CN105753785A - Edaravone compound and preparation method thereof - Google Patents
Edaravone compound and preparation method thereof Download PDFInfo
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- CN105753785A CN105753785A CN201610168940.0A CN201610168940A CN105753785A CN 105753785 A CN105753785 A CN 105753785A CN 201610168940 A CN201610168940 A CN 201610168940A CN 105753785 A CN105753785 A CN 105753785A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of medicines and particularly relates to an edaravone compound. An X-ray diffraction diagram of the compound is shown in figure 1. The invention further relates to a preparation method of the edaravone compound. Crude edaravone is dissolved in cyclohexane-acetone at certain temperature, the pH value is adjusted to be 3-5, then temperature is slowly reduced for crystallization, white powder is obtained after filtering, washing and drying under reduced pressure and put into a planetary ball mill, the planetary ball mill operates for certain time until the white powder has constant weight, and the product is obtained. The disclosed edaravone in a new crystal form has good solubility, facilitates preparation of injection and has higher bioavailability.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically, the preparation method relating to a kind of edaravone compound and this edaravone compound.
Background technology
Edaravone (Edaravone) is the one in pyrazolone derivative, and chemistry 3-methyl-1-phenyl-2-pyrazolin-5-one by name, molecule is for C10H10N2O, structural formula is as follows:
Edaravone is a kind of cerebral protective agent (free radical scavenger).Clinical research prompting N-acetyl Aspartic Acid (NAA) is the mark of specific viable neuronal cell, and cerebral infarction their early stage content sharply reduces.Acute period of cerebral infarction patient give Edaravone, can suppress the minimizing of periinfarct regional cerebral blood flow, makes after morbidity NAA content in the 28th day brain significantly raised compared with glycerol control group.Preclinical study is pointed out, and rat gives Edaravone at ischemia/ischemia-reperfusion posterior vein, can stop the progress of cerebral edema and cerebral infarction, and alleviate adjoint nervous symptoms, it is suppressed that delayed neuronal death.Study mechanism is pointed out, and Edaravone can scavenging free radicals, it is suppressed that lipid peroxidation, thus suppressing the oxidative damage of brain cell, vascular endothelial cell, neurocyte.
Application number be 201410039270.3 Chinese invention patent disclose a kind of Edaravone novel crystal forms that a kind of preparation technology is easily operated, yield is high, purity is high.This invention uses ester-acetone soln dissolve Edaravone product and carry out crystallize and make it have good stability, but does not solve the problem that Edaravone dissolubility in aqueous is low.
Application number be 201310292202.3 Chinese invention patent disclose a kind of edaravone compound and preparation method thereof, and also have the pharmaceutical composition of this edaravone compound.This invention uses ethanol/DMF solution to dissolve Edaravone, uses ether that it is carried out crystallize, and the product obtained has good dissolubility and dissolution velocity, but the gain of Edaravone bioavailability is inconspicuous.
For improving Edaravone dissolubility in water and strengthening its bioavailability, the special proposition present invention.
Summary of the invention
It is an object of the invention to overcome existing technological deficiency, it is provided that a kind of dissolubility is better, the edaravone compound that bioavailability is more excellent.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that
A kind of edaravone compound, it is characterised in that the main diffraction peak of the x-ray diffraction pattern of described compound is as follows:
The X-ray diffracting spectrum of above-mentioned edaravone compound powder substantially as shown in, is a kind of new edaravone crystal form.
The preparation method that present invention also offers a kind of edaravone compound, this preparation method comprises the steps:
(1) Edaravone crude product being added cyclohexane-acetone solution, heat to 60～70 DEG C of dissolvings 10～40 minutes, the volume ratio of its cyclohexane and acetone is 1:4～6, and the amount ratio of Edaravone crude product and mixed solution is 1g:15～25ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 3～5, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 5～30 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder；
(5) when nitrogen protection, white powder described in step (4) is put into planetary ball mill and is ground 20～90 minutes, after taking-up, obtain product 45 DEG C of constant weights.
Described in the step (5) of above-mentioned preparation method, the ball radius of planetary ball mill is 3～5mm, and the weight ratio of abrading-ball and Edaravone powder is 1:2～4, it is preferable that 1:3.
Described in the step (5) of above-mentioned preparation method, the revolution rotating speed of planetary ball mill is 100～300 revs/min, preferably revolution rotating speed is 180 revs/min, rotation rotating speed is 200～400 revs/min, the speed that preferably is selected from walking around is 270 revs/min of alternate run times is 10～30 minutes, it is preferable that the alternate run time is 15 minutes.
Planetary ball mill utilizes the rolling at a high speed in grinding pot of abrasive material and test portion, material is produced powerful mechanical force, can not only cause physical change, and diminish with particle size, specific surface area constantly increases, produce energy conversion and make the crystal structure of internal batch and chemical reactivity change.
The present invention adopts mechanical ball milling mode that products obtained therefrom is ground on the basis of Edaravone recrystallization, it is surprised to find that Edaravone creates the crystalline structure different from after recrystallization in the process, and the change due to crystal structure so that it is the dissolubility in water and absorbability in vivo there occurs beyond thought change.
Compared with prior art, the edaravone compound of the present invention has the bioavailability of better dissolution properties and Geng Gao.
Accompanying drawing explanation
Fig. 1 is the X-ray diffraction spectrogram of the edaravone compound of the embodiment of the present invention 1 preparation.
Fig. 2 is the X-ray diffraction spectrogram of the edaravone compound of comparative example 1 of the present invention preparation.
Fig. 3 is that the edaravone compound of the embodiment of the present invention 1 preparation is to the blood concentration-time curve after beasle dog gastric infusion.
Fig. 4 is that the edaravone compound of comparative example 1 of the present invention preparation is to the blood concentration-time curve after beasle dog gastric infusion.
Fig. 5 is that the edaravone compound of comparative example 2 of the present invention preparation is to the blood concentration-time curve after beasle dog gastric infusion.
Detailed description of the invention
Being below the specific embodiment of the present invention, described embodiment is to further describe the present invention, rather than the restriction present invention.
Embodiment 1
(1) Edaravone crude product 10g being added cyclohexane-acetone solution, heat to 65 DEG C of dissolvings 35 minutes, the volume ratio of its cyclohexane and acetone is 1:5, and the amount ratio of Edaravone crude product and mixed solution is 1g:20ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 4.5, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 5 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder；
(5) when nitrogen protection; the middle abrading-ball 5g of white powder described in step (4), diameter to be the little abrading-ball 25g of 3～5mm, diameter be 6～8mm is put into planetary ball mill; revolution speed is 180 revs/min; rotational velocity is 270 revs/min; the alternate-running time is 15min, takes out and obtain product 45 DEG C of constant weights after grinding 60 minutes.
Obtaining 8.13g Edaravone powder, yield 81.3% through said method, detecting purity through HPLC is 99.91%, and X-ray diffracting spectrum is as shown in Figure 1.
Embodiment 2
(1) Edaravone crude product 10g being added cyclohexane-acetone solution, heat to 60 DEG C of dissolvings 40 minutes, the volume ratio of its cyclohexane and acetone is 1:4, and the amount ratio of Edaravone crude product and mixed solution is 1g:15ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 3, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 10 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder；
(5) when nitrogen protection; the middle abrading-ball 4g of white powder described in step (4), diameter to be the little abrading-ball 16g of 3～5mm, diameter be 6～8mm is put into planetary ball mill; revolution speed is 100 revs/min; rotational velocity is 400 revs/min; the alternate-running time is 30min, takes out and obtain product 45 DEG C of constant weights after grinding 90 minutes.
Obtaining 7.96g Edaravone powder through said method, it is 99.83% that yield 79.6% detects purity through HPLC.
Embodiment 3
(1) Edaravone crude product 10g being added cyclohexane-acetone solution, heat to 70 DEG C of dissolvings 10 minutes, the volume ratio of its cyclohexane and acetone is 1:6, and the amount ratio of Edaravone crude product and mixed solution is 1g:25ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 5, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 30 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder；
(5) when nitrogen protection; the middle abrading-ball 4g of white powder described in step (4), diameter to be the little abrading-ball 36g of 3～5mm, diameter be 6～8mm is put into planetary ball mill; revolution speed is 300 revs/min; rotational velocity is 200 revs/min; the alternate-running time is 10min, takes out and obtain product 45 DEG C of constant weights after grinding 20 minutes.
Obtaining 7.54g Edaravone powder through said method, it is 99.81% that yield 75.4% detects purity through HPLC.
Comparative example 1
Step (1)～(4) that comparative example 1 is in the preparation method using this specification to record prepare, and compared with embodiment 1～3, are distinctive in that and do not use ball mill that the Edaravone powder after recrystallization is carried out mechanical force process.
(1) Edaravone crude product 10g being added cyclohexane-acetone solution, heat to 65 DEG C of dissolvings 35 minutes, the volume ratio of its cyclohexane and acetone is 1:5, and the amount ratio of Edaravone crude product and mixed solution is 1g:20ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 4.5, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 5 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder, obtains product 45 DEG C of constant weights.
Obtaining 7.19g Edaravone powder through said method, it is 99.78% that yield 71.9% detects purity through HPLC, and X-ray diffracting spectrum is as in figure 2 it is shown, main diffraction peak is as follows:
Comparative example 2
Use commercially available edaravone raw material medicine, originate from Wuhan medication chemistry company limited of Jiang Minhua Thailand.
Test example 1 dissolubility is tested
Use counterbalanced procedure to measure dissolubility, under 20 DEG C of conditions of temperature, by the constant temperature stirring in pure water of above-mentioned edaravone compound, use HPLC to calculate the concentration of Edaravone in upper solution after standing and be its dissolubility.
The dissolubility of the edaravone compound embodiment of the present invention 1～3 prepared compares with comparative example 1, comparative example 2, and obtained experimental result is in Table 1.
Table 1 Edaravone sample dissolubility in water
As shown in Table 1, compared with comparative example 2 commercially available product Edaravone, edaravone compound provided by the invention and comparative example 1 have bigger dissolubility；And embodiment 1～3 adopts the Edaravone that the dissolubility that mechanical ball milling method after recrystallization prepares Edaravone is substantially better than in comparative example 1 only to use recrystallization to prepare.It follows that edaravone crystal form change is served the effect of key by mechanical ball milling in preparation method of the present invention, substantially increase dissolubility.
Test example 2 bioavailability is tested
One, tested medicine:
The edaravone compound prepared by the embodiment of the present invention 1, comparative example 1 and comparative example 2 three kinds of sample compositions of commercially available product edaravone raw material medicine.
Two, zoopery:
Take the healthy male beagle dogs 15 that weight range is 10～15kg, it is divided into embodiment 1 group, comparative example 1 group and comparative example 2 groups, often group 5 carries out test only according to " chemicals Non-clinical Pharmacokinetics investigative technique guideline ([H] GPT5-1) ", test front 12 h fast and can't help water, hind leg vein blood is taken in 12 hours interior different time points after gastric infusion, it is placed in the centrifuge tube that heparin sodium processes at 4 DEG C of temperature with the centrifugal 10min of 4000r/min, take supernatant and be stored in-80 DEG C of refrigerators, extract with organic reagent afterwards and use HPLC-MS to detect, acquired results be computed arrange after in Table 2.
Table 2 is administered orally the pharmacokinetic parameter of Edaravone beasle dog
| Pharmacokinetic parameter | Embodiment 1 group | Comparative example 1 group | Comparative example 2 groups |
| Cmax(mg/L) | 8.68±0.56 | 8.27±0.47 | 7.62±0.43 |
| Tmax(h) | 0.29±0.08 | 0.35±0.01 | 0.41±0.12 |
| AUC0-12h(mg·L-1·h-1) | 20.50±2.57 | 12.86±2.11 | 7.93±0.82 |
| Ke(h-1) | 0.46±0.07 | 0.75±0.23 | 1.78±0.37 |
| T1/2(h) | 1.51±0.29 | 0.92±0.11 | 0.39±0.05 |
As shown in Table 2, the minimum (AUC of bioavailability of beasle dog oral contrast example 2 commercially available product Edaravone0-12h=7.93 ± 0.82mg L-1·h-1), embodiment 1 provided by the invention and comparative example 1 have better bioavailability；And compare the comparative example 1 not using mechanical ball milling step to prepare, embodiment 1 can reach higher blood drug level (C within the shorter timemax=8.68 ± 0.56mg/L, Tmax=0.29 ± 0.08h), also have longer half-life (T1/2=1.51 ± 0.29h).It follows that edaravone crystal form change is served the effect of key by mechanical ball milling in preparation method of the present invention, substantially increase bioavailability.
The data of summary test example and result, it is known that the edaravone compound of the present invention compares existing commercially available product edaravone raw material medical instrument better dissolubility, it is possible to improve the bioavailability of Edaravone better.In the preparation method of the present invention, the improvement of crystal formation is served the effect of key by mechanical ball milling step.
Edaravone compound prepared by other embodiments of the present invention has been also carried out above-mentioned test, and the result of its acquisition is similar.
Above the present invention is described in detail; its object is to allow those of ordinary skill in the art will appreciate that present disclosure and to be carried out; can not limit the scope of the invention with this; the equivalence that all spirit according to the present invention are done changes or modifies, and all should be encompassed in protection scope of the present invention.
Claims (10)
1. an edaravone compound, it is characterised in that when the angle of diffraction of the X-ray powder diffraction of described compound is 2 θ, characteristic peak includes: 11.8 ± 0.1 °, 14.7 ± 0.1 °, 17.2 ± 0.1 °, 20.2 ± 0.1 °, 24.7 ± 0.1 °, 29.3 ± 0.1 °, 36.2 ± 0.1 °.
2. edaravone compound according to claim 1, it is characterised in that the diffraction maximum of the x-ray diffraction pattern of described compound includes:
。
3. edaravone compound according to claim 2, it is characterised in that the X-ray diffracting spectrum of described compound is substantially as shown in.
4. the preparation method of the edaravone compound described in a claims 1 to 3 any one, it is characterised in that described preparation method comprises the steps:
(1) being added by Edaravone crude product in the cyclohexane-acetone solution of 60～70 DEG C, dissolve 10～40 minutes, the volume ratio of its cyclohexane and acetone is 1:4～6, and the amount ratio of Edaravone crude product and mixed solution is 1g:15～25ml；
(2) adding phosphorus acid for adjusting pH in the solution of step (1) is after 3～5, adds activated carbon decolorizing and also stirs sucking filtration；
(3) by the solution slow cooling after step (2) decarburization to 5～30 DEG C of crystallizes；
(4) collecting by filtration the crystal of precipitation, use cyclohexane-acetone solution washing, drying under reduced pressure also obtains white powder；
(5) when nitrogen protection, white powder described in step (4) is put into planetary ball mill and is ground 20～90 minutes, after taking-up, obtain product 45 DEG C of constant weights.
5. preparation method according to claim 4, it is characterised in that pH value described in step (2) is 4.5.
6. preparation method according to claim 4, it is characterised in that milling time described in step (5) is 60 minutes.
7. the preparation method according to claim 4 any one, it is characterized in that, planetary ball mill described in step (5) also includes middle abrading-ball and little abrading-ball, described middle ball radius is 6～8mm, the diameter of described little abrading-ball be 3～5mm and, the weight ratio of middle abrading-ball and little abrading-ball is 1:4～9, it is preferable that 1:5.
8. preparation method according to claim 7, it is characterised in that the weight ratio of described middle abrading-ball and little abrading-ball weight sum and Edaravone powder is 1:2～4, it is preferable that 1:3.
9. preparation method according to claim 4, it is characterized in that, described in step (5), the revolution rotating speed of planetary ball mill is 100～300 revs/min, it is preferable that revolution rotating speed is 180 revs/min, rotation rotating speed is 200～400 revs/min, it is preferable that rotation rotating speed is 270 revs/min.
10. preparation method according to claim 4, it is characterised in that the alternate run time of planetary ball mill described in step (5) is 10～30 minutes, it is preferable that the alternate run time is 15 minutes.
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| CN111138365A (en) * | 2019-12-30 | 2020-05-12 | 海南全星制药有限公司 | Edaravone compound and pharmaceutical composition thereof |
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| UA121366C2 (en) * | 2019-04-17 | 2020-05-12 | Сіа Емтеко Холдинг | COMPOUND OF PHENYLMETHYLPYRAZOLONE, WHICH HAS A NEW CRYSTALLINE FORM, AND METHOD OF OBTAINING IT |
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