CN103864757A - Preparation method for azelnidipine epsilon-crystal-form substance - Google Patents
Preparation method for azelnidipine epsilon-crystal-form substance Download PDFInfo
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- CN103864757A CN103864757A CN201210548448.8A CN201210548448A CN103864757A CN 103864757 A CN103864757 A CN 103864757A CN 201210548448 A CN201210548448 A CN 201210548448A CN 103864757 A CN103864757 A CN 103864757A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a preparation method for azelnidipine epsilon-crystal-form substance. Additionally, the invention also discloses the advantage effect of the azelnidipine epsilon-crystal-form substance as a drug active component in prevention of diseases.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, specifically, relate to Azelnidipine (Azelnidipine) hydrate, and pharmaceutical composition and application.
Background technology
At Chinese patent CN1752086A(publication number) in recorded " a kind of improved method of preparing Azelnidipine " of people's inventions such as Lin Fengru.Wherein, related to a kind of synthetic method of preparing Azelnidipine, by compound (1), compound (2) with compound (3) in suitable solvent, stirring reaction 1-20 hour, suction filtration, filtrate washing, organic solvent extraction, soda lye wash, dry, concentrating under reduced pressure, methanol crystallization, then turn brilliant high yield, the high purity Azelnidipine finished product of obtaining.The method is simple to operate, yield is high, finished product purity is high, with low cost.
At Chinese patent CN101103979A(publication number) in recorded Liao Juan invention " a kind of Azelnidipine medicinal composition and preparation method thereof ".Wherein, relate to one and be used for the treatment of hypertensive composition, be particularly related to a kind of stripping completely, good stability and the high calcium ion antagonist pharmaceutical composition of bioavailability, it is characterized in that comprising: (A) basic auxiliary of calcium channel blocker (B) significant quantity and (C) nonionic surface active agent; Wherein (A): (B): (C) be 0.1:1:1～10:1:1.
At Chinese patent CN101336921A(publication number) in recorded " a kind of rosuvastatin azelnidipine composition " of people's inventions such as Sun Guirong.Wherein, related to a kind of rosuvastatin azelnidipine composition, said composition is the organic salt being formed by organic acid Rosuvastatin and organic bases Azelnidipine, and its mol ratio is 1:1.Rosuvastatin azelnidipine composition, can be applied in the above-mentioned treatment of preparation rosuvastatin azelnidipine medicinal compositions used jointly with pharmaceutically acceptable carrier.For reduce blood pressure and blood lipid level, reduce the treatment of myocardial infarction and cerebral apoplexy simultaneously.This invention stable physical-chemical indexes, the quality of production is easy to control, and expense is convenient.
At Chinese patent CN101336921A(publication number) in recorded " a kind of Azelnidipine composition " of people's inventions such as Sun Guirong.Wherein, related to a kind of Azelnidipine composition, be made up of Azelnidipine and beta-cyclodextrin, wherein the consumption of beta-cyclodextrin is 3～15 times of Azelnidipine in weight ratio, and Azelnidipine by envelope in cyclodextrin hydrophobic internal cavities.The Azelnidipine composition bioavailability of this invention is obviously improved compared with the ordinary preparation of Azelnidipine, for the oral preparations of further development of new Azelnidipine is laid a good foundation.
At Chinese patent CN101486705A(publication number) in recorded " a kind of preparation method of Azelnidipine alpha crystal form " of people's inventions such as Zhao Mingmei.Wherein, relate to a kind of preparation method of Azelnidipine alpha crystal form, be dissolved in completely in two-phase organic solvent by the Azelnidipine of non-alpha-crystal form, heating in water bath is to certain temperature, under agitation condition, in this solution, add alkane, crystal seed, the cooling crystal that makes is separated out, and the crystalline product that collection is separated out is the Azelnidipine of alpha-crystal form.Described two-phase organic solvent comprises two kinds of components: the derivative of low boiling ester class, benzene or benzene, its volume ratio are 1～3:15.The disposable yield of this preparation method reaches 85%～90%, and purity is more than 99.5%, and outward appearance is good, and quality is good.Organic solvent is easy to reclaim, and is conducive to environmental protection, has reduced the loss of Azelnidipine composition and/or the waste of organic solvent, has significantly reduced the manufacturing cost of product, has large-scale industrial production prospect.
At Chinese patent CN101591329A(publication number) in recorded " a kind of method of preparing chiral azelnidipine and acceptable salt thereof " of people's inventions such as Wang Yuli.Wherein, related to a kind of method of cost-effective fractionation racemization Azelnidipine preparation (S)-(+)-Azelnidipine and (R)-(-)-Azelnidipine and Phenylsulfonic acid thereof, tosic acid, (D)-(+)-camphorsulfonic acid, (L)-(-)-camphorsulfonic acid, taurine, Homotaurine salt.Compared with the way of preparing optical activity Azelnidipine and salt thereof with the expensive plant and instrument of existing needs and the few high performance liquid chromatography for the treatment of capacity, this invention adopts conventional chiral selectors and solvent recrystallization method for splitting cheap and easy to get, processing sample amount is large, simple to operate, do not need special instrument, be applicable to industrial production.
In Chinese patent CN101756977A(publication No.) in recorded people's inventions such as You Guangzhi " sustained release preparation of Azelnidipine and preparation method thereof ".Wherein, relate to and comprise the sustained release preparation being formed by Azelnidipine, medicinal slow-release material and other pharmaceutical excipient.This sustained release preparation is divided into quick-release and slowly-releasing two portions, can be the double-layer tablets being pressed into through bi-layer tablet press, or is made label, immediate release drug and done the tablet of outer dressing by slow releasing pharmaceutical, or by the slow releasing capsule of quick-release and slowly-releasing two portions ingredients.The sustained release preparation of this invention can make drug effect rapid, can maintain for a long time again the effective concentration of medicine, has more preferably result for the treatment of.
In Chinese patent CN101829067A(publication No.) in recorded people's inventions such as You Guangzhi " osmotic pump controlled release tablet of Azelnidipine and preparation method thereof ".Wherein, relate to osmotic pump controlled release tablet of Azelnidipine and preparation method thereof, this osmotic pump controlled release tablet is made up of label, semi-permeable membranes, drug release hole three parts, wherein label is become by cyclodextrin inclusion compound, osmotic pressure promotor and other vehicle group of Azelnidipine, and semi-permeable membranes comprises film forming material and softening agent.Send elsewhere bright controlled release tablet can be in 24 hours sustained release medicine, there is more preferably result for the treatment of.
In Chinese patent CN101863879A(publication No.) in recorded " a kind of preparation method of alpha crystalline azelnidipine " of people's inventions such as Huang Yaozong.Wherein, relate to a kind of preparation method of alpha crystalline azelnidipine, the method is for to change Azelnidipine crude product into Azelnidipine methylate; Again Azelnidipine methylate is uniformly dispersed in normal heptane solvent; Heating underpressure distillation is except desolventizing; , filter, be dried etc. cooling according to usual method obtains medicinal alpha crystalline azelnidipine.This inventive method is prepared medicinal alpha crystalline azelnidipine, simple to operate, yield is high, purity is high, with low cost, the alpha crystalline azelnidipine yield that the method makes is about 95%(in Azelnidipine methylate), purity HPLC content >99.5%.
At Chinese patent CN101596195A(publication number) in recorded bright " combination of oral medication reducing blood pressure " of Zou Yuan grey hair.Wherein, relate to one and treat hypertensive combination of oral medication, it is characterized in that containing Azelnidipine and candesartan Cilexetil, the complementary action on mechanism of action by Azelnidipine and candesartan Cilexetil, ensureing under the prerequisite of curative effect, reduce dosage, and the untoward reaction that brings of long-term prescription.
In Japanese Patent JP2010083888 (A) (publication number), record " the METHOD FOR PREPARING AZELNIDIPINE CRYSTAL " of people's inventions such as ROSSI ROBERTO.Wherein, related to by the method for the brilliant α type of the brilliant β type of Azelnidipine sample preparation and the preparation method of the brilliant β type of Azelnidipine.The brilliant α type of Azelnidipine can be by being dissolved in brilliant β type in aprotic solvent, adds precipitation solvent to obtain, and the brilliant β type of Azelnidipine can use toluene recrystallization to obtain.
In master thesis in 2007 of University Of Tianjin, record refined " the synthesizing of Azelnidipine " completing of Liao Chen state.Wherein, synthetic and the brilliant α type of Azelnidipine and the brilliant β type Study on Crystallization of Azelnidipine have been related to.
For a person skilled in the art, with respect to prior art, still there are such needs in this area: a kind of new Azelnidipine crystal formation stable, that biological activity is high.
Summary of the invention
The polymorphism research that the inventor exists from Azelnidipine solid matter is started with, by screening polymorph technical study, on new crystal aspect of material, surprisedly found a kind of Azelnidipine dihydrate solid matter and ε crystal formation, this stable crystal form is good and biological activity is high.
The object of this invention is to provide a kind of Azelnidipine dihydrate.
Second object of the present invention is to provide the ε crystal formation of Azelnidipine dihydrate.
The 3rd object of the present invention is to provide the preparation method of above-mentioned Azelnidipine dihydrate and ε crystal formation thereof.
The 4th object of the present invention is to provide the pharmaceutical composition that comprises above-mentioned Azelnidipine dihydrate.
The 5th object of the present invention is to provide the application of Azelnidipine dihydrate as dihydropyridine type calcium antagonists.
In embodiments of the invention, Azelnidipine, English name azelnidipine, chemistry 3,5-pyridine dicarboxylic acid by name, Isosorbide-5-Nitrae-dihydropyridine-2-amino-6-methyl, molecular structure is as follows:
In embodiments of the invention, the invention provides Azelnidipine dihydrate, molecular structure is shown below:
On the other hand, the invention provides the ε crystal formation of Azelnidipine dihydrate, (CuK in the time using powder x-ray diffraction analysis
αradiation) show as Height%=100 peak position in 2 θ=19.5 ± 0.2 ° or
place, and, in 2 θ=5.8 ± 0.2 ° or
2 θ=12.6 ± 0.2 ° or
2 θ=16.0 ± 0.2 ° or
2 θ=20.2 ± 0.2 ° or
2 θ=23.8 ± 0.2 ° or
with 2 θ=24.3 ± 0.2 ° or
the diffraction peak that place exists Height% to be greater than 20.
Preferably, the ε crystal formation of Azelnidipine dihydrate provided by the invention, (CuK in the time using powder x-ray diffraction analysis
αradiation), the position of its diffraction peak respectively 2 θ (°) ± 0.2 ° value or
value has following expression:
And diffraction peak relative intensity value allows Height% ± 10% variation range; Particularly preferably, as shown in Figure 1.
In embodiments of the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, the infrared absorption spectrum of its KBr pressed disc method is 3629, 3439, 3327, 3221, 3066, 3032, 2978, 2934, 2860, 2828, 1676, 1639, 1560, 1524, 1487, 1451, 1386, 1373, 1346, 1315, 1297, 1247, 1217, 1182, 1162, 1155, 1131, 1103, 1085, 1071, 1027, 1003, 921, 905, 858, 845, 824, 814, 801, 790, 765, 751, 744, 703, 695, 677cm
-1± 2cm
-1there is absorption peak.More preferably, the infrared spectrogram of Azelnidipine dihydrate ε crystal formation solid matter of the present invention as shown in Figure 2.
In embodiment provided by the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, its melting point values is 98 DEG C ± 2 DEG C.
In embodiment provided by the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, contains 2 endotherm(ic)peaks in its differential thermal analysis DSC collection of illustrative plates, respectively 89 DEG C ± 3 DEG C and 101 DEG C ± 3 DEG C positions.Preferably, the DSC collection of illustrative plates of Azelnidipine dihydrate ε crystal formation solid matter of the present invention as shown in Figure 3.
In embodiment provided by the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, two molecular water weight losses of 5.8 % by weight of having an appointment within the scope of 60 DEG C～95 DEG C in its thermogravimetric analysis TGA collection of illustrative plates, two molecular water weight losses of described approximately 5.8 % by weight can change in the limit of error of surveying instrument.Preferably, the TGA collection of illustrative plates of Azelnidipine dihydrate ε crystal formation solid matter of the present invention as shown in Figure 4
In embodiments of the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention is the photoactive racemic modification of irrotationality.
The third aspect, the invention provides the preparation method of Azelnidipine dihydrate and ε crystal formation solid matter thereof, comprises the steps:
Using Azelnidipine methylate sample to be more than or equal under 75% condition and to place 12 hours to 10 days at 20-45 DEG C, humidity, prepare Azelnidipine dihydrate, is ε crystal form samples.
In embodiment provided by the invention, the preparation method of described Azelnidipine dihydrate and ε crystal formation solid matter thereof, wherein, described be more than or equal to and under 75% condition, be preferably 22-27 DEG C, humidity and be more than or equal under 90% condition at 20-45 DEG C, humidity, or be more than or equal under 75% condition at 35-42 DEG C, humidity; More preferably, be under 95% condition at 25 DEG C, humidity, or be under 80% condition at 40 DEG C, humidity.Described placement is preferably 2-8 days for 1-10 days, is more preferably 4-6 days, particularly preferably 5 days.
Fourth aspect, the invention provides the pharmaceutical composition that comprises Azelnidipine dihydrate and ε crystal formation solid matter thereof, and preferably, described pharmaceutical composition can be prepared into oral tablet, capsule, pill, injection, slowly-releasing or control-released agent or pulvis.Described pharmaceutical composition can be for orally using.The above-mentioned Azelnidipine dihydrate of the present invention or its ε crystal formation solid matter have perhaps multifactor impact on the dosage of effective constituent, for example: cause the difference of dosage every day for preventing different with the purposes for the treatment of; Ill character is different from ill severity and cause the different of dosage every day; The difference of Gender, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, the absorption existing between crystal form samples and Plasma Concentration are not equal, and also causing the present invention is 0.01～200mg/kg body weight in suitable dose scope every day that uses Azelnidipine ε crystal formation composition, is preferably 1～100mg/kg body weight.When use, should formulate Azelnidipine ε crystal formation effective constituent total dose scheme according to actual prevention and treatment different situations demand, and can be divided into repeatedly or single administration mode completes.
The 5th aspect, the invention provides above-mentioned Azelnidipine hydrate and ε crystal formation solid matter thereof the purposes as dihydropyridine type calcium antagonists.Azelnidipine dihydrate of the present invention and ε crystal formation solid matter thereof can be used as dihydropyridine type calcium antagonists, for hypertensive treatment.
Through evidence, compared with prior art, biology sorption after medicine and pharmaceutical composition oral administration thereof that Azelnidipine hydrate provided by the invention and ε crystal formation solid matter thereof are developed as activeconstituents, in gi tract or blood, reach rapidly peak concentration value, thus the advantage function of bringing into play in disease preventing and treating and application.
Brief description of the drawings
What Fig. 1 represented is the x-ray diffractogram of powder spectrum of Azelnidipine dihydrate ε crystal form samples.
What Fig. 2 represented is the infrared absorpting light spectra of Azelnidipine dihydrate ε crystal form samples.
What Fig. 3 represented is the DSC collection of illustrative plates of Azelnidipine dihydrate ε crystal form samples.
What Fig. 4 represented is the TGA collection of illustrative plates of Azelnidipine dihydrate ε crystal form samples.
Plasma concentration curve after the Azelnidipine dihydrate ε crystal form samples oral absorption of what Fig. 5 represented is embodiment 1 in rat body.
Embodiment
For better explanation technical scheme of the present invention, spy provides following examples, but the present invention is not limited to this.
1.PXRD
(1) laboratory apparatus: Japanese Rigaku D/max-2550 powder x-ray diffraction
(2) experiment condition: CuK
αradiation, graphite monochromator, pipe is pressed 40kv, pipe stream 150mA, 2 θ sweep limit 3-80 °, 8 °/point of sweep velocitys, 0.02 ° of step-length.Slit condition: divergent slit is 1 °, limit for height slit is 10mm, and anti-scatter slit is 1 °, and reception slit is 0.15mm.
2.DSC
(1) laboratory apparatus: Switzerland Mettler DSC1 thermal analyzer
(2) experiment condition: initial temperature is made as 30 DEG C, final temperature is set to 230 DEG C, and temperature rise rate is set to 10 DEG C/min.
3.TGA
(1) laboratory apparatus: Switzerland Mettler DSC1 thermal analyzer
(2) experiment condition: initial temperature is made as 30 DEG C, final temperature is set to 500 DEG C, and temperature rise rate is set to 10 DEG C/min.
4.IR
(1) laboratory apparatus: Britain PE (Spectrum400) infrared spectrometer
(2) experiment condition: spectral scan scope 4000-650cm
-1, adopt attenuated total reflectance attenuated total refraction (ATR) detection method.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 5 days, prepare Azelnidipine dihydrate under 25 DEG C, humidity 95% condition, is ε crystal form samples.The x-ray diffractogram of powder of this ε crystal form samples is composed as shown in Figure 1; Infrared absorpting light spectra as shown in Figure 2; DSC collection of illustrative plates as shown in Figure 3; TGA collection of illustrative plates is as Fig. 4, is presented at 5.7% the weightlessness of having an appointment within the scope of 60 DEG C～95 DEG C in TGA collection of illustrative plates, shows to have the weight loss of two molecular waters.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 5 days, prepare Azelnidipine dihydrate under 40 DEG C, humidity 80% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 10 days, prepare Azelnidipine dihydrate under 20 DEG C, humidity 75% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 8 days, prepare Azelnidipine dihydrate under 20 DEG C, humidity 85% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 6 days, prepare Azelnidipine dihydrate under 45 DEG C, humidity 80% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 4 days, prepare Azelnidipine dihydrate under 45 DEG C, humidity 90% condition, is ε crystal form samples.
Embodiment 7
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 9 days, prepare Azelnidipine dihydrate under 22 DEG C, humidity 95% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 5 days, prepare Azelnidipine dihydrate under 27 DEG C, humidity 90% condition, is ε crystal form samples
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 2 days, prepare Azelnidipine dihydrate under 35 DEG C, humidity 75% condition, is ε crystal form samples.
The preparation method of Azelnidipine ε crystal form samples:
Using Azelnidipine methylate (being prepared by the flat 11-116570 of TOHKEMY and Chinese patent CN200510104895 method) sample to place and within 1 day, prepare Azelnidipine dihydrate under 42 DEG C, humidity 88% condition, is ε crystal form samples.
Azelnidipine ε crystal formation is Absorption Characteristics and Plasma Concentration feature in rat body:
Fasting 12h before rat administration, freely drinks water.Take rat body weight, by 200mgkg
-1azelnidipine dosage calculate, the Azelnidipine sample of different crystal forms is packed in solid delivery device, by oral cavity, medicinal powder is directly inserted in rat stomach.Respectively at the different time points of 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 9.0h, 12.0h, 24.0h, 36.0h, 48.0h, 60.0h, 72.0h after administration by rat intraocular corner of the eyes venous blood sampling approximately 400 μ L.Get blood according to blood sampling time point from the angular vein of rat, put in heparinization Ep pipe, adopt under 4 DEG C and 5000 revs/min of conditions centrifugal blood sample 10 minutes, get 150 μ L blood plasma, add and in 10 μ L, mark (50 μ gmL
-1nimodipine), then add 300 μ L acetonitriles, after vortex oscillation 3min, again sample is adopted to the centrifugal 10min of 13400rpm speed, get 400 μ L supernatant liquors, dry up with nitrogen.Contain water with 50 μ L(: mixed solution acetonitrile=12.5 μ L:37.5 μ L) redissolves residue, after vortex oscillation 3min, in the centrifugal 5min of 13400rpm.Get supernatant 35 μ L and carry out HPLC detection.
Testing conditions: detection system: Aligent 1200, chromatographic column: Agilent XDB-C18(250mm × 4.6mm, 5 μ are m), column temperature: 30 DEG C, moving phase: acetonitrile: water=78:22(v/v), flow velocity: 1mL/min, sample size: 20 μ L, detect wavelength: 254nm.
Measure and absorb and Plasma Concentration for three kinds of different crystal formations of Azelnidipine (α type, by Chinese patent CN87107150 method preparation, β type, is prepared by Chinese patent CN87107150 method, and the ε type that obtains of the embodiment of the present invention 1), result is as follows:
| C max | T max | t 1/2 | AUC （0-∞） | |
| α type | 1.68±0.43 | 48.00±12.00 | 17.68±13.41 | 84.21±39.17 |
| β type | 0.44±0.05 | 27.00±28.62 | 2.74±1.86 | 20.54±11.42 |
| ε type | 1.75±0.57 | 36.00±0.00 | 8.78±4.93 | 40.84±12.40 |
The above results shows, Azelnidipine ε crystal formation of the present invention absorbs and is better than other crystal formations, has absorption rate fast, and the dominant that Plasma Concentration is high, effect plateau is long is learned feature.
Following table provides rat oral and takes the activeconstituents detecting in blood after Azelnidipine ε crystal form samples.
Plasma concentration curve after the oral absorption of Azelnidipine ε crystal form samples in rat body as shown in Figure 5.
Azelnidipine sheet
(1) plain tablet recipe
(2) coating fluid prescription
Gastric soluable film bag agent 80g
Ethanol (80%) is appropriate
Be mixed with 1000ml
Preparation technology: (1) takes Azelnidipine (the ε type that the embodiment of the present invention 1 obtains) by recipe quantity, pregelatinized Starch, Microcrystalline Cellulose, PvPk30, micropowder silica gel, Magnesium Stearate are for subsequent use; (2) Azelnidipine and Microcrystalline Cellulose are mixed, grind altogether, cross 100 mesh sieve three times, mix, then add pregelatinized Starch to mix 60 mesh sieves, mix; (3) (wherein ethanol is 50% ethanol to add 5%PvPk30 ethanolic soln; The collocation method of 5%PvPk30 ethanolic soln, for taking 50% ethanol as solvent, is made into PvPk30 5% solution.) softwood processed in right amount, softwood is granulated with 20 mesh sieves, and dry 2～4h, granulates.(4) add again micropowder silica gel and Magnesium Stearate to mix, measure work in-process content, calculate and answer compressing tablet weight.(5) suppress plain sheet.(6) dressing: 1. take the agent of gastric soluable film bag, add in 80% ethanolic soln, induction stirring mixes makes 8%(g/v) suspension for subsequent use; 2. the plain sheet of above-mentioned preparation is put in coating pan, with hot blast (30～40 DEG C) preheating 5 minutes; 3. regulate dressing flow quantity, be evenly sprayed onto on the plain sheet of rotation, make it evenly moistening, 70 DEG C of blowing hot-airs are dry, and repetitive operation, obtains uniform coating membrance; 4. through 30～40 DEG C dry 10 minutes, be more slowly down to room temperature, to obtain final product.(7) packaging.
Claims (10)
1. the preparation method of the ε crystal formation of Azelnidipine dihydrate, comprises the steps:
Use Azelnidipine methylate sample to be greater than under 75% condition and to place 12 hours to 10 days at 20-45 DEG C, humidity, prepare the ε crystal form samples of Azelnidipine.
2. preparation method according to claim 1, wherein, described is more than or equal under 75% condition for 22-27 DEG C, humidity are more than or equal under 90% condition at 20-45 DEG C, humidity, or is more than or equal under 75% condition at 35-42 DEG C, humidity.
3. preparation method according to claim 2, wherein, described is more than or equal under 75% condition for being under 95% condition at 25 DEG C, humidity at 20-45 DEG C, humidity, or is under 80% condition at 40 DEG C, humidity.
4. preparation method according to claim 1, wherein, described placement is 2-8 days in 12 hours to 10 days, is more preferably 4-6 days, particularly preferably 5 days.
5. preparation method according to claim 1, wherein, uses Azelnidipine methylate sample to place the ε crystal form samples for preparing Azelnidipine for 5 days under 25 DEG C, humidity 95% condition.
6. preparation method according to claim 1, wherein, uses Azelnidipine methylate sample to place the ε crystal form samples for preparing Azelnidipine for 5 days under 40 DEG C, humidity 80% condition.
7. according to the preparation method described in any one in claim 1 to 6, wherein, described Azelnidipine dihydrate ε crystal formation, (CuK in the time using powder x-ray diffraction analysis
αradiation) show as Height%=100 peak position in 2 θ=19.5 ± 0.2 ° or
place, and, in 2 θ=5.8 ± 0.2 ° or
2 θ=12.6 ± 0.2 ° or
2 θ=16.0 ± 0.2 ° or
2 θ=20.2 ± 0.2 ° or
2 θ=23.8 ± 0.2 ° or
with 2 θ=24.3 ± 0.2 ° or
the diffraction peak that place exists Height% to be greater than 20.
8. preparation method according to claim 7, wherein, described Azelnidipine dihydrate ε crystal formation, (CuK in the time using powder x-ray diffraction analysis
αradiation), its diffraction peak position respectively 2 θ (°) ± 0.2 ° value or
value has following expression:
9. preparation method according to claim 8, wherein, described Azelnidipine dihydrate ε crystal formation, the infrared absorption spectrum of its KBr pressed disc method is 3629, 3439, 3327, 3221, 3066, 3032, 2978, 2934, 2860, 2828, 1676, 1639, 1560, 1524, 1487, 1451, 1386, 1373, 1346, 1315, 1297, 1247, 1217, 1182, 1162, 1155, 1131, 1103, 1085, 1071, 1027, 1003, 921, 905, 858, 845, 824, 814, 801, 790, 765, 751, 744, 703, 695, 677cm
-1± 2cm
-1there is absorption peak.
10. preparation method according to claim 8, wherein, the melting point values of described Azelnidipine dihydrate ε crystal formation is 98 DEG C ± 2 DEG C.
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| CN101486705A (en) * | 2009-03-05 | 2009-07-22 | 青岛黄海制药有限责任公司 | Preparation of Azelnidipine alpha crystal form |
| CN101863879A (en) * | 2009-04-16 | 2010-10-20 | 四川科伦药物研究有限公司 | Preparation method of alpha crystalline azelnidipine |
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| CN101486705A (en) * | 2009-03-05 | 2009-07-22 | 青岛黄海制药有限责任公司 | Preparation of Azelnidipine alpha crystal form |
| CN101863879A (en) * | 2009-04-16 | 2010-10-20 | 四川科伦药物研究有限公司 | Preparation method of alpha crystalline azelnidipine |
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