CN107089946A - A kind of Norfloxacin and vanillic aldehyde eutectic and preparation method thereof - Google Patents
A kind of Norfloxacin and vanillic aldehyde eutectic and preparation method thereof Download PDFInfo
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- CN107089946A CN107089946A CN201710310135.1A CN201710310135A CN107089946A CN 107089946 A CN107089946 A CN 107089946A CN 201710310135 A CN201710310135 A CN 201710310135A CN 107089946 A CN107089946 A CN 107089946A
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- norfloxacin
- eutectic
- vanillic aldehyde
- crystal
- water
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
- C07C47/58—Vanillin
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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
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to technical field of organic pharmaceutical co-crystal, and in particular to a kind of Norfloxacin and vanillic aldehyde eutectic and preparation method thereof.The Norfloxacin of the present invention and vanillic aldehyde eutectic, using Norfloxacin bulk drug as active constituents of medicine API, vanillic aldehyde is eutectic formation, and its XRD spectra 2 θ is 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657,30.320 have series of features peak.The preparation method of eutectic is as follows：Norfloxacin, vanillic aldehyde are dissolved in 90~100 DEG C of water, and the mol ratio of Norfloxacin and vanillic aldehyde is 1:1, the mass ratio of Norfloxacin and water is 1:300~500, reacting liquid filtering, filtrate cooling, separate out crystal, filter, are dried to obtain crystal i.e. Norfloxacin and vanillic aldehyde eutectic after dissolving.The present invention is further to widen the solid forms of Norfloxacin, and the physicochemical properties of modified medicaments add the solubility in water, and possibility is provided to improve drug effect and bioavilability.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, and in particular to a kind of new Norfloxacin eutectic and preparation method thereof.
Background technology
" pharmaceutical co-crystals " are medicine activity component (API) and physiologically acceptable part (CCF) by molecular recognition,
On the premise of not destroying API itself chemical bonds, pass through intermolecular force (hydrogen bond, halogen key, pi accumulation effect and Van der Waals force) shape
Into specific crystal structure.Pharmaceutical co-crystals based on crystal engineering, are substantially a kind of Supramolecular self assembly systems, are heating power
, dynamics, the balance result of molecular recognition.For active constituents of medicine, the form of its crystalline state can have influence on all of it
Many physicochemical properties, such as fusing point, solubility, stability, bioavilability.Because the formation of pharmaceutical co-crystals will not be destroyed
The covalent bond of active constituents of medicine, therefore, it is possible to provide a kind of more preferable means for changing active constituents of medicine physicochemical property.Medicine
The research of thing crystal formation has very important meaning in pharmacy industry.U.S.'s food and Drug Administration (FDA) is common for medicine
Brilliant Development Trend, is issued in August, 2016《Regulatory Classification of Pharmaceutical
Co‐Crystals Guidance for Industry》.Guideline recommendation, can be by after medicine and certain auxiliary material formation eutectic
Pharmaceutical co-crystals are managed and controlled as " combination product of fixed dosage ".Therefore, eutectic is without separately as new bulk drug
(API) register.European drug administration (EMA) has issued " Reflection paper on the use of in March, 2015
Cocrystals of active substances in medicinal products " eutectics can then be made with similar pharmaceutical salts
It is managed and controls for bulk drug (two similar drugs manage archives).For imitation medicine company, how medicine is developed
Novel crystal forms ahead of time introduce imitation medicine to the market so as to breaking patent protection of the original medicine company to crystal formation, are in recent years one
Individual most important the problem of.
Big drug firm is paid attention to deeply abroad for drug crystal forms research, but pharmaceutical field still belongs to the starting stage at home.
Norfloxacin (Norfloxacin, also known as Noroxin, Fulgram), broad-spectrum antibiotic, especially to aerobic gram negative bacilli
Antibacterial activity is high, has good antibacterial action in vitro to following bacterium：Most of bacterium of enterobacteriaceae, including bacillus citrate
The Enterobacters such as category, enterobacter cloacae, clostridium perfringen, EHEC, Klebsiella, proteus, Salmonella, will
Congratulate Pseudomonas, vibrio, Yersinia etc..Norfloxacin also has antibacterial activity to multi-drug resistant bacteria in vitro.To Penicillin-resistant
NEISSERIA GONORRHOEAE, haemophilus influenzae and moraxelle catarrhalis also have good antibacterial action.Norfloxacin soluble,very slightly in water, is caused
Make its bioavilability relatively low.The slightly soluble in dimethylformamide, ethanol.It is water-soluble in order to change it, increase bioavilability,
The domestic niacin norfloxacin of synthesis in succession, niacin norfloxacin and mono succinate acyl Norfloxacin.
Basavoju etc. has studied in detail the eutectic and salt (Basavoju et al., Crystal of Norfloxacin
Growth&Design,Vol.6,No.12,2006).Research shows, itself and Pyrazinamide formation eutectic, with butanedioic acid, the third two
Acid, maleic acid then forming salt.Chloroform is employed for solvent with Pyrazinamide formation eutectic, and eutectic species have a molecule
Chloroform exist, limit its application in medicine.
The present invention is active constituents of medicine from bulk drug Norfloxacin, is formed using edible spices vanillic aldehyde as eutectic
Thing.The Norfloxacin that the present invention is used, molecular formula is C16H18FN3O3, the chemical entitled fluoro- Isosorbide-5-Nitraes of 1- ethyls -6--dihydro -4- oxygen
Generation -7- (1- piperazinyls) -3- quinoline carboxylic acids.The part used in the present invention is vanillic aldehyde, and molecular formula is C8H8O3, it is chemical entitled
Vanillin.
Present invention selection Norfloxacin medicine and flavorant are active component, using water as solvent, using industrially most easy
The solution crystal process of operation prepares their eutectic, opens up the diversity of drug molecule.
The content of the invention
It is an object of the invention to provide a kind of Norfloxacin of new structure and vanillic aldehyde eutectic and preparation method thereof, and
Its crystal structure is tested, it is characterized and tested.Flucloxacillin and the θ of vanillic aldehyde eutectic 2 that the present invention is prepared
In 6.780,7.760,9.440,10.380,11.757,13.899,15.280,17.100,18. 559,20.620,22.381,
23.018,24.420,25.080,27.657,30.320 have series of features peak,
The preparation method of the Norfloxacin and vanillic aldehyde eutectic, it is characterised in that step is as follows：Norfloxacin, vanillic aldehyde
It is dissolved in 90~100 DEG C of water, the mol ratio of Norfloxacin and vanillic aldehyde is 1:1, the mass ratio of Norfloxacin and water is 1:300~
500, reacting liquid filtering, filtrate cooling, separate out crystal, are filtrated to get crystal i.e. Norfloxacin and vanillic aldehyde eutectic after dissolving.
The present invention is further to widen the solid forms of Norfloxacin, and the physicochemical properties of modified medicaments are added
Solubility in water, possibility is provided to improve drug effect and bioavilability.
Brief description of the drawings
Fig. 1 Norfloxacin XRDs；
Fig. 2 vanillic aldehyde XRDs；
Fig. 3 Norfloxacins and vanillic aldehyde eutectic XRD；
Fig. 4 Norfloxacins DSC schemes；
Fig. 5 vanillic aldehydes DSC schemes；
Fig. 6 Norfloxacins are schemed with vanillic aldehyde eutectic DSC；
Fig. 7 Norfloxacin infrared spectrograms；
Fig. 8 vanillic aldehyde infrared spectrograms；
Fig. 9 Norfloxacins and vanillic aldehyde eutectic infrared spectrogram.
Embodiment
As shown in Figure 3, the XRD of Norfloxacin of the invention and vanillic aldehyde eutectic is not that Norfloxacin XRD is (attached
Fig. 1) the simple superposition of the XRD (accompanying drawing 2) of vanillic aldehyde, it has obvious characteristic peak, 2 θ 6.780,7.760,9.440,
10.380,11.757,13.899,15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,
27.657,30.320 have series of features peak, are new crystal formations.
Norfloxacin and vanillic aldehyde eutectic that the present invention is prepared, its DSC show that eutectic point is 217.1 DEG C (Fig. 6), should
Spectrogram and the fusing point peak that two kinds of raw materials are not present, Norfloxacin fusing point are 222.9 DEG C (Fig. 4), and vanillic aldehyde fusing point is 86.3 DEG C of (figures
5), but generate new characteristic peak, this is also the mark of eutectic formation.
The Norfloxacin and vanillic aldehyde eutectic prepared is invented, its infared spectrum (Fig. 9), is not that Norfloxacin is infrared
The simple superposition of collection of illustrative plates (Fig. 7) and vanillic aldehyde infared spectrum (Fig. 8), is also the mark of eutectic formation.
Specific embodiment 1
104g deionized waters are added in 250ml three-necked flasks, Norfloxacin 348mg, vanillic aldehyde 166mg is slowly added to,
100 DEG C are warming up to, Norfloxacin and vanillic aldehyde are dissolved, and reaction solution fast filtering, filtrate are placed in 250ml beakers after dissolving, from
So cooling, is placed 24 hours, is separated out crystal, is filtered, is dried to obtain 502 milligrams of needle-like white crystals, i.e. Norfloxacin and chinese cymbidium
Plain eutectic.The solubility that Norfloxacin, Norfloxacin and vanillic aldehyde eutectic are measured in 25 DEG C of pure water kinds is as shown in table 1, from table
Understand, eutectic of the invention substantially increases the solubility in water, substantially increase biological utilisation compared with Norfloxacin
Degree；And also it is beneficial to the process operation of follow-up pharmacy procedure.
The solubility of the Norfloxacin of table 1, Norfloxacin and vanillic aldehyde eutectic in 25 DEG C of pure water kinds
| Compound | Solubility (mg/mL) |
| Norfloxacin | 0.28 |
| Norfloxacin and vanillic aldehyde eutectic | 27.8 |
Specific embodiment 2
174g deionized waters are added in 250ml three-necked flasks, Norfloxacin 348mg, vanillic aldehyde 166mg is slowly added to,
90 DEG C are warming up to, Norfloxacin and vanillic aldehyde are dissolved, and reaction solution fast filtering, filtrate are placed in 250ml beakers after dissolving, natural
Cooling, is placed 24 hours, is separated out crystal, is filtered, is dried to obtain 502 milligrams of needle-like white crystals, i.e. Norfloxacin and vanillic aldehyde
Eutectic.The solubility measured in eutectic water is as shown in table 2.
The solubility of the Norfloxacin of table 2, Norfloxacin and vanillic aldehyde eutectic in 25 DEG C of pure water kinds
| Compound | Solubility (mg/mL) |
| Norfloxacin | 0.28 |
| Norfloxacin and vanillic aldehyde eutectic | 27.9 |
Claims (2)
1. a kind of Norfloxacin and vanillic aldehyde eutectic, it is characterised in that using Norfloxacin bulk drug as active constituents of medicine API,
Vanillic aldehyde be eutectic formation, its θ of XRD spectra 2 6.780,7.760,9.440,10.380,11.757,13.899,
15.280,17.100,18.559,20.620,22.381,23.018,24.420,25.080,27.657,30.320 existing characteristics
Peak.
2. the preparation method of a kind of Norfloxacin as claimed in claim 1 and vanillic aldehyde eutectic, it is characterised in that step is as follows：Promise
Flucloxacillin, vanillic aldehyde are dissolved in 90~100 DEG C of water, and the mol ratio of Norfloxacin and vanillic aldehyde is 1:1, the matter of Norfloxacin and water
Amount is than being 1:300~500, reacting liquid filtering, filtrate cooling, separate out crystal after dissolving, filter, be dried to obtain crystal i.e. promise fluorine sand
Star and vanillic aldehyde eutectic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710310135.1A CN107089946B (en) | 2017-05-05 | 2017-05-05 | Norfloxacin and vanillin eutectic crystal and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710310135.1A CN107089946B (en) | 2017-05-05 | 2017-05-05 | Norfloxacin and vanillin eutectic crystal and preparation method thereof |
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| Publication Number | Publication Date |
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| CN107089946A true CN107089946A (en) | 2017-08-25 |
| CN107089946B CN107089946B (en) | 2020-04-03 |
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| CN201710310135.1A Expired - Fee Related CN107089946B (en) | 2017-05-05 | 2017-05-05 | Norfloxacin and vanillin eutectic crystal and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402458A (en) * | 2021-08-15 | 2021-09-17 | 广东温氏大华农生物科技有限公司 | Enrofloxacin eutectic crystal and preparation method thereof |
| CN114805046A (en) * | 2022-04-25 | 2022-07-29 | 东华理工大学 | Eutectic structure of vanillin and amide compound and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009136408A1 (en) * | 2008-04-09 | 2009-11-12 | Institute Of Life Sciences | Synergistic pharmaceutical cocrystals |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN103265483A (en) * | 2013-05-24 | 2013-08-28 | 常州大学 | Co-crystal of norfloxacin and phthalic acid and preparation method thereof |
| CN106279020A (en) * | 2016-08-10 | 2017-01-04 | 杭州新博思生物医药有限公司 | A kind of norfloxacin form D and preparation method thereof, preparation and application |
-
2017
- 2017-05-05 CN CN201710310135.1A patent/CN107089946B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009136408A1 (en) * | 2008-04-09 | 2009-11-12 | Institute Of Life Sciences | Synergistic pharmaceutical cocrystals |
| CN102188365A (en) * | 2011-05-11 | 2011-09-21 | 中山大学 | Indissolvable medicament cocrystallizing solid dispersoid and preparation method thereof |
| CN103265483A (en) * | 2013-05-24 | 2013-08-28 | 常州大学 | Co-crystal of norfloxacin and phthalic acid and preparation method thereof |
| CN106279020A (en) * | 2016-08-10 | 2017-01-04 | 杭州新博思生物医药有限公司 | A kind of norfloxacin form D and preparation method thereof, preparation and application |
Non-Patent Citations (1)
| Title |
|---|
| 闻聪等: "药物共晶在药学中的应用", 《中国新药杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113402458A (en) * | 2021-08-15 | 2021-09-17 | 广东温氏大华农生物科技有限公司 | Enrofloxacin eutectic crystal and preparation method thereof |
| CN115536583A (en) * | 2021-08-15 | 2022-12-30 | 广东温氏大华农生物科技有限公司 | Enrofloxacin-vanillin eutectic crystal and preparation method thereof |
| CN114805046A (en) * | 2022-04-25 | 2022-07-29 | 东华理工大学 | Eutectic structure of vanillin and amide compound and preparation method thereof |
| CN114805046B (en) * | 2022-04-25 | 2023-05-12 | 东华理工大学 | Eutectic structure of vanillin and amide compound and preparation method thereof |
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| CN107089946B (en) | 2020-04-03 |
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