CN116359381A - Separation method, detection method, rotigotine or pharmaceutical salt composition, pharmaceutical preparation and application thereof - Google Patents
Separation method, detection method, rotigotine or pharmaceutical salt composition, pharmaceutical preparation and application thereof Download PDFInfo
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- CN116359381A CN116359381A CN202310280149.9A CN202310280149A CN116359381A CN 116359381 A CN116359381 A CN 116359381A CN 202310280149 A CN202310280149 A CN 202310280149A CN 116359381 A CN116359381 A CN 116359381A
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- KFQYTPMOWPVWEJ-INIZCTEOSA-N rotigotine Chemical compound CCCN([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 KFQYTPMOWPVWEJ-INIZCTEOSA-N 0.000 title claims abstract description 136
- 229960003179 rotigotine Drugs 0.000 title claims abstract description 136
- 150000003839 salts Chemical class 0.000 title claims abstract description 118
- 239000000203 mixture Substances 0.000 title claims abstract description 67
- 238000000926 separation method Methods 0.000 title claims abstract description 56
- 238000001514 detection method Methods 0.000 title claims abstract description 48
- 239000000825 pharmaceutical preparation Substances 0.000 title description 3
- 239000000126 substance Substances 0.000 claims abstract description 54
- 239000012071 phase Substances 0.000 claims abstract description 50
- 239000008346 aqueous phase Substances 0.000 claims abstract description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 239000012074 organic phase Substances 0.000 claims abstract description 8
- 238000003908 quality control method Methods 0.000 claims abstract description 8
- 238000007689 inspection Methods 0.000 claims abstract description 4
- 239000012535 impurity Substances 0.000 claims description 248
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 88
- 150000001875 compounds Chemical class 0.000 claims description 62
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 claims description 33
- 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 32
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 22
- 229910002027 silica gel Inorganic materials 0.000 claims description 22
- 239000000945 filler Substances 0.000 claims description 17
- 238000002347 injection Methods 0.000 claims description 17
- 239000007924 injection Substances 0.000 claims description 17
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 238000010828 elution Methods 0.000 claims description 13
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 10
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 9
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 9
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 9
- 239000013558 reference substance Substances 0.000 claims description 8
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000000825 ultraviolet detection Methods 0.000 claims description 4
- 239000007853 buffer solution Substances 0.000 claims description 3
- 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
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 abstract description 7
- 238000011002 quantification Methods 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 63
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 56
- 239000000523 sample Substances 0.000 description 36
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 28
- 239000008363 phosphate buffer Substances 0.000 description 18
- 239000003085 diluting agent Substances 0.000 description 12
- 238000013375 chromatographic separation Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- FGDQGIKMWOAFIK-UHFFFAOYSA-N acetonitrile;phosphoric acid Chemical compound CC#N.OP(O)(O)=O FGDQGIKMWOAFIK-UHFFFAOYSA-N 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 150000007522 mineralic acids Chemical class 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000005696 Diammonium phosphate Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- -1 (S) -6- (n-propyl (2- (thiophen-3-yl) ethyl) amino) -5,6,7, 8-tetrahydronaphthalen-1-ol Chemical compound 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 229940098778 Dopamine receptor agonist Drugs 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000005793 Restless legs syndrome Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- 229960001467 bortezomib Drugs 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- CEXBONHIOKGWNU-NTISSMGPSA-N hydron;(6s)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol;chloride Chemical compound [Cl-].CCC[NH+]([C@@H]1CC2=CC=CC(O)=C2CC1)CCC1=CC=CS1 CEXBONHIOKGWNU-NTISSMGPSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
-
- 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
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
The invention discloses a separation method, a detection method, a composition containing rotigotine or medicinal salt thereof, a medicinal preparation and application of a substance A in rotigotine or the composition thereof, rotigotine medicinal salt or the composition thereof; the separation and detection method comprises the following steps: separating the rotigotine or the composition thereof and the rotigotine medicinal salt or the composition thereof by adopting a high performance liquid chromatography, wherein a mobile phase in the high performance liquid chromatography comprises an aqueous phase and an organic phase, and the pH value of the aqueous phase is 6.0-8.0; the separation and detection method has the advantages of good separation degree, symmetrical peak shape, high sensitivity and accurate quantification of the substance A, overcomes the defect of rotigotine quality control, and can be used for quality inspection or quality control of rotigotine or a composition thereof, rotigotine medicinal salt or a composition thereof.
Description
Technical Field
The invention relates to the technical field of detection, in particular to rotigotine or a composition thereof, a separation method of rotigotine medicinal salt or a composition thereof, a detection method, a composition of rotigotine or a medicinal salt thereof, a medicinal preparation and application.
Background
Rotigotine is known by the general name Rotigotine and by the chemical name (6S) -6- [ propyl- [2- (2-thienyl) ethyl ]]-amino group]-5,6,7, 8-tetrahydro-1-naphthol having the formula C 19 H 25 NOS, which is a non-ergot selective dopamine receptor agonist (D1/D2/D3), for the treatment of Parkinson's disease and restless leg syndrome, acts by stimulating dopamine receptors in the body and mimicking the neurotransmitter dopamine, the structural formula of rotigotine is shown below;
impurity research is an extremely important research content in the process of drug development. According to the existing synthesis process of rotigotine, the following diagram is shown. The applicant has deduced that there may be impurity structures as shown in formula L.
Although the European pharmacopoeia (European Pharmacopoeia 10.0) discloses that impurities B-K (European pharmacopoeia (European Pharmacopoeia 10.0) pages 3748-3750) may be present in rotigotine.
However, the applicant has serious tailing of the main peak of rotigotine detected according to European pharmacopoeia, and cannot accurately determine the impurity content shown in the formula L of rotigotine, so that quality hidden trouble is brought to rotigotine.
In patent CN 110726786a, an HPLC separation analysis method for rotigotine and its important intermediate is provided, in which only the separation of impurities RG03 (the above impurity H), RG02 (not the impurities carried in the european pharmacopoeia) and rotigotine are described, and other impurities in the european pharmacopoeia and the impurities represented by formula L are not taken into consideration, so that the product quality cannot be effectively controlled.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a separation method, a detection method, a composition containing rotigotine or a medicinal salt thereof, a medicinal preparation and application of a substance A in rotigotine or a composition thereof, a rotigotine medicinal salt or a composition thereof, wherein the separation and detection method has the advantages of good separation degree, symmetrical peak shape, high sensitivity and accurate quantification of the substance A, overcomes the defect of quality control of rotigotine, and can be used for quality inspection or quality control of rotigotine or a composition thereof, and the rotigotine medicinal salt or a composition thereof.
The first aspect of the invention provides a method for separating a substance A from rotigotine or a composition thereof, a rotigotine medicinal salt or a composition thereof, which comprises the following steps:
separating the rotigotine or the composition thereof and the rotigotine medicinal salt or the composition thereof by adopting a high performance liquid chromatography, wherein a mobile phase in the high performance liquid chromatography comprises an aqueous phase and an organic phase, and the pH value of the aqueous phase is 6.0-8.0;
wherein the substance a comprises: a compound represented by formula L or a salt thereof;
in some embodiments of the invention, the separation method is a separation method of substance a in rotigotine or a composition thereof.
In some embodiments of the invention, the separation method is a separation method of substance a in rotigotine drug substance.
In the present invention, the compound represented by the formula L or a salt thereof is an impurity L, and in some embodiments of the present invention, the compound represented by the formula L is an impurity L.
In some embodiments of the invention, the pharmaceutically acceptable salt of rotigotine is a salt of rotigotine with an inorganic or organic acid; the inorganic acid is selected from one or more of hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid and nitric acid; the organic acid is selected from one or more of citric acid, fumaric acid, maleic acid, acetic acid, benzoic acid, lactic acid, methanesulfonic acid, naphthalene sulfonic acid and p-benzene methanesulfonic acid.
In some specific embodiments of the invention, the pharmaceutically acceptable salt of rotigotine is the hydrochloride salt of rotigotine or the hydrobromide salt of rotigotine.
In some embodiments of the invention, the organic phase is acetonitrile or methanol, preferably acetonitrile.
In some embodiments of the invention, the aqueous phase is a buffer, preferably an inorganic salt buffer; the inorganic salt is preferably one or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate.
In the present invention, the inorganic salt buffer is a mixed solution of an inorganic salt and an inorganic acid corresponding to the inorganic salt. The inorganic salt buffer solution is obtained by regulating the pH value of an inorganic salt solution by inorganic acid corresponding to inorganic salt.
In some embodiments of the invention, the aqueous phase has a pH of 7.4 to 7.8.
In some embodiments of the invention, the pH of the aqueous phase is 6.0, 7.0, 7.4, 7.6, 7.8 or 8.0.
In some embodiments of the invention, the mobile phase consists of an organic phase and an aqueous phase.
In some embodiments of the invention, the high performance liquid chromatography separation further comprises: separating by chromatography column with octadecyl bonded silica gel or octyl bonded silica gel as filler.
In some embodiments of the present invention, the octadecyl bonded silica gel is used as filler, and the column is preferably 4.6mm×250mm,5 μm in size, and is a shim-pack VP-ODS.
In some embodiments of the present invention, the octyl-bonded silica gel is used as filler in a chromatographic column Agilent XDB C8, preferably having a specification of 4.6mm by 150mm,5 μm.
In some embodiments of the invention, the high performance liquid chromatography separation is performed under the following chromatographic conditions:
flow rate: 1.0-1.5 ml/min; and/or the separation method further comprises: high performance liquid chromatography separation was performed using the following chromatographic conditions:
column temperature: 25-35 ℃; and/or
Sample injection volume: 5-20 mu L; and/or
Mobile phase: a: buffer, B: acetonitrile, in volume percent, gradient elution conditions were as follows:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 2 | 90 | 10 |
| 12 | 50 | 50 |
| 30 | 15 | 85 |
| 35 | 15 | 85 |
| 35.1 | 90 | 10 |
| 45 | 90 | 10 |
。
In some embodiments of the invention, the high performance liquid chromatography separation chromatograph is:
chromatographic column: chromatographic column with octadecyl bonded silica gel or octyl bonded silica gel as filler;
column temperature: 25-35 ℃;
sample injection volume: 5-20 mu L;
mobile phase: a: phosphate buffer, B: acetonitrile, in volume percent, was subjected to gradient elution as follows;
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 2 | 90 | 10 |
| 12 | 50 | 50 |
| 30 | 15 | 85 |
| 35 | 15 | 85 |
| 35.1 | 90 | 10 |
| 45 | 90 | 10 |
Flow rate: 1.0 to 1.5ml/min.
In some embodiments of the invention, the sample volume is 5 μl, 10 μl, 20 μl, preferably 10 μl.
In some embodiments of the invention, the substance a is a compound of formula L or a salt thereof.
In some embodiments of the invention, the substance a is a compound of formula L.
In some embodiments of the invention, the substance a is a salt of a compound of formula L.
In some embodiments of the invention, the salt of the compound of formula L is the hydrobromide salt of the compound of formula L.
In some embodiments of the invention, the substance a further comprises one or more of impurity B or a salt thereof, impurity C or a salt thereof, impurity D or a salt thereof, impurity E, impurity F or a salt thereof, impurity J or a salt thereof, impurity H or a salt thereof, impurity I or a salt thereof, impurity G or a salt thereof, and impurity K, the structural formulas of impurity B, impurity C, impurity D, impurity E, impurity F, impurity J, impurity H, impurity I, impurity G, and impurity K being as follows:
in some embodiments of the invention, the substance a further comprises one or more of impurity B, impurity C, impurity D, impurity E, impurity F, impurity J, impurity H, impurity I, impurity G, and impurity K.
In the present invention, impurity 1 is the compound represented by the formula L or a salt thereof; the impurity 2 is one or more selected from the group consisting of impurity B or a salt thereof, impurity C or a salt thereof, impurity D or a salt thereof, impurity E, impurity F or a salt thereof, impurity J or a salt thereof, impurity H or a salt thereof, impurity I or a salt thereof, impurity G or a salt thereof, and impurity K.
In some embodiments of the invention, the impurity 1 is a compound represented by the formula L.
In some embodiments of the invention, the substance a comprises: impurity 1 and impurity 2.
In some embodiments of the invention, the substance a is impurity 1 and impurity 2.
In some embodiments of the invention, the impurity 2 is one or more selected from the group consisting of impurity B, impurity C, impurity D, impurity E, impurity F, impurity J, impurity H, impurity I, impurity G, and impurity K.
In some embodiments of the invention, the impurity 2 is the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity G, the impurity H, the impurity I, the impurity J, and the impurity K.
In some embodiments of the invention, the substance a is a compound of formula L, the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity G, the impurity H, the impurity I, the impurity J, and the impurity K.
In some embodiments of the invention, the substance a is a compound of formula L, the impurity B, the impurity C, the impurity D, the impurity F, the impurity G, the impurity H, the impurity I, and the impurity K.
The second invention provides a detection method of a substance A in rotigotine or a composition thereof, rotigotine medicinal salt or a composition thereof, which comprises the separation method of the first aspect;
in some embodiments of the invention, the detection method is a detection method of substance a in rotigotine or a composition thereof.
In some embodiments of the invention, the detection method is a detection method of substance a in rotigotine drug substance.
In some embodiments of the invention, the detection method further comprises: using ultraviolet detection to determine the content of the substance a; the detection wavelength of the ultraviolet detection is preferably 218-222 nm, more preferably 220nm.
In some embodiments of the invention, the chromatographic conditions are:
chromatographic column: chromatographic column with octadecyl bonded silica gel or octyl bonded silica gel as filler;
column temperature: 25-35 ℃;
sample injection volume: 5-20 mu L;
mobile phase: a: phosphate buffer, B: acetonitrile, in volume percent, was subjected to gradient elution as follows;
flow rate: 1.0-1.5 ml/min;
ultraviolet detector detection wavelength: 218-222 nm.
In a third aspect the present invention provides a composition comprising bortezomib, or a pharmaceutically acceptable salt thereof, and a substance a comprising: a compound represented by formula L or a salt thereof;
the content of the compound shown in the formula L or the salt thereof is less than or equal to 0.05wt%; preferably less than or equal to 0.03wt%; more preferably less than or equal to 0.015wt%.
In some embodiments of the invention, the rotigotine or pharmaceutically acceptable salt thereof has a purity of greater than or equal to 99.5wt%, preferably greater than or equal to 99.9wt%.
In some embodiments of the invention, the maximum mono-impurity content in the composition, excluding the compound of formula L or a salt thereof, is less than or equal to 0.03wt%, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%.
Substance a according to the third aspect of the present invention is substance a according to the first aspect.
In some embodiments of the invention, consists of rotigotine or a pharmaceutically acceptable salt thereof and substance a.
In some embodiments of the present invention, the content of the impurity B or a salt thereof, the impurity C or a salt thereof, the impurity D or a salt thereof, the impurity E, the impurity F or a salt thereof, the impurity G or a salt thereof, the impurity H or a salt thereof, the impurity I or a salt thereof, the impurity J or a salt thereof, the impurity K is 0.03wt% or less, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%.
In some embodiments of the present invention, the content of the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity G, the impurity H, the impurity I, the impurity J, the impurity K is 0.03wt% or less, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%.
In some embodiments of the invention, the impurity B or salt thereof content in the composition is less than or equal to 0.03wt%, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.005wt% or less.
In some embodiments of the invention, the impurity C or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.005wt% or less.
In some embodiments of the invention, the impurity D or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.004wt% or less.
In some embodiments of the invention, the impurity E content in the composition is less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.006wt% or less.
In some embodiments of the invention, the impurity F or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.006wt% or less.
In some embodiments of the invention, the impurity G or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.004wt% or less.
In some embodiments of the invention, the impurity H or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.005wt% or less.
In some embodiments of the invention, the impurity I or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.004wt% or less.
In some embodiments of the invention, the impurity J or salt thereof is present in the composition in an amount of less than or equal to 0.03wt%; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.006wt% or less.
In some embodiments of the invention, the impurity K content in the composition is less than or equal to 0.03wt%, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%; more preferably 0.002wt% or less.
In a fourth aspect the present invention provides a pharmaceutical formulation comprising a composition according to the third aspect and one or more pharmaceutically acceptable excipients.
The fifth aspect of the present invention is the use of substance a as an impurity standard or control in quality control or quality control of rotigotine or a composition thereof, a pharmaceutically acceptable salt of rotigotine or a composition thereof, a pharmaceutical formulation containing rotigotine or a pharmaceutically acceptable salt thereof; the substance a comprises: a compound represented by formula L or a salt thereof.
In some embodiments of the invention, the composition is a composition according to the third aspect.
In some embodiments of the invention, the pharmaceutical formulation is the pharmaceutical formulation of the fourth aspect.
The invention has the beneficial effects that:
(1) In the separation and detection method provided by the invention, the pH of the mobile phase is critical to chromatographic peak separation, so that compounds with similar structures can be effectively separated in the pH range of the mobile phase, rotigotine or a composition thereof, rotigotine medicinal salt or a composition thereof can be effectively separated, the peak shape can be improved, the problem of accurate quantification of the substance A in a rotigotine sample is solved, and the effective detection of the rotigotine or the composition thereof, the rotigotine medicinal salt or the composition thereof is ensured. Substance a includes a compound represented by formula L or a salt thereof, i.e., the present invention achieves effective detection of a compound represented by formula L. Preferably, the invention aims at separating and detecting the rotigotine or the substance A in the composition thereof, and can realize accurate quantification of the compound shown in the formula L. Furthermore, the rotigotine adopted by the invention is high-purity rotigotine, namely, the effective detection of the compound shown in the formula L of the high-purity rotigotine is ensured.
(3) The separation and detection method has the advantages of simple operation, wide range of selectable chromatographic columns, wide range of mobile phase pH, column temperature, flow velocity and sample volume, and good durability.
(4) The invention provides application of a substance A as an impurity standard substance or a reference substance in quality inspection or quality control of the composition or the pharmaceutical preparation. The compound shown in the formula L or the salt thereof has low content in rotigotine or the composition thereof, rotigotine medicinal salt or the composition thereof, and the purity of the rotigotine medicinal salt is high, so that the quality of the rotigotine or the composition thereof, the quality of the rotigotine medicinal salt or the composition thereof and the quality and the safety of medicines are improved, and the control and the improvement are facilitated.
Furthermore, the separation and detection method can separate and detect rotigotine samples and medicinal salts thereof.
Furthermore, the invention can realize the separation and detection of the compound shown in the formula L or the salt thereof, and can also realize the separation of various impurities (impurities B-K or the salt thereof). The method has the advantages that various impurities can achieve baseline separation, the separation degree between the impurities and the medicinal components (rotigotine or medicinal salts thereof) is high, the specificity is better, the peak shape is symmetrical, under the detection wavelength of the method, the impurities are greatly absorbed, the requirements on instruments and equipment are low, the method has good durability and good sensitivity, and the sample injection precision and repeatability are good.
(5) Compared with European pharmacopoeia, the invention has the advantages of more effectively detected impurities, better specificity, higher sensitivity and more symmetrical peak shape, and provides a basis for the establishment of quality standards of rotigotine or the composition thereof, rotigotine medicinal salt or the composition thereof.
(6) The prior art (Liu Zhuolin. Research on related substances of rotigotine bulk drug [ D ]. Shandong: university of smoke desk, 2020) discloses detection of impurities in rotigotine starting materials, intermediates, final products and bulk drugs, and chromatographic conditions of the disclosed detection methods are different. In the detection method disclosed by the prior art and related to the impurity 35, the mobile phase condition different from that of the invention is adopted, and compared with the prior art, the method has the advantages that the range of the selectable chromatographic column is wider, the pH value of the mobile phase, the column temperature and the flow velocity range are wider, and the method has better durability. The prior art only discloses that the impurity 35 is controlled according to unknown single impurities in intermediates and final products, the single impurity limit is only less than or equal to 0.10%, the invention can realize effective control of rotigotine or a composition thereof, rotigotine medicinal salt or a compound shown in a formula L in the composition thereof or the salt thereof, has higher detection sensitivity and high sample purity, and further, can effectively control various impurities (impurities B-K) in European pharmacopoeia, can effectively separate each peak, and has better symmetry of each peak.
Drawings
FIG. 1 is a diagram of the system applicability solution specificity of example 1;
FIG. 2 is a diagram of the system applicability solution specificity of example 2;
FIG. 3 is a diagram of the system applicability solution specificity of example 3;
FIG. 4 is a diagram of the system applicability solution specificity of example 4;
FIG. 5 is a specific spectrum of the system applicability solution 1 in example 5;
FIG. 6 is a specific spectrum of the system applicability solution 2 in example 5;
FIG. 7 is a specific spectrum of the system applicability solution 3 in example 5;
FIG. 8 is a graph showing the specificity of the sample in example 6 at a flow rate of 1.5ml/min and a column temperature of 35 ℃;
FIG. 9 is a graph showing the specificity of the flow rate of 1.0ml/min at a column temperature of 25℃in example 6;
FIG. 10 is a graph of the specificity at pH7.4 in example 7;
FIG. 11 is a graph of the specificity at pH7.8 in example 7;
FIG. 12 is a specific spectrum of the system applicability solution 1 in the comparative example;
fig. 13 is a solution reference diagram for the applicability of the european pharmacopoeia system in the comparative example.
Detailed Description
In order that the invention may be more readily understood, the invention will be described in detail below with reference to the following examples, which are given by way of illustration only and are not limiting of the scope of application of the invention.
The structures of the compound L, impurity B, impurity C, impurity D, impurity E, impurity F, impurity J, impurity H, impurity I, impurity G, impurity K and rotigotine involved in the examples of the present invention are shown in the following table:
TABLE 1
Wherein, the impurities B to K are all impurities in European pharmacopoeia.
The European pharmacopoeia of the invention is pages European Pharmacopoeia 10.03748-3750.
The specific conditions are not noted in the examples of the present invention, and are carried out according to conventional conditions or conditions suggested by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In the embodiment of the invention, the reference substance of the compound shown in the formula L (impurity L), the reference substance of the impurities B-K and the rotigotine and the medicinal salt thereof are all commercial products.
In the embodiment of the invention, the reference substance of the compound (impurity L) shown in the formula L is hydrobromide of the compound shown in the formula L, and is hereinafter referred to as a compound L reference substance.
The high performance liquid chromatograph is Agilent 1100 (Agilent technology (China) Co., ltd.) or Shimazdu2030 (Shimadzu corporation (China) Co., ltd.); chromatographic column: shim-pack VP-ODS,4.6 mm. Times.250 mm,5 μm (Shimadzu corporation, china Co., ltd.), agilent XDB C8,4.6 mm. Times.150 mm,5 μm (Agilent technologies, china Co.).
Example 1
A separation and detection method of rotigotine related substances comprises the following steps:
structure confirmation of compound L: compound L was (S) -6- (n-propyl (2- (thiophen-3-yl) ethyl) amino) -5,6,7, 8-tetrahydronaphthalen-1-ol and the nuclear magnetic resonance spectrum was as shown in the following table.
TABLE 2
The nuclear magnetic resonance structure numbers are as follows:
sample preparation:
10.37mg of compound L reference substance is taken and placed in a measuring flask of 10ml, a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (volume ratio of phosphoric acid solution to acetonitrile is 85:15)) is added for dissolution and dilution to scale, shaking is carried out, then 1.5ml to 100ml of the solution is taken and placed in the measuring flask, the diluent is used for dilution to scale, shaking is carried out, and the solution is taken as compound L stock solution. A 10.10mg sample of rotigotine was taken and placed in a 10ml measuring flask, to which 1ml of stock solution of compound L was added, dissolved with the above-mentioned diluent and diluted to scale, as a system applicability solution.
Chromatographic conditions:
adopting an Agilent 1100 high performance liquid chromatograph, and selecting octadecyl bonded silica gel as filler to obtain chromatographic column shim-pack VP-ODS (4.6 mm×250mm,5 μm); with acetonitrile-phosphate buffer (mobile phase: A: phosphate buffer, which was adjusted to 10mmol/L KH with phosphoric acid) 2 P0 4 The pH value of the solution is 6.0; b: acetonitrile) as mobile phase, the following chromatographic conditions were used for separation:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 3 Table 3
The chromatographic separation results are shown in fig. 1 (system applicability solution specific spectrogram), and the specific information of chromatographic peaks of rotigotine and compound L are shown in the following table:
TABLE 4 Table 4
Example 2
A separation and detection method of rotigotine related substances comprises the following steps:
taking the system applicability solution in the embodiment 1, adopting an Agilent 1100 high performance liquid chromatograph, and selecting a chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) with octyl bonded silica gel as a filler; acetonitrile-phosphate buffer (mobile phase: A: phosphate buffer, which was obtained by adjusting pH of a diammonium hydrogen phosphate solution of 10mmol/L to 6.0 with phosphoric acid; B: acetonitrile) was used as the mobile phase, and separation was performed using the following chromatographic conditions:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 5
The chromatographic separation results are shown in fig. 2 (system applicability solution specific spectrogram), and the specific information of chromatographic peaks of rotigotine and compound L are shown in the following table:
TABLE 6
Example 3
A method for detecting rotigotine impurities comprises the following steps:
taking the system applicability solution in the embodiment 1, adopting an Agilent 1100 high performance liquid chromatograph, and selecting a chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) with octyl bonded silica gel as a filler; acetonitrile-phosphate buffer (mobile phase: A: phosphate buffer, which was obtained by adjusting pH of a 10mmol/L diammonium hydrogen phosphate solution to 7.0 with phosphoric acid; B: acetonitrile) was used as the mobile phase, and separation was performed using the following chromatographic conditions:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 7
The chromatographic separation results are shown in fig. 3 (system applicability solution specific spectrogram), and the specific information of chromatographic peaks of rotigotine and compound L are shown in the following table:
TABLE 8
Example 4
A method for detecting rotigotine impurities comprises the following steps:
taking the system applicability solution in the embodiment 1, adopting an Agilent 1100 high performance liquid chromatograph, and selecting a chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) with octyl bonded silica gel as a filler; acetonitrile-phosphate buffer (A: phosphate buffer obtained by adjusting pH of 10mmol/L diammonium hydrogen phosphate solution to 8.0 with phosphoric acid; B: acetonitrile) is used as mobile phase, and the following chromatographic conditions are adopted for separation:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 9
The chromatographic separation results are shown in fig. 4 (system applicability solution specific spectrogram), and the specific information of chromatographic peaks of rotigotine and compound L are shown in the following table:
table 10
According to examples 1 to 4, the chromatographic column using octadecyl or octyl bonded silica gel as the filler can well separate rotigotine from the compound L under the condition of the pH of the mobile phase of 6.0 to 8.0, the main peak shape is symmetrical, the symmetry factor is more than 0.5, the symmetry factor of the compound L can be 0.54 to 0.76, and the symmetry factor of the rotigotine can be 0.54 to 0.83.
Example 5
A method for detecting rotigotine impurities comprises the following steps:
sample preparation:
system applicability solution 1: the system applicability solution was the same as in example 1.
System applicability solution 2: the reference substances of impurity B, impurity C, impurity D, impurity E, impurity G, impurity H, impurity I, impurity K and rotigotine were weighed in appropriate amounts, dissolved and diluted with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution: acetonitrile: 85: 15)) to prepare a mixed solution containing about 1.5. Mu.g of impurity B, 2. Mu.g of impurity C, 1. Mu.g of impurity D, 0.3. Mu.g of impurity E, 2. Mu.g of impurity G, 1. Mu.g of impurity H, 1. Mu.g of impurity I, 1. Mu.g of impurity K and 1mg of rotigotine per 1 mg.
System applicability solution 3: the control of impurity B, impurity C, impurity D, impurity F, impurity G, impurity I and impurity J was weighed in appropriate amounts, dissolved with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution: acetonitrile: 85: 15)) and diluted to prepare a mixed solution containing about 1.5. Mu.g of impurity B, 2. Mu.g of impurity C, 1. Mu.g of impurity D, 2. Mu.g of impurity G, 1. Mu.g of impurity F, 1. Mu.g of impurity I and 1. Mu.g of impurity J per 1 mg.
Detection limit solution: impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H, impurity I, impurity J, impurity K, and compound L control were dissolved in a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution and acetonitrile: 85:15)) and diluted to their respective detection limit concentrations.
Test article solution 1: a suitable amount of rotigotine sample was taken, dissolved and diluted to a solution of about 1mg/ml with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution to acetonitrile volume ratio 85:15)).
Test article solution 2: a suitable amount of rotigotine hydrochloride sample was taken, dissolved with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution and acetonitrile volume ratio 85:15)) and diluted to a solution of about 2 mg/ml.
Sample solution 3: a suitable amount of rotigotine hydrobromide sample was taken, dissolved with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution and acetonitrile volume ratio 85:15)) and diluted to a solution of about 0.5 mg/ml.
Control solution: the control of impurity B, impurity C, impurity D, impurity G, impurity H, impurity I and impurity K was weighed in appropriate amounts, dissolved with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution: acetonitrile: 85: 15)) and diluted to prepare a mixed solution containing about 1.5. Mu.g of impurity B, 2. Mu.g of impurity C, 1. Mu.g of impurity D, 2. Mu.g of impurity G, 1. Mu.g of impurity H, 1. Mu.g of impurity I and 1. Mu.g of impurity K per 1 mg.
Adding a standard solution to a test sample: rotigotine samples 10mg were weighed, dissolved with control solution and diluted quantitatively to 10ml, and 6 portions were prepared in parallel.
Chromatographic conditions:
adopting an Agilent 1100 high performance liquid chromatograph, and selecting a chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) with octyl bonded silica gel as a filler; acetonitrile-phosphate buffer (A: phosphate buffer obtained by adjusting pH of 10mmol/L diammonium hydrogen phosphate solution to 7.6 with phosphoric acid; B: acetonitrile) is used as mobile phase, and the following chromatographic conditions are adopted for separation:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
* The sample injection volume is 5-20 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 11
* The sample injection volume of the sample solution 2 is 5 mu L, the sample injection volume of the sample solution 3 is 20 mu L, and the sample injection volumes of the rest samples are 10 mu L.
The chromatographic separation results of the system applicability solution are shown in fig. 5 to 7 (specific spectrograms of the system applicability solutions 1 to 3), and the specific information of chromatographic peaks of rotigotine and each impurity are shown in the following table. The peak shapes of the impurities and rotigotine are symmetrical (the symmetry factor is more than 0.5), the tail of the peak shape in European pharmacopoeia is serious (as in comparative example 12), the separation degree between the peaks is obviously more than 1.5, and the method can effectively separate the impurities (impurities B-K) and the compound L in European pharmacopoeia. The separation degree of the impurity H (EP-H) and the impurity G (EP-G) in the European pharmacopoeia is not lower than 1.5 as the requirement of system applicability, and the separation degree of the method in the embodiment is obviously superior to the requirement of the European pharmacopoeia.
Table 12
According to the detection limit results of each impurity, as shown in the following table, the worst concentration of the sample (1 mg/ml) can be 0.03wt%, and the baseline noise of the method in European pharmacopoeia is large (comparative example 13), the neglect limit is 0.05wt%, and the detection sensitivity of the method is high.
TABLE 13
| Impurity(s) | Signal to noise ratio | Concentration (μg/ml) | Relative to the concentration of the test sample |
| Impurity B | 5.6 | 0.051 | 0.005wt％ |
| Impurity C | 6.6 | 0.045 | 0.005wt％ |
| Impurity D | 11.1 | 0.040 | 0.004wt％ |
| Impurity E | 8.4 | 0.257 | 0.03wt％ |
| Impurity F | 4.0 | 0.062 | 0.006wt％ |
| Impurity G | 4.0 | 0.044 | 0.004wt％ |
| Impurity H | 4.4 | 0.048 | 0.005wt％ |
| Impurity I | 4.4 | 0.042 | 0.004wt％ |
| Impurity J | 7.6 | 0.063 | 0.006wt％ |
| Impurity K | 7.0 | 0.015 | 0.002wt％ |
| Compound L | 6.7 | 0.042 | 0.004wt％ |
The control solution was sampled 6 times continuously, the relative standard deviation of the peak areas of the impurities is shown in Table 14, and RSD is less than 3.0%, which indicates that the precision of the method is better. In 6 parts of sample labeling solution, the peak area external standard method is adopted to calculate, the average labeling recovery rate and RSD of the labeling recovery rate of each impurity are shown in table 14, the average labeling recovery rate is between 90% and 108%, the RSD of the labeling recovery rate is less than 3.0%, and the repeatability and accuracy of the method are high.
TABLE 14
In this example, rotigotine and its rotigotine pharmaceutical salt samples were detected, and according to the detection results of each batch, as shown in the following table, the peak area normalization method was used to calculate that the impurity was not more than 0.05wt%, and the purity was greater than 99.5wt%, indicating that the rotigotine and its rotigotine pharmaceutical salt samples were very high in purity.
TABLE 15
Example 6
A detection method of rotigotine related substances comprises the following steps:
sample preparation:
system applicability solution: the impurity B, the impurity C, the impurity D, the impurity G, the impurity H, the impurity I, the impurity K and the rotigotine control are weighed in proper amounts, dissolved and diluted with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution: acetonitrile volume ratio 85:15)) to prepare a mixed solution containing about 10 μg of the impurity B, 10 μg of the impurity C, 10 μg of the impurity D, 15 μg of the impurity G, 15 μg of the impurity H, 5 μg of the impurity I, 20 μg of the impurity K and 1mg of rotigotine per 1 mg.
Chromatographic conditions: the durability of the temperature and flow rate was examined on the basis of example 5
A chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) using Shimadzu 2030 high performance liquid chromatograph and octyl bonded silica gel as filler is adopted; acetonitrile-phosphate buffer (A: phosphate buffer obtained by adjusting pH of 10mmol/L diammonium hydrogen phosphate solution to 7.6 with phosphoric acid; B: acetonitrile) is used as mobile phase, and the following chromatographic conditions are adopted for separation:
the flow rate is: (1) 1.5ml/min; (2) 1.0ml/min
The column temperature is: (1) 35 ℃; (2) 25 DEG C
The wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
table 16
After the flow rate and the column temperature are adjusted, the chromatographic separation results of the components are shown in figure 8 (specific spectrogram at the flow rate of 1.5ml/min and the column temperature of 35 ℃) and figure 9 (specific spectrogram at the flow rate of 1.0ml/min and the column temperature of 25 ℃), and the chromatographic peak specific information of rotigotine and each impurity is shown in the following table, and the effective separation can still be carried out between the peaks. The method of the invention has better durability to column temperature and flow rate.
TABLE 17
Note that: compound L was contained in rotigotine control.
Example 7
A detection method of rotigotine related substances comprises the following steps:
sample preparation:
system applicability solution: the impurity B, the impurity C, the impurity D, the impurity K, the impurity G, the impurity H, the impurity I and the rotigotine control are weighed in proper amounts, dissolved and diluted with a diluent (0.5 VOL% phosphoric acid solution-acetonitrile (phosphoric acid solution: acetonitrile volume ratio 85:15)) to prepare a mixed solution containing about 1.5 μg of impurity B, 2 μg of impurity C, 1 μg of impurity D, 2 μg of impurity G, 1 μg of impurity H, 1 μg of impurity I, 1 μg of impurity K and 1mg of rotigotine per 1 mg.
Chromatographic conditions: adjusting the pH in the buffer based on example 5
A chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) using Shimadzu 2030 high performance liquid chromatograph and octyl bonded silica gel as filler is adopted; acetonitrile-phosphate buffer (A: phosphate buffer, which was adjusted to pH (1) 7.4 from 10mmol/L of diammonium phosphate solution, (2) 7.8; B: acetonitrile) as mobile phase, was separated using the following chromatographic conditions:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
TABLE 18
After adjusting the pH of the buffer, the results of chromatographic separation of the respective components are shown in FIG. 10 (specific spectrum at pH 7.4) and FIG. 11 (specific spectrum at pH 7.8), and specific information on chromatographic peaks of rotigotine and respective impurities are shown in the following table. The buffer salt is between pH7.4 and 7.8, rotigotine and each impurity peak can still be effectively separated, and the symmetry of each peak is still better (tailing factor is less than 2.0). The separation and detection method has strong durability to pH.
Table 19pH7.4 chromatographic separation results
| Compounds of formula (I) | Retention time (min) | Minimum degree of separation | Theoretical plate number | Tailing factor |
| Impurity B | 7.449 | 31.5 | 33175 | 1.5 |
| Impurity C | 12.588 | 9.3 | 94599 | 1.2 |
| Impurity D | 16.541 | 6.1 | 108282 | 1.1 |
| Impurity G | 23.655 | 3.1 | 184220 | 1.1 |
| Impurity H | 27.291 | 9.4 | 169941 | 1.0 |
| Impurity I | 29.777 | 9.4 | 202113 | 1.0 |
| Impurity K | 14.036 | 9.3 | 142232 | 1.2 |
| Compound L | 17.825 | 6.1 | 106821 | 1.1 |
| Rotigotine | 20.033 | 10.9 | 179103 | 1.2 |
Table 20 chromatographic separation results at pH7.8
| Compounds of formula (I) | Retention time (min) | Minimum degree of separation | Theoretical plate number | Tailing factor |
| Impurity B | 7.966 | 32.4 | 37599 | 1.6 |
| Impurity C | 13.229 | 6.0 | 107168 | 1.2 |
| Impurity D | 17.311 | 6.6 | 114022 | 1.0 |
| Impurity G | 23.957 | 3.6 | 185183 | 1.1 |
| Impurity H | 27.923 | 9.1 | 167761 | 0.6 |
| Impurity I | 30.365 | 9.1 | 206388 | 0.9 |
| Impurity K | 14.162 | 6.0 | 142254 | 1.2 |
| Compound L | 18.760 | 6.6 | 101665 | 1.3 |
| Rotigotine | 20.761 | 10.1 | 267978 | 1.2 |
Note that: compound L was contained in rotigotine control.
Example 8
A detection method of rotigotine related substances comprises the following steps:
sample preparation:
system applicability solution: system applicability solution under example 7
Chromatographic conditions: adjusting the detection wavelength on the basis of example 5
A chromatographic column Agilent XDB C8 (4.6 mm multiplied by 150mm,5 μm) using Shimadzu 2030 high performance liquid chromatograph and octyl bonded silica gel as filler is adopted; acetonitrile-phosphate buffer (mobile phase: A: phosphate buffer, which was adjusted to pH 7.6 with 10mmol/L diammonium phosphate solution by phosphoric acid; B: acetonitrile) was used as mobile phase, and separation was performed using the following chromatographic conditions:
the flow rate is 1.2ml/min;
the column temperature is 30 ℃;
the wavelength of the ultraviolet detector is 218nm and 222nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
table 21
Under different detection wavelengths, the theoretical plate numbers of rotigotine and each impurity peak are higher and are larger than 5000, which indicates that when the wavelength is changed to a certain extent, the response of rotigotine and each impurity is still better.
Table 22 results of detection results at different wavelengths
Note that: compound L was contained in rotigotine control.
Comparative example
A method for detecting rotigotine impurities, reference being made to the method for analysis of substances of interest of the european pharmacopoeia (EP 10.0), comprising the steps of:
a chromatographic column Agilent XDB C8 (4.6 mm x 150mm,5 μm) using the system applicability solution of example 1, agilent 1100 hplc, with octyl bonded silica gel as filler; the separation was performed with 0.03VOL% trifluoroacetic acid solution (mobile phase a) -0.02VOL% trifluoroacetic acid acetonitrile solution (mobile phase B) using the following chromatographic conditions:
the flow rate is 2.0ml/min;
column temperature is 40 ℃;
the wavelength of the ultraviolet detector is 220nm;
the sample injection volume is 10 mu L;
the mobile phase is calculated according to the volume percentage, and the gradient elution conditions are as follows:
table 23
Under the condition of an acid mobile phase (pH is 2-3), the compound L is completely wrapped by rotigotine (9.410 min) in a system applicability solution (a specific spectrogram of the system applicability solution 1 in FIG. 12), the compound L and the compound L cannot be effectively separated, the symmetry factor of rotigotine Gao Tingfeng is 0.20, the peak tailing is serious, the theoretical plate number is 2776, and the column efficiency is poor.
In the system applicability reference diagram in the european pharmacopoeia (fig. 13, the european pharmacopoeia system applicability solution reference diagram), in fig. 13, impartiality B is Impurity B), impartiality C is Impurity C, impartiality G is Impurity G, and impartiality H is Impurity H; the impuity G (Impurity G) is just baseline separated from the impuity H (Impurity H), and the baseline noise is large. The rotigotine test sample solution in example 5 was tested by this method, and the related impurities were not detected in each batch, and the separation and detection ability of the impurities were inferior to those of the method of the present invention.
In conclusion, the rotigotine related substance analysis method provided by the invention has the advantages of good specificity, symmetrical peak shape and good detection sensitivity. The rotigotine sample detected by the method has high purity, the purity of the sample is more than 99.5 weight percent, and the detection amount of the compound L is small and is less than 0.05 weight percent. The applicant found that under acidic conditions, the peak of rotigotine is easy to tailing, when the pH value of the mobile phase is closer to the pKa (dissociation constant of acid and alkali) of rotigotine, the peak shape of rotigotine can be improved, the retention is enhanced, and substances similar to the structure of rotigotine can be separated. Generally, the pH of the mobile phase is acidic or neutral because the chromatographic column does not tolerate high pH, but the applicant selects neutral to alkaline (pH 6.0-8.0, preferably pH 7.4-7.8) aqueous phase as mobile phase A and organic phase as mobile phase B according to the pKa property of rotigotine, so that the pH value of the mobile phase is close to the pKa of rotigotine. The mobile phase of the invention is adopted, and preferably, an alkali-resistant chromatographic column (a chromatographic column with octadecyl bonded silica gel or octyl bonded silica gel as a filler) is adopted for separation, so that the effect is achieved.
What has been described above is merely a preferred example of the present invention. It should be noted that other equivalent modifications and improvements will occur to those skilled in the art, and are intended to be within the scope of the present invention, as a matter of common general knowledge in the art, in light of the technical teaching provided by the present invention.
Claims (10)
1. A method for separating substance a from rotigotine or a composition thereof, a pharmaceutically acceptable salt of rotigotine or a composition thereof, comprising:
separating the rotigotine or the composition thereof and the rotigotine medicinal salt or the composition thereof by adopting a high performance liquid chromatography, wherein a mobile phase in the high performance liquid chromatography comprises an aqueous phase and an organic phase, and the pH value of the aqueous phase is 6.0-8.0;
wherein the substance a comprises: a compound represented by formula L or a salt thereof;
2. the separation process according to claim 1, characterized in that the organic phase is acetonitrile or methanol, preferably acetonitrile; and/or
The aqueous phase is a buffer solution, preferably an inorganic salt buffer solution; the inorganic salt is preferably one or more of disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate; and/or
The pH value of the water phase is 7.4-7.8; and/or
The mobile phase consists of an organic phase and an aqueous phase.
3. The separation method according to claim 1 or 2, characterized in that the separation method further comprises: separating by high performance liquid chromatography with octadecyl bonded silica gel or octyl bonded silica gel as filler;
preferably, the separation method further comprises: high performance liquid chromatography separation was performed using the following chromatographic conditions:
flow rate: 1.0-1.5 ml/min; and/or
Column temperature: 25-35 ℃; and/or
Sample injection volume: 5-20 mu L; and/or
Mobile phase: a: buffer, B: acetonitrile, in volume percent, gradient elution conditions were as follows:
4. the separation method according to claim 1 or 2, wherein the substance a is a compound of formula L or a salt thereof, preferably a compound of formula L.
5. The separation method according to claim 1 or 2, wherein the substance a further comprises one or more of an impurity B or a salt thereof, an impurity C or a salt thereof, an impurity D or a salt thereof, an impurity E or an impurity F or a salt thereof, an impurity J or a salt thereof, an impurity H or a salt thereof, an impurity I or a salt thereof, an impurity G or a salt thereof, and an impurity K, the structural formulas of the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity J, the impurity H, the impurity I, the impurity G, and the impurity K are as follows:
6. a method for detecting substance a in rotigotine or a composition thereof, a pharmaceutically acceptable salt of rotigotine or a composition thereof, comprising the isolation method of any one of claims 1 to 5;
preferably, the detection method further comprises: using ultraviolet detection to determine the content of the substance; the detection wavelength of the ultraviolet detection is preferably 218-222 nm, more preferably 220nm.
7. A composition, comprising: rotigotine or a pharmaceutically acceptable salt thereof and substance a, which comprises: a compound represented by formula L or a salt thereof;
the content of the compound shown in the formula L or the salt thereof is less than or equal to 0.05wt%; preferably less than or equal to 0.03wt%; more preferably less than or equal to 0.015wt%;
preferably, the rotigotine or pharmaceutically acceptable salt thereof has a purity of greater than or equal to 99.5wt%, preferably greater than or equal to 99.9wt%.
8. The composition according to claim 7, wherein the substance a is a compound of formula L or a salt thereof, preferably a compound of formula L; or (b)
The substance A further comprises one or more of an impurity B or a salt thereof, an impurity C or a salt thereof, an impurity D or a salt thereof, an impurity E, an impurity F or a salt thereof, an impurity J or a salt thereof, an impurity H or a salt thereof, an impurity I or a salt thereof, an impurity G or a salt thereof and an impurity K, wherein the impurity B, the impurity C, the impurity D, the impurity E, the impurity F, the impurity J, the impurity H, the impurity I, the impurity G and the impurity K have the following structural formulas:
the content of the impurity B or a salt thereof, the impurity C or a salt thereof, the impurity D or a salt thereof, the impurity E, the impurity F or a salt thereof, the impurity G or a salt thereof, the impurity H or a salt thereof, the impurity I or a salt thereof, the impurity J or a salt thereof, the impurity K is 0.03wt% or less, respectively; preferably less than or equal to 0.02wt%; more preferably less than or equal to 0.015wt%.
9. A pharmaceutical formulation comprising a composition according to claim 7 or 8, and one or more pharmaceutically acceptable excipients.
10. The substance A is used as an impurity standard substance or a reference substance in quality inspection or quality control of rotigotine or a composition thereof, rotigotine medicinal salt or a composition thereof and a medicinal preparation containing the rotigotine or the medicinal salt thereof; the substance a comprises: a compound represented by formula L or a salt thereof;
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| CN202310280149.9A CN116359381A (en) | 2023-03-22 | 2023-03-22 | Separation method, detection method, rotigotine or pharmaceutical salt composition, pharmaceutical preparation and application thereof |
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| CN202310280149.9A CN116359381A (en) | 2023-03-22 | 2023-03-22 | Separation method, detection method, rotigotine or pharmaceutical salt composition, pharmaceutical preparation and application thereof |
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