CN102503935B - Azelnidipine crystal form, preparation method for same and officinal composition thereof - Google Patents
Azelnidipine crystal form, preparation method for same and officinal composition thereof Download PDFInfo
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- CN102503935B CN102503935B CN 201110390234 CN201110390234A CN102503935B CN 102503935 B CN102503935 B CN 102503935B CN 201110390234 CN201110390234 CN 201110390234 CN 201110390234 A CN201110390234 A CN 201110390234A CN 102503935 B CN102503935 B CN 102503935B
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Abstract
The invention provides a novel azelnidipine crystal form, a preparation method for the same and an officinal composition thereof. The X-ray powder diffraction characteristic absorption peak value 2theta of the novel azelnidipine crystal form is 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 and 27.19. The preparation method for the novel azelnidipine crystal form includes the steps: mixing amorphous azelnidipine with methylbenzene according to amount ratio ranging from 1:4 to 1:6 (w/v) prior to heating, adding activated carbon with stirring and filtering, adding cyclohexane into filtrate with the amount ratio of the cyclohexane to the methylbenzene ranging from 1:2 to 2:1 (v/v), and obtaining the novel azelnidipine crystal form by means of crystallization, filtration and drying. The novel azelnidipine crystal form is durable in drug properties, small in static electricity, higher in stability, high in yield and suitable for mass production.
Description
Technical field
The invention belongs to field of medicaments, relate in particular to a kind of Azelnidipine new crystal and preparation method thereof and medicinal compositions.
Background technology
Essential hypertension is common, frequently-occurring disease, and the patient is year by year ascendant trend, has become one of main killer of human health now.Antihypertensive drugs Azelnidipine (azelindipine) is the altogether a kind of long-acting dihydropyridine calcium ion antagonist of (SANKYO) Co., Ltd. and UBE Industries Ltd. joint development of Japan three, in May, 2003 in Japanese Initial Public Offering.
The pharmacotoxicological effect mechanism of Azelnidipine is to have potent L-type calcium channel antagonistic action, can reduce the free calcium concentration in the vascular smooth muscle cell, distends the blood vessels blood pressure drops.The pharmacodynamic study demonstration, the onset mitigation of Azelnidipine hypotensive effect and effect are lasting.In addition, Azelnidipine and vascular tissue have high-affinity, can reducing heart rate, have the effect of good atherosclerosis and cardioprotection, and can be used for atherosclerotic treatment.On the other hand, the Azelnidipine side effect is less, except antihypertensive function, causes hardly water and sodium retention, thereby in hypertension therapeutic renal function is had beneficial effect.In addition, Azelnidipine is different with amlodipine, and it stimulates sympathetic activity hardly, thereby the hyperfunction occurrence degree of the palpitaition that causes is low.
The present document of relevant Azelnidipine polycrystalline research and few except amorphous Azelnidipine exists, has reported that it has two stable crystal forms: 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 at present preparation mainly is alpha-crystal form.Alpha-crystal form has desirable stripping, but static is larger, is unfavorable for production operation.
Summary of the invention
For the large shortcoming with being unfavorable for production operation of Azelnidipine alpha crystal form static in the prior art, the invention provides a kind of Azelnidipine new crystal and preparation method thereof and medicinal compositions.Azelnidipine new crystal provided by the invention has the purposes identical with known Azelnidipine compound itself, also is dihydropyridine calcium ion antagonist, can be used for making the hypertensive medicine for the treatment of.And its fusing point of Azelnidipine new crystal of the present invention is in the middle of alpha-crystal form and beta crystal, and is not only stable high, and electrostatic interaction is little, and simple to operate, productive rate is high, is fit to scale operation.
For achieving the above object, the present invention adopts following technical proposals to be achieved:
A kind of Azelnidipine 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 Azelnidipine new crystal of the present invention is at 160～165 ℃.
The present invention also provides the preparation method of Azelnidipine new crystal, unbodied Azelnidipine is mixed with 1: 4～1: 6 (w/v) amount ratio with toluene, be heated to 30～60 ℃, add again gac, agitation and filtration, add hexanaphthene in the filtrate, the amount ratio of described hexanaphthene and toluene is 1: 2～2: 1 (v/v), makes the Azelnidipine new crystal through crystallization, filtration, drying again.
To further improvement in the technical proposal: described hexanaphthene is preferably the equal-volume ratio with the amount ratio of toluene.
The present invention also provides the medicinal compositions that contains described Azelnidipine new crystal, and described composition contains the Azelnidipine new crystal for the treatment of significant quantity.
To further improvement in the technical proposal: described composition contains pharmaceutically acceptable auxiliary material or carrier.
To further improvement in the technical proposal: described composition contains 2%～15% described Azelnidipine new crystal, and surplus is its pharmaceutically acceptable auxiliary material or carrier.
To further improvement in the technical proposal: the formulation of described composition is tablet, capsule, granule.
Compared with prior art, advantage of the present invention and positively effect are: its fusing point of Azelnidipine new crystal of the present invention's preparation has satisfactory stability in the middle of alpha-crystal form and beta crystal, be convenient to storage, transportation and medicament manufacturing; And described Azelnidipine 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 reading the specific embodiment of the present invention by reference to the accompanying drawings, other characteristics of the present invention and advantage will become clearer.
Description of drawings
Fig. 1 is the X-ray diffracting spectrum of Azelnidipine new crystal among the present invention.
Fig. 2 is the DSC collection of illustrative plates of Azelnidipine 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 Azelnidipine beta crystal among the present invention.
Embodiment
Below in conjunction with the drawings and specific embodiments technical scheme of the present invention is described in further detail.
Embodiment 1
Amorphous Azelnidipine 10g is fully mixed with 40ml toluene, be heated to 30～40 ℃.Then add gac 2～3g, agitation and filtration, filtrate is stirred the lower 40ml of adding hexanaphthene, continues stirring and crystallizing, after filtration, drying, gets the new crystal 9.5g of Azelnidipine, yield 95%, 163.4 ℃ of fusing points.
Be heated to 40～50 ℃, all the other get the new crystal 9.4g of Azelnidipine with above-mentioned operation, yield 94%, 162.1 ℃ of fusing points.
Be heated to 50～60 ℃, all the other get the new crystal 9.4g of Azelnidipine with above-mentioned operation, yield 94%, 162.7 ℃ of fusing points.
Through above-mentioned evidence, the heating for dissolving temperature range is at 30～60 ℃.Heating temperature is higher, and the required crystallization time is longer, so 30～40 ℃ of preferred temperature.
Embodiment 2
Amorphous Azelnidipine 10g is fully mixed with 40ml toluene, be heated to 30～40 ℃.Then add gac 2～3g, agitation and filtration, filtrate is stirred the lower 40ml of adding hexanaphthene, continues stirring and crystallizing, after filtration, drying, gets the new crystal 9.5g of Azelnidipine, yield 95%, 163.8 ℃ of fusing points.
With toluene and each 50ml of hexanaphthene, all the other get the new crystal 9.4g of Azelnidipine with above-mentioned operation, yield 94%, 163.7 ℃ of fusing points.
With toluene and each 60ml of hexanaphthene, all the other get the new crystal 9.3g of Azelnidipine with above-mentioned operation, yield 93%, 162.2 ℃ of fusing points.
Above-mentioned experimental result shows: the amorphous Azelnidipine of 10g, preferred toluene consumption is 40～60ml.Experimental studies have found that when the 10g Azelnidipine is mixed with 40～60ml toluene, the strength of solution of formation is fit to generate new crystal.
Embodiment 3
Amorphous Azelnidipine 10g is fully mixed with 40ml toluene, be heated to 30～40 ℃.Then add gac 2～3g, agitation and filtration, filtrate is stirred the lower 20ml of adding hexanaphthene, continues stirring and crystallizing, after filtration, drying, gets the new crystal 8.9g of Azelnidipine, yield 89%, 164.1 ℃ of fusing points.
Add the 40ml hexanaphthene, all the other get the new crystal 9.5g of Azelnidipine with above-mentioned operation, yield 95%, 163.1 ℃ of fusing points.
Add the 80ml hexanaphthene, all the other get the new crystal 9.6g of Azelnidipine with above-mentioned operation, yield 96%, 162.9 ℃ of fusing points.
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 Azelnidipine new crystal is almost completely separated out.
Embodiment 4
The new crystal of Azelnidipine, differential scanning calorimetric analysis are presented at 160～165 ℃ and have located single absorption peak as shown in Figure 2.The X-ray powder diffraction of this crystal formation as shown in Figure 1, test condition: X-ray tube is the copper target, wavelength
0.019 ° of step-length; 3.000 °-29.992 ° of sweep limits.Feature represents 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, Azelnidipine new crystal
Embodiment 5
The Azelnidipine new crystal is carried out study on the stability, choose the Azelnidipine 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, Azelnidipine new crystal stability experiment result
Experimental result shows: the Azelnidipine new crystal of the present invention's preparation has good stable crystal form, is convenient to storage, transportation and medicament manufacturing.
Embodiment 6
The present embodiment preparation contains the pharmaceutical composition of the Azelnidipine new crystal of significant quantity, and described pharmaceutical composition is the medically acceptable pharmaceutical preparation that Azelnidipine new crystal and pharmaceutical excipient are made into.
Prescription: Azelnidipine new crystal 4g, Microcrystalline Cellulose 64g, sodium bicarbonate 20g, polyvinylpolypyrrolidone 5g, Sodium Hydroxymethyl Stalcs 2g, Magnesium Stearate 1g makes 1000.
Preparation method: Azelnidipine new crystal, Microcrystalline Cellulose, sodium bicarbonate, polyvinylpolypyrrolidone and Sodium Hydroxymethyl Stalcs are crossed respectively 80 mesh sieves, mix, add 65% alcohol granulation.Wet grain placed 50 ℃ of loft drier inner dryings approximately 3 hours, crossed 20 mesh sieves, then added the Magnesium Stearate mixing, compressing tablet and get final product.Stripping is: 86%.
Azelnidipine new crystal 8g, all the other are with above-mentioned operation, and stripping is: 90%.
Azelnidipine new crystal 16g, all the other are with above-mentioned operation, and stripping is: 88%.
Embodiment 7
Prescription: Azelnidipine new crystal 4g, lactose 64g, sodium bicarbonate 20g, low-substituted hydroxypropyl cellulose 5g, Sodium Hydroxymethyl Stalcs 2g, Magnesium Stearate 1g makes 1000.
Preparation technology: Azelnidipine new crystal, lactose, sodium bicarbonate, low-substituted hydroxypropyl cellulose and Sodium Hydroxymethyl Stalcs are crossed respectively 80 mesh sieves, mix, add 65% alcohol granulation.Wet grain placed 50 ℃ of loft drier inner dryings approximately 3 hours, crossed 20 mesh sieves, then added the Magnesium Stearate mixing, and the can capsule gets final product.Stripping is: 90%.
Azelnidipine new crystal 8g, all the other are with above-mentioned operation, and stripping is: 89%.
Azelnidipine 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 by the preparation of pharmaceutics routine techniques.These preparations should comprise and contain at least the 4mg, the 8mg that make through the present invention and the Azelnidipine crystallisate of 16mg.Also can adjust according to formulation the therapeutic dose that makes it obtain being fit to.
The pharmaceutical preparation that the present invention relates to, the formulation of its oral administration can contain vehicle commonly used, such as 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 the vehicle such as Xylo-Mucine, hydroxypropylcellulose, Vltra tears, Microcrystalline Cellulose, starch, yellow soda ash, sodium bicarbonate, micropowder silica gel, ethanol, potassium primary phosphate, N.F,USP MANNITOL, lactose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, Magnesium Stearate and talcum powder.
Above embodiment is only in order to illustrating technical scheme of the present invention, but not limits it; Although with reference to previous embodiment the present invention is had been described in detail, 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 appropriate technical solution break away from the spirit and scope of the present invention's technical scheme required for protection.
Claims (2)
1. the preparation method of an Azelnidipine new crystal, it is characterized in that: unbodied Azelnidipine is mixed with 1:4 ~ 1:6 w/v amount ratio with toluene, be heated to 30 ~ 60 ℃, add again gac, agitation and filtration, add hexanaphthene in the filtrate, the amount ratio of described hexanaphthene and toluene is 1:2 ~ 2:1 v/v, makes the Azelnidipine new crystal through crystallization, filtration, drying again;
The X-ray powder diffraction charateristic avsorption band 2 θ values of described Azelnidipine new crystal 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.
2. the preparation method of Azelnidipine new crystal according to claim 1, it is characterized in that: described hexanaphthene is preferably the equal-volume ratio with the amount ratio of toluene.
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| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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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| 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 (2)
| Title |
|---|
| 孙晋瑞等.阿折地平的合成.《齐鲁药事》.2005,第24卷(第6期),365-366. |
| 阿折地平的合成;孙晋瑞等;《齐鲁药事》;20051231;第24卷(第6期);365-366 * |
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