochloride Oxidative demage solution：
The melitracen hydrochloride mother liquor 2.5mL is weighed, 30% hydrogen peroxide 0.3mL is added, with the dilution dilution agent constant volume
To 25mL；
K. test solution：Flupentixol and melitracen capsule 1 is taken, is placed in 25mL measuring bottles, adds per intragranular is tolerant
The diluent dissolving constant volume to obtain the final product；
The results are shown in table below for methodology validation：
Although reference be made herein to invention has been described for explanatory embodiment of the invention, and above-described embodiment is only this hair
Bright preferable embodiment, embodiment of the present invention are not limited by the above embodiments, it should be appreciated that people in the art
Member can be designed that a lot of other modification and implementations, these modifications and implementations will be fallen in principle disclosed in the present application
Within scope and spirit.
Claims (10)
1. a kind of detection method of flupentixol and melitracen compound medicine, it is characterised in that：The detection method includes following
Content：Using HPLC analytical method, wherein chromatographic column filler is octadecylsilane chemically bonded silica, in Detection wavelength
Under 250~300nm, to be eluted to material medicine and/or reference substance solution, mobile phase condition is as follows：
Mobile phase A：Phosphate buffer, pH are 7.40~7.60；
Mobile phase B：Including acetonitrile；
Mobile phase C：Including methanol；
Mobile phase elution requirement is：
2. the detection method of flupentixol and melitracen compound medicine according to claim 1, it is characterised in that：The phosphorus
Phthalate buffer is made of dihydric phosphate, alkali and water, or is made of phosphoric acid hydrogen disalt, acid and water；The wherein described biphosphate
Salt includes one or more in potassium dihydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate, and the alkali includes sodium hydroxide, hydrogen-oxygen
One or more in change potassium, ammonium hydroxide, the phosphoric acid hydrogen disalt includes in dipotassium hydrogen phosphate, disodium hydrogen phosphate, diammonium hydrogen phosphate
It is one or more, the acid includes phosphoric acid, hydrochloric acid, one or more in acetic acid.
3. the detection method of flupentixol and melitracen compound medicine according to claim 2, it is characterised in that：The phosphorus
Phthalate buffer is made of dihydric phosphate, sodium hydroxide and water, wherein a concentration of 0.01~0.05mol/ of potassium dihydrogen phosphate
L, preferably 0.01mol/L.
4. the detection method of flupentixol and melitracen compound medicine according to claim 1, chromatographic column column temperature is 35~
45 DEG C, preferably 40 DEG C；Further, 0.95~1.05mL/min of flow velocity of the mobile phase, further be selected from 0.98~
1.02mL/min。
5. the detection method of flupentixol and melitracen compound medicine according to claim 1, it is characterised in that：Detect wave
A length of 254~280nm, preferably 270nm.
6. the detection method of flupentixol and melitracen compound medicine according to claim 1, it is characterised in that：The original
Expect that the solvent of drug and/or reference substance solution includes phosphate buffer：Methanol=40:60~35:65, it is further 35:65.
7. the detection method of flupentixol and melitracen compound medicine according to claim 1, it is characterised in that：The inspection
Survey method includes the following steps：
(1) standard reference material of impurity A and impurity G is taken, the impurity storing solution of impure A, impurity G are made after dissolving；
(2) Flupenthixol Hydrochloride standard reference material, melitracen hydrochloride standard reference material, impurity Lu-28-159 standard controls are taken
The second storing solution is made in product after being dissolved using diluent；
(3) the impurity storing solution is measured, is added in second storing solution, with impure A, impurity G is made after dilution dilution agent,
The system suitability solution of impurity Lu-28-159, Flupentixol and melitracen；
(4) Flupenthixol Hydrochloride bulk pharmaceutical chemicals are weighed, after being dissolved with diluent, 30% hydrogenperoxide steam generator is added thereto, it is quiet
It sets, until when the degradation rate that wherein Flupentixol is calculated through chromatography test and usable floor area normalization method reaches 5%~10%
Until, as Flupenthixol Hydrochloride oxidative degradation solution；
(5) after taking the flupentixol and melitracen compound medicine for examination to add diluent dissolving, filtering, test solution is obtained；
(6) the system suitability solution, Flupenthixol Hydrochloride oxidative degradation solution injection liquid chromatograph, record gained spectrum are taken
Figure；
(7) the test solution injection liquid chromatograph, record gained spectrogram are taken；
(8) system solvent peak and auxiliary material peak will be deducted in obtained test solution spectrogram, it is impurity Lu-28-159, impurity G, miscellaneous
Matter A, compared with the chromatographic peak of corresponding position in system suitability solution spectrogram, unknown oxidative degradation impurity 1~6 and hydrochloric acid fluorine
The Flupentixol oxidation impurities 1~6 of corresponding position compare in piperazine thioxanthene oxidative degradation solution spectrogram, other unknown impurities and U.S.
Other impurity peaks of litracen corresponding position compare, and go out each impurity content by external standard method with calculated by peak area respectively；
Further, the impurity Lu-28-159 standard reference materials use the salt form of impurity Lu-28-159.
8. the detection method of oxidation impurities in a kind of flupentixol and melitracen compound medicine, it is characterised in that：It is wanted using right
1-6 any one the methods are sought, flupentixol and melitracen compound medicine to be checked is detected；The oxidation impurities are fluorine
One or more in piperazine thioxanthene oxidation impurities 1-6, the relative retention time of Flupentixol oxidation impurities 1-6 is as follows：With fluorine piperazine
Thioxanthene chromatographic peak is with reference to peak, the corresponding Flupentixol oxidation impurities of two chromatographic peaks of relative retention time about 0.42~0.43
1, Flupentixol oxidation impurities 2；The corresponding Flupentixol oxidation impurities of 1 chromatographic peak of relative retention time about 0.46 3；Relatively
The corresponding Flupentixol oxidation impurities of 1 chromatographic peak of retention time about 0.50 4；The two of relative retention time about 0.67~0.70
The corresponding Flupentixol oxidation impurities 5 of a chromatographic peak, Flupentixol oxidation impurities 6.
9. the new recognizable impurity of flupentixol and melitracen compound medicine, it is characterised in that：The impurity is Flupentixol
It is one or more in oxidation impurities 1~6, it is detected using the method described in claim 1~6 any one, gained color
With Flupentixol chromatographic peak for reference to peak, the relative retention time of Flupentixol oxidation impurities 1~6 is as follows in spectrogram：It is opposite to protect
Stay the corresponding Flupentixol oxidation impurities 1 of two chromatographic peaks, the Flupentixol oxidation impurities 2 of time about 0.42~0.43；Relatively
The corresponding Flupentixol oxidation impurities of 1 chromatographic peak of retention time about 0.46 3；1 chromatography of relative retention time about 0.50
The corresponding Flupentixol oxidation impurities in peak 4；The corresponding Flupentixol of two chromatographic peaks of relative retention time about 0.67~0.70
Oxidation impurities 5, Flupentixol oxidation impurities 6.
10. a kind of flupentixol and melitracen compound medicine, it is characterised in that：In the compound medicine, dopant species and content
It is as follows：
The wherein described Flupentixol oxidation impurities are the Flupentixol oxidation impurities 1~6 described in claim 9.
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| GB2595140A (en) * | 2019-01-10 | 2021-11-17 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| CN109771386A (en) * | 2019-01-10 | 2019-05-21 | 广东赛烽医药科技有限公司 | A kind of Flupentixol and Melitracen Tablets agent and preparation method thereof |
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| WO2020143395A1 (en) * | 2019-01-10 | 2020-07-16 | 广东赛烽医药科技有限公司 | Flupentixol melitracen tablet and preparation method therefor |
| CN109771386B (en) * | 2019-01-10 | 2021-10-08 | 广东赛烽医药科技有限公司 | Flupentixol melitracen tablet and preparation method thereof |
| CN109674754B (en) * | 2019-01-10 | 2021-10-08 | 广东赛烽医药科技有限公司 | Flupentixol and melitracen pharmaceutical composition and preparation thereof |
| CN109674754A (en) * | 2019-01-10 | 2019-04-26 | 广东赛烽医药科技有限公司 | A kind of flupentixol and melitracen pharmaceutical composition and its preparation |
| GB2595141A (en) * | 2019-01-10 | 2021-11-17 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol melitracen tablet and preparation method therefor |
| GB2595140B (en) * | 2019-01-10 | 2023-06-14 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol/melitracen pharmaceutical composition and preparation thereof |
| GB2595141B (en) * | 2019-01-10 | 2023-06-14 | Guangdong Scient Finder Pharmaceutical Tech Co Ltd | Flupentixol melitracen tablet and preparation method therefor |
| CN115850232A (en) * | 2023-02-16 | 2023-03-28 | 广州佳途科技股份有限公司 | Preparation method and application of flupentixol EP impurity H |
| CN117257782A (en) * | 2023-11-07 | 2023-12-22 | 广州医科大学 | Application of melitracin in reversing Oritinib resistance |
| CN117257782B (en) * | 2023-11-07 | 2024-08-30 | 广州医科大学 | Application of melitracin in reversing Oritinib resistance |
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