CN105646195A - Fenbufen pharmaceutical co-crystal and preparing method thereof - Google Patents
Fenbufen pharmaceutical co-crystal and preparing method thereof Download PDFInfo
- Publication number
- CN105646195A CN105646195A CN201610072609.9A CN201610072609A CN105646195A CN 105646195 A CN105646195 A CN 105646195A CN 201610072609 A CN201610072609 A CN 201610072609A CN 105646195 A CN105646195 A CN 105646195A
- Authority
- CN
- China
- Prior art keywords
- fenbufen
- pharmaceutical
- crystals
- dmf
- crystal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/50—Use of additives, e.g. for stabilisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/22—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing two or more pyridine rings directly linked together, e.g. bipyridyl
Abstract
The invention discloses a fenbufen pharmaceutical co-crystal. The molecular formula of the fenbufen pharmaceutical co-crystal is [2(Cl6Hl4O3).(ClOH8N2)]. Two fenbufen molecules and one 4,4'-dipyridyl molecule are combined through intermolecular hydrogen bonds to form the molecular structure of the fenbufen pharmaceutical co-crystal, and the molecular structure belongs to a monoclinic system, and the space group is P21/c. The invention further discloses a preparing method for the fenbufen pharmaceutical co-crystal. The preparing method comprises the following steps that fenbufen and 4,4'-dipyridyl molecule are put into a dried mortar according to the molar ratio of 2: 1; two drops of DMF reagent are added into the mortar, then, grinding begins, DMF is refilled constantly during grinding, and grinding is conducted for 50-70 min; then, a sample obtained after grinding is put into air to be dried for 2 h, and the fenbufen pharmaceutical co-crystal is obtained. A co-crystal strategy is adopted, after the co-crystal is formed, a relative stable structure is formed through fenbufen, and the chemical stability of fenbufen is further improved.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, relate to a kind of fenbufen pharmaceutical co-crystals and preparation method thereof.
Background technology
Pharmaceutical co-crystals refers to active pharmaceutical ingredient (activepharmaceuticalingredients, and eutectic formation (co-crystalformers APIs), CCFs) it is combined in same structure cell so that hydrogen bond, Van der Waals force, pi-pi accumulation and other non-covalent bond effects are connected between, having at least one in pharmaceutical co-crystals component is the APIs of molecule-type or ion-type, and wherein APIs and the CCFs of pure state is at room temperature solid. Pharmaceutical co-crystals is as the medicine existing forms of a kind of novelty, compared with other solid forms of medicine such as polymorphic, salt, hydrate or solvate, its some physics, chemistry, biopharmaceutical character, obvious advantage is had such as dissolubility, dissolution rate, bioavailability, heat stability and moisture resistance etc., therefore, pharmaceutical co-crystals has shown wide Research Prospects in medicine.
Nineteen fifty-five, " crystal engineering " concept that Pepinsky et al. proposes and " supramolecular chemistry " thought hereafter, be all that the development of pharmaceutical co-crystals provides new approaches. In the last few years, along with the further investigation to eutectic, it was recognized that eutectic is inherently a kind of Supramolecular self assembly system, it is the balance result of kinetics, thermodynamics, molecular recognition. In molecular self-assembling process, interaction between molecule and steric effect can affect the formation of Supramolecular Network to some extent, and then directly affects the composition of crystal. In eutectic system, form between the synthesis unit of eutectic often more than one active force, but multi-acting force influences each other and reaches balance, makes the result of stable lattice. Compared with other active forces, hydrogen bond is due to its bond energy big (4-120kJ/mol), and there is directivity, become most important active force in eutectic, in the synthesis and structural research work in past, common and stronger hydrogen bond includes N-H ... N, O-H ... O, N-H ... O and O-H ... N, therefore, it is possible to the synthesis unit forming these hydrogen bonds has carboxylic acid-carboxylic acid, carboxylic acid-amide, acyl amine-amide, carboxylic acid-pyridine etc.Still further aspect, owing to the formation of hydrogen bond does not change the covalent structure of active drug molecule itself, the series of properties making compound self is retained to greatest extent, so utilizing the thought of crystal engineering and supramolecular chemistry, design and synthesize pharmaceutical co-crystals, become and improve the topmost means of pharmacopathology character.
Summary of the invention
It is an object of the invention to provide a kind of fenbufen pharmaceutical co-crystals and preparation method thereof, solve the problem that the fenbufen pharmaceutical chemistry stability existed in prior art is not high.
The technical solution adopted in the present invention is: a kind of fenbufen pharmaceutical co-crystals, the molecular formula of this fenbufen pharmaceutical co-crystals is: [2 (C16H14O3) (C10H8N2)], two fenbufen molecules and one 4,4 '-bipyridyl molecule is combined by intermolecular hydrogen bonding and constitutes the molecular structure of fenbufen pharmaceutical co-crystals, belonging to monoclinic system, space group is P21/ c, cell parameter is: ��=97.55 (3) ��,Its XRD characteristic diffraction peak occurs in 8.9-9.3 ��, 10.8-11.3 ��, 11.7-12.3 ��, 13.8-14.3 ��, 15.8-17.1 ��, 17.2-18.3 ��, 18.6-19.7 ��, 19.8-20.4 ��, 22.4 ��, 23.3 ��, 23.6-24.9 ��, 25.4-26.2 ��, 28.4 ��, 29.9 �� places.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, comprise the following steps:
For 2:1, raw material fenbufen and 4,4 '-bipyridyl are placed in dry mortar in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min; Then the sample after grinding is placed in air drying 2h and obtains fenbufen pharmaceutical co-crystals.
Further, the DMF reagent added in process of lapping is accumulative less than 1mL, and milling time is 1h.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, also comprise the following steps: raw material fenbufen is respectively placed in from 4,4'-Bipyridine in two different glass containers for 2:1 in molar ratio; In two glass containers, add the mixed solvent of ethanol and DMF respectively and glass container is placed in the water-bath of 50 DEG C and heats until powder solid dissolves; Solution in two glass containers is mixed and filters after being placed in the water-bath of 50 DEG C heated and stirred and being incubated 30min; Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
Further, the volume ratio of ethanol and DMF is 4:1.
Further, fenbufen is respectively as follows: fenbufen with the solid-to-liquid ratio of 4,4'-Bipyridine with mixed solvent: mixed solvent=254.0mg:5.0mL; 4,4 '-bipyridyl: mixed solvent=96.0mg:5.0mL.
Further, fenbufen pharmaceutical co-crystals is obtained after at room temperature filtrate being placed 5 days.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, further comprising the steps of: for 2:1, raw material fenbufen and 4,4'-Bipyridine to be placed in dry mortar in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min; Then the sample after grinding is placed in air drying 2h; It is transferred in glass container by grinding the powder obtained and adds the mixed solvent of ethanol and DMF; By glass container, it filters after being placed in 50 DEG C water baths heated and stirred and being incubated 30 minutes; Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
The invention has the beneficial effects as follows: the present invention adopts eutectic strategy, the compound prepared can modify original medicine activity component-fenbufen effectively, and after forming eutectic, fenbufen defines metastable structure, not by the interference of solvent molecule so that it is chemical stability improves further. Additionally, due to have employed solution evaporation method and liquid phase assisted milling method in the preparation process of cocrystalization compound, and the product obtained all has significantly high purity, and therefore operation is simple for two kinds of methods, with low cost, is conducive to large-scale popularization in the industrial production; Still further aspect, from the angle of intellectual property protection, due to the formation of pharmaceutical co-crystals, thus extending the market cycle of original medicine, has broad application prospects.
Accompanying drawing explanation
Fig. 1 is the molecular structure of fenbufen cocrystalization compound of the present invention, lone pair electrons ... �� effect and one-dimensional banded structure.
The XRD spectra of the fenbufen cocrystalization compound that Fig. 2 is the spectrogram of theoretical modeling and embodiment 1 obtains, the wherein simulation of 1-software, the sample in 2-embodiment 1.
The XRD spectra of the fenbufen cocrystalization compound that Fig. 3 is the spectrogram of theoretical modeling and embodiment 3 obtains, the wherein simulation of 1-software, the sample in 3-embodiment 3.
Fig. 4 is the infrared spectrum of the fenbufen cocrystalization compound that embodiment obtains.
Fig. 5 is the DSC curve of the fenbufen cocrystalization compound that embodiment obtains.
Fig. 6 is the TG curve of the fenbufen cocrystalization compound that embodiment obtains.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
A kind of fenbufen pharmaceutical co-crystals, its molecular formula is [2 (C16H14O3)��(C10H8N2)], belonging to monoclinic system, space group is P21/c, and cell parameter is: ��=97.55 (3) ��,Its XRD characteristic diffraction peak occurs in 8.9-9.3o, 10.8-11.3o, 11.7-12.3o, 13.8-14.3o, 15.8-17.1o, 17.2-18.3o, 18.6-19.7o, 19.8-20.4o, 22.4o, 23.3o, 23.6-24.9o, 25.4-26.2o, 28.4o, 29.9o place; As shown in Figure 1, two fenbufen molecules and one 4,4 '-bipyridyl molecule passes through intermolecular hydrogen bonding (O1-H1O ... N1,2.620 (2), < (3) ��, (DHA)=173) combining constitutes the molecular structure of fenbufen pharmaceutical co-crystals, and such molecule passes through lone pair electrons further ... (O2 and N1 pyridine ring barycenter Cg spacing is in �� effectPyridine ring-Cg-anion angle ��=80.8o) formed along the axial banded structure of a.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, comprise the following steps:
For 2:1, raw material fenbufen and 4,4 '-bipyridyl are placed in dry mortar in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min; Then the sample after grinding is placed in air drying 2h and obtains fenbufen pharmaceutical co-crystals.
Further, the DMF reagent added in process of lapping is accumulative less than 1mL, and milling time is 1h.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, it is also possible to comprise the following steps: raw material fenbufen is respectively placed in from 4,4'-Bipyridine in two different glass containers for 2:1 in molar ratio; In two glass containers, add the mixed solvent of ethanol and DMF respectively and glass container is placed in the water-bath of 50 DEG C and heats until powder solid dissolves; Solution in two glass containers is mixed and filters after being placed in the water-bath of 50 DEG C heated and stirred and being incubated 30min;Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
Further, the volume ratio of ethanol and DMF is 4:1.
Further, fenbufen is respectively as follows: fenbufen with the solid-to-liquid ratio of 4,4'-Bipyridine with mixed solvent: mixed solvent=254.0mg:5.0mL; 4,4 '-bipyridyl: mixed solvent=96.0mg:5.0mL.
Further, fenbufen pharmaceutical co-crystals is obtained after at room temperature filtrate being placed 5 days.
Further, the preparation method of a kind of fenbufen pharmaceutical co-crystals, further comprising the steps of is that raw material fenbufen and 4,4'-Bipyridine are placed in dry mortar by 2:1 in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min; Then the sample after grinding is placed in air drying 2h; It is transferred in glass container by grinding the powder obtained and adds the mixed solvent of ethanol and DMF; By glass container, it filters after being placed in 50 DEG C water baths heated and stirred and being incubated 30 minutes; Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
Embodiment 1:
Step 1
Weigh: reactant is by fenbufen: the mol ratio of 4,4 '-bipyridyl=2:1 feeds intake. Analytical balance accurately weighs 1.0mmol (254.0mg) fenbufen and 0.5mmol (96.0mg) 4,4'-Bipyridine, inserts in glass container.
Step 2
Stirring and dissolving: measure ethanol and DMF (volume ratio the is 4:1) mixed solvent of 10.0mL with graduated cylinder, by fenbufen and 4,4 '-bipyridyl is dissolved in the above-mentioned mixed solvent of 5.0mL respectively, is placed in the water-bath of 50 degrees Celsius and heats until powder solid dissolves.
Step 3
Mix and blend filters: fenbufen and 4,4'-Bipyridine solution is mixed, is placed in 50 DEG C water baths and is incubated 30 minutes, filters.
Step 4
Solvent room temperature is volatilized: is placed under room temperature condition by filtrate, by solvent slow vaporization method, obtains the colourless eutectic of stable needle-like after about one week. Single crystal X-ray diffraction is it is shown that its cell parameter is: ��=90.00o, ��=97.551 (7) o, ��=90.00o,
Step 5
Powder x-ray diffraction analysis: its characteristic diffraction peak occurs in 8.9-9.3o, 10.8-11.3o, 11.7-12.3o, 13.8-14.3o, 15.8-17.1o, 17.2-18.3o, 18.6-19.7o, 19.8-20.4o, 22.4o, 23.3o, 23.6-24.9o, 25.4-26.2o, 28.4o, 29.9o place, the sample peak of the calculated powder XRD spectra that this crystal data obtained with single crystal X-ray diffraction experiment simulates above-mentioned fenbufen pharmaceutical co-crystals by Mercury software is substantially identical, illustrate that the fenbufen pharmaceutical co-crystals prepared by volatility process has significantly high purity (Fig. 2).
Embodiment 2:
Step 1
Weigh: reactant is by fenbufen: the mol ratio of 4,4 '-bipyridyl=2:1 feeds intake. Analytical balance accurately weighs 1.0mmol (254.0mg) fenbufen and 0.5mmol (96.0mg) 4,4'-Bipyridine, is placed in clean dry agate mortar stand-by.
Step 2
Grind: dripping two DMF reagent in above-mentioned solid, start to grind 1 hour, constantly add DMF in this process, cumulative amount is 1.0mL, the sample after grinding is placed in air drying 2 hours.
Step 3
Mix and blend filters: be transferred in glass container by above-mentioned powder, adds ethanol and DMF (volume ratio the is 4:1) mixed solvent of 10.0mL, is placed in 50 DEG C water baths heated and stirred and is incubated 30 minutes, filters.
Step 4
Solvent room temperature is volatilized: be placed under room temperature condition by filtrate, by solvent slow vaporization method, after about ten days, obtain the colourless eutectic of needle-like, and single-crystal X-ray diffraction analysis shows, this crystal has identical cell parameter with the crystal in embodiment 1 before, and namely both are same substance.
Embodiment 3:
Step 1
Weigh: reactant is by fenbufen: the mol ratio of 4,4 '-bipyridyl=2:1 feeds intake. Analytical balance accurately weighs 1.0mmol (254.0mg) fenbufen and 0.5mmol (96.0mg) 4,4'-Bipyridine, is placed in clean dry mortar stand-by.
Step 2
Grind: dripping two DMF reagent in above-mentioned solid, start to grind 1 hour, constantly add DMF in this process, cumulative amount is 1.0mL, the sample after grinding is placed in air drying 2 hours.
Step 3
Powder x-ray diffraction analysis: its characteristic diffraction peak occurs in 8.9-9.3o, 10.8-11.3o, 11.7-12.3o, 13.8-14.3o, 15.8-17.1o, 17.2-18.3o, 18.6-19.7o, 19.8-20.4o, 22.4o, 23.3o, 23.6-24.9o, 25.4-26.2o, 28.4o, 29.9o place, the powder X-ray RD spectrogram peak that this crystal data obtained with the single crystal X-ray diffraction experiment in embodiment 1 simulates above-mentioned fenbufen pharmaceutical co-crystals by Mercury software is substantially identical, illustrate that the fenbufen pharmaceutical co-crystals prepared by polishing has significantly high purity (Fig. 3).
The single crystal structure determination of fenbufen pharmaceutical co-crystals compound:
In embodiment 1, the mono-crystalline structures of cocrystalization compound measures on the XcaliburEos diffractometer of Agilent company of the U.S., at 293K temperature, adopts the MoK alpha ray through graphite monochromator monochromatizationScan mode is �� scanning. When setting diffraction experiment, required current/voltage is 40mA and 50kV.
The purity testing of fenbufen pharmaceutical co-crystals compound:
Liquid phase volatility process in embodiment 1 and sample that in embodiment 3 prepared by liquid assisted milling method have been carried out powder X-ray RD diffraction experiment (shown in Fig. 2 and Fig. 3). Powder x-ray diffraction data are to measure on the D8 type x-ray diffractometer of BRUKER company of Germany. Test condition: Cu-K �� target Tube voltage 40kV, tube current 10mA, scanning speed is 0.2o/min.
The Infrared Characterization of fenbufen pharmaceutical co-crystals compound:
Infrared spectrum is to complete in the Equinox55 type Fourier transform infrared spectrometer of BRUKER company of Germany. Scanning wave band is 4000��400cm-1, and sample adopts KBr solid preform, resolution: 1cm-1. Its infrared spectrum presents the series of features absworption peak (Fig. 4) of hydroxyl, carbonyl and aromatic rings. The infrared spectrum of the cocrystalization compound absworption peak at 3035cm-1 and 2915cm-1 place is it is believed that the vibration absorption peak of O-H, C-H and hydrogen bond, the vibration absorption peak that peak is C=O that 1673cm-1 place is strong and sharp-pointed, 1603 and 1409cm-1 place be aromatic skeleton vibration absorption peak.
Differential scanning calorimetry (DSC) test of fenbufen pharmaceutical co-crystals compound:
The DSC curve of cocrystalization compound is to measure on U.S.'s PE company DSC4000 type differential scanning calorimeter. Measurement atmosphere is nitrogen, gas flow rate 20.0cm3/min, and heating rate is 10.00 DEG C/min, and test temperature range is 30-300 DEG C. In this temperature range, only there is a sharp-pointed exothermic peak (Fig. 5) within the scope of 153-165 DEG C in its DSC curve, to should the thermal decomposition process of compound.
Thermogravimetric (TG) test of fenbufen pharmaceutical co-crystals compound:
The thermogravimetric of compound is that the TG/DTA6300 thermal analyzer utilizing PerkinElmer company is analyzed.Adopt A12O3Crucible, and use sky A12O3Crucible is as reference, and heating rate is 10 DEG C/min, and measurement atmosphere is air, and as shown in Figure 6, cocrystalization compound starts weightlessness when being approximately in 146 DEG C, until when 540 DEG C weightless completely.
The fusing point test of fenbufen pharmaceutical co-crystals compound:
The fusing point test of cocrystalization compound is to complete on the X-5 type micro melting point apparatus of Gongyi Yu Hua instrument company. Test result shows, the fusing point of this cocrystalization compound is at 155.9-158.1 DEG C, and melting range is 2.2 DEG C, it was shown that the pharmaceutical co-crystals prepared by polishing has significantly high purity.
Claims (8)
1. a fenbufen pharmaceutical co-crystals, it is characterized in that, the molecular formula of this fenbufen pharmaceutical co-crystals is: [2 (C16H14O3) (C10H8N2)], two fenbufen molecules and one 4,4 '-bipyridyl molecule is combined by intermolecular hydrogen bonding and constitutes the molecular structure of fenbufen pharmaceutical co-crystals, belonging to monoclinic system, space group is P21/ c, cell parameter is:��=97.55 (3) ��,Its XRD characteristic diffraction peak occurs in 8.9-9.3 ��, 10.8-11.3 ��, 11.7-12.3 ��, 13.8-14.3 ��, 15.8-17.1 ��, 17.2-18.3 ��, 18.6-19.7 ��, 19.8-20.4 ��, 22.4 ��, 23.3 ��, 23.6-24.9 ��, 25.4-26.2 ��, 28.4 ��, 29.9 �� places.
2. the preparation method of a fenbufen pharmaceutical co-crystals, it is characterised in that comprise the following steps:
For 2:1, raw material fenbufen and 4,4 '-bipyridyl are placed in dry mortar in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min; Then the sample after grinding is placed in air drying 2h and obtains fenbufen pharmaceutical co-crystals.
3. the preparation method of a kind of fenbufen pharmaceutical co-crystals according to claim 2, it is characterised in that the DMF reagent added in process of lapping is accumulative less than 1mL, and milling time is 1h.
4. the preparation method of a fenbufen pharmaceutical co-crystals, it is characterised in that comprise the following steps: raw material fenbufen is respectively placed in from 4,4'-Bipyridine in two different glass containers for 2:1 in molar ratio; In two glass containers, add the mixed solvent of ethanol and DMF respectively and glass container is placed in the water-bath of 50 DEG C and heats until powder solid dissolves; Solution in two glass containers is mixed and filters after being placed in the water-bath of 50 DEG C heated and stirred and being incubated 30min; Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
5. the preparation method of a kind of fenbufen pharmaceutical co-crystals according to claim 4, it is characterised in that the volume ratio of ethanol and DMF is 4:1.
6. the preparation method of a kind of fenbufen pharmaceutical co-crystals according to claim 4, it is characterised in that the solid-to-liquid ratio of fenbufen and 4,4'-Bipyridine and mixed solvent is respectively as follows: fenbufen: mixed solvent=254.0mg:5.0mL; 4,4 '-bipyridyl: mixed solvent=96.0mg:5.0mL.
7. the preparation method of a kind of fenbufen pharmaceutical co-crystals according to claim 4, it is characterised in that obtain fenbufen pharmaceutical co-crystals after at room temperature filtrate being placed 5 days.
8. the preparation method of a fenbufen pharmaceutical co-crystals, it is characterised in that comprise the following steps: for 2:1, raw material fenbufen and 4,4'-Bipyridine are placed in dry mortar in molar ratio; In mortar, add two DMF reagent, then start to grind, the process ground constantly is added DMF again, grind 50��70min;Then the sample after grinding is placed in air drying 2h; It is transferred in glass container by grinding the powder obtained and adds the mixed solvent of ethanol and DMF; By glass container, it filters after being placed in 50 DEG C water baths heated and stirred and being incubated 30 minutes; Filtrate is placed under room temperature condition, within 4-7 days, obtains fenbufen pharmaceutical co-crystals by the volatilization of solvent slow vaporization method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510431492 | 2015-07-22 | ||
| CN2015104314924 | 2015-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105646195A true CN105646195A (en) | 2016-06-08 |
Family
ID=56489125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610072609.9A Pending CN105646195A (en) | 2015-07-22 | 2016-02-02 | Fenbufen pharmaceutical co-crystal and preparing method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105646195A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106995404A (en) * | 2017-05-18 | 2017-08-01 | 洛阳师范学院 | One kind 9,9-bis- (3,4-dihydroxy phenyl) fluorenes and the eutectic and preparation method of the formation of 4,4 '-bipyridyl |
| CN107056628A (en) * | 2017-03-21 | 2017-08-18 | 北京师范大学 | Fenbufen meglumine salt and preparation method and application |
| CN107188799A (en) * | 2017-05-09 | 2017-09-22 | 中国食品药品检定研究院 | Fenbufen eutectic and preparation method and application |
| CN114436823A (en) * | 2022-01-26 | 2022-05-06 | 东南大学 | Fenbufen pharmaceutical co-crystal and preparation method thereof |
-
2016
- 2016-02-02 CN CN201610072609.9A patent/CN105646195A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056628A (en) * | 2017-03-21 | 2017-08-18 | 北京师范大学 | Fenbufen meglumine salt and preparation method and application |
| CN107188799A (en) * | 2017-05-09 | 2017-09-22 | 中国食品药品检定研究院 | Fenbufen eutectic and preparation method and application |
| CN107188799B (en) * | 2017-05-09 | 2020-10-30 | 中国食品药品检定研究院 | Fenbufen eutectic crystal and preparation method and application thereof |
| CN106995404A (en) * | 2017-05-18 | 2017-08-01 | 洛阳师范学院 | One kind 9,9-bis- (3,4-dihydroxy phenyl) fluorenes and the eutectic and preparation method of the formation of 4,4 '-bipyridyl |
| CN114436823A (en) * | 2022-01-26 | 2022-05-06 | 东南大学 | Fenbufen pharmaceutical co-crystal and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105646195A (en) | Fenbufen pharmaceutical co-crystal and preparing method thereof | |
| CN102046175B (en) | The heterocyclic fused gamma-carbolines solid replaced | |
| CN105330606B (en) | 2-aminopyridine is the 5 FU 5 fluorouracil pharmaceutical co-crystals and its preparation method and application of presoma | |
| Sanphui et al. | Phase transformation in conformational polymorphs of nimesulide | |
| CN105111215B (en) | A kind of crystal form and preparation method thereof of cyclin-dependent kinase inhibitor | |
| CN104356072A (en) | 5-fluorouracil drug eutectic crystal and preparation method thereof | |
| CN102276594B (en) | Iloperidone medicinal cocrystal and preparation method thereof | |
| CN102503886B (en) | Agomelatine-isonicotine eutectic crystal and compound and preparation method thereof | |
| Ross et al. | Coprocessing of pharmaceutical cocrystals for high quality and enhanced physicochemical stability | |
| CN110590858B (en) | Cobalt-containing coordination compound with low-temperature phase change and preparation method thereof | |
| CN103360331B (en) | Novel lamotrigine pharmaceutical co-crystal and preparation method thereof | |
| Torres-Moya et al. | High thermal stability, pH responsive organogels of 2 H-benzo [d] 1, 2, 3-triazole derivatives as pharmaceutical crystallization media | |
| CN107043376A (en) | A kind of Li Gelieting novel crystal forms and preparation method thereof | |
| Fontanillo et al. | In situ synthesis-gelation at room temperature vs. heating–cooling procedure. Fine tuning of molecular gels derived from succinic acid and L-valine | |
| CN102344478B (en) | Crystal of 17 alpha-acetoxyl group-11 beta-(4-N, N-dimethylamino phenyl)-19-norpregna-4, 9- diene-3, 20- ketone and preparation method thereof | |
| Edelsztein et al. | Self-assembly of a silylated steroid-based organogelator and its use as template for the in situ sol–gel polymerization of tetraethyl orthosilicate | |
| Zhou et al. | Solubility and dissolution thermodynamic properties of 2-Cyano-4′-methylbiphenyl in binary solvent mixtures | |
| JP2022525125A (en) | E crystal form of braiaconitine A and its manufacturing method and application | |
| CN107021917B (en) | Novel crystal form of pimavanserin hemitartrate and preparation method thereof | |
| CN102060777B (en) | Novel phenytoin medicament eutecticum and preparation method thereof | |
| CN105481780B (en) | 2- aminopyrimidine is the 5 FU 5 fluorouracil pharmaceutical co-crystals and its preparation method and application of presoma | |
| CN102153552B (en) | Two novel paliperidone drug eutectics and preparation method of the novel paliperidone drug eutectics | |
| Xu et al. | Polymorphs and amorphous state of glipizide: preparation and solid-state transformations | |
| CN102321141B (en) | Amorphous substance of 17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregn-4,9-diene-3,20-diketone and preparation method thereof | |
| CN108659038B (en) | Polymorphic substance of 1-stearoyl-2-valoyl-sn-glycerol-3-phosphatidylcholine and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160608 |