CN101225075A - Cinepazide maleate crystal system and method for making same - Google Patents
Cinepazide maleate crystal system and method for making same Download PDFInfo
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Abstract
The invention relates to maleate cinepazide crystal forms and preparation methods, belonging to the medicine technical field, which comprises maleate cinepazide crystal form A, crystal form B, polymorphism containing crystal form B, and the preparation methods of the crystal forms.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to (E)-1-{4-[(3 ', 4 ', 5 '-trimethoxy cinnamoyl)]-1 piperazine } acetyl-pyrrole pyridine maleic acid salt is cinepazide maleate crystal form and preparation method thereof.
2, background technology
Cinepazide Maleate is a known compound, and chemistry is by name: (E)-1-{4-[(3 ', 4 ', 5 '-trimethoxy cinnamoyl)]-1 piperazine acetyl-pyrrole pyridine maleic acid salt, structural formula is as follows:
Cinepazide Maleate is a calcium ion channel blocker, by stoping Ca
2+Stride in the film intravasation smooth muscle cell, make vascular smooth muscle relaxation, the cerebrovascular, coronary vasodilator and peripheral blood vessel expansion, thus the alleviating vascular spasm, reduce vascular resistance, blood flow increasing; Strengthen the effect of adenosine and cyclic monophosphate; Improve erythrocytic snappiness and distortion by kapillary ability, microcirculation improvement; Blood viscosity lowering has provide protection to the organ of ischemic, is mainly used in the treatment cardiovascular and cerebrovascular diseases clinically.
At present, the existing document that Cinepazide Maleate is carried out study on the synthesis.For example US3634411 discloses a kind of preparation method of Cinepazide Maleate; The study on the synthesis of vasodilator cinepazide (Chinese Journal of New Drugs, 2003/08) has been reported a kind of synthetic method of Cinepazide Maleate; CN200410009826 provides a kind of novel synthesis of Cinepazide Maleate; CN200610103455 provides a kind of preparation method of improved Cinepazide Maleate.
At present, still do not report about the research of cinepazide maleate crystal form.Crystal formation is the critical nature of compound, and is all influential to the stability of medicine and product quality homogeneity, bioavailability, preparation etc.Therefore, we have carried out systematic research to the crystal formation of Cinepazide Maleate.
3, summary of the invention
The inventor experimental studies have found that through a large amount of systems; (E)-1-{4-[(3 '; 4 ', 5 '-trimethoxy cinnamoyl)] piperazine-1 } acetyl-pyrrole pyridine maleic acid salt is that Cinepazide Maleate exists multiple crystal formation, can exist with A crystal formation, B crystal formation or polymorphous form.Cinepazide Maleate B crystal formation is the stable crystal formation of Cinepazide Maleate, Cinepazide Maleate A crystal formation or crystallization such as amorphous or noncrystalline form all can transform to Cinepazide Maleate B crystal formation, formation contains the polymorphic of Cinepazide Maleate B crystal formation, even all changes into Cinepazide Maleate B crystal formation.
The present invention also provides the preparation method of Cinepazide Maleate A crystal formation, B crystal formation.
Cinepazide Maleate A crystal formation of the present invention uses the Cu-Ka radiation, and the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 7.5 ± 0.1,19.7 ± 0.1,22.9 ± 0.1.
Further limit, Cinepazide Maleate A crystal formation of the present invention, use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 7.5 ± 0.1,15.5 ± 0.1,17.4 ± 0.1,18.5 ± 0.1,19.7 ± 0.1,21.1 ± 0.1,22.9 ± 0.1,23.8 ± 0.1,24.6 ± 0.1.
The X-ray powder diffraction of Cinepazide Maleate A crystal formation of the present invention is seen Fig. 1.
The fusing point of Cinepazide Maleate A crystal formation of the present invention is 127-130 ℃.
The preparation method of Cinepazide Maleate A crystal formation of the present invention comprises following method, but is not limited to following method:
Under the lucifuge condition, add in moisture or the anhydrous polar solvent in the Cinepazide Maleate, reflux splashes in the moisture or anhydrous low polar solvent of vigorous stirring, drips off the back continuation and stirs, and places, and filters and collects crystal, and drying gets Cinepazide Maleate A crystal formation.
Above-mentioned moisture or anhydrous polar solvent comprises moisture or anhydrous alcohols (as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, phenylcarbinol etc.), moisture or anhydrous acetonitrile, moisture or dry DMF, moisture or anhydrous DMSO etc.
Above-mentioned moisture or anhydrous low polar solvent comprises moisture or anhydrous alkanes (as normal hexane, normal heptane, hexanaphthene, sherwood oil etc.), moisture or anhydrous ester class (as ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, methyl benzoate, ethyl benzoate, propyl benzoate etc.), moisture or anhydrous ketone (as acetone, 2-butanone, pimelinketone etc.), moisture or anhydrous aromatic hydrocarbons (as benzene,toluene,xylene etc.), moisture or anhydrous ethers (as THF, ether, isopropyl ether, methyl tertiary butyl ether) etc.
Cinepazide Maleate B crystal formation of the present invention uses the Cu-Ka radiation, and the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 9.0 ± 0.1,16.1 ± 0.1,19.8 ± 0.1,21.7 ± 0.1,22.0 ± 0.1.
Further limit, Cinepazide Maleate B crystal formation of the present invention, use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 9.0 ± 0.1,16.1 ± 0.1,19.8 ± 0.1,21.7 ± 0.1,22.0 ± 0.1,25.9 ± 0.1,27.4 ± 0.1.
The X-ray powder diffraction of Cinepazide Maleate B crystal formation of the present invention is seen Fig. 2.
Cinepazide Maleate B crystal formation of the present invention, its fusing point are 170-172 ℃.
The preparation method of Cinepazide Maleate B crystal formation of the present invention comprises following method, but is not limited to following method:
Method one: under the lucifuge condition, Cinepazide Maleate add moisture or anhydrous polar solvent in, reflux, cooling is placed, filter and collect crystal, drying, Cinepazide Maleate B crystal formation.
Above-mentioned moisture or anhydrous polar solvent comprises water, moisture or anhydrous alcohols (as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, phenylcarbinol etc.), moisture or anhydrous acetonitrile, moisture or dry DMF, moisture or anhydrous DMSO etc.
Method two: under the lucifuge condition, Cinepazide Maleate adds in the moisture or anhydrous low polar solvent, reflux, slowly drip moisture then or anhydrous polar solvent to solid refluxes after just dissolving again, cooling is placed, filter and collect crystal, drying gets Cinepazide Maleate B crystal formation.
Above-mentioned moisture or anhydrous low polar solvent comprises moisture or anhydrous alkanes (as normal hexane, normal heptane, hexanaphthene, sherwood oil etc.), moisture or anhydrous ester class (as ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, methyl benzoate, ethyl benzoate, propyl benzoate etc.), moisture or anhydrous ketone (as acetone, 2-butanone, pimelinketone etc.), moisture or anhydrous aromatic hydrocarbons (as benzene,toluene,xylene etc.), moisture or anhydrous ethers (as THF, ether, isopropyl ether, methyl tertiary butyl ether) etc.
Above-mentioned moisture or anhydrous polar solvent comprises water, moisture or anhydrous alcohols (as methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, phenylcarbinol etc.), moisture or anhydrous acetonitrile, moisture or dry DMF, moisture or anhydrous DMSO etc.
Contain Cinepazide Maleate B crystal formation in the Cinepazide Maleate polymorphic of the present invention.Cinepazide Maleate B crystal formation and Cinepazide Maleate A crystal formation or other crystal formation or the amorphous polymorphic of forming with any ratio all belong to protection scope of the present invention.The Cinepazide Maleate B crystal formation that contains in the preferred Cinepazide Maleate polymorphic account for the polymorphic gross weight more than 30% and contain the characteristic peak of B crystal formation.
The crystallization condition difference of same compound, especially recrystallisation solvent difference, gained crystallized form also may be different.The inventor screens the Cinepazide Maleate recrystallisation solvent, water, methyl alcohol, ethanol, acetonitrile, ethyl acetate, ether, THF or its mixed solution all meet the speciality as the Cinepazide Maleate recrystallisation solvent, can be used as Cinepazide Maleate crystalline solvent; Chloroform, acetone do not meet the speciality as the Cinepazide Maleate recrystallisation solvent, single mixed solution with chloroform or acetone or both arbitrary proportions is as the Cinepazide Maleate recrystallisation solvent, used quantity of solvent is too big, be difficult for implementing, can't suitability for industrialized production, be not suitable as the Cinepazide Maleate recrystallisation solvent; But chloroform or acetone can with water, methyl alcohol, ethanol, the coupling of acetonitrile isopolarity solvent as the Cinepazide Maleate recrystallisation solvent.
Usually, have the compound of multiple crystal formation, it is the most stable having only a kind of crystal formation.Polymorphic form has from less stable to the tendency that changes than stable form.The formation of so-called " than stable form ", it can be unstable crystal formation or amorphous to stablizing crystal conversion, or the unstable crystal formation in the polymorphic form is to stablizing crystal conversion, and stablizing the per-cent of crystal formation in polymorphic form constantly increases, and unstable crystal formation reduces gradually even disappears.So the inventor has investigated the stable crystal form of Cinepazide Maleate A crystal formation and B crystal formation, to determine which kind of crystal formation is to stablize crystal formation.
Investigate under 25 ℃, 60 ℃, illumination (8 ℃, 4500lx) condition the stable crystal form of Cinepazide Maleate A crystal formation and B crystal formation.A crystal formation, B crystal formation are placed the environment of corresponding conditions respectively, and the X-ray powder diffraction is done in sampling after 2 days.Analyze to find that the X-ray powder diffraction that the A crystal formation is placed sample after 2 days under the trend that the oriented B crystal formation of A crystal formation transforms, 25 ℃ of conditions is seen Fig. 3; And the B crystal formation does not change.As seen from the experiment, Cinepazide Maleate B crystal formation is the stable crystal formation of Cinepazide Maleate, and Cinepazide Maleate A crystal formation or crystallization such as amorphous or noncrystalline form all can transform to Cinepazide Maleate B crystal formation.
Because Cinepazide Maleate under illumination condition, easily produces cis-isomeride, may cause untoward reaction.The inventor studies the chemical stability of Cinepazide Maleate B crystal formation, and contrasts with the listing Cinepazide Maleate.
Trial-product: Cinepazide Maleate B crystal formation, self-control; The listing Cinepazide Maleate is provided the accurate word H20020124 of traditional Chinese medicines by the Beijing Sihuan Pharmaceutical Co., Ltd.
The investigation condition:
Hot conditions placed trial-product respectively under 60 ℃ of conditions of high temperature and placed 10 days, in the 10th day sampling and measuring.
High humidity environment is put trial-product respectively in the watch-glass, and putting relative humidity was to place 10 days under 92.5% condition, in the 10th day sampling and measuring.
Strong illumination was put trial-product respectively in the lighting box that illumination is 4500Lx and was placed 10 days, in the 10th day sampling and measuring.
Investigate index: cis-isomeride, other impurity.
Table 1 study on the stability
| The investigation time | The investigation condition | The listing Cinepazide Maleate | Cinepazide Maleate B crystal formation | ||
| Cis-isomeride (%) | Other impurity (%) | Cis-isomeride (%) | Other impurity (%) | ||
| 0 |
-60 ℃ of high humidity illumination | 0.043 0.054 0.053 0.418 | 0.082 0.134 0.124 0.131 | 0.037 0.041 0.031 0.115 | 0.026 0.044 0.045 0.033 |
Test-results and conclusion: after placing 10 days under high temperature, high humidity, the illumination condition, in the listing Cinepazide Maleate, cis-isomeride and other foreign matter content all obviously raise, and especially the cis isomerism body burden significantly raises under illumination condition; In the Cinepazide Maleate B crystal formation, cis-isomeride and other foreign matter content raise to some extent.Cinepazide Maleate B crystal formation compares with the listing Cinepazide Maleate, cis-isomeride and other foreign matter content raise all not obvious, chemical stability is better, and cis-isomeride has bigger toxicity, bigger to the drug safety influence, so Cinepazide Maleate B crystal formation has better clinical application security.
4, description of drawings
Fig. 1 is the powder x-ray diffraction figure that Cinepazide Maleate A crystal formation utilizes monochromator to obtain.Length axis is represented diffracted intensity (kcps), and axis of abscissa is represented diffraction angle (2 θ).
Fig. 2 is the powder x-ray diffraction figure that Cinepazide Maleate B crystal formation utilizes monochromator to obtain.Length axis is represented diffracted intensity (kcps), and axis of abscissa is represented diffraction angle (2 θ).
Fig. 3 is the Cinepazide Maleate A crystal formation powder x-ray diffraction figure that sampling utilizes monochromator to obtain after placing 2 days under 25 ℃ of conditions.Length axis is represented diffracted intensity (kcps), and axis of abscissa is represented diffraction angle (2 θ).
5, embodiment
The embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation one of embodiment 1 Cinepazide Maleate A crystal formation
Under the lucifuge, Cinepazide Maleate (5g) adds anhydrous methanol 25ml, and heating makes the 5min that refluxes behind the material dissolution, be added dropwise in the 30min in the anhydrous diethyl ether of 150ml vigorous stirring, drip off the back and continue to stir 2h, room temperature is placed 5h, filters and collects crystal, room temperature high vacuum drying under reduced pressure 6h, get Cinepazide Maleate A crystal formation (4.5g), fusing point 127-129 ℃, it is 99.6% that the HPLC method is surveyed content.
The preparation two of embodiment 2 Cinepazide Maleate A crystal formations
With reference to embodiment 1 operation, the solvent anhydrous diethyl ether is changed to tetrahydrofuran (THF) (THF), get Cinepazide Maleate A crystal formation (3g), fusing point 128-130 ℃, content 99.4%.
The preparation one of embodiment 3 Cinepazide Maleate B crystal formations
Under the lucifuge, Cinepazide Maleate (2g), add anhydrous acetonitrile 40ml, heating makes the 5min that refluxes behind the material dissolution, and the room temperature cooling is placed 24h and collected crystal with after-filtration, reduced pressure at room temperature 10h, get Cinepazide Maleate B crystal formation (1.1g), fusing point 170-172 ℃, it is 99.7% that the HPLC method is surveyed content.
The preparation two of embodiment 4 Cinepazide Maleate B crystal formations
Under the lucifuge, Cinepazide Maleate (2g), add anhydrous propanone 30ml, reflux slowly is added dropwise to methyl alcohol then to the 5min that refluxes again after solid just dissolves, the room temperature cooling, place 24h and collect crystal with after-filtration, reduced pressure at room temperature 10h gets Cinepazide Maleate B crystal formation (0.8g), fusing point 170-172 ℃, it is 99.6% that the HPLC method is surveyed content.
The preparation three of embodiment 5 Cinepazide Maleate B crystal formations
With reference to embodiment 4 operations, solvent methanol is changed to water, get Cinepazide Maleate B crystal formation 0.7g, fusing point 170-172 ℃, it is 99.6% that the HPLC method is surveyed content.
The preparation four of embodiment 6 Cinepazide Maleate B crystal formations
With reference to embodiment 4 operations, solvent methanol is changed to ethanol, get Cinepazide Maleate B crystal formation 1.6g, fusing point 170-172 ℃, it is 99.5% that the HPLC method is surveyed content.
The preparation five of embodiment 7 Cinepazide Maleate B crystal formations
With reference to embodiment 4 operations, solvent methanol is changed to acetonitrile, get Cinepazide Maleate B crystal formation 1.5g, fusing point 170-172 ℃, it is 99.7% that the HPLC method is surveyed content.
The preparation six of embodiment 8 Cinepazide Maleate B crystal formations
With reference to embodiment 4 operations, solvent acetone is changed to ethyl acetate, get Cinepazide Maleate B crystal formation 0.9g, fusing point 170-172 ℃, it is 99.5% that the HPLC method is surveyed content.
The preparation seven of embodiment 9 Cinepazide Maleate B crystal formations
Under the lucifuge, Cinepazide Maleate (2g), add anhydrous methanol 10ml, heating makes the 5min that refluxes behind the material dissolution, and-10 ℃ of coolings are down placed 24h and collected crystal with after-filtration, reduced pressure at room temperature 10h, get Cinepazide Maleate B crystal formation (1.5g), fusing point 170-172 ℃, it is 99.8% that the HPLC method is surveyed content.
Claims (10)
1. cinepazide maleate crystal form is characterized in that, is Cinepazide Maleate A crystal formation, perhaps Cinepazide Maleate B crystal formation, perhaps Cinepazide Maleate polymorphic.
2. cinepazide maleate crystal form as claimed in claim 1, it is characterized in that, described Cinepazide Maleate A crystal formation: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 7.5 ± 0.1,19.7 ± 0.1,22.9 ± 0.1.
3. cinepazide maleate crystal form as claimed in claim 2, it is characterized in that, described Cinepazide Maleate A crystal formation: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 7.5 ± 0.1,15.5 ± 0.1,17.4 ± 0.1,18.5 ± 0.1,19.7 ± 0.1,21.1 ± 0.1,22.9 ± 0.1,23.8 ± 0.1,24.6 ± 0.1.
4. as the preparation method of claim 2 or 3 described Cinepazide Maleate A crystal formations, it is characterized in that, under the lucifuge condition, add in moisture or the anhydrous polar solvent reflux in the Cinepazide Maleate, splash in the moisture or anhydrous low polar solvent of vigorous stirring, drip off the back and continue to stir, place, filter and collect crystal, drying gets Cinepazide Maleate A crystal formation.
5. cinepazide maleate crystal form as claimed in claim 1, it is characterized in that, described Cinepazide Maleate B crystal formation: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 9.0 ± 0.1,16.1 ± 0.1,19.8 ± 0.1,21.7 ± 0.1,22.0 ± 0.1.
6. cinepazide maleate crystal form as claimed in claim 5, it is characterized in that, described Cinepazide Maleate B crystal formation: use the Cu-Ka radiation, the X-ray powder diffraction of representing with 2 θ angles has characteristic peak 9.0 ± 0.1,16.1 ± 0.1,19.8 ± 0.1,21.7 ± 0.1,22.0 ± 0.1,25.9 ± 0.1,27.4 ± 0.1.
7. as the preparation method of claim 5 or 6 described Cinepazide Maleate B crystal formations, it is characterized in that under the lucifuge condition, Cinepazide Maleate adds in moisture or the anhydrous polar solvent, reflux, cooling is placed, filter and collect crystal, drying gets Cinepazide Maleate B crystal formation.
8. as the preparation method of claim 5 or 6 described Cinepazide Maleate B crystal formations, it is characterized in that, under the lucifuge condition, Cinepazide Maleate adds in the moisture or anhydrous low polar solvent, reflux, slowly drip moisture then or anhydrous polar solvent to solid refluxes after just dissolving again, cooling is placed, and filters and collects crystal, drying gets Cinepazide Maleate B crystal formation.
9. cinepazide maleate crystal form as claimed in claim 1 is characterized in that, contains Cinepazide Maleate B crystal formation in the described Cinepazide Maleate polymorphic.
10. cinepazide maleate crystal form as claimed in claim 9 is characterized in that, the Cinepazide Maleate B crystal formation that contains in the described Cinepazide Maleate polymorphic account for the polymorphic gross weight more than 30% and contain the characteristic peak of B crystal formation.
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| CN200910162811A CN101659646A (en) | 2008-02-01 | 2008-04-24 | Cinepazide maleate crystal forms and preparation method thereof |
| CNB2008100939669A CN100548998C (en) | 2008-02-01 | 2008-04-24 | cinepazide maleate crystal form and preparation method thereof |
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| CN101735172B (en) * | 2008-11-04 | 2012-07-11 | 北京四环制药有限公司 | Cinepazide monohydrate, crystal forms and preparation method thereof |
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| CN101708179B (en) * | 2009-08-17 | 2011-06-01 | 北京四环制药有限公司 | Cinepazide medicinal composition with high safety, preparation method and application thereof |
| CN102100695B (en) * | 2009-08-17 | 2012-01-11 | 北京四环制药有限公司 | High-safety medicinal composition of cinepazide, and preparation method and application thereof |
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| CN101735172B (en) * | 2008-11-04 | 2012-07-11 | 北京四环制药有限公司 | Cinepazide monohydrate, crystal forms and preparation method thereof |
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