CN102503935A - Novel azelnidipine crystal form, preparation method for same and officinal composition thereof - Google Patents
Novel azelnidipine crystal form, preparation method for same and officinal composition thereof Download PDFInfo
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- CN102503935A CN102503935A CN2011103902348A CN201110390234A CN102503935A CN 102503935 A CN102503935 A CN 102503935A CN 2011103902348 A CN2011103902348 A CN 2011103902348A CN 201110390234 A CN201110390234 A CN 201110390234A CN 102503935 A CN102503935 A CN 102503935A
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- 229950004646 azelnidipine Drugs 0.000 title claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 48
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供了一种阿折地平新晶型及其制备方法和药用组合物，阿折地平新晶型的X-射线粉末衍射特征吸收峰2θ值为5.68、11.33、12.34、13.18、13.55、15.00、16.26、18.16、20.60、21.50、23.09、23.66、24.62、27.19。所述阿折地平新晶型的制备方法为：将无定形的阿折地平与甲苯以1:4~1:6（w/v）用量比混合，加热，再加入活性炭搅拌过滤，滤液中加入环己烷，环己烷与甲苯的用量比为1:2~2:1（v/v），再经析晶、过滤、干燥制得阿折地平新晶型。本发明所述阿折地平新结晶药性持久，静电较小，具有更高的稳定性，产品收率高，适合大规模生产。
The invention provides a new crystal form of Azeldipine, a preparation method thereof and a pharmaceutical composition. The 2θ values of the X-ray powder diffraction characteristic absorption peaks of the new crystal form of Azeldipine are 5.68, 11.33, 12.34, 13.18, 13.55, 15.00, 16.26, 18.16, 20.60, 21.50, 23.09, 23.66, 24.62, 27.19. The preparation method of the new crystal form of Azedipine is as follows: mixing amorphous Azedipine and toluene at a dosage ratio of 1:4 to 1:6 (w/v), heating, adding activated carbon to stir and filter, adding to the filtrate Cyclohexane, the dosage ratio of cyclohexane and toluene is 1:2~2:1 (v/v), and then crystallized, filtered, and dried to obtain the new crystal form of Azeldipine. The new crystal of azhedipine in the present invention has long-lasting drug properties, less static electricity, higher stability, high product yield and is suitable for large-scale production.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to a kind of CS 905 new crystal and preparation method thereof and medicinal compsns.
Background technology
Essential hypertension is common, frequently-occurring disease, and the patient is ascendant trend year by year, has become one of main killer of human health now.Antihypertensive drugs CS 905 (azelindipine) is the altogether a kind of long-acting dihydropyridine calcium ion antagonist developed jointly of (SANKYO) Co., Ltd. and Co., Ltd. of Ube Industries Ltd. of Japan three, in May, 2003 in Japanese Initial Public Offering.
The pharmacotoxicological effect mechanism of CS 905 is to have strong effect L-type calcium channel antagonistic action, can reduce the free calcium concentration in the VSMC, distends the blood vessels blood pressure drops.Pharmacodynamic study shows that onset mitigation of CS 905 hypotensive effect and effect are lasting.In addition, CS 905 and vascular tissue have high-affinity, and the ability reducing heart rate has good atherosclerosis and protection action of the heart, can be used for atherosclerosis therapy.On the other hand, the CS 905 spinoff is less, except antihypertensive function, causes water and sodium retention hardly, thereby in hypertension therapeutic, renal function is had beneficial effect.In addition, CS 905 is different with amlodipine, and it stimulates sympathetic activity hardly, thereby the hyperfunction occurrence degree of the palpitaition that causes is low.
The document of at present relevant CS 905 polycrystalline research is also few, except that amorphous CS 905 exists, has reported that it has two stable crystal formations: alpha-crystal form (mp122～123 ℃, AUC
0-24173.4 ± 51.6) and beta crystal (mp196～198 ℃, AUC
0-2466.7+20.3).Because the beta crystal bioavailability is low, what be used for preparation at present mainly is alpha-crystal form.Alpha-crystal form has the ideal stripping, but static is bigger, is unfavorable for production operation.
Summary of the invention
To Azelnidipine alpha crystal form static in the prior art big with the shortcoming that is unfavorable for production operation, the invention provides a kind of CS 905 new crystal and preparation method thereof and medicinal compsns.CS 905 new crystal provided by the invention has and the identical purposes of known CS 905 compound itself, also is dihydropyridine calcium ion antagonist, can be used for making the hypertensive medicine of treatment.And its fusing point of CS 905 new crystal of the present invention is in the middle of alpha-crystal form and beta crystal, and not only stability is high, and electrostatic interaction is little, and is simple to operate, and productive rate is high, is fit to scale operation.
For realizing the foregoing invention purpose, the present invention adopts following technical proposals to be achieved:
A kind of CS 905 new crystal, the X-ray powder diffraction charateristic avsorption band 2 θ values of this crystal formation are 5.68,11.33,12.34,13.18,13.55,15.00,16.26,18.16,20.60,21.50,23.09,23.66,24.62,27.19.
The fusing point of CS 905 new crystal according to the invention is at 160～165 ℃.
The present invention also provides the preparation method of CS 905 new crystal; Unbodied CS 905 is mixed with 1: 4～1: 6 (w/v) amount ratio with toluene, be heated to 30～60 ℃, add gac again; Agitation and filtration; Add hexanaphthene in the filtrating, the amount ratio of said hexanaphthene and toluene is 1: 2～2: 1 (v/v), makes the CS 905 new crystal through crystallization, filtration, drying again.
Further improvement to technique scheme: said hexanaphthene is preferably the equal-volume ratio with the amount ratio of toluene.
The present invention also provides the medicinal compsns that contains said CS 905 new crystal, and said compsn contains the CS 905 new crystal of treating significant quantity.
Further improvement to technique scheme: said compsn contains pharmaceutically acceptable auxiliary material or carrier.
Further improvement to technique scheme: said compsn contains 2%～15% said CS 905 new crystal, and surplus is its pharmaceutically acceptable auxiliary material or carrier.
Further improvement to technique scheme: the formulation of said compsn is tablet, capsule, granule.
Compared with prior art, advantage of the present invention and positively effect are: its fusing point of CS 905 new crystal of the present invention's preparation has satisfactory stability property in the middle of alpha-crystal form and beta crystal, be convenient to storage, transportation and medicament manufacturing; And said CS 905 new crystal static is little, in product and preparation production process, sticks to and obviously is less than alpha-crystal form on wrapping material and the production unit, is beneficial to operation, can not cause waste and environmental pollution.Also have, this crystal formation production operation is simple, and productive rate is high, is fit to scale operation.
After advantages embodiment of the present invention, other characteristics of the present invention and advantage will become clearer.
Description of drawings
Fig. 1 is the X-ray diffracting spectrum of CS 905 new crystal among the present invention.
Fig. 2 is the DSC collection of illustrative plates of CS 905 new crystal among the present invention.
Fig. 3 is the DSC collection of illustrative plates of Azelnidipine alpha crystal form among the present invention.
Fig. 4 is the DSC collection of illustrative plates of CS 905 beta crystal among the present invention.
Embodiment
Below in conjunction with accompanying drawing and embodiment technical scheme of the present invention is done further detailed explanation.
Embodiment 1
With amorphous CS 905 10g and 40ml toluene thorough mixing, be heated to 30～40 ℃.Add gac 2～3g then, agitation and filtration adds the 40ml hexanaphthene under the filtrating stirring, continues stirring and crystallizing, through filtration, drying, gets the new crystal 9.5g of CS 905, yield 95%, 163.4 ℃ of fusing points.
Be heated to 40～50 ℃, all the other get the new crystal 9.4g of CS 905, yield 94%, 162.1 ℃ of fusing points with above-mentioned operation.
Be heated to 50～60 ℃, all the other get the new crystal 9.4g of CS 905, yield 94%, 162.7 ℃ of fusing points with above-mentioned operation.
Through above-mentioned evidence, the heating for dissolving TR is at 30～60 ℃.Heating temperature is high more, and the required crystallization time is long more, so 30～40 ℃ of preferred temperature.
Embodiment 2
With amorphous CS 905 10g and 40ml toluene thorough mixing, be heated to 30～40 ℃.Add gac 2～3g then, agitation and filtration adds the 40ml hexanaphthene under the filtrating stirring, continues stirring and crystallizing, through filtration, drying, gets the new crystal 9.5g of CS 905, yield 95%, 163.8 ℃ of fusing points.
With toluene and each 50ml of hexanaphthene, all the other get the new crystal 9.4g of CS 905, yield 94%, 163.7 ℃ of fusing points with above-mentioned operation.
With toluene and each 60ml of hexanaphthene, all the other get the new crystal 9.3g of CS 905, yield 93%, 162.2 ℃ of fusing points with above-mentioned operation.
Above-mentioned experimental result shows: the amorphous CS 905 of 10g, preferred toluene consumption is 40～60ml.Experimental study finds that when the 10g CS 905 mixes with 40～60ml toluene the strength of solution of formation is fit to generate new crystal.
Embodiment 3
With amorphous CS 905 10g and 40ml toluene thorough mixing, be heated to 30～40 ℃.Add gac 2～3g then, agitation and filtration adds the 20ml hexanaphthene under the filtrating stirring, continues stirring and crystallizing, through filtration, drying, gets the new crystal 8.9g of CS 905, yield 89%, 164.1 ℃ of fusing points.
Add the 40ml hexanaphthene, all the other get the new crystal 9.5g of CS 905, yield 95%, 163.1 ℃ of fusing points with above-mentioned operation.
Add the 80ml hexanaphthene, all the other get the new crystal 9.6g of CS 905, yield 96%, 162.9 ℃ of fusing points with above-mentioned operation.
Above-mentioned experimental result shows: hexanaphthene is 1: 2～2: 1 with the volumetric usage ratio of toluene, preferred equal-volume ratio.Hexanaphthene is crossed that I haven't seen you for ages and is caused productive rate to reduce, and when reaching 1: 1, the CS 905 new crystal is almost completely separated out.
Embodiment 4
The new crystal of CS 905, differential scanning calorimetric analysis is as shown in Figure 2, is presented at 160～165 ℃ and has located single absorption peak.The X-ray powder diffraction of this crystal formation is as shown in Figure 1; Test condition: X-ray tube is the copper target, 0.019 ° of wavelength
step-length; 3.000 °-29.992 ° of sweep limits.Characteristic representes to see table 1 with 2 θ diffraction angle, spacing D and relative intensity.
2 θ diffraction angle, spacing D and the relative intensity of table 1, CS 905 new crystal
Embodiment 5
The CS 905 new crystal is carried out study on the stability; Choose the CS 905 new crystal sample of same lot number; Get and be tiled in right amount in three plates; Place respectively under 4500 ± 500xl illumination, 60 ℃ of high temperature, relative humidity 92.5% high humidity and carry out stability experiment, test result is as shown in table 2.
Table 2, CS 905 new crystal stability experiment result
Experimental result shows: the CS 905 new crystal of the present invention's preparation has good stable crystal form property, is convenient to storage, transportation and medicament manufacturing.
Embodiment 6
The present embodiment preparation contains the pharmaceutical composition of the CS 905 new crystal of significant quantity, and said pharmaceutical composition is the medically acceptable pharmaceutical prepn that CS 905 new crystal and pharmaceutical excipient are made into.
Prescription: CS 905 new crystal 4g, Microcrystalline Cellulose 64g, sodium hydrogencarbonate 20g, PVPP 5g, Sodium Hydroxymethyl Stalcs 2g, Magnesium Stearate 1g processes 1000.
Preparing method: CS 905 new crystal, Microcrystalline Cellulose, sodium hydrogencarbonate, PVPP and Sodium Hydroxymethyl Stalcs are crossed 80 mesh sieves respectively, mix, add 65% alcohol granulation.Wet grain placed 50 ℃ of loft drier inner dryings about 3 hours, crossed 20 mesh sieves, added the Magnesium Stearate mixing then, and compressing tablet promptly gets.Stripping is: 86%.
CS 905 new crystal 8g, all the other are with above-mentioned operation, and stripping is: 90%.
CS 905 new crystal 16g, all the other are with above-mentioned operation, and stripping is: 88%.
Embodiment 7
Prescription: CS 905 new crystal 4g, lactose 64g, sodium hydrogencarbonate 20g, low-substituted hydroxypropyl cellulose 5g, Sodium Hydroxymethyl Stalcs 2g, Magnesium Stearate 1g processes 1000.
Preparation technology: CS 905 new crystal, lactose, sodium hydrogencarbonate, low-substituted hydroxypropyl cellulose and Sodium Hydroxymethyl Stalcs are crossed 80 mesh sieves respectively, mix, add 65% alcohol granulation.Wet grain placed 50 ℃ of loft drier inner dryings about 3 hours, crossed 20 mesh sieves, added the Magnesium Stearate mixing then, and the can capsule gets final product.Stripping is: 90%.
CS 905 new crystal 8g, all the other are with above-mentioned operation, and stripping is: 89%.
CS 905 new crystal 16g, all the other are with above-mentioned operation, and stripping is: 87%.
The pharmaceutical composition that the present invention makes can be used in oral administration, can be with tablet, powder, granule and capsule form to patient's administration, and preferred tablet, capsule or granule.Preparation of the present invention can be through the preparation of pharmaceutics routine techniques.These preparations should comprise the CS 905 crystallisate that contains the 4mg, 8mg and the 16mg that make through the present invention at least.Also can adjust the therapeutic dose that makes it obtain being fit to according to formulation.
The pharmaceutical prepn that the present invention relates to, the formulation of its oral administration can contain vehicle commonly used, like tackiness agent, weighting agent, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent, can carry out dressing to tablet in case of necessity.This oral drug preparation specifically can contain vehicle such as Xylo-Mucine, hydroxypropylcellulose, Vltra tears, Microcrystalline Cellulose, starch, yellow soda ash, sodium hydrogencarbonate, micropowder silica gel, ethanol, potassium primary phosphate, N.F,USP MANNITOL, lactose, PVPP, low-substituted hydroxypropyl cellulose, sodium starch glycolate, Magnesium Stearate and talcum powder.
Above embodiment is only in order to explaining technical scheme of the present invention, but not limits it; Although the present invention has been carried out detailed explanation with reference to previous embodiment, for the person of ordinary skill of the art, still can make amendment to the technical scheme that previous embodiment is put down in writing, perhaps part technical characterictic wherein is equal to replacement; And these modifications or replacement do not make the essence of relevant art scheme break away from the spirit and the scope of the present invention's technical scheme required for protection.
Claims (8)
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| CN 201110390234 CN102503935B (en) | 2011-11-30 | 2011-11-30 | A kind of Azelnidipine crystal form and its preparation method and pharmaceutical composition |
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| CN 201110390234 CN102503935B (en) | 2011-11-30 | 2011-11-30 | A kind of Azelnidipine crystal form and its preparation method and pharmaceutical composition |
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| CN102503935A true CN102503935A (en) | 2012-06-20 |
| CN102503935B CN102503935B (en) | 2013-10-23 |
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| CN 201110390234 Expired - Fee Related CN102503935B (en) | 2011-11-30 | 2011-11-30 | A kind of Azelnidipine crystal form and its preparation method and pharmaceutical composition |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319458A (en) * | 2012-03-20 | 2013-09-25 | 北京晶润宏达医药科技有限公司 | Novel gamma-polymorph of Azelnidipine and applications thereof |
| CN104693181A (en) * | 2015-03-12 | 2015-06-10 | 河北医科大学 | Azelnidipine-maleic acid co-amorphous substance and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101336921A (en) * | 2008-08-08 | 2009-01-07 | 青岛黄海制药有限责任公司 | Rosuvastatin azelnidipine composition |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101336921A (en) * | 2008-08-08 | 2009-01-07 | 青岛黄海制药有限责任公司 | Rosuvastatin azelnidipine composition |
Non-Patent Citations (1)
| Title |
|---|
| 孙晋瑞等: "阿折地平的合成", 《齐鲁药事》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319458A (en) * | 2012-03-20 | 2013-09-25 | 北京晶润宏达医药科技有限公司 | Novel gamma-polymorph of Azelnidipine and applications thereof |
| CN103319458B (en) * | 2012-03-20 | 2015-11-25 | 北京晶润宏达医药科技有限公司 | Azelnidipine γ crystal-form substances and application thereof |
| CN104693181A (en) * | 2015-03-12 | 2015-06-10 | 河北医科大学 | Azelnidipine-maleic acid co-amorphous substance and preparation method thereof |
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| CN102503935B (en) | 2013-10-23 |
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