CN116535440A - Novel solvent compound of disodium levo-ornidazole phosphate, and preparation method and application thereof - Google Patents
Novel solvent compound of disodium levo-ornidazole phosphate, and preparation method and application thereof Download PDFInfo
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- CN116535440A CN116535440A CN202310498951.5A CN202310498951A CN116535440A CN 116535440 A CN116535440 A CN 116535440A CN 202310498951 A CN202310498951 A CN 202310498951A CN 116535440 A CN116535440 A CN 116535440A
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- disodium
- ornidazole
- phosphate
- solvent compound
- solvent
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- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 84
- 239000010452 phosphate Substances 0.000 title claims abstract description 84
- 239000002904 solvent Substances 0.000 title claims abstract description 83
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 81
- 150000001875 compounds Chemical class 0.000 title claims abstract description 68
- IPWKIXLWTCNBKN-ZCFIWIBFSA-N (2s)-1-chloro-3-(2-methyl-5-nitroimidazol-1-yl)propan-2-ol Chemical compound CC1=NC=C([N+]([O-])=O)N1C[C@H](O)CCl IPWKIXLWTCNBKN-ZCFIWIBFSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 199
- 239000013078 crystal Chemical group 0.000 claims abstract description 57
- 239000000843 powder Substances 0.000 claims abstract description 3
- 229960002313 ornidazole Drugs 0.000 claims description 89
- IPWKIXLWTCNBKN-UHFFFAOYSA-N Madelen Chemical compound CC1=NC=C([N+]([O-])=O)N1CC(O)CCl IPWKIXLWTCNBKN-UHFFFAOYSA-N 0.000 claims description 76
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 67
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 44
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- 238000002425 crystallisation Methods 0.000 claims description 33
- 230000008025 crystallization Effects 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 239000012065 filter cake Substances 0.000 claims description 20
- 238000004090 dissolution Methods 0.000 claims description 16
- TWHXWYVOWJCXSI-UHFFFAOYSA-N phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O TWHXWYVOWJCXSI-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000007605 air drying Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 230000008569 process Effects 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000003643 water by type Substances 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- YEDTWOLJNQYBPU-UHFFFAOYSA-N [Na].[Na].[Na] Chemical compound [Na].[Na].[Na] YEDTWOLJNQYBPU-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 150000004688 heptahydrates Chemical class 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004042 decolorization Methods 0.000 description 4
- LBDROUOCQSGOFI-UHFFFAOYSA-N methanol;phosphoric acid Chemical compound OC.OP(O)(O)=O LBDROUOCQSGOFI-UHFFFAOYSA-N 0.000 description 4
- 150000004686 pentahydrates Chemical class 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000000630 rising effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 150000004687 hexahydrates Chemical class 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- -1 phosphate ester Chemical class 0.000 description 3
- XVNVFKZODWAQKN-UHFFFAOYSA-N phosphoric acid;heptahydrate Chemical compound O.O.O.O.O.O.O.OP(O)(O)=O XVNVFKZODWAQKN-UHFFFAOYSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000000842 anti-protozoal effect Effects 0.000 description 2
- 239000003904 antiprotozoal agent Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- BWAUQTFFVCLSOS-UHFFFAOYSA-N sodiosodium hydrate Chemical compound O.[Na].[Na] BWAUQTFFVCLSOS-UHFFFAOYSA-N 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- IVWWFWFVSWOTLP-YVZVNANGSA-N (3'as,4r,7'as)-2,2,2',2'-tetramethylspiro[1,3-dioxolane-4,6'-4,7a-dihydro-3ah-[1,3]dioxolo[4,5-c]pyran]-7'-one Chemical compound C([C@@H]1OC(O[C@@H]1C1=O)(C)C)O[C@]21COC(C)(C)O2 IVWWFWFVSWOTLP-YVZVNANGSA-N 0.000 description 1
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 description 1
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- RXCMFQDTWCCLBL-UHFFFAOYSA-N 4-amino-3-hydroxynaphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(N)=C(O)C=C(S(O)(=O)=O)C2=C1 RXCMFQDTWCCLBL-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 235000019788 craving Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004031 devitrification Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- VURAHXZCFTZGFJ-UHFFFAOYSA-N phosphoric acid;hexahydrate Chemical compound O.O.O.O.O.O.OP(O)(O)=O VURAHXZCFTZGFJ-UHFFFAOYSA-N 0.000 description 1
- KXLZIIWFTPMYKT-UHFFFAOYSA-N phosphoric acid;pentahydrate Chemical compound O.O.O.O.O.OP(O)(O)=O KXLZIIWFTPMYKT-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PTIBVSAWRDGWAE-UHFFFAOYSA-K trisodium;phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O PTIBVSAWRDGWAE-UHFFFAOYSA-K 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/78—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by condensation or crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/02—Monohydroxylic acyclic alcohols
- C07C31/04—Methanol
-
- 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a methanol-containing disodium levo-ornidazole phosphate solvent compound and a crystal form and a preparation method thereof. The crystalline form features thereof, a= 7.3965 (4) a, b= 8.9181 (5) a, c= 28.7030 (16) a, α=90°, β=90°, γ=90°, v= 1893.33 (18) a 3, having characteristic peaks at 6.2, 11.7, 12.4, 13.6, 15.2, 15.6, 15.9, 18.2, 18.4, 19.9, 22.1, 23.5, 23.9, 24.3, 24.8, 26.8, 27.1, 27.7, 31.2, 32.2, 33.5 of X-powder diffraction 2θ. The solvent compound crystal form can be obtained in a methanol system with a certain proportion, and can be used for preparing higher-purity disodium levo-ornidazole phosphate.
Description
Technical Field
The invention belongs to the field of chemical substance crystallization, and particularly relates to a novel solvent compound of disodium levo-ornidazole phosphate, a preparation method and application thereof, and a novel crystal form of disodium levo-ornidazole phosphate.
Background
Ornidazole as the nitroimidazole antibacterial agent has good application in the fields of anaerobic bacteria and antiprotozoal infection, and is a third-generation nitroimidazole derivative which is prepared by new development after metronidazole and has higher curative effect, shorter treatment course, better tolerance and wider in-vivo distribution. The antimicrobial action of ornidazole is through reduction of the nitro group of its formula to an amino group in an anaerobic environment or through interaction with cellular components in the form of free radicals, resulting in the death of the microorganism.
The ornidazole is clinically applied in large-volume injection, has extremely poor water solubility and low melting point, and has strong acidity when being prepared into an infusion preparation, and phlebitis is easy to generate when a patient takes the ornidazole; and the toxic degradation product 2-methyl-5-nitroimidazole is higher during high-temperature sterilization of transfusion, which brings great unsafe for clinical medication.
The L-ornidazole has similar therapeutic effect as the L-enantiomer of ornidazole. The method is better than the ornidazole, and the centering inhibition is far lower than that of the ornidazole, so that the side reaction in the use process of the ornidazole is far lower than that of the ornidazole, and the method has great value under the craving of continuously improving the requirements of people on the safety of medicaments.
In order to solve the problem of poor water solubility of ornidazole products, domestic researchers carry out phospho-esterification modification on the structure of the ornidazole products. The structure of the phosphate ester of l-ornidazole is proposed in patent CN200610166893.2, and further, the structure of the pentahydrate of disodium phosphate of l-ornidazole is proposed in patent CN 200710188487.0. In subsequent studies, researchers have proposed the crystalline form of disodium oxynitrate heptahydrate and a method for preparing the same in CN 201910115156.7.
In the research of disodium left ornidazole phosphate, the company unexpectedly obtains a new solvent compound crystal form of disodium left ornidazole phosphate, wherein the solvent compound crystal form of disodium left ornidazole phosphate is different from the existing hydrate crystal form, and the crystal form is a crystal which is completely different from the existing hydrate and is formed under the participation of a methanol solvent, so that the formation and existence of the crystal can remove partial water-soluble impurities in the original compound, and the disodium left ornidazole phosphate with higher purity is obtained. And it was found that the disodium levo-ornidazole phosphate present as this crystal had a higher stability than the conventional hydrate crystal. The crystal form of the sodium disodium oxynitrate solvent compound disclosed by the invention is used as a key process intermediate, and has extremely important practical value in obtaining the sodium disodium oxynitrate with high purity and high stability. As a crystal form with more excellent stability, a new application choice with stability advantage is provided for the application of the raw material.
Disclosure of Invention
The invention provides a novel solvent compound of disodium left ornidazole phosphate, a preparation method and application thereof, and aims to provide a novel solvent compound of disodium left ornidazole phosphate with a stable space structure and a crystal form thereof, which can provide support for obtaining disodium left ornidazole phosphate with higher purity and can also provide a novel raw material selection with better stability for preparing disodium left ornidazole phosphate preparations.
The disodium ornidazole phosphate solvent compound has the following structural formula:
which contains one molecule of crystallized methanol and four molecules of crystallized water.
One of the main features of the disodium levo-ornidazole phosphate solvent compounds of the present invention is crystalline methanol containing one molecule.
Another feature of the disodium levo-ornidazole phosphate solvent compound of the present invention is that it contains four molecules of water of crystallization. When there are a plurality of crystal waters, the crystal waters are slightly lost or increased by the temperature and humidity of the surrounding environment due to the difference in the binding energy of the different crystal waters, compared to the crystal methanol. Therefore, the states of three crystal waters and five crystal waters should be understood as the protection scope of this patent.
The disodium levo-ornidazole phosphate solvent compounds of the present invention are generally present as crystals having the structural units shown in fig. 2.
The invention provides a single crystal crystallographic structure parameter and a structure refinement parameter of a crystal form of a disodium ornidazole phosphate solvent compound, which are as follows:
the test data is only one kind of test for describing the product, and the data can be slightly changed according to different measurement conditions, and the patent protection scope is still understood.
The invention also provides an X-ray powder diffraction pattern and characteristic peak data of the crystal form of the disodium ornidazole phosphate solvent compound.
The solvent compound may further have characteristic peaks at these 2 theta angular positions: 6.2, 11.7, 12.4, 13.6, 15.2, 15.6, 15.9, 18.2, 18.4, 19.9, 22.1, 23.5, 23.9, 24.3, 24.8, 26.8, 27.1, 27.7, 31.2, 32.2, 33.5.
The characteristic peak of the crystal form in the invention adopts a common expression method in the field, and the allowable error is 0.2 when the characteristic peak is accurate to 0.1 degree under the common condition. In practical measurements, large deviations may occur due to particle size, sample height, preferential orientation or sample transparency effects, and should still be understood as falling within the scope of the patent claims.
The invention relates to a sodium disodium phosphate solvent compound, in particular to a sodium disodium phosphate crystal containing one molecule of crystal methanol and four molecules of crystal water, which has a stable lattice structure. Compared with the existing pentahydrate, hexahydrate and heptahydrate, the compound has better stability. The stability test result shows that the impurity increase degree is obviously lower than that of the hydrate crystal form without methanol when the crystal form is placed under the same condition.
The disodium levo-ornidazole phosphate solvent compound mentioned in the present invention may be obtained by using one or more solvents selected from methanol, dichloromethane, ethyl acetate, acetone and ethanol.
In general, the solvent compounds mentioned in the present invention can be prepared by the following process: dissolving sodium ornidazole phosphate (hydrate) in 6-10 times of (W/W) absolute methanol, decolorizing with 0.1-1% (W/V) active carbon for 20min, filtering, stirring, then dropwise adding 5-15 times of (W/W) dichloromethane (acetone, ethanol and ethyl acetate) for crystallizing for 1-4 hours, carrying out suction filtration, and drying a filter cake at 20-30 ℃ for 3 hours. Obtaining the disodium ornidazole phosphate solvent compound.
In the process of obtaining the disodium ornidazole phosphate solvent compound, the invention has the unexpected discovery that the proper water addition can effectively promote the formation of crystals. In the solvent system, the water is added, so that the disodium l phosphate crystals can be formed more effectively and rapidly, the use amount of the organic solvent can be reduced effectively, and the crystalline product can be obtained better.
In the prior art, the disodium salt hydrate of levo-ornidazole phosphate has good solubility in water and methanol, and it is an inconceivable matter to obtain a precipitate in a mixture of two readily soluble solvents. However, during the present solvent compound acquisition, it has surprisingly been found that, by controlling the methanol/water ratio, disodium levo-ornidazole phosphate can be successfully precipitated as a solvent compound. And the obtained solvent compound has good solubility in water and methanol alone.
Thus, the solvent compounds mentioned in the present invention can also be prepared by the following process: dissolving sodium ornidazole phosphate (hydrate) in 6-10 times of (W/W) absolute methanol, decolorizing with 0.1-1% (W/V) active carbon for 20min, filtering, stirring the filtrate, dropwise adding 0.1-2.0 times of (W/W) water, dropwise adding 5-15 times of (W/W) dichloromethane (acetone, ethanol and ethyl acetate), crystallizing for 1-4 hours, suction filtering, and drying the filter cake at 20-30 ℃ for 3 hours. Obtaining the disodium ornidazole phosphate solvent compound.
Even more, we can also use methanol and water alone to obtain the disodium salt of the ornidazole phosphate solvent compound: taking disodium (hydrate) of the ornidazole phosphate, adding 6-10 times of (W/W) absolute methanol, stirring at room temperature for dissolution, filtering, dripping water with the dosage of 0.1-2.0 times, stirring uniformly, and crystallizing. And after crystallization is completed, filtering, and air-drying the filter cake at 25 ℃ to obtain a finished product.
In the process, the water is added into the filtered methanol solution to gradually precipitate the disodium oxynitrate solvent compound, and the precipitation of the solvent compound is increased along with the increase of the water addition in a specified range. The limitation of the amount of water to be added is defined as 0.1 to 2.0, and the lower limit is defined as 0.1 only for distinguishing from the case where water is not added. The upper limit of 2.0 also merely indicates that the crystallization process has a higher yield at the addition of the multiple, but the solvent compound cannot be obtained at an addition of the multiple of 2.0. Therefore, in practical application, the limit range is understood not to be a strict limit, and the water adding amount is within the range of 0-2.0, even if the water adding amount exceeds 2.0 times, the scope of protection of the patent is also understood.
Although the solubility of the disodium left ornidazole phosphate in water is 10-20 times that of methanol, in normal knowledge, the solubility of the disodium left ornidazole phosphate can be increased by adding water. However, the addition of water in the present process is not intended to increase the solubility of the disodium salt of l-ornidazole, and during the crystallization of the disodium salt of l-ornidazole, we recognize that the addition of water herein may promote the precipitation of the solvate of disodium salt of l-ornidazole. This anomalous phenomenon depends on the unique nature of the disodium salt solvate of levo-ornidazole phosphate, which, although difficult to understand, we should therefore recognize this unusual devitrification phenomenon.
The solvent usage amount regulation involved in the process of preparing the disodium ornidazole phosphate solvent compound is defined as reasonable usage amount determined under the current technical condition. It will be appreciated by those skilled in the art that, outside the specified range, the solvent which promotes precipitation is additionally added, including but not limited to the addition amount of methanol, methylene chloride, acetone, ethyl acetate, and the target solvent compound can be obtained as well. In addition, the solvent used for crystallization is increased by a fixed or non-fixed ratio beyond the range of the present invention, and is also understood to be within the scope of the present patent protection.
In the preparation method, the activated carbon is added to adsorb and remove impurities from the solution as a conventional operation, so that the process is not essentially influenced, and obviously, the process of removing or properly changing the operation steps is understood to be in the protection scope of the patent.
The preparation process is characterized in that after the sample is dissolved by absolute methanol, inorganic impurities are removed, a proper amount of water is added to precipitate crystals with solvent compounds, and then an organic solvent for promoting precipitation can be added to further improve the yield. In order to achieve the aim of removing inorganic impurities, the introduction of water should be avoided during the dissolution process, methanol can be used as a solvent, preferably anhydrous methanol, the solvent moisture should be strictly controlled when analytically pure and industrial grade methanol is used, and the removal efficiency of inorganic salts in a methanol/water mixed system containing higher moisture is rapidly reduced, so that the purpose of removing salts cannot be achieved.
Another feature of the preparation process mentioned in the present invention is that the addition of water can effectively enhance the formation of crystals.
The preparation process mentioned in the present invention is further characterized in that the methanol/water/precipitation-promoting solvent is added in stages, as a sequential process, the desalination-crystallization is carried out in stages, each stage having its different value. Thus, this sequential process exists as a feature of the manufacturing process.
The novel crystal form of the sodium l-ornidazole phosphate obtained by the invention has unique dissolution property and unusual stable characteristics.
When the sodium disodium oxynitrate solvent compound forms crystals, the position of water is replaced by a part of methanol, and a coordination bond is formed between oxygen in a methanol molecule and sodium in disodium oxynitrate, so that a novel crystal with remarkable stability is finally formed, and a novel crystal form completely different from the existing pentahydrate, hexahydrate and heptahydrate is generated due to the difference between the methanol molecule and water molecules. The present solvent compounds exhibit stability characteristics superior to those exhibited by the original hydrate crystalline form due to the introduction of crystalline methanol.
The novel solvent compound crystal form of the levo-ornidazole can be applied to preparing the higher-purity disodium levo-ornidazole phosphate. During the formation of the new crystal form, inorganic salt impurities in the compound can be effectively removed through ordered operation, and phosphoric acid with higher purity can be obtained to be used as disodium ornidazole.
The disodium oxynitrate solvent compound has better stability, can solve the defect of poor stability of disodium oxynitrate hydrate, and can be used in preparations with higher requirements on the stability of bulk drugs.
The disodium ornidazole phosphate solvent compound can be used for preparing proper dosage forms for resisting anaerobic infection and antiprotozoal infection.
Drawings
Fig. 1: crystal photograph of disodium ornidazole phosphate methanol solvent compound
Fig. 2: single crystal structural unit schematic diagram of disodium ornidazole phosphate methanol solvent compound
Fig. 3: molecular stacking structure diagram (a, b, c-axis) of disodium ornidazole phosphate methanol solvent compound single crystal structure
Fig. 4: x-ray diffraction pattern of disodium ornidazole phosphate methanol solvent compound
Fig. 5: contrast image of sodium disodium oxynitrate heptahydrate crystal (refer to patent CN 109748934)
Fig. 6: x-ray diffraction contrast diagram of disodium oxynitrate heptahydrate
Detailed Description
Comparative example 1 the disodium l phosphate starting material used in examples 1-14 was the same batch prepared using the technique of patent CN200610166893.2 by the company.
Comparative example 1
And (3) taking 20g of disodium left ornidazole phosphate, adding 200g of mixed solvent (water: ethanol=1:20, V/V) for dissolving, filtering, adding a small amount of sample as seed crystal, standing at 5-25 ℃ until solid is separated out, filtering, and drying a filter cake at 20-30 ℃ to obtain 15.8g of disodium left ornidazole phosphate heptahydrate. (ethanol content: 0.03%, water content 27.3%), the X-powder diffraction pattern of which is shown in fig. 6, was compared to that of the crystalline form described in patent CN 201910115156.7.
Example 1
Taking 50g of disodium ornidazole phosphate hydrate, adding 300g of absolute methanol, dissolving at room temperature, adding 1.5g of active carbon, decoloring at room temperature for 20min, filtering, stirring the filtrate, then dropwise adding 662.5g of dichloromethane, crystallizing for 3 hours, filtering, and drying the filter cake at 30 ℃ for 3 hours. 42.0g of finished product (methanol: 8.1%, methylene chloride: none, water: 16.1%) was obtained.
Example 2
50g of disodium ornidazole phosphate hydrate is taken, 380g of absolute methanol is added for dissolution at room temperature, 1.5g of active carbon is decolorized at room temperature for 20min, filtering is carried out, filtrate is stirred, 813g of acetone is added dropwise, crystallization is completed for 3 hours, filtering is carried out, and a filter cake is dried at 30 ℃ for 3 hours, thus obtaining 37.9g of finished product (containing 7.6% of methanol, 0.04% of acetone and 15.4% of water).
Example 3
50g of disodium ornidazole phosphate hydrate is taken, 396g of absolute methanol is added for dissolution, 1.5g of active carbon is decolorized, filtration is carried out, 902g of ethyl acetate is added to the filtrate for crystallization, stirring is carried out for 3 hours, filtration is carried out, and a filter cake is dried at 25 ℃ to obtain 40.5g of finished product (containing 8.2% of methanol, 0.02% of ethyl acetate and 16.5% of water).
Example 4
100g of disodium ornidazole phosphate hydrate is taken, 750g of absolute methanol is added for dissolution, 3.0g of activated carbon is decolorized for 20min, filtration is carried out, 800g of methylene dichloride is added dropwise into the filtrate for crystallization, stirring is carried out for 3 hours, filtration is carried out, a filter cake is dried at 30 ℃ for 3 hours, and 77.6g of finished product (containing 7.6% of methanol, 0.02% of methylene dichloride and 15.3% of water) is obtained.
Example 5
100g of disodium ornidazole phosphate hydrate is taken, 1000g of absolute methanol is added for dissolution, 3.0g of activated carbon is decolorized for 20min, filtration is carried out, 1500g of methylene dichloride is added into the filtrate for crystallization, stirring is carried out for 4 hours, filtration is carried out, and a filter cake is dried at 30 ℃ for 3 hours, thus obtaining 37.9g of finished product (containing 7.8% of methanol, 0.01% of methylene dichloride and 16.4% of water).
Example 6
100g of disodium ornidazole phosphate hydrate is taken, 800g of absolute methanol is added, the mixture is dissolved at room temperature, 3.0g of activated carbon is decolorized at room temperature for 20min, the mixture is filtered, 10.0g of water is added into the filtrate, 800g of dichloromethane is dropwise added, stirring is continued, the mixture is filtered after crystallization is completed, and the filter cake is dried at 30 ℃ for 3 hours, thus 86.5g of finished product (containing 7.7% of methanol, 0.01% of dichloromethane and 15.6% of water) is obtained.
Example 7
100g of disodium ornidazole phosphate hydrate is taken, 800g of absolute methanol is added, the mixture is dissolved at room temperature, 3.0g of activated carbon is decolorized at room temperature for 20min, the mixture is filtered, 50g of water is added into the filtrate, the mixture is stirred, 800g of dichloromethane is dropwise added, stirring crystallization is continued, after crystallization is completed, the mixture is filtered, and a filter cake is dried at 30 ℃ for 3 hours, so that 87.9g of finished product (containing 8.1% of methanol, no% of acetone and 15.0% of water) is obtained.
Example 8
100g of disodium ornidazole phosphate hydrate is taken, 800g of methanol is added, the mixture is dissolved at room temperature, 3.0g of activated carbon is added, the decolorization is carried out at room temperature for 20min, the mixture is filtered, 200.0g of water is added into the filtrate, 800g of dichloromethane is dropwise added, stirring crystallization is continued, after crystallization is completed, the mixture is filtered, and a filter cake is dried under reduced pressure at 25 ℃ to obtain 35.9g of finished product (containing 7.9% of methanol, no dichloromethane and 16.5%).
Example 9
100g of disodium ornidazole phosphate hydrate is taken, 800g of methanol is added, the mixture is dissolved at room temperature, 3.0g of activated carbon is added, the decolorization is carried out at room temperature for 20min, the mixture is filtered, 60g of water is added into the filtrate, 800g of absolute ethyl alcohol is added for crystallization, stirring and crystallization are continued, after the crystallization is completed, the mixture is filtered, and a filter cake is air-dried at 25 ℃ to obtain 88.5g of finished product (containing 7.6% of methanol, 0.04% of ethanol and 15.8% of water).
Example 10
Taking 100g of disodium ornidazole phosphate, adding 800g of methanol, dissolving at room temperature, adding 3.02g of activated carbon, decoloring at room temperature for 20min, filtering, adding 100g of filtrate, adding 600g of acetone for crystallization, continuously stirring for crystallization, filtering, and air-drying a filter cake at 25 ℃ after the crystallization is completed to obtain 87.4g of finished product (containing 8.1% of methanol, no acetone and 16.4% of water).
Example 11
Taking 100g of disodium ornidazole phosphate, adding 800g of methanol for dissolution, 10g of acetone for stirring and dissolution at room temperature, adding 3.0g of activated carbon for decolorization, adding 100g of water, then dropwise adding 800g of absolute ethyl alcohol, continuously stirring for crystallization, filtering after crystallization is complete, and air-drying a filter cake at 25 ℃ to obtain 88.9g of finished product (containing 7.8% of methanol, 0.02% of acetone, 15.9% of ethanol).
Example 12
Taking 100g of disodium l-ornidazole phosphate, adding 750g of methanol, stirring at room temperature for dissolution, filtering, adding 20g of water, stirring uniformly, standing for crystallization. After crystallization is completed, filtering is carried out, and the filter cake is air-dried at 25 ℃. 28.1g of finished product (methanol: 7.7% and water: 16.9%) was obtained.
Example 13
Taking 100g of disodium l-ornidazole phosphate, adding 750g of methanol, stirring at room temperature for dissolution, filtering, adding 100g of water, stirring uniformly, and crystallizing. After crystallization is completed, filtering is carried out, and the filter cake is air-dried at 25 ℃. 71.3g of finished product (methanol: 7.9% and water: 15.1%) were obtained.
Example 14
Taking 100g of disodium ornidazole phosphate, adding 900g of methanol for dissolution, stirring at room temperature for dissolution, adding 1.0g of activated carbon for decolorization, adding 100g of water, then dropwise adding 800g of absolute ethyl alcohol/acetone mixed solution (1:1, W/W), continuously stirring for crystallization, filtering after crystallization is complete, and air-drying a filter cake at 25 ℃ to obtain 85.7g of finished product (containing 7.5% of methanol, 0.01% of acetone, 0.03% of ethanol and 15.5% of water).
Example 15
The dissolution of disodium ornidazole phosphate in methanol solvent and hydrate was compared.
Taking the solvent compound prepared in example 13 and the disodium levo-ornidazole phosphate heptahydrate prepared in comparative example 1, the solubility in different solvents was examined, and the results were as follows:
the results show that the solubility of the disodium ornidazole phosphate solvent compound and the hydrate in water and methanol are completely different, and the solubility of the disodium ornidazole phosphate solvent compound and the hydrate in ethanol is different. In hypertonic DMSO, the two dissolution conditions are close.
Example 16
Comparison of free phosphate of disodium Ornidazole phosphate MeOH Compound and hydrate
Test article:
seven crystal waters of disodium levo-ornidazole phosphate: comparative example 1
Six crystal waters of disodium levo-ornidazole phosphate: prepared according to patent CN201610125343.X of this company
Five crystal waters of disodium levo-ornidazole phosphate: prepared according to patent CN200710188487.0 of the company
Disodium ornidazole phosphate solvent compound: examples 1 to 14
Assay: accurately weighing 20mg of disodium left ornidazole phosphate, placing in a 25mL measuring flask, and adding 15mL of water to dissolve; taking standard phosphate solution [ 0.35g of monopotassium phosphate which is precisely weighed and dried for 2 hours at 105 ℃, placing the standard phosphate solution into a 1000ml measuring flask, adding 10ml of sulfuric acid solution (3-10) and a proper amount of water to dissolve, diluting to a scale, and shaking uniformly; diluting again 10 times to 4.0ml when in use, placing into another 25ml measuring flask, and adding water to about 11ml; 2.5ml of ammonium molybdate sulfuric acid test solution and 1ml of 1-amino-2-naphthol-4-sulfonic acid solution are precisely added, water is added to the scale, the mixture is shaken uniformly, and the mixture is placed at 20 ℃ for 30 to 50 minutes. The free phosphate content was calculated by measuring absorbance at a wavelength of 740nm by ultraviolet-visible spectrophotometry. The results are shown in Table 1
Table 1: free phosphate examination results in example 16
The results show that the free phosphate of the disodium oxynitrate methanol solvent compound prepared by the method is obviously lower than that of the comparative example 1, and the residual free phosphate of the original product can be well removed by preparing the solvent compound of the invention, so that the purity of the finished product is improved. As an important intermediate in the purification process, the method has important use value in the acquisition of high-purity compounds.
Example 17
Stability comparison of disodium Ornidazole phosphate MeOH Compound and hydrate
The sodium disodium salt phosphate solvent compound (examples 7, 9, 12 and 13) and sodium disodium salt phosphate heptahydrate prepared in comparative example 1, and pentahydrate and hexahydrate mentioned in example 16 were taken and placed at 60 ℃ to examine the stability indexes of different crystal forms for 10 days, including appearance properties, moisture, related substances and contents.
Appearance characteristics: visual method
Moisture content: moisture determination method (Fei Xiushi method)
Related substances: high performance liquid chromatography (self-contrast without correction factor)
The content is as follows: high performance liquid chromatography (external standard method)
The measurement results are shown in Table 2
Table 2: example 17 stability study data:
the result shows that the stability of the disodium ornidazole phosphate solvent compound is obviously better than that of the disodium ornidazole phosphate hydrate, and the introduction of the solvent methanol can obtain a lattice structure with better stability, and the obtained new crystal form has better stability than that of the conventional hydrate crystal. The crystalline forms of the solvent compounds mentioned in the present invention may provide a selection of disodium levo-ornidazole phosphate that is advantageous in terms of stability.
Example 18
Preparation of sodium l-ornidazole phosphate for injection
Prescription 1:
400g of disodium ornidazole phosphate solvent compound (calculated by disodium ornidazole phosphate)
110g of citric acid
2L of water for injection
1000 bottles were made
Prescription 2:
400g of disodium ornidazole phosphate heptahydrate (calculated by disodium ornidazole phosphate)
110g of citric acid
2L of water for injection
1000 bottles were made
Prescription 3:
400g of disodium ornidazole phosphate hexahydrate (calculated as disodium ornidazole phosphate)
110g of citric acid
2L of water for injection
1000 bottles were made
Prescription 4:
400g of disodium ornidazole phosphate pentahydrate (calculated as disodium ornidazole phosphate)
110g of citric acid
2L of water for injection
1000 bottles were made
Adding citric acid into 0.16L of injection water with prescription amount, stirring and dissolving, continuously adding the sodium disodium oxynitrate solvent compound with prescription amount, stirring, adding 0.04L of injection water after completely dissolving, continuously stirring uniformly, and filtering with a 0.22 μm microporous filter membrane until the clarity is qualified.
Measuring the content of the intermediate disodium oxynitrate, subpackaging the measured content into tube penicillin bottles, half-adding the tube penicillin bottles, and filling the tube penicillin bottles into a freeze dryer.
The temperature of the plate layer is set to be-45 ℃, the cooling rate is 40 ℃/h, and the plate layer is kept for 4 hours;
regulating the temperature to-30 ℃, and keeping the temperature rising rate at 20 ℃/h for 2 hours;
adjusting the temperature value to-20 ℃, and keeping the temperature rising speed to 20 ℃/h for 10 h;
regulating the temperature to-15 ℃, and keeping the temperature rising rate at 20 ℃/h for 12 hours;
adjusting the temperature to-5 ℃, and keeping the temperature rising rate at 10 ℃/h for 0.5 h;
the temperature was adjusted to 15℃and the heating rate was 5℃per hour, and the mixture was kept for 1 hour.
And after freeze-drying, pressing a plug and rolling a cover to obtain the sodium l-ornidazole phosphate for injection.
Taking the disodium levo-ornidazole phosphate for injection prepared by the above prescriptions, and respectively measuring appearance, moisture, solvent residue, phosphate, related substances and content. The results are shown in Table 3
Table 3: freeze-drying assay results for different prescriptions
In the sodium disodium left ornidazole phosphate finished product for injection prepared by freeze-drying different prescriptions, residual solvents cannot be detected, phosphate residues are close to the results in the raw materials, free phosphate is removed from the raw materials, the impurity content in the product can be effectively reduced, and other indexes have no obvious difference.
Claims (9)
1. The invention provides a novel disodium oxynitrate solvent compound shown in a formula I:
Ⅰ
which contains 1 molecule of methanol and 4 molecules of water.
2. The disodium oxynitrate solvent compound of claim 1, wherein the crystal system of the crystal form is an orthorhombic crystal system, P212121 is a space group, and the unit cell parameter calculation unit cell volume is a= 7.3965 (4) a, b= 8.9181 (5) a, c= 28.7030 (16) a, a=90 °, b=90 °, γ=90 °, v= 1893.33 (18) a 3; the X powder diffraction 2 theta has characteristic peaks at 6.2, 11.7, 12.4, 13.6, 15.2, 15.6, 15.9, 18.2, 18.4, 19.9, 22.1, 23.5, 23.9, 24.3, 24.8, 26.8, 27.1, 27.7, 31.2, 32.2 and 33.5.
3. The invention provides a preparation method of a crystal form of a disodium ornidazole phosphate solvent compound, which is characterized by comprising the following steps of: dissolving sodium ornidazole phosphate (hydrate) in 6-10 times of (W/W) absolute methanol, decolorizing with 0.1-1% (W/V) active carbon for 20min, filtering, stirring the filtrate, dropwise adding 0.1-2.0 times of (W/W) water, dropwise adding 5-15 times of (W/W) solvent for crystallizing for 1-4 hours, filtering, and drying the filter cake at 20-30 ℃ for 3 hours to obtain the sodium ornidazole phosphate solvent compound.
4. The method for preparing a crystal form of a disodium ornidazole phosphate solvent compound according to claim 3, wherein the solvent is one or more of dichloromethane, ethanol, acetone and ethyl acetate.
5. The invention provides a preparation method of a crystal form of a disodium ornidazole phosphate solvent compound, which is characterized by comprising the following steps of: taking disodium ornidazole phosphate (hydrate), adding 6-10 times of (W/W) absolute methanol, stirring at room temperature for dissolution, filtering, dripping water with the dosage of 0.1-2.0 times, stirring uniformly, crystallizing, filtering after crystallization is complete, and air-drying a filter cake at 25 ℃ to obtain the disodium ornidazole phosphate solvent compound.
6. The process for preparing a disodium salt of ornidazole phosphate solvent according to claims 3 and 5, characterized in that methanol is used as the core crystallization solvent.
7. The process for preparing a disodium oxynitrate solvent compound according to claim 3 or 5, wherein water is used as an important auxiliary crystallization solvent, which is effective in improving crystallization efficiency.
8. Use of a solvent compound according to claims 1-2 for the preparation of high purity disodium levo-ornidazole phosphate.
9. Use of a solvent compound according to claims 1-2 for the preparation of high purity disodium levo-ornidazole phosphate for injection.
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