CN103864757B - The preparation method of Azelnidipine ε crystal-form substances - Google Patents
The preparation method of Azelnidipine ε crystal-form substances Download PDFInfo
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- CN103864757B CN103864757B CN201210548448.8A CN201210548448A CN103864757B CN 103864757 B CN103864757 B CN 103864757B CN 201210548448 A CN201210548448 A CN 201210548448A CN 103864757 B CN103864757 B CN 103864757B
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- 0 CC(C)OC(C(C1c2cccc([N+]([O-])=O)c2)=C(C)NC(*)=C1C(OC(C1)CN1C(c1ccccc1)c1ccccc1)=O)=O Chemical compound CC(C)OC(C(C1c2cccc([N+]([O-])=O)c2)=C(C)NC(*)=C1C(OC(C1)CN1C(c1ccccc1)c1ccccc1)=O)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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 the preparation method of Azelnidipine ε crystal-form substances.In addition, the advantage function that the new ε crystal-form substances of this Azelnidipine plays in disease preventing and treating as active constituents of medicine is also disclosed.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, specifically, relate to Azelnidipine (Azelnidipine) hydrate, and pharmaceutical composition and application.
Background technology
Describe in Chinese patent CN1752086A (publication number) " a kind of method preparing Azelnidipine of improvement " of people's inventions such as Lin Fengru.Wherein, relate to a kind of synthetic method preparing Azelnidipine, by compound (1), compound (2) and compound (3) in suitable solvent, stirring reaction 1-20 hour, suction filtration, filtrate is washed, organic solvent extraction, soda lye wash, dry, concentrating under reduced pressure, methanol crystallization, then turn brilliant high yield, high purity Azelnidipine finished product.The method is simple to operate, yield is high, finished product purity is high, with low cost.
Describe in Chinese patent CN101103979A (publication number) 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, in particular to a kind of stripping completely, good stability and the high calcium ion antagonist pharmaceutical composition of bioavailability, it is characterized in that comprising: the basic auxiliary of (A) calcium channel blocker (B) significant quantity and (C) nonionic surface active agent; Wherein (A): (B): (C) is 0.1: 1: 1 ~ 10: 1: 1.
Describe in Chinese patent CN101336921A (publication number) " a kind of rosuvastatin azelnidipine composition " of people's inventions such as Sun Guirong.Wherein, relate to a kind of rosuvastatin azelnidipine composition, said composition is the organic salt 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 reducing blood pressure and blood lipid level, the treatment reducing myocardial infarction and cerebral apoplexy simultaneously.This invention stable physical-chemical indexes, the quality of production is easy to control, and expense is convenient.
Describe in Chinese patent CN101336921A (publication number) " a kind of Azelnidipine composition " of people's inventions such as Sun Guirong.Wherein, relate 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 with mass ratio range, 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.
Describe in Chinese patent CN101486705A (publication number) " 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, Azelnidipine by non-alpha-crystal form is dissolved in two-phase organic solvent completely, heating in water bath is to certain temperature, in this solution, alkane, crystal seed is added under agitation condition, cooling makes crystal separate out, and collects the Azelnidipine that the crystalline product of separating out is alpha-crystal form.Described two-phase organic solvent comprises two kinds of components: low boiling ester class, benzene or benzene derivate, 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, decreases the loss of Azelnidipine composition and/or the waste of organic solvent, considerably reduce the manufacturing cost of product, have large-scale industrial production prospect.
Describe in Chinese patent CN101591329A (publication number) " a kind of method preparing chiral azelnidipine and acceptable salt thereof " of people's inventions such as Wang Yuli.Wherein, relate to the method for a kind 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.With the expensive plant and instrument of existing needs and the few high performance liquid chromatography for the treatment of capacity is prepared compared with the way of optical activity Azelnidipine and salt thereof, 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.
Describe in Chinese patent CN101756977A (publication No.) people's inventions such as You Guangzhi " sustained release preparation of Azelnidipine and preparation method thereof ".Wherein, the sustained release preparation comprising and be made up of Azelnidipine, medicinal slow-release material and other pharmaceutical excipient is related to.This sustained release preparation is divided into quick-release and slowly-releasing two portions, can be the double-layer tablets be pressed into through bi-layer tablet press, or make label by slow releasing pharmaceutical, tablet that immediate release drug makes outer dressing, or the slow releasing capsule be made up of quick-release and slowly-releasing two portions medicine.The sustained release preparation of this invention can make drug effect rapid, can maintain again the effective concentration of medicine for a long time, have more preferably result for the treatment of.
Describe in Chinese patent CN101829067A (publication No.) people's inventions such as You Guangzhi " osmotic pump controlled release tablet of Azelnidipine and preparation method thereof ".Wherein, osmotic pump controlled release tablet relating to Azelnidipine and preparation method thereof, this osmotic pump controlled release tablet is made up of label, semi-permeable membranes, drug release hole three part, wherein label is become by the cyclodextrin inclusion compound of Azelnidipine, osmotic pressure promotor and other vehicle group, and semi-permeable membranes comprises film forming material and softening agent.Send elsewhere bright controlled release tablet can in 24 hours sustained release drugs, there is more preferably result for the treatment of.
Describe in Chinese patent CN101863879A (publication No.) " 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 change Azelnidipine crude product into Azelnidipine methylate; Again Azelnidipine methylate is uniformly dispersed in normal heptane solvent; Heating underpressure distillation is except desolventizing; Medicinal alpha crystalline azelnidipine is obtained according to usual method cooling, filtration, drying etc.This inventive method prepares medicinal alpha crystalline azelnidipine, simple to operate, yield is high, purity is high, with low cost, the alpha crystalline azelnidipine yield that the method obtains is about 95% (in Azelnidipine methylate), purity HPLC content > 99.5%.
Describe in Chinese patent CN101596195A (publication number) " combination of oral medication reduced blood pressure " that Zou Yuan grey hair is bright.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, under the prerequisite ensureing curative effect, reduce dosage, and the untoward reaction that long-term prescription brings.
Describe in Japanese Patent JP2010083888 (A) (publication number) " the METHOD FOR PREPARING AZELNIDIPINE CRYSTAL " of people's inventions such as ROSSI ROBERTO.Wherein, relate to the preparation method by the method for the brilliant α type of Azelnidipine brilliant β type sample preparation and Azelnidipine crystalline substance β type.The brilliant α type of Azelnidipine, by being dissolved in aprotic solvent by brilliant β type, adding precipitation solvent and obtains, and the brilliant β type of Azelnidipine can use re crystallization from toluene to obtain.
Describe in master thesis in 2007 of University Of Tianjin " synthesis of Azelnidipine " that Chen Guobin completes.Wherein, relate to the synthesis of Azelnidipine and the brilliant α type of Azelnidipine and brilliant β type Study on Crystallization.
For a person skilled in the art, relative to prior art, still there are such needs in this area: a kind of stable, that biological activity is high new Azelnidipine crystal formation.
Summary of the invention
The polymorphism research that the present inventor exists from Azelnidipine solid matter is started with, by screening polymorph technical study, new crystal aspect of material has surprisedly found a kind of Azelnidipine dihydrate solid matter and ε crystal formation, and this stability of 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.
3rd object of the present invention is to provide the preparation method of above-mentioned Azelnidipine dihydrate and ε crystal formation thereof.
4th object of the present invention is to provide the pharmaceutical composition comprising above-mentioned Azelnidipine dihydrate.
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, (the CuK when 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
there is the diffraction peak that Height% is greater than 20 in place.
Preferably, the ε crystal formation of Azelnidipine the dihydrate provided by the invention, (CuK when using powder x-ray diffraction analysis
αradiation), the position of its diffraction peak respectively in 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 the present embodiment of 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 the present embodiment of the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, containing 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 the present embodiment of the invention, the ε crystal formation solid matter of Azelnidipine dihydrate provided by the invention, have an appointment within the scope of 60 DEG C ~ 95 DEG C in its thermogravimetric analysis TGA collection of illustrative plates 5.8 % by weight two molecular water weight losses, the two molecular water weight losses of described about 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:
Use Azelnidipine methylate sample 20-45 DEG C, humidity places 12 little of 10 days under being more than or equal to 75% condition, preparing Azelnidipine dihydrate, is ε crystal form samples.
In the present embodiment of the invention, the preparation method of described Azelnidipine dihydrate and ε crystal formation solid matter thereof, wherein, described 20-45 DEG C, under humidity is preferably 22-27 DEG C under being more than or equal to 75% condition, humidity is more than or equal to 90% condition, or 35-42 DEG C, under humidity is more than or equal to 75% condition; More preferably, 25 DEG C, under humidity is 95% condition, or 40 DEG C, under humidity is 80% condition.Described placement is preferably 2-8 days in 1-10 days, is more preferably 4-6 days, particularly preferably 5 days.
Fourth aspect, the invention provides the pharmaceutical composition comprising 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 used for and orally uses.The above-mentioned Azelnidipine dihydrate of the present invention or its ε crystal formation solid matter have multifactor impact perhaps on the dosage of effective constituent, such as: the difference causing dosage every day for the purposes difference of prevention and therapy; 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 existed between crystal form samples and Plasma Concentration are equal, also cause the present invention to be 0.01 ~ 200mg/kg body weight at Suitable dosage ranges every day of use Azelnidipine ε crystal formation composition, are preferably 1 ~ 100mg/kg body weight.Azelnidipine ε crystal formation effective constituent total dose scheme should be formulated according to the prevention of reality and treatment different situations demand during use, and can be divided into repeatedly or single administration mode complete.
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 as dihydropyridine type calcium antagonists, for hypertensive treatment.
Prove through test, compared with prior art, biological absorption effect after the medicine that Azelnidipine hydrate provided by the invention and ε crystal formation solid matter thereof are developed as activeconstituents and pharmaceutical composition oral administration thereof, peak concentration value is reached rapidly in gi tract or blood, thus the advantage function played in disease preventing and treating and application.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of Azelnidipine dihydrate ε crystal form samples that what Fig. 1 represented is.
The infrared absorpting light spectra of Azelnidipine dihydrate ε crystal form samples that what Fig. 2 represented is.
The DSC collection of illustrative plates of Azelnidipine dihydrate ε crystal form samples that what Fig. 3 represented is.
The TGA collection of illustrative plates of Azelnidipine dihydrate ε crystal form samples that what Fig. 4 represented is.
The plasma concentration curve that what Fig. 5 represented is after the Azelnidipine dihydrate ε crystal form samples oral absorption of embodiment 1 in rat body.
Embodiment
For technical scheme of the present invention is better described, 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 pressure 40kv, pipe stream 150mA, 2 θ sweep limit 3-80 °, sweep velocity 8 °/point, step-length 0.02 °.Slit condition: divergent slit is 1 °, limit for height slit is 10mm, and antiscatter slits is 1 °, and reception slit is 0.15mm.
2.DSC
(1) laboratory apparatus: Switzerland Mettler DSC1 thermal analyzer
(2) experiment condition: initial temperature is set to 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 set to 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.
Embodiment 1
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 25 DEG C, place under humidity 95% condition and prepare Azelnidipine dihydrate in 5 days, be ε crystal form samples.The x-ray diffractogram of powder spectrum of this ε crystal form samples 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 have an appointment as being presented in Fig. 4, TGA collection of illustrative plates within the scope of 60 DEG C ~ 95 DEG C 5.7% weightlessness, show the weight loss having two molecular waters.
Embodiment 2
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 40 DEG C, place under humidity 80% condition and prepare Azelnidipine dihydrate in 5 days, be ε crystal form samples.
Embodiment 3
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 20 DEG C, place under humidity 75% condition and prepare Azelnidipine dihydrate in 10 days, be ε crystal form samples.
Embodiment 4
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 20 DEG C, place under humidity 85% condition and prepare Azelnidipine dihydrate in 8 days, be ε crystal form samples.
Embodiment 5
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 45 DEG C, place under humidity 80% condition and prepare Azelnidipine dihydrate in 6 days, be ε crystal form samples.
Embodiment 6
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 45 DEG C, place under humidity 90% condition and prepare Azelnidipine dihydrate in 4 days, be ε crystal form samples.
Embodiment 7
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 22 DEG C, place under humidity 95% condition and prepare Azelnidipine dihydrate in 9 days, be ε crystal form samples.
Embodiment 8
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 27 DEG C, place under humidity 90% condition and prepare Azelnidipine dihydrate in 5 days, be ε crystal form samples
Embodiment 9
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 35 DEG C, place under humidity 75% condition and prepare Azelnidipine dihydrate in 2 days, be ε crystal form samples.
Embodiment 10
The preparation method of Azelnidipine ε crystal form samples:
Use Azelnidipine methylate (being prepared by JP Laid-Open 11-116570 and Chinese patent CN200510104895 method) sample 42 DEG C, place under humidity 88% condition and prepare Azelnidipine dihydrate in 1 day, be ε crystal form samples.
Embodiment 11
Azelnidipine ε crystal formation is in rat body absorption characteristic sum Plasma Concentration feature:
Before rat administration, fasting 12h, freely drinks water.Take rat body weight, by 200mgkg
-1azelnidipine dosage calculate, the Azelnidipine sample of different crystal forms is loaded in solid form 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 about 400 μ L.Get blood according to blood sampling time point from the angular vein of rat, put in heparinization Ep pipe, to adopt centrifugal for blood sample 10 minutes under 4 DEG C and 5000 revs/min of conditions, get 150 μ L blood plasma, add mark (50 μ gmL in 10 μ L
-1nimodipine), then add 300 μ L acetonitriles, after vortex oscillation 3min, again sample is adopted 13400rpm centrifugation 10min, get 400 μ L supernatant liquors, dry up with nitrogen.With the mixed solution redissolution residue of 50 μ L (containing water: acetonitrile=12.5 μ L: 37.5 μ L), after vortex oscillation 3min, in the centrifugal 5min of 13400rpm.Get supernatant 35 μ L and carry out HPLC detection.
Testing conditions: detection system: Aligent1200, chromatographic column: Agilent XDB-C18 (250mm × 4.6mm, 5 μm), column temperature: 30 DEG C, moving phase: acetonitrile: water=78: 22 (v/v), flow velocity: 1mL/min, sample size: 20 μ L, determined wavelength: 254nm.
For crystal formation (the α type that Azelnidipine three kinds is different, by the preparation of Chinese patent CN87107150 method, β type, prepared by Chinese patent CN87107150 method, and the ε type of the embodiment of the present invention 1 acquisition) measuring absorption and Plasma Concentration, 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, the dominant feature that Plasma Concentration is high, effect plateau is long.
Following table provides the activeconstituents detected in blood after rat oral takes 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.
Embodiment 12
Azelnidipine tablet
(1) plain tablet recipe
Specification: 8mg/ sheet
(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, and micropowder silica gel, Magnesium Stearate are for subsequent use; (2) by Azelnidipine and Microcrystalline Cellulose mixing, grind altogether, cross 100 mesh sieve three times, mixing, then add pregelatinized Starch and mixed 60 mesh sieves, mixing; (3) (wherein ethanol is 50% ethanol to add 5%PvPk30 ethanolic soln; The collocation method of 5%PvPk30 ethanolic soln is with 50% ethanol for solvent, PvPk30 is made into the solution of 5%.) softwood processed in right amount, softwood 20 mesh sieves are granulated, and dry 2 ~ 4h, granulates.(4) add micropowder silica gel and Magnesium Stearate mixing again, measure work in-process content, calculate and answer compressing tablet weight.(5) plain sheet is suppressed.(6) dressing: 1. take the agent of gastric soluable film bag, add in 80% ethanolic soln, the suspension that 8% (g/v) is made in induction stirring mixing is 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, blowing hot-air 70 DEG C of dryings, repetitive operation, obtains uniform coating membrance; 4. through 30 ~ 40 DEG C of dryings 10 minutes, be more slowly down to room temperature, obtain final product.(7) pack.
Claims (11)
1. the preparation method of the ε crystal formation of Azelnidipine dihydrate, comprises the steps:
Use Azelnidipine methylate sample 20-45 DEG C, humidity places 12 little of 10 days under being more than or equal to 75% condition, prepare the ε crystal formation of Azelnidipine dihydrate;
Wherein, described Azelnidipine dihydrate ε the crystal formation, (CuK when using powder x-ray diffraction analysis
αradiation) show as Height%=100 peak position in 2 θ=19.5 ± 0.2 °
place, and, in 2 θ=5.8 ± 0.2 °
2 θ=12.6 ± 0.2 °
2 θ=16.0 ± 0.2 °
2 θ=20.2 ± 0.2 °
2 θ=23.8 ± 0.2 °
with 2 θ=24.3 ± 0.2 °
there is the diffraction peak that Height% is greater than 20 in place.
2. preparation method according to claim 1, under wherein, described temperature, humidity condition are 22-27 DEG C, humidity is more than or equal to 90% condition, or 35-42 DEG C, under humidity is more than or equal to 75% condition.
3. preparation method according to claim 2, wherein, described temperature, humidity condition for 25 DEG C, under humidity is 95% condition, or 40 DEG C, under humidity is 80% condition.
4. preparation method according to claim 1, wherein, described storage period is 2-8 days.
5. preparation method according to claim 4, wherein, described storage period is 4-6 days.
6. preparation method according to claim 5, wherein, the described time is 5 days.
7. preparation method according to claim 1, wherein, use Azelnidipine methylate sample 25 DEG C, place the ε crystal formation preparing Azelnidipine dihydrate for 5 days under humidity 95% condition.
8. preparation method according to claim 1, wherein, use Azelnidipine methylate sample 40 DEG C, place the ε crystal formation preparing Azelnidipine dihydrate for 5 days under humidity 80% condition.
9. preparation method according to claim 1, wherein, described Azelnidipine dihydrate ε the crystal formation, (CuK when using powder x-ray diffraction analysis
αradiation), its diffraction peak position is ° value in 2 θ (°) ± 0.2 respectively
value has following expression:
10. preparation method according to claim 9, 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.
11. preparation methods according to claim 10, wherein, the melting point values of described Azelnidipine dihydrate ε crystal formation is 98 DEG C ± 2 DEG C.
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| 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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| 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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