CN103319457B - The preparation method of Azelnidipine γ crystal formation - Google Patents
The preparation method of Azelnidipine γ crystal formation Download PDFInfo
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- CN103319457B CN103319457B CN201210074686.XA CN201210074686A CN103319457B CN 103319457 B CN103319457 B CN 103319457B CN 201210074686 A CN201210074686 A CN 201210074686A CN 103319457 B CN103319457 B CN 103319457B
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Abstract
The invention discloses the preparation method of a kind of new brilliant γ type material of Azelnidipine.The new brilliant γ type material of the Azelnidipine adopting preparation method of the present invention to obtain, as active constituents of medicine, has good stability, absorption rate is fast, Plasma Concentration is high, acts on the advantage of plateau length.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, more particularly, relate to the preparation method of a kind of new γ crystal-form substances of Azelnidipine.
Background technology
Azelnidipine is a kind of dihydropyridine type calcium antagonists, English name azelnidipine, chemistry 3,5-pyridine dicarboxylic acid by name, Isosorbide-5-Nitrae-dihydropyridine-2-amino-6-methyl, and molecular structure is as follows:
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, add alkane, crystal seed 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 (application publication number) 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 (application publication number) 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 (application publication number) " 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, that yield is high, purity is high, with low cost, present method is obtained alpha crystalline azelnidipine yield 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) " METHODFORPREPARINGAZELNIDIPINECRYSTAL " of people's inventions such as ROSSIROBERTO.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 synthesis and the brilliant α type of Azelnidipine, the crystallization of brilliant β type and the unformed research of Azelnidipine, and, this author thinks that Azelnidipine alpha type and β type two kinds of crystal formations belong to stable crystal formation, and Azelnidipine is unformed is unstable crystal formation; In addition, the biological activity of Azelnidipine different crystal forms is different, and the biological activity of α type is the strongest, is 2.6 times of β type.
Above-mentioned patent is all synthesis about pharmaceutical preparation or composition and compound and chirality process of preparing.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 new γ crystal formation of Azelnidipine solid matter, and this crystal formation has well stable and biological activity is high.
The object of this invention is to provide a kind of preparation method of Azelnidipine γ crystal-form substances.
In embodiments of the invention, the new γ crystal-form substances of Azelnidipine prepared by the present invention, uses CuK
αthe powder x-ray diffraction analysis of radiation, its x-ray diffractogram of powder spectrum shows as Height%=100 peak position in 2 θ=19.9 ± 0.2 °,
place.The new γ crystal-form substances of Azelnidipine provided by the invention, its x-ray diffractogram of powder spectrum as shown in Figure 1.
In the present embodiment of the invention, Azelnidipine γ crystal-form substances prepared by the present invention, the infrared absorption spectrum of its KBr pressed disc method 3342,3315,3060,3026,2977,2835,2834,2774,2092,1674,1617,1551,1525,1486,1452,1384,1372,1346,1314,1285,1212,1177,1103,1079,1066,1028,922,903,825,805,790,744,703,679cm
-1± 2cm
-1there is absorption peak.More preferably, the diffuse reflectance infrared spectroscopy peak position that presents of the new γ crystal-form substances of Azelnidipine of the present invention as shown in Figure 2.
In the present embodiment of the invention, Azelnidipine γ crystal-form substances prepared by the present invention, its melting point values is 107 DEG C ± 2 DEG C.
In the present embodiment of the invention, Azelnidipine γ crystal-form substances prepared by the present invention, when temperature rise rate is not containing neither endothermic nor exothermic peak in the DSC collection of illustrative plates of per minute 10 DEG C.Preferably, the DSC collection of illustrative plates of Azelnidipine γ crystal-form substances of the present invention as shown in Figure 3.
In the present embodiment of the invention, Azelnidipine γ crystal-form substances prepared by the present invention, its sample belongs to the photoactive racemic modification of irrotationality.
The invention provides the preparation method of above-mentioned Azelnidipine γ crystal-form substances, comprise the following steps: to use a kind of solvent in tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, methyl alcohol or 95 to 100 volume % ethanol, at arbitrary temperature between normal temperature to above-mentioned solvent refluxing, Azelnidipine sample is dissolved completely, and under envrionment temperature 4 DEG C ~ 80 DEG C, ambient moisture 10% ~ 75%, normal pressure or vacuum pressure condition, above-mentioned solvent is removed, and obtain the new γ crystal form samples of Azelnidipine.
The invention provides the preparation method of Azelnidipine γ crystal-form substances, comprise the following steps: to use tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, 95 to 100 volume % ethanol, methyl alcohol, normal hexane, hexanaphthene, methylene dichloride, water, or any mixed solvent that two or more dissolves each other in sherwood oil, at arbitrary temperature between normal temperature to described mixed solvent backflow, Azelnidipine sample to be dissolved completely and through envrionment temperature 4 DEG C ~ 80 DEG C, ambient moisture 10% ~ 75%, under normal pressure or vacuum pressure condition, above-mentioned mixed solvent is removed, and obtain the new γ crystal form samples of Azelnidipine.
In the preparation method of above-mentioned Azelnidipine γ crystal-form substances provided by the invention, described in the dissolve each other volume ratio of mixed solvent be arbitrary proportion, do not limit.
The invention provides the preparation method of Azelnidipine γ crystal-form substances, comprise the following steps: to use tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, methyl alcohol, or a kind of solvent in 95 to 100 volume % ethanol, or use tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, 95 to 100 volume % ethanol, methyl alcohol, normal hexane, hexanaphthene, methylene dichloride, water, or two or more mixed solvent dissolved each other in sherwood oil, after Azelnidipine sample being dissolved completely at arbitrary temperature between normal temperature to described solvent refluxing, add insoluble precipitation and obtain the new γ crystal form samples of Azelnidipine.Here, described insoluble precipitation refers to the solvent that can not dissolve Azelnidipine, can be selected from hexanaphthene, normal hexane.
The invention provides the preparation method of Azelnidipine γ crystal-form substances, comprise the following steps: to use Azelnidipine sample as raw materials and adopt physical mechanics lattice damage and molecular transposition rotating crystal method to prepare γ crystal formation solid matter or prepare the new γ crystal form samples of Azelnidipine by the pressure condition of change physics, temperature condition.
In the preparation method of above-mentioned Azelnidipine γ crystal-form substances provided by the invention, described Azelnidipine sample optionally can be arbitrary crystal formation or their mixture such as α, β, amorphous or solvate.The ratio of described Azelnidipine and above-mentioned solvent is under optimal temperature, Azelnidipine can be dissolved complete.
In addition, the invention provides the pharmaceutical composition comprising the new γ crystal-form substances of Azelnidipine prepared by aforesaid method.This pharmaceutical composition comprises the new γ crystal-form substances of Azelnidipine and the pharmaceutically vehicle of pharmacologically significant quantity.Here, the crystal form purity of the new γ crystal-form substances of described Azelnidipine is 1 ~ 100 % by weight.The pharmaceutical composition comprising the new γ crystal-form substances of Azelnidipine of the present invention can be tablet, capsule, pill, solid particulate agent or injection etc., and can be slowly-releasing or control-released agent.Those skilled in the art according to the method for existing pharmaceutics, can make above-mentioned formulation.The pharmaceutical composition of the new γ crystal-form substances of described Azelnidipine, wherein, Azelnidipine new γ crystal-form substances as its every daily ingestion dosage of activeconstituents in 0.1mg ~ 500mg scope.
Azelnidipine new γ crystal-form substances is as the drug products for administration dosage of activeconstituents: the medicinal tablet using Azelnidipine new γ crystal form samples to manufacture as active constituents of medicine or other preparations, it is characterized in that containing the activeconstituents of the new γ crystal formation of Azelnidipine as medicine, daily dosage is 8mg, 2 times/each 1 4mg conventional tablet every day can be prepared into respectively, every day 1 time/each 1 8mg conventional tablet or other formulations.
Need the problem illustrated: the Azelnidipine that the present invention relates to new γ crystal formation pharmaceutical composition has 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 new γ crystal formation composition, are preferably 1 ~ 100mg/kg body weight.Azelnidipine new γ 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.
Azelnidipine prepared by the present invention new γ crystal-form substances class is preventing or disease therapy as dihydropyridine type calcium antagonists medicine.The new γ crystal-form substances of the Azelnidipine that preparation method of the present invention obtains ensure that prevention that its Absorption Characteristics in vivo, effectively bioavailability, effective blood drug concentration, stable time of continuing and reaching makes the most of the advantage, therapeutic action and application.
Prove, Azelnidipine prepared by the present invention new γ crystal formation solid matter good stability compared with prior art, there is absorption rate fast, the advantage that Plasma Concentration is high, effect plateau is long through test.
Accompanying drawing explanation
The x-ray diffractogram of powder spectrum of Azelnidipine γ crystal form samples that what Fig. 1 represented is.
The infrared absorpting light spectra of Azelnidipine γ crystal form samples that what Fig. 2 represented is.
The DSC collection of illustrative plates of Azelnidipine γ crystal form samples that what Fig. 3 represented is.
The plasma concentration curve that what Fig. 4 represented is after Azelnidipine γ crystal form samples oral absorption 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 RigakuD/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 MettlerDSC1 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 10K/min.
3.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
Azelnidipine new γ crystal-form substances preparation method
The preparation method of the new γ crystal form samples of Azelnidipine, 150mg Azelnidipine sample is placed in 100ml round-bottomed flask to add 30ml tetrahydrofuran (THF) and under 40 DEG C of heated reflux condition, sample is dissolved completely, be filtered hot in 100ml round-bottomed flask, remove solvent method through 40 DEG C of vacuum and obtain Azelnidipine γ crystal form samples.Detect PXRD (see Fig. 1), IR (see Fig. 2), the DSC (see Fig. 3) of Azelnidipine γ crystal form samples.
Embodiment 2
The preparation method of the new γ crystal form samples of Azelnidipine:
The preparation method of the new γ crystal form samples of Azelnidipine, 147mg Azelnidipine sample is placed in the tetrahydrofuran (THF) that 100ml round-bottomed flask adds 40ml mixing: sherwood oil=20ml:20ml makes sample dissolve completely under 40 DEG C of heated reflux condition, be filtered hot in 100ml round-bottomed flask, remove solvent method through 40 DEG C of vacuum and obtain Azelnidipine γ crystal form samples.Detect PXRD (same to Fig. 1), IR (same to Fig. 2), the DSC (same to Fig. 3) of Azelnidipine γ crystal form samples.
Embodiment 3
The preparation method of the new γ crystal form samples of Azelnidipine:
The preparation method of the new γ crystal form samples of Azelnidipine, it is characterized in that 200mg Azelnidipine sample is placed in 100ml round-bottomed flask adds 10ml dioxane, under heating in water bath 80 DEG C of conditions, sample is dissolved completely, add 150ml hexanaphthene under agitation, room temperature left standstill after 1 day, suction filtration, sample, through normal temperature drying under reduced pressure 4h, obtains Azelnidipine γ crystal form samples.Detect PXRD (same to Fig. 1), IR (same to Fig. 2), the DSC (same to Fig. 3) of Azelnidipine γ crystal form samples.
Embodiment 4
The preparation method of the new γ crystal form samples of Azelnidipine:
The preparation method of the new γ crystal form samples of Azelnidipine, is characterized in that 200mg Azelnidipine sample to obtain Azelnidipine γ crystal form samples through lattice physical disruption methods (after 110 DEG C of meltings rapidly cooling or through grinding).Detect PXRD (same to Fig. 1), IR (same to Fig. 2), the DSC (same to Fig. 3) of Azelnidipine γ crystal form samples.
Embodiment 5
Azelnidipine tablet
(1) plain tablet recipe
Specification: 8mg/ sheet
(2) coating fluid prescription
Preparation technology: (1) takes Azelnidipine (the new γ crystal formation of Azelnidipine that in the embodiment of the present invention 1 to 4, either method is obtained) by recipe quantity, pregelatinized Starch, Microcrystalline Cellulose, PvPk
30, 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) 5%PvPk is added
30ethanolic soln (50% ethanol) 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.
Test example 1 estimation of stability
Respectively stability study is carried out to Azelnidipine three kinds of crystal formations (α type, β type, and embodiment of the present invention acquisition γ type).Adopt the influence factor method that Chinese Pharmacopoeia (version in 2010) specifies, under crystal formation medicine is placed on high temperature, high humidity, illumination condition, respectively at sampling in 0 day, 5 days, 10 days, PXRD method is adopted to detect, to examine or check the stability of crystal-form substances state.
Laboratory apparatus is the comprehensive testing chamber for medicine stability adopting upper sea blue leopard testing installation company limited, model LHH-250GSP.
1.1 high temperature test
Take Azelnidipine sample 100mg in open containers, place 10 days at 60 DEG C of temperature, respectively at the 0th day, the 5th day and sampling in the 10th day.
1.2 high wet tests
Take Azelnidipine sample 100mg in culture dish, be placed in stable case, place 10 days under 25 DEG C of relative humidity 90% ± 5% conditions, respectively at the 0th day, the 5th day and sampling in the 10th day.
1.3 exposure experiments to light
Take Azelnidipine bulk drug sample 100mg in open containers, put in the lighting box that fluorescent lamp is housed and place 10 days, respectively at the 0th day, the 5th day and sampling in the 10th day.
Aforementioned stable test-results shows, and Azelnidipine three kinds of crystal formations (α type, β type, and the embodiment of the present invention obtains γ type) stable crystal form, PXRD collection of illustrative plates does not change.
Test example 2 Azelnidipine different crystal forms is in the contrast of rat body absorption and Plasma Concentration
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: AgilentXDB-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 the different crystal formation of Azelnidipine three kinds (α type, β type, and the embodiment of the present invention obtains γ type and measures and absorb and Plasma Concentration (see Fig. 4), 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 |
| γ type | 2.88±0.13 | 32.00±6.93 | 5.38±0.99 | 71.91±13.07 |
* note: because the some Plasma Concentration at 60 hours when No. 2 animal plasmas of brilliant α type Azelnidipine detect is 1.608 μ gmL in experimentation
-1, the some detectable level of 72 hours is 0, causes No. 2 basic pharmacokinetic parameters of rat and 1, No. 3 rat has larger difference.
The above results shows, the new γ crystal formation of Azelnidipine of the present invention absorbs and is better than other crystal formations, has absorption rate fast, and Plasma Concentration is high, its long dominant feature of effect platform.
Following table provides the activeconstituents detected in blood after rat oral takes the new γ crystal form samples of Azelnidipine.
Claims (9)
1. the preparation method of Azelnidipine γ crystal formation, comprises the steps:
Use a kind of solvent in tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, methyl alcohol or 95 to 100 volume % ethanol, at arbitrary temperature between normal temperature to described solvent refluxing, Azelnidipine is dissolved completely, and through envrionment temperature 4 DEG C ~ 80 DEG C, ambient moisture 10% ~ 75%, normal pressure or vacuum pressure condition, above-mentioned solvent is removed, and obtain Azelnidipine γ crystal formation;
Here, described Azelnidipine γ crystal formation, uses the alpha-emitting powder x-ray diffraction analysis of CuK, and its x-ray diffractogram of powder spectrum is Fig. 1.
2. Azelnidipine γ crystal formation preparation method according to claim 1, wherein, described solvent is tetrahydrofuran (THF).
3. the preparation method of Azelnidipine γ crystal formation, comprises the steps:
Use any mixed solvent that two or more dissolves each other in tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, 95 to 100 volume % ethanol, methyl alcohol, normal hexane, hexanaphthene, methylene dichloride, water or sherwood oil, at arbitrary temperature between normal temperature to described mixed solvent backflow, Azelnidipine is dissolved completely, and through envrionment temperature 4 DEG C ~ 80 DEG C, ambient moisture 10% ~ 75%, normal pressure or vacuum pressure condition, above-mentioned mixed solvent is removed, and obtain Azelnidipine γ crystal formation;
Here, described Azelnidipine γ crystal formation, uses the alpha-emitting powder x-ray diffraction analysis of CuK, and its x-ray diffractogram of powder spectrum is Fig. 1.
4. Azelnidipine γ crystal formation preparation method according to claim 3, wherein, described mixed solvent is tetrahydrofuran (THF) and sherwood oil.
5. Azelnidipine γ crystal formation preparation method according to claim 4, wherein, the volume ratio of tetrahydrofuran (THF) and sherwood oil is 1:1.
6. the preparation method of Azelnidipine γ crystal formation, comprises the steps:
Use tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, methyl alcohol, or a kind of solvent in 95 to 100 volume % ethanol, or use tetrahydrofuran (THF), acetone, ethyl acetate, chloroform, dioxane, acetonitrile, Virahol, n-propyl alcohol, propyl carbinol, 95 to 100 volume % ethanol, methyl alcohol, normal hexane, hexanaphthene, methylene dichloride, water, or two or more mixed solvent dissolved each other in sherwood oil, after Azelnidipine being dissolved completely under normal temperature to the arbitrary temperature between described solvent or mixed solvent backflow, add insoluble precipitation and obtain Azelnidipine γ crystal formation, here, describedly insolublely hexanaphthene or normal hexane is precipitated as,
Here, described Azelnidipine γ crystal formation, uses the alpha-emitting powder x-ray diffraction analysis of CuK, and its x-ray diffractogram of powder spectrum is Fig. 1.
7. Azelnidipine γ crystal formation preparation method according to claim 6, wherein, described solvent is dioxane.
8. the preparation method of Azelnidipine γ crystal formation, comprises and uses Azelnidipine as raw materials and adopt physical mechanics lattice damage and molecular transposition rotating crystal method to prepare γ crystal formation or prepare Azelnidipine γ crystal formation by the change pressure condition of physics, temperature condition;
Here, described Azelnidipine γ crystal formation, uses the alpha-emitting powder x-ray diffraction analysis of CuK, and its x-ray diffractogram of powder spectrum is Fig. 1.
9. Azelnidipine γ crystal formation preparation method according to any one of claim 1 to 8, wherein, to use Azelnidipine be optionally the arbitrary crystal formation in α, β, amorphous or solvate or their mixture.
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| CN87107150A (en) * | 1986-10-09 | 1988-05-04 | 三共株式会社 | Dihydrogen pyridine derivative and its production and use |
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| CN87107150A (en) * | 1986-10-09 | 1988-05-04 | 三共株式会社 | Dihydrogen pyridine derivative and its production and use |
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| 阿折地平的合成;孙晋瑞 等;《齐鲁药事》;20051231;第24卷(第6期);第365-366页 * |
| 阿折地平的合成及其结晶的研究;陈国斌;《化学工业与工程》;20090131;第26卷(第1期);第15-18页 * |
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