CN103351342B - A kind of Edaravone pharmaceutical co-crystal and preparation method thereof - Google Patents
A kind of Edaravone pharmaceutical co-crystal and preparation method thereof Download PDFInfo
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- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 title claims abstract description 142
- 229950009041 edaravone Drugs 0.000 title claims abstract description 139
- 239000013078 crystal Substances 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 78
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 77
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 77
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 77
- 229960004853 betadex Drugs 0.000 claims abstract description 77
- 230000005496 eutectics Effects 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 239000000470 constituent Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000012046 mixed solvent Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- 238000002329 infrared spectrum Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000000354 decomposition reaction Methods 0.000 claims description 6
- 230000004580 weight loss Effects 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 125000006850 spacer group Chemical group 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 2
- 230000004323 axial length Effects 0.000 claims description 2
- 238000010583 slow cooling Methods 0.000 claims description 2
- 210000004958 brain cell Anatomy 0.000 abstract description 3
- 230000004792 oxidative damage Effects 0.000 abstract description 3
- 238000005502 peroxidation Methods 0.000 abstract description 3
- 230000002000 scavenging effect Effects 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- 210000003556 vascular endothelial cell Anatomy 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 229950005162 benexate Drugs 0.000 description 11
- IAXUQWSLRKIRFR-SAABIXHNSA-N chembl2104696 Chemical compound C1C[C@@H](CNC(=N)N)CC[C@@H]1C(=O)OC1=CC=CC=C1C(=O)OCC1=CC=CC=C1 IAXUQWSLRKIRFR-SAABIXHNSA-N 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000011160 research Methods 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 238000010586 diagram Methods 0.000 description 8
- 238000005755 formation reaction Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 208000026106 cerebrovascular disease Diseases 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 229910017488 Cu K Inorganic materials 0.000 description 2
- 229940123457 Free radical scavenger Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000003727 cerebral blood flow Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000003223 protective agent Substances 0.000 description 2
- 239000002516 radical scavenger Substances 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- -1 2-pyrazoline keto-acid Chemical class 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000005389 magnetism Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000005232 molecular self-assembly Methods 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to technical field of organic pharmaceutical co-crystal, be specifically related to the preparation method of a kind of novel Edaravone pharmaceutical co-crystal and this pharmaceutical co-crystals.The invention discloses a kind of Edaravone pharmaceutical co-crystal, pharmaceutical co-crystals is active constituents of medicine with Edaravone, take beta-cyclodextrin as eutectic formation; An Edaravone molecule, the basic structural unit of a beta-cyclodextrin molecule and 10.5 water molecules composition Edaravone pharmaceutical co-crystal; Carbonylic oxygen atom wherein in Edaravone molecule and imido nitrogen atom are as hydrogen bond receptor, and the hydroxyl in beta-cyclodextrin molecule forms two kinds of different intermolecular hydrogen bondings as hydrogen bond donor; The antioxygenation of Edaravone mainly passes through scavenging free radicals, anti-lipid peroxidation, thus suppresses the oxidative damage of brain cell, vascular endothelial cell, neurocyte.Eutectic prepared by the present invention remains the pharmacologically active of Edaravone itself, and all improves significantly to its solvability, stability and bioavailability aspect.Solubility test result shows, and the solubleness of this pharmaceutical co-crystals is Edaravone solubleness more than 6 times.
Description
Technical field
The invention belongs to technical field of organic pharmaceutical co-crystal, be specifically related to the preparation method of a kind of novel Edaravone pharmaceutical co-crystal and this pharmaceutical co-crystals.
Background technology
Supramolecular chemistry be research intermolecular mutually concluding and the complexity that formed in order and there is the science of the molecule aggregates of ad hoc structure and function.Supramolecular chemistry has following notable feature: the strong bonding force that a. forms super molecular compound is weak interaction force superposition and collaborative result between differing molecular, is the general performance of multi-acting force; B. the super molecular compound of differing molecular self-assembly demonstrates New function diverse with former self assembly molecule.Its core content is the molecular recognition and Supramolecular self assembly of being undertaken by the synergy of intermolecular weak interaction.
Active constituents of medicine (active pharmaceutical ingredients, API) with suitable eutectic formation (cocrystal former, CCF) H-bonding self-assembly is passed through, or by the non covalent bond with saturability and directivity (as the Van der Waals force of aromatic hydrocarbons or phenyl ring, π-πconjugation and halogen key) assemble a kind of novel texture formed, i.e. pharmaceutical co-crystals.The design of pharmaceutical co-crystals is equal to supramolecular Design and synthesis.Britain Camb structural database (CSD) is the main source of the structure of matter microscopic information about molecular designing and design of material.Pharmaceutical co-crystals preparation method mainly contains falling temperature method, solvent evaporation method, polishing, suspendible method etc.
With the active constituents of medicine that crystalline form exists, be mainly salt, polymorphic and solvate (comprising hydrate).The same medicine of different crystal forms, may there were significant differences in the physico-chemical properties such as stability, solubleness and bioavailability and biological property, thus affect the curative effect of medicine.Simultaneously; how to develop the new crystal of medicine, thus original medicine company can be broken to the patent protection of crystal formation, ahead of time imitation medicine is introduced to the market; be a vital problem in recent years, will directly have influence on market and the international competitiveness of imitation medicine and bulk drug company.Drug crystal forms is studied and is characterized in American-European pharmaceutical industry and has been comparative maturity and dark valued field, but pharmaceutical industry still belongs to the starting stage at home.The crystallized form of API has a great impact its physico-chemical property and biological property, comprises solvability, stability, dispersion rate, metabolic stability and bioavailability etc.
Pharmaceutical co-crystals research is also an important component part of drug crystal forms research.Why pharmaceutical co-crystals has very large magnetism to be to pharmaceutical industry, and it providing one does not need destruction and produces covalent linkage just to reach the physics of modified medicaments activeconstituents (API) or the chance of chemical property.Pharmaceutical co-crystals majority is formed based on hydrogen bond, is generally formed by the connection of hydrogen bond receptor and hydrogen-bond donating body.The pharmaceutical co-crystals formed by hydrogen bond neither needs to form new covalent linkage, does not need again to destroy existing covalent linkage; While the pharmacological properties retaining medicine itself, reach the object of the physico-chemical property of modified medicaments, this point is that the application of pharmaceutical co-crystals in pharmaceutical industry provides more wide development space.When not changing medicines structure and the pharmacological properties of itself, the new crystal of formation can improve solvability, dissolution rate, bioavailability, the stability of medicine, and reduction is drawn moist, improves mechanical property etc.Therefore, obtain and morely there is novelty, practicality and creationary pharmaceutical co-crystals have important practical significance, particularly some water-insoluble drugs.In recent years, pharmaceutical co-crystals research more and more received the concern of people.Present stage, abroad start increase gradually and go deep into the research of pharmaceutical co-crystals; And it is domestic also relatively less to its research.For imitation medicine, the research of pharmaceutical co-crystals also can break Yuan Yan medicine company to the patent protection of drug crystal forms, is beneficial to and is introduced to the market by imitation medicine.
Edaravone (Edaravone), trade(brand)name: must deposit, chemical name is: 3-methyl isophthalic acid-phenyl-2-pyrazoles woods-5-ketone, molecular formula: C
10h
10n
2o; Molecular weight: 174.20, structural formula is:
The structural research of Edaravone shows, the Edaravone molecule of fragrant heterocyclic shows different configurations in the solvent of opposed polarity, and as 1,2-pyrazoline keto-acid configuration, 2,4-pyrazoline keto-acids, enol form etc., therefore Edaravone also exists polymorphic.Chinese patent CN102060771, CN 102643234 and Acta Cryst. E, 2008,64:01924 report three kinds of crystal formations of Edaravone.
Edaravone is a kind of cerebral protective agent (free-radical scavengers).Acute period of cerebral infarction patient give Edaravone, can suppress the minimizing of periinfarct regional cerebral blood flow.Its Main Function mechanism is by scavenging free radicals, anti-lipid peroxidation, thus suppresses the oxidative damage of brain cell, vascular endothelial cell, neurocyte.Current Edaravone is clinical in injection system administration, and injection take propylene glycol as solvent, adds stablizer and oxidation inhibitor simultaneously, flushes the ampoules with nitrogen filling.The inconvenience of Edaravone injection Clinical practice, oral being difficult to absorbs.Still there is no oral preparations at present, but have some to utilize beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin etc. and Edaravone to make inclusion compound to improve its solubleness and dissolution rate, the research report of stability etc.As (Int J Pharm. 2009 such as Sato T., 372 (1-2): 33-8) hydroxypropyl-beta-cyclodextrin/Edaravone (mass ratio 20:1) is mixed with need testing solution with citrate buffer (pH4.5), lucifuge 50 DEG C is deposited and is carried out investigation discovery to its thermostability in 14 days, in solution, Edaravone relative content is reduced to 93.7%, and the solution Edaravone relative content adding the S-WAT of 0.1 ~ 0.6 mass ratio, halfcystine or benzotriazole can keep stablizing constant.Beta-cyclodextrin inclusion compound Edaravone is made beta-cyclodextrin/Edaravone inclusion compound (mass ratio 6 ~ 50:1) by Ren Yong etc. (Chinese patent CN101953832) under condition of different pH, light (4500 ± 500LX), heat (40 DEG C) the accelerated stability test-results of 10 days show, the edaravone raw material content of non-inclusion declines obviously (equal to 95%), and prepare Edaravone content relatively stable (being all greater than 96.6%) in inclusion compound under neutrallty condition, the less stable (about 95.2%) of Edaravone in inclusion compound prepared by acidic conditions (pH4.5).The oral preparations of beta-cyclodextrin inclusion compound Edaravone, compared with commercially available injection, its absolute bioavailability can reach more than 55%; Compared with common suspension formulation, its relative bioavailability is up to about 1000%.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of novel Edaravone pharmaceutical co-crystal and this pharmaceutical co-crystals, and its structure is characterized.The preparation of this pharmaceutical co-crystals improves the solvability of bulk drug, stability and bioavailability, and provides an approach for the research and development of Edaravone oral preparations.
In order to realize technical purpose of the present invention, concrete technical scheme of the present invention is as follows:
A kind of Edaravone pharmaceutical co-crystal, pharmaceutical co-crystals is active constituents of medicine with Edaravone, take beta-cyclodextrin as eutectic formation; An Edaravone molecule, the basic structural unit of a beta-cyclodextrin molecule and 10.5 water molecules composition Edaravone pharmaceutical co-crystal; Carbonylic oxygen atom wherein in Edaravone molecule and imido nitrogen atom are as hydrogen bond receptor, and the hydroxyl in beta-cyclodextrin molecule forms two kinds of different intermolecular hydrogen bondings as hydrogen bond donor; The pharmaceutical co-crystals formed belongs to oblique system, C 2(5
#) spacer, its unit cell parameters: axial length a=18.942(4), b=24.354(5), c=15.608(3), shaft angle β=110.802(20) o, V=6731.5(3)
3, Z=2.
As further improvement, pharmaceutical co-crystals of the present invention has use Cu K as shown in Figure 1
αthe X-ray powder diffraction pattern of radiation, is expressed as with diffraction angle 2 θ ° ± 0.1: 6.0,6.1,7.2,9.6,10.0,11.8,12.0,12.3,12.6,14.5,15.4,15.7,17.5,17.6,17.8,18.5,18.7,18.9,19.8,20.7,21.4,23.4,23.9,24.1,26.0 etc.
As further improvement, the display of the thermogravimetric spectrogram (TG) of pharmaceutical co-crystals of the present invention, within the scope of room temperature to 150 DEG C, its rate of weight loss is 12.7%, containing 10.5 parts of water in structure; Its differential thermal spectrogram (DSC) shows, and at 73.5 DEG C, there are three endotherm(ic)peaks at 95.5 DEG C and 117.0 DEG C of places, for this pharmaceutical co-crystals loses the endotherm(ic)peak of water; The decomposition temperature of eutectic is 274.1 DEG C (summit values).
As further improvement, infrared spectrum (IR) display of pharmaceutical co-crystals of the present invention, at 3413,2926,1719,1632,1499,1321,1079,1031,757,701cm
-1there is charateristic avsorption band at place.
Present invention also offers a kind of preparation method of Edaravone pharmaceutical co-crystal, concrete steps are as follows:
Be the mixed solvent that the Edaravone of 1:1 and beta-cyclodextrin join alcohol and water by mol ratio, be heated to 50 ~ 80 DEG C, to stir or ultrasonic until after dissolving completely, continue to stir or ultrasonic 0.5 hour, Slow cooling, static crystallization, obtains Edaravone eutectic.
As further improvement, alcohol of the present invention is methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol.
As further improvement, alcohol of the present invention is preferably ethanol.
As further improvement, in mixed solvent of the present invention, the volume ml of alcohol and the volume ml of water is than being 1:1 ~ 1:10, and in reaction soln system, solutes content is 30 ~ 50mg/ml.
Beneficial effect of the present invention is as follows:
Edaravone is a kind of cerebral protective agent (free-radical scavengers).Injection develops (trade(brand)name: RADICUT) by Mitsubishi Tokyo drugmaker, gets permission listing, be used for the treatment of nerve injury symptom, alleviate the paralysis of daily routines obstacle and cerebral infarction acute attack April calendar year 2001 in Japan.The clinical treatment for acute cerebral infarction, can suppress the minimizing of periinfarct regional cerebral blood flow.Its antioxygenation mainly passes through scavenging free radicals, anti-lipid peroxidation, thus suppresses the oxidative damage of brain cell, vascular endothelial cell, neurocyte.Eutectic prepared by the present invention remains the pharmacologically active of Edaravone itself, and all improves significantly to its solvability, stability and bioavailability aspect.Solubility test result shows, and the solubleness of this pharmaceutical co-crystals is Edaravone solubleness more than 6 times.
Accompanying drawing explanation
Fig. 1 is the eutectic XRD spectra that the XRD spectra of Edaravone/beta-cyclodextrin eutectic obtains with simulation;
Fig. 2 is the stacking diagram of the XRD spectra of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic;
Fig. 3 is thermal weight loss (TG) figure of Edaravone/beta-cyclodextrin eutectic;
Fig. 4 is the stacking diagram of the TG figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic;
Fig. 5 is the DSC figure of Edaravone/beta-cyclodextrin eutectic;
Fig. 6 is the stacking diagram of DSC figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride, Edaravone/beta-cyclodextrin eutectic;
Fig. 7 is infrared spectra (IR) figure of Edaravone/beta-cyclodextrin eutectic;
Fig. 8 is the stacking diagram of the IR figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic.
Embodiment
The invention provides the preparation method of a kind of novel Edaravone pharmaceutical co-crystal and this pharmaceutical co-crystals, active constituents of medicine (API) used in technical scheme of the present invention is Edaravone (Edaravone), chemical name is: 3-methyl-1-phenyl-2-pyrazolin-5-one, and molecular formula is: C
10h
10n
2o, its structural formula is as shown in a formula.
The eutectic formation (cocrystal former, CCF) used in the present invention is beta-cyclodextrin (beta-CD), and molecular formula is: C
42h
70o
35, its structural formula is as shown in b formula.Beta-cyclodextrin can increase solubleness and the stability of insoluble drug, promotes drug absorption, covers adverse drug smell, as pharmaceutical carrier, be widely used in various drug delivery system at present.
a b
The Edaravone that the present invention prepares/beta-cyclodextrin eutectic belongs to oblique system, C 2(5
#) spacer, unit cell parameters is: a=18.942(4), b=24.354(5), c=15.608(3) and, β=110.802(20) o, V=6731.5(3)
3, Z=2.X ray diffracting spectrum is presented at diffraction angle (2 θ, ± 0.1 °): 6.0,6.1,7.2,9.6,10.0,11.8,12.0,12.3,12.6,14.5,15.4,15.7,17.5,17.6,17.8,18.5,18.7,18.9,19.8,20.7,21.4, there is feature diffract spectral line at the places such as 23.4,23.9,24.1,26.0.Its crystalline structure can be summarized as follows: an Edaravone molecule, the basic structural unit of a beta-cyclodextrin molecule and 10.5 water molecules composition Edaravone pharmaceutical co-crystal; Carbonylic oxygen atom wherein in Edaravone molecule on pyrazole ring, imido nitrogen atom are as the acceptor of hydrogen bond, hydroxyl on beta-cyclodextrin forms two kinds of different hydrogen bonds as hydrogen bond donor, water molecules simultaneously in structure both with beta-cyclodextrin, again with Edaravone, simultaneously form hydrogen bond with water molecules again, constitute a complicated hydrogen bond network.Thermogravimetric spectrogram (TG) display of Edaravone/beta-cyclodextrin eutectic, within the scope of room temperature to 150 DEG C, its rate of weight loss is 12.7%, shows in structure containing 10.5 parts of crystal water; Its differential thermal spectrogram (DSC) shows, and at 73.5 DEG C, there are three endotherm(ic)peaks at 95.5 DEG C and 117.0 DEG C of places, for this pharmaceutical co-crystals loses the endotherm(ic)peak of water; The decomposition temperature (summit value) of Edaravone/beta-cyclodextrin eutectic is 274.1 DEG C, and after generating eutectic, the thermostability of Edaravone improves (decomposition temperature that Edaravone generates before eutectic is 140 DEG C) greatly.Its infrared spectrum (IR) shows, at 3413,2926,1719,1632,1499,1321,1079,1031,757,701cm
-1there is charateristic avsorption band at place.
Solvent selected by the present invention is the mixed solvent system of alcohol and water, and most preferably being the mixed solvent of second alcohol and water composition, is very safe solvent system.
The present invention adopts heated and stirred and ultrasonic method to form eutectic, then adopts the method for cooling crystallization to separate out eutectic.The pharmaceutical co-crystals structure that two kinds of methods prepare is identical.These two kinds of methods are easy to operation, are convenient to realize suitability for industrialized production.
Concrete steps are as follows:
Method 1:
(1) be that the Edaravone of 1:1 and beta-cyclodextrin join in the mixed solvent of alcohol and water (volume ratio 1:1 ~ 1:10, mL/mL) by mol ratio, in reaction system, the ratio of solute and solution is 30 ~ 50mg/ml;
(2) 50 ~ 80 DEG C of reflux, stir, and continue to stir 0.5h after dissolving completely again.
(3) stop stirring, Temperature fall, namely place 12 ~ 24h after being down to room temperature again has crystal to separate out, and precipitate is described Edaravone/beta-cyclodextrin eutectic.
Method 2:
(1) be that the Edaravone of 1:1 and beta-cyclodextrin join in the mixed solvent of alcohol and water (volume ratio 1:1 ~ 1:10, mL/mL) by mol ratio, in reaction system, the ratio of solute and solution is 30 ~ 50mg/ml;
Ultrasonic under (2) 50 ~ 80 DEG C of conditions, continue ultrasonic 0.5h again after dissolving completely;
(3) stop ultrasonic, Temperature fall, namely place 12 ~ 24h after being down to room temperature again has crystal to separate out, and precipitate is described Edaravone/beta-cyclodextrin eutectic.
In the present invention, the instrument of detection of drugs eutectic structure and performance is as follows:
X-ray powder diffraction instrument: Rigaku company, model is D/Max-2550PC, Cu-K α (λ=1.54056) radiation, tube voltage 40KV, tube current 250mA, sweep velocity 5o/min, walk θ-2 θ continuous sweep of wide 0.02 o, sweep limit 3-40 o (2 θ).
Thermal Synthetic Analysis instrument: TA company of the U.S., model is SDTQ600, sweep gas: nitrogen 120 ml/min, heat-up rate 10 DEG C/min, temperature range: room temperature ~ 350 DEG C.
Differential scanning calorimeter: TA company of the U.S., model is DSCQ100, sweep gas: nitrogen 120 ml/min, heat-up rate 10/min, temperature range: room temperature ~ 350 DEG C.
Fourier infrared spectrograph: German Bruker company, model is Vector 22, scanning wave-number range: 4000-400cm-1.Be further elaborated below by specific embodiment and in conjunction with Figure of description technical scheme of the present invention, the preparation of Edaravone pharmaceutical co-crystal is specific as follows:
Embodiment 1:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:7) of 6ml second alcohol and water, is heated to 50 ~ 80 DEG C, reacts 0.5h under stirring.Stop stirring, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 2:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:1) of 10ml first alcohol and water, is heated to 50 ~ 65 DEG C, reacts 0.5h under stirring.Stop stirring, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 3:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:5) of 8ml isopropyl alcohol and water, is heated to 50 ~ 80 DEG C, reacts 0.5h under stirring.Stop stirring, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 4:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:6) of 9ml n-propyl alcohol and water, is heated to 50 ~ 80 DEG C, reacts 0.5h under stirring.Stop stirring, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 5:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:7) of 6ml second alcohol and water, is heated to 50 ~ 80 DEG C, ultrasonic reaction 0.5h.Stop ultrasonic, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 6:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:1) of 10ml first alcohol and water, is heated to 50 ~ 65 DEG C, ultrasonic reaction 0.5h.Stop ultrasonic, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 7:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:5) of 8ml isopropyl alcohol and water, is heated to 50 ~ 80 DEG C, ultrasonic reaction 0.5h.Stop ultrasonic, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Embodiment 8:
Precision takes Edaravone 39.9mg and beta-cyclodextrin 260.1mg, adds the mixed solvent (volume ratio 1:6) of 9ml n-propyl alcohol and water, is heated to 50 ~ 80 DEG C, ultrasonic reaction 0.5h.Stop ultrasonic, Temperature fall, namely leave standstill 12 ~ 24h after being down to room temperature has crystal to separate out, and is described Edaravone/beta-cyclodextrin eutectic.
Fig. 1 is the eutectic XRD spectra that the XRD spectra of Edaravone/beta-cyclodextrin eutectic obtains with simulation; Described pharmaceutical co-crystals is expressed as with diffraction angle 2 θ ° ± 0.1: 6.0,6.1,7.2,9.6,10.0,11.8,12.0,12.3,12.6,14.5,15.4,15.7,17.5,17.6,17.8,18.5,18.7,18.9,19.8,20.7,21.4,23.4,23.9,24.1,26.0 etc.
Fig. 2 is the stacking diagram of the XRD spectra of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic; In figure, the XRD spectra of Edaravone and Benexate Hydrochloride is the simple superposition of the XRD spectra of edaravone raw material medicine and beta-cyclodextrin, and the spectrogram of Edaravone pharmaceutical co-crystal had both been different from bulk drug Edaravone is also different from eutectic formation beta-cyclodextrin, more be different from inclusion compound, proving have new thing to generate mutually, is the eutectic structure of the Edaravone for preparing and beta-cyclodextrin.
Fig. 3 is thermal weight loss (TG) figure of Edaravone/beta-cyclodextrin eutectic; Within the scope of room temperature to 150 DEG C, its rate of weight loss is 12.7%, containing 10.5 parts of water in structure.
Fig. 4 is the stacking diagram of the TG figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic; From figure: Edaravone/Benexate Hydrochloride, within the scope of room temperature to 110 DEG C, its weightlessness is 12.8%, is beta-cyclodextrin dehydration process; In 110 DEG C to 230 DEG C temperature ranges, its weightless for 8.9%(calculated value be 11.6%), for losing the process of a part Edaravone, notable difference is not had before the thermostability of Edaravone in inclusion compound and inclusion are described, and the thermostability of Edaravone improves greatly in Edaravone/beta-cyclodextrin eutectic, decomposition temperature (summit value) is 274.1 DEG C.
Fig. 5 is the DSC figure of Edaravone/beta-cyclodextrin eutectic; As we know from the figure: at 73.5 DEG C, there are three endotherm(ic)peaks at 95.5 DEG C and 117.0 DEG C of places, for this pharmaceutical co-crystals loses the endotherm(ic)peak of crystal water; The melting peak of Edaravone disappears in the drawings, further illustrates the formation of eutectic.The decomposition temperature of eutectic is 274.1 DEG C (summit values), and after Edaravone makes eutectic, its thermostability significantly improves.
Fig. 6 is the stacking diagram of DSC figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride, Edaravone/beta-cyclodextrin eutectic; As we know from the figure: the inclusion compound of Edaravone/beta-cyclodextrin has an endotherm(ic)peak at 103.8 DEG C of places, be the endotherm(ic)peak of beta-cyclodextrin dehydration; In the endotherm(ic)peak at 128.9 DEG C of places, be the melting peak of Edaravone, scheme completely different from the DSC of Edaravone/beta-cyclodextrin eutectic.
Fig. 7 is infrared spectra (IR) figure of Edaravone/beta-cyclodextrin eutectic; As we know from the figure, at 3413,2926,1719,1632,1499,1321,1079,1031,757,701cm
-1there is charateristic avsorption band at place.Wherein 3413cm
-1for O-H stretching vibration, 2926 cm
-1for C-H stretching vibration in-CH2-, 1719 cm
-1for C=O stretching vibration, 1632 cm
-1for C=N stretching vibration, 1499 cm
-1for phenyl ring skeletal vibration, 1321 is O-H flexural vibration, 1079 cm
-1with 1031 cm
-1for C-O stretching vibration, 757 cm
-1with 701 cm
-1for the vibration of monosubstituted phenyl ring C-H face outer corners.
Fig. 8 is the stacking diagram of the IR figure of Edaravone, beta-cyclodextrin, Edaravone/Benexate Hydrochloride and Edaravone/beta-cyclodextrin eutectic; As we know from the figure: the infrared spectrum of Edaravone/beta-cyclodextrin eutectic and Edaravone/Benexate Hydrochloride has certain difference, the infrared spectrum of inclusion compound is the simple superposition of Edaravone and beta-cyclodextrin infrared spectrum.
What more than enumerate is only some embodiments of the present invention; obviously, the invention is not restricted to above embodiment, many distortion can also be had; all distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (6)
1. an Edaravone pharmaceutical co-crystal, is characterized in that, described pharmaceutical co-crystals is active constituents of medicine with Edaravone, take beta-cyclodextrin as eutectic formation; An Edaravone molecule, the basic structural unit of a beta-cyclodextrin molecule and 10.5 water molecules composition Edaravone pharmaceutical co-crystal; Carbonylic oxygen atom wherein in Edaravone molecule and imido nitrogen atom are as hydrogen bond receptor, and the hydroxyl in beta-cyclodextrin molecule forms two kinds of different intermolecular hydrogen bondings as hydrogen bond donor; The pharmaceutical co-crystals formed belongs to oblique system, C 2 (5
#) spacer, its unit cell parameters: axial length
shaft angle β=110.802 (20) °,
z=2.
2. Edaravone pharmaceutical co-crystal according to claim 1, is characterized in that, described pharmaceutical co-crystals has use Cu K as shown in Figure 1
αthe X-ray powder diffraction pattern of radiation, is expressed as with diffraction angle 2 θ ° ± 0.1: 6.0,6.1,7.2,9.6,10.0,11.8,12.0,12.3,12.6,14.5,15.4,15.7,17.5,17.6,17.8,18.5,18.7,18.9,19.8,20.7,21.4,23.4,23.9,24.1,26.0.
3. Edaravone pharmaceutical co-crystal according to claim 1, is characterized in that, the thermogravimetric spectrogram TG of described pharmaceutical co-crystals shows, and within the scope of room temperature to 150 DEG C, its rate of weight loss is 12.7%, containing 10.5 parts of water in structure; Its differential thermal spectrogram DSC shows, and at 73.5 DEG C, there are three endotherm(ic)peaks at 95.5 DEG C and 117.0 DEG C of places, for this pharmaceutical co-crystals loses the endotherm(ic)peak of water; The decomposition temperature of eutectic is summit value 274.1 DEG C.
4. Edaravone pharmaceutical co-crystal according to claim 1, is characterized in that, the infrared spectrum IR of described pharmaceutical co-crystals shows, at 3413,2926,1719,1632,1499,1321,1079,1031,757,701cm
-1there is charateristic avsorption band at place.
5. the preparation method of an Edaravone pharmaceutical co-crystal according to claim 1, it is characterized in that, concrete steps are as follows: be the mixed solvent that the Edaravone of 1:1 and beta-cyclodextrin join alcohol and water by mol ratio, be heated to 50 ~ 80 DEG C, stirring or ultrasonic until after dissolving completely, continue to stir or ultrasonic 0.5 hour, Slow cooling, leave standstill crystallization, obtain Edaravone eutectic, described alcohol is methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol, in described mixed solvent, the volume ml of alcohol and the volume ml of water is than being 1:1 ~ 1:10, in reaction soln system, solutes content is 30 ~ 50mg/mL.
6. the preparation method of Edaravone pharmaceutical co-crystal according to claim 5, is characterized in that, described alcohol is preferably ethanol.
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| WO2011111070A2 (en) * | 2010-03-09 | 2011-09-15 | Bdr Pharmaceuticals International Pvt. Ltd. | Novel injectable combination |
| CN102526036A (en) * | 2011-12-29 | 2012-07-04 | 石家庄中硕药业集团有限公司 | Butylphthalide- and edaravone-containing compound injection and preparation method thereof |
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