CN104592009B - Naproxen pharmaceutical co-crystal and preparation method thereof - Google Patents
Naproxen pharmaceutical co-crystal and preparation method thereof Download PDFInfo
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- CN104592009B CN104592009B CN201510066977.8A CN201510066977A CN104592009B CN 104592009 B CN104592009 B CN 104592009B CN 201510066977 A CN201510066977 A CN 201510066977A CN 104592009 B CN104592009 B CN 104592009B
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- naproxen
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- crystal
- eutectic
- aminopyrazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D241/20—Nitrogen atoms
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- 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
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- 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
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
-
- 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
Abstract
The invention discloses a naproxen pharmaceutical co-crystal and a preparation method thereof, relates to the field of pharmaceutical co-crystal, and aims sat solving the problem that a naproxen medicine is relatively small in solubility in a water solution. A structural formula of the naproxen pharmaceutical co-crystal is [2(C14H14O3).C4H5N3], wherein two naproxen molecules and one 2-aminopyrazine molecule are bonded together through a hydrogen bond to form a basic structure unit; and the naproxen pharmaceutical co-crystal is a monoclinic system. The naproxen pharmaceutical co-crystal is prepared from the naproxen and 2-aminopyrazine as raw materials by a liquid-assisted grinding method and a solvent evaporation method. The naproxen pharmaceutical co-crystal disclosed by the invention has relatively high solubility in the water solution and reaches 0.308g/L. A solvent molecule of any crystal does not exist in the co-crystal structure, so that the skeletal structure of the crystal can still be kept after being put at a room temperature for a year; and the chemical property is stable.
Description
Technical field
The present invention relates to pharmaceutical co-crystals field is and in particular to naproxen drugs eutectic and preparation method thereof.
Background technology
In recent years, preparing pharmaceutical co-crystals using supramolecular chemistry and crystal engineering thought becomes chemistry and medicine
Study hotspot, pharmaceutical co-crystals are gained great popularity due to its unique physicochemical properties.Pharmaceutical co-crystals refer to pharmaceutically active group
Divide (active pharmaceutical ingredients, API) and other physiologically acceptable acid, alkali or non-ionic
The eutectic formation such as compound (co-crystal formers, CCFs), by hydrogen bond, Van der Waals force, pi-pi accumulation effect, halogen key
The crystal being combined into etc. non-covalent bond effect power, wherein API are solid at room temperature with the pure state of CCFs.Active medicine divides
The pharmaceutical co-crystals that sub Yu suitable compound is formed have many advantages, such as：(1) due to the introducing of CCFs, change pharmaceutically active and divide
The sub three-dimensional packed structures of itself, and then change its dissolubility and rate of dissolution, final raising medicine biology in vivo
Utilization rate；(2) because the main drive in pharmaceutical co-crystals forming process is the noncovalent interaction such as hydrogen bond, Van der Waals force, not
Change the covalent structure of medical compounds itself, therefore, remain the physiologically active of medicine to greatest extent；(3) according to research
Find, the fusing point of pharmaceutical co-crystals, often between the fusing point of medicine activity component and eutectic formation, therefore, it can by choosing
The eutectic formation selecting higher melt suitably to improve the stability of medicine；(4) some drug molecules with chirality, it is right
Reflect isomers and larger difference is had on physiologically active, enantiomter can be realized by the eutectic formation selecting suitable
Separation, enormously simplify the production preparation flow of chiral drug.Based on These characteristics, the synthesis of pharmaceutical co-crystals and property make it
Go out tempting application prospect in materia medica, biomedical fields.Naproxen, as a class antipyretic-antalgic non-steroidal anti-inflammatory
Medicine, has been used for the synthesis of pharmaceutical co-crystals compound at present.
Content of the invention
The invention aims to solving the less problem of naproxen drugs solubility in aqueous, and provide one kind
New naproxen drugs eutectic and preparation method thereof.
The structural formula of naproxen drugs eutectic of the present invention is [2 (C14H14O3)·C4H5N3], two naproxen molecules and one
2- Aminopyrazine molecule forms basic structural unit by Hydrogenbond together, and this naproxen drugs eutectic is monoclinic system,
Space group is P21, cell parameter is：Axial lengthβ=
91.65 (3) °,Its XRD characteristic diffraction peak occur in 9.64 °, 11.84 °, 15.28 °, 16.68 °,
18.00 °, 19.02 °, 20.04 °, 22.33 °, 23.30 °, 24.74 °, at 26.35 °.
The preparation method of naproxen drugs eutectic of the present invention is realized according to the following steps：
It is 2 in molar ratio:1 bulk drug naproxen and 2- Aminopyrazine are placed in agate mortar, add in agate mortar
Enter acetonitrile, be then ground, constantly add acetonitrile during grinding again, grind 30～60min, obtain naproxen drugs
Eutectic.
The preparation method of naproxen drugs eutectic of the present invention is realized according to the following steps：
It is 2 in molar ratio:Bulk drug naproxen is placed in agate mortar with 2- Aminopyrazine and is ground, to grinding by 1
Add ethanol and acetonitrile in mixed-powder afterwards, filter after stirring 30～40min under room temperature, receive after filtrate is placed 8～12 days
Collection solid formation, obtains naproxen drugs eutectic.
The present invention relates to the preparation method of new naproxen drugs eutectic, from bulk drug naproxen as active medicine group
Divide API, the molecular structural formula of naproxen is2- Aminopyrazine is medicine presoma, 2- Aminopyrazine
Molecular structural formula beHigh-quality monocrystalline is prepared using liquid phase assisted milling method and solvent evaporation method, and has carried out list
The mensure of solubility in crystal structure analysis, the infrared, relevant characterization such as fusing point, DSC, fluorescence, powder X-ray RD and the aqueous solution.Result table
Bright, the structural formula of this naproxen drugs cocrystalization compound is [2 (C14H14O3)·C4H5N3], the naproxen -2- of two methods preparation
Aminopyrazine powder all has very high purity and degree of crystallinity, and this cocrystalization compound has larger dissolving in aqueous
Degree, reach 0.308g/L, considerably beyond The Human Metabolome Database provide pure state naproxen drugs in water
In solubility (0.0159g/L).
It is common with the medicine of 2- Aminopyrazine that the present invention is prepared for naproxen using liquid phase assisted milling method and solvent evaporation method
Brilliant.Synthetic method preparation process is simple used by this cocrystalization compound, yield and purity higher it is adaptable to extensive continuous productive process,
With low cost.
Brief description
Fig. 1 is the molecular structure of naproxen drugs eutectic of the present invention, and wherein A and B represents naproxen molecule；
Fig. 2 is the XRD spectra of the naproxen drugs eutectic that naproxen, 2- Aminopyrazine and embodiment one obtain, wherein 1
Naproxen drugs eutectic, 2 naproxens, 3 2- Aminopyrazine；
Fig. 3 is the XRD spectra of naproxen drugs eutectic that simulation and embodiment one obtain, and wherein 1 naproxen drugs are altogether
Crystalline substance, 2 software simulations；
The infrared spectrum of the naproxen drugs cocrystalization compound that Fig. 4 obtains for embodiment；
The DSC curve of the naproxen drugs cocrystalization compound that Fig. 5 obtains for embodiment；
Fig. 6 is the solid state fluorescence curve of naproxen, 2- Aminopyrazine and naproxen drugs eutectic, wherein 1 naproxen；
Fig. 7 is the enlarged drawing at A in Fig. 6, wherein 2 2- Aminopyrazine, 3 naproxen drugs eutectics；
Fig. 8 is the calibration curve of solubility experiment；
Fig. 9 is the solubility curve of naproxen drugs cocrystalization compound.
Specific embodiment
Specific embodiment one：The structural formula of present embodiment naproxen drugs eutectic is [2 (C14H14O3)·C4H5N3],
Two naproxen molecules and a 2- Aminopyrazine molecule form basic structural unit by Hydrogenbond together, this naproxen
Pharmaceutical co-crystals are monoclinic system, and space group is P21, cell parameter is：Axial length β=91.65 (3) °,Its XRD characteristic diffraction peak occur in 9.64 °, 11.84 °,
15.28 °, 16.68 °, 18.00 °, 19.02 °, 20.04 °, 22.33 °, 23.30 °, 24.74 °, at 26.35 °.
Naproxen drugs eutectic described in present embodiment passes through two naproxen molecules and a 2- Aminopyrazine molecule
Form the crystallography asymmetric cell of naproxen drugs eutectic by intermolecular O/N-H ... N/O Hydrogenbond together, wherein,
Amino hydrogen (- N1H2) in naproxen molecule A and 2- Aminopyrazine and pyrazine ring N2 atom are connected to form hydrogen bond ring, and naproxen
Molecule B then forms single hydrogen bond with N3 atom remaining on pyrazine ring, as shown in Figure 1.Carboxyl key in two naproxen molecules
Long by respectively 1.297 (4),With 1.326 (4),Show two naproxens
The all non-dehydrogenation of carboxyl in molecule.Additionally, in amino remaining hydrogen atom and naproxen molecule B in next repetitive carbonyl
Base forms hydrogen bond, and then is formed along the axial one-dimensional hydrogen-bonded chain of a.
Specific embodiment two：The preparation method of present embodiment naproxen drugs eutectic is implemented according to the following steps：
It is 2 in molar ratio:1 bulk drug naproxen and 2- Aminopyrazine are placed in agate mortar, add in agate mortar
Enter acetonitrile, be then ground, constantly add acetonitrile during grinding again, grind 30～60min, obtain naproxen drugs
Eutectic.
Specific embodiment three：Present embodiment is continuous again during grinding from unlike specific embodiment two
Add acetonitrile, grind 40～50min.Other steps and parameter are identical with specific embodiment two.
Specific embodiment four：The preparation method of present embodiment naproxen drugs eutectic is implemented according to the following steps：
It is 2 in molar ratio:Bulk drug naproxen is placed in agate mortar with 2- Aminopyrazine and is ground, to grinding by 1
Add ethanol and acetonitrile in mixed-powder afterwards, filter after stirring 30～40min under room temperature, receive after filtrate is placed 8～12 days
Collection solid formation, obtains naproxen drugs eutectic.
Present embodiment and specific embodiment two are prepared for one kind and have good chemical stability, high-purity, high yield
Naproxen drugs eutectic, and by the introducing of CCF, effective reduce naproxen fusing point while, improve it water-soluble, for this
The application of class pharmaceutical co-crystals provides early stage theoretical and experimental basis.
Specific embodiment five：Present embodiment from the volume ratio of ethanol and acetonitrile unlike specific embodiment four is
1:1.Other steps and parameter are identical with specific embodiment four.
Specific embodiment six：Present embodiment and mixed-powder unlike specific embodiment four or five and ethanol and
The solid-to-liquid ratio of acetonitrile is (0.550～0.555) g：(8～10) mL.Other steps and parameter and specific embodiment four or five phases
With.
Specific embodiment seven：To filter at room temperature unlike one of present embodiment and specific embodiment four to six
Liquid collects solid formation after placing 10 days.One of other steps and parameter and specific embodiment four to six are identical.
Embodiment one：The preparation method of the present embodiment naproxen drugs eutectic is implemented according to the following steps：
It is 2 in molar ratio:The 2- Aminopyrazine of the naproxen of bulk drug 0.460g and 0.095g is placed in agate mortar by 1
In, add 3～5 acetonitriles in agate mortar, be then ground, constantly add 1mL acetonitrile again during grinding, grind
Mill 40min, obtains naproxen drugs eutectic.
The present embodiment prepares naproxen drugs eutectic, cocrystalization compound [2 (C using liquid phase assisted milling method14H14O3)·
C4H5N3] there is good chemical stability.Due to there is not the solvent molecule of any crystallization in this pharmaceutical co-crystals structure, therefore
Place, under room temperature condition, the skeleton structure remaining to keep its crystal for a year, and no any denaturalization phenomenon.
Embodiment two：The preparation method of the present embodiment naproxen drugs eutectic is implemented according to the following steps：
It is 2 in molar ratio:1 the 2- Aminopyrazine of the naproxen of bulk drug 0.460g and 0.095g is placed in agate mortar
It is ground, in the mixed-powder to after grind, sequentially add the ethanol of 5mL and the acetonitrile of 5mL, mistake after stirring 30min under room temperature
Filter, collects solid formation after filtrate is placed 10 days, obtains naproxen drugs eutectic.
It is colourless bulk crystals that the present embodiment adopts the naproxen drugs eutectic of solvent evaporation method preparation, and its chemical formula is
C32H33N3O6, yield is 90% (being calculated with element N).
The purity testing of naproxen drugs cocrystalization compound：
The powder sample that embodiment one liquid phase assisted milling method is obtained has carried out powder X-ray RD diffraction experiment.Powder X-ray-penetrate
Line diffraction data is to measure on the D8 type x-ray diffractometer of German BRUKER company.Test condition：Cu-K α target Tube voltage 40kV, tube current 10mA, sweep speed is 0.2 °/min.By to grind after sample with
Two kinds of raw materials of pure state compare and understand, its characteristic diffraction peak position and diffracted intensity all there occurs significant change, should
Result shows, the effect of grinding promotes material to there occurs reaction, and creates new thing phase, as shown in Figure 2.Meanwhile, to solvent
The monocrystal that volatility process obtains has carried out Advances in crystal X-ray diffraction experiment.Mono-crystalline structures are in Agilent company of the U.S.
Measure on Xcalibur Eos diffractometer, at a temperature of 293K, using the MoK through graphite monochromator monochromatizationαRayScan mode scans for ω.Set during diffraction experiment required Current Voltage as 40mA and 50kV.
In order to further determine that the thing phase of sample and purity after grinding, the present embodiment is obtained using single crystal diffraction experiment
Crystal data simulates the calculated powder XRD spectra of above-mentioned naproxen drugs eutectic by Mercury software, finds that its feature is spread out
Penetrate peak and occur in 9.64,11.84,15.28,16.68,18.00,19.02,20.04,22.33,23.30,24.74,26.35 °
Place, this is substantially identical with the sample peak after grinding, illustrates that the naproxen drugs eutectic being obtained by polishing is had very high
Purity (Fig. 3).
The IR Characterization of naproxen drugs cocrystalization compound：
Infrared spectrum is to complete on the Equinox 55 type FTIS of German BRUKER company.Sweep
Retouching wave band is 4000～400cm-1, sample is using KBr solid preform, resolution ratio：1cm-1.Amino, carbonyl is assumed in its infrared spectrum
The series of features absworption peak (Fig. 4) of base, hydroxyl and aromatic rings.The infrared spectrum of cocrystalization compound is in 3420cm-1And 3210cm-1The absworption peak at place is believed that the vibration absorption peak of carboxyl O-H, amino N-H and hydrogen bond, 1697cm-1Locating strong and sharp peak is C
The vibration absorption peak of=O, 1633 and 1420cm-1Locate as aromatic skeleton vibration absorption peak.1275-1020cm-1In the range of a series of
Absworption peak be naproxen molecule in C-O singly-bound stretching vibration peak.
Differential scanning calorimetry (DSC) test of naproxen drugs cocrystalization compound：
The DSC curve of cocrystalization compound is to measure on U.S.'s PE company DSC4000 type differential scanning calorimeter.Test gas
Atmosphere is nitrogen, gas flow rate 20.0cm3/ min, heating rate is 10.00 DEG C/min, and test temperature is interval to be 30-300 DEG C.?
In 30-300 DEG C of temperature range, its DSC curve a sharp exothermic peak (Fig. 5) only in the range of 96-109 DEG C, right
Should compound thermal decomposition process.
The fusing point test of naproxen drugs cocrystalization 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, at 97.4-99.7 DEG C, melting range is 2.3 DEG C to the fusing point of this cocrystalization compound, shows to prepare by polishing
Pharmaceutical co-crystals have very high purity.
The fluorescence property test of naproxen drugs cocrystalization compound：
The fluorescence spectrum of material medicine and cocrystalization compound is the LS-55 type fluorescence using Perkin Elmer company of the U.S.
Spectrometer is analyzed.Test utilizes solid sample holder, resolution ratio：0.5nm, slit width：Incident 15nm, outgoing 2.5nm, sweep
Retouch speed：700nm/min.As shown in Figure 6 and Figure 7, compared to naproxen and 2- Aminopyrazine, cocrystalization compound change is revealed relatively low
Bluish violet fluorescent emission.The fluorescence emission peak of 2- Aminopyrazine is located at 428nm.The fluorescence emission peak of naproxen is located at
At 355nm, and the fluorescence emission peak of cocrystalization compound is located at 382nm, and fluorescence intensity is had compared with the fluorescence intensity of raw material
Obvious reduction.
The solubility test of naproxen drugs cocrystalization compound：
The solubility of cocrystalization compound adopts calibration curve method to determine, the absorbance of each sample is by Japanese Shimadzu Corporation
UV-2550 ultraviolet-uisible spectrophotometer measure.
(1) selection of optimal absorption wavelength
Prepare the saturated aqueous solution of 2- Aminopyrazine and naproxen respectively, and carry out purple in 200-800nm wave-length coverage
Outer absorption spectrum scanning.Result shows, 2- Aminopyrazine stronger absworption peak at 228nm, and Nabumetone under this wavelength
Raw no substantially absorption, noiseless each other, therefore, select the solubility test experiment that this wavelength carries out pharmaceutical co-crystals.
(2) drafting of directrix curve
The 2- Aminopyrazine accurately weighing 0.0478g is placed in 50mL volumetric flask, and adding water is configured to 10.00mmol/L and stocks
Liquid, takes the stock solution of 10.00mL to be placed in 100mL volumetric flask to be diluted to the use liquid of 1mmol/L, pipette 0.50 respectively, 1.00,
2.00th, 3.00, the titer being diluted to variable concentrations echelon using liquid of 4.00mL, measures its absorption photometric value respectively, and then
Obtaining its calibration curve equation is y=11.43377x+0.00176, R2=0.99994, calibration curve is as shown in Figure 8.
(3) solubility test of cocrystalization compound
Take 0.16g cocrystalization compound to add to 500mL deionized water, be placed in stirring on magnetic stirring apparatus.When sample quilt
When stirring to 0,60,120,180,240,260,280,300 and 320min, draw 20mL solution with syringe respectively, through micropore
(0.45 μm) filtration of filter membrane, pipettes 10.00mL filtrate in 100mL volumetric flask, is then diluted with water to scale, mixes
Afterwards, measure its absorbance (A) at 228nm, the equilibration time of cocrystalization compound is the suction starting to occur neighboring samples mensure
Corresponding time when luminosity (A) value difference is less than ± 0.004, its solubility curve is as shown in Figure 9.Result shows, this Nabumetone
Raw cocrystalization compound reaches dissolution equilibrium in 240min, and its solubility is about 0.555mmol/L (about 0.308g/L).
Claims (7)
1. naproxen drugs eutectic, the structural formula of this naproxen drugs eutectic is [2 (C14H14O3)·C4H5N3], two naproxens
Molecule and a 2- Aminopyrazine molecule form basic structural unit by Hydrogenbond together, and this naproxen drugs eutectic is
Monoclinic system, space group is P21, cell parameter is：Axial length β=91.65 (3) °,Its XRD characteristic diffraction peak occur in 9.64 °, 11.84 °, 15.28 °,
16.68 °, 18.00 °, 19.02 °, 20.04 °, 22.33 °, 23.30 °, 24.74 °, at 26.35 °.
2. the preparation method of naproxen drugs eutectic as claimed in claim 1 is it is characterised in that the system of naproxen drugs eutectic
Preparation Method is realized according to the following steps：
It is 2 in molar ratio:1 bulk drug naproxen and 2- Aminopyrazine are placed in agate mortar, add second in agate mortar
Nitrile, is then ground, and constantly adds acetonitrile during grinding again, grinds 30～60min, obtains naproxen drugs altogether
Brilliant.
3. naproxen drugs eutectic according to claim 2 preparation method it is characterised in that grind during again
Constantly add acetonitrile, grind 40～50min.
4. the preparation method of naproxen drugs eutectic as claimed in claim 1 is it is characterised in that the system of naproxen drugs eutectic
Preparation Method is realized according to the following steps：
It is 2 in molar ratio:Bulk drug naproxen is placed in agate mortar with 2- Aminopyrazine and is ground by 1, to after grind
Add ethanol and acetonitrile in mixed-powder, filter after stirring 30～40min under room temperature, collect solid after filtrate is placed 8～12 days
Phase thing, obtains naproxen drugs eutectic.
5. the preparation method of naproxen drugs eutectic according to claim 4 is it is characterised in that the volume of ethanol and acetonitrile
Than for 1:1.
6. naproxen drugs eutectic according to claim 4 preparation method it is characterised in that mixed-powder and ethanol and
The solid-to-liquid ratio of acetonitrile is (0.550～0.555) g：(8～10) mL.
7. the preparation method of naproxen drugs eutectic according to claim 4 is it is characterised in that put filtrate at room temperature
Solid formation is collected after putting 10 days.
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