CN102952144A - Crystal forms of asenapine maleate, and preparation method and medical composition thereof - Google Patents
Crystal forms of asenapine maleate, and preparation method and medical composition thereof Download PDFInfo
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Abstract
The invention discloses crystal forms of asenapine maleate, and a preparation method and medical composition thereof. The crystal forms A and B of asenapine maleate are stable in crystal form and high in micronization performance, and have a favorable dissolution rate in a water system after being subjected to micronization. Thus, the crystal forms are suitable for being prepared with the conventional medical auxiliary materials into the medical composition, and can be used for preparing an oral solid preparation having a fine dissolution rate.
Description
Technical field
The present invention relates to crystal formation, preparation method and the pharmaceutical composition thereof of asenapine maleate, be specifically related to a kind of new crystal A and B, preparation method and pharmaceutical composition thereof of asenapine maleate.This new crystal A and B stable crystal form, the micronization performance is strong, is fit to form composition with conventional pharmaceutical excipient, for the manufacture of the oral solid formulation with good dissolution rate.
Background technology
Asenapine maleate (asenapine ma1eate) is a kind of compound that central nervous system suppresses activity, antihistamine and medmain activity that has, chemical name is trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7]-oxepin [4,5-c] pyrroles maleate also.Research has confirmed that the asenapine maleate is a kind of antagonist of serotonin, norepinephrine and Dopamine HCL of broad-spectrum high efficacy, has stronger antipsychotic activity, and can be used for the treatment of dysthymia disorders.
The physico-chemical properties such as the solvability of the crystal formation of medicine and grain diameter influence's medicine, dissolution rate, and then can affect bioavailability and the pharmacodynamic parameter of medicine.Chinese invention patent CN1079670C discloses the pharmaceutical composition that contains the asenapine maleate of a kind of hypogloeeis or orally administering, with hypogloeeis or the administration of orally administering mode.Because this medicine dissolution is in saliva, thereby its particle diameter is very important.When drug particles is small, only need spends the short period of time and just can reach the high density level.The less particle diameter of bulk drug is described thus and dissolution rate is particularly important fast.
Chinese invention patent CN1861604A discloses a kind of crystal formation of A Sena product maleate, embodiment 16 discloses a kind of orthorhombic pharmaceutical composition of asenapine maleate that contains, said composition is by joining the micronized iris of asenapine maleate in gelatin/Osmitrol, and freezing and sublimation ices to obtain the freeze-drying sheet, adopt special preparation technique, to carry the dissolution rate of this product, illustrate that this iris dissolution rate is low, be unfavorable for sublingual administration.This patent also discloses the method for this iris type of preparation from the ethanol water mixed solution simultaneously, and prepares oblique crystal in straight alcohol solution.For obtaining the iris type, the asenapine maleate is dissolved in the ethanol/water mixing solutions, stir 72h after the cooling after, to-10 ℃ of restir a few hours, perhaps slowly cool to room temperature, add the iris kind after, at 20 ± 5 ℃ of lower cooling 48 ± 6h.This technique recrystallization time is long, and need be cooled to-10 ℃, and energy consumption is large, and cost is high; It is comparatively strict that processing condition require, and prepared monoclinic form and iris type stablize relatively poorly, and under general preservation condition, the two exists mutually and transforms, and brings uncertainty to pharmaceutical engineering, has larger defective.Simultaneously, by embodiment 2 and example 3, find that this crystallization processes requirement is harsh, can't the revision test result.And this patent also further discloses this iris and has carried out d95＜30 μ m after the micronization in embodiment 9～15, grindability can be low, and dissolution rate is slow.Can't obtain the drug substance of high polycrystalline purity after the oblique crystal micronization, the oblique crystal physical stability is poor.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of new crystal A and B, preparation method and pharmaceutical composition thereof of asenapine maleate, this new crystal A and B stable crystal form, the micronization performance is strong, be fit to make pharmaceutical composition with conventional pharmaceutical excipient, for the preparation of the oral solid formulation with good dissolution rate, the said preparation friability is little, should carry.The advantages such as new crystal A of the present invention and B preparation method are simple to operate, and kinetic energy requires low, and the cycle is short, and repeatability is strong.
The new crystal A of asenapine maleate of the present invention, the powder x-ray diffraction collection of illustrative plates that obtains with the Cu-K alpha-ray is 10.0 ± 0.1 ° in 2 θ reflection angle values, 12.0 ± 0.1 °, 15.1 ± 0.1 °, 19.9 located characteristic peak for ± 0.1 ° and 30.4 ± 0.1 °, it is 10.0 ± 0.1 ° in 2 θ reflection angle values particularly, 10.6 ± 0.1 °, 12.0 ± 0.1 °, 15.1 ± 0.1 °, 19.9 ± 0.1 °, 22.2 ± 0.1 °, 24.3 ± 0.1 °, 25.2 ± 0.1 °, 25.9 ± 0.1 °, located characteristic peak for 30.4 ± 0.1 °.
The new crystal B of asenapine maleate of the present invention, the powder x-ray diffraction collection of illustrative plates that obtains with the Cu-K alpha-ray is 6.6 ± 0.1 ° in 2 θ reflection angle values, 18.6 ± 0.1 °, 27.4 located characteristic peak for ± 0.1 ° and 28.0 ± 0.1 °, be 6.6 ± 0.1 ° in 2 θ reflection angle values particularly, 9.3 ± 0.1 °, 13.2 ± 0.1 °, 15.0 ± 0.1 °, 16.8 ± 0.1 °, 18.6 ± 0.1 °, 20.1 ± 0.1 °, 21.2 ± 0.1 °, 27.4 ± 0.1 °, located characteristic peak for 28.0 ± 0.1 °.
The new crystal A of asenapine maleate of the present invention adopts the solvent crystallization preparation, use industrial nontoxic mixed solvent dehydrated alcohol/normal heptane, dehydrated alcohol/sherwood oil or dehydrated alcohol/ether commonly used to get final product, room temperature or refrigeration can make, condition safety, stable.Concrete steps are as follows:
1) asenapine maleate 100g is dissolved in 60 ℃ to the ethanol solution that refluxes, the dehydrated alcohol consumption is 400ml～500ml;
2) naturally cool to room temperature, add n-heptane, sherwood oil or diethyl ether solution, stir 10min～10h, wherein the add-on of n-heptane, sherwood oil or diethyl ether solution is 40ml～100ml;
3) leave standstill crystallization, filter, filter cake dehydrated alcohol/normal heptane, dehydrated alcohol/sherwood oil, or dehydrated alcohol/ether mixing solutions drip washing;
4) 30 ℃～80 ℃ vacuum-drying 5～24h, and get final product.
Asenapine maleate new crystal B of the present invention adopts the solvent crystallization preparation, only uses industrial innoxious solvent dehydrated alcohol room temperature commonly used to refrigerate to crystallization complete, can make product safety, condition safety, stable.Concrete steps are as follows:
1) asenapine maleate 100g is dissolved in 60 ℃ to the ethanol solution that refluxes, the dehydrated alcohol consumption is 200ml～500ml;
2) naturally cool to room temperature, leave standstill crystallization;
3) filter filter cake dehydrated alcohol drip washing;
4) 30 ℃～80 ℃ vacuum-drying 5～24h, and get final product.
Asenapine maleate new crystal A of the present invention is that melting range is 125.0 ℃～127.5 ℃ specific polymorphic, and new crystal B is that melting range is 138.5～140.0 ℃ specific polymorphic.By several different methods such as infrared spectroscopy (IR), dsc (DSC), X-ray powder diffraction (XRD) they are characterized (referring to Fig. 1,2,3,4 and 6,7,8,9), the result shows that asenapine maleate new crystal A of the present invention and B are different from monoclinic form and the iris type of existing bibliographical information.
Measure the size-grade distribution (referring to Fig. 5,10) of asenapine maleate new crystal A of the present invention and B crystallization with laser diffractometry.The result shows: D after the new crystal A micronization
(0.5)＜7 μ m, D
(0.9)＜15 μ m, grindability is strong; And after the new crystal A micronization, can obtain the drug substance (comprise 10% or another kind of crystal formation still less, 5% or another kind of crystal formation still less, or undetectable another kind of crystal formation) of high polycrystalline purity.D after the new crystal B micronization
(0.5)＜7 μ m, D
(0.9)＜15 μ m, grindability is strong; After the micronization, new crystal B can obtain the drug substance (comprise 10% or another kind of crystal formation still less, 5% or another kind of crystal formation still less, or undetectable another kind of crystal formation) of high polycrystalline purity.
Asenapine maleate new crystal A of the present invention and B are carried out infrared spectroscopy (IR) analysis.The result shows, new crystal A is at 3403 ± 2cm
-1, 2953 ± 2cm
-1, 2586 ± 2cm
-1, 1701 ± 2cm
-1, 1575 ± 2cm
-1, 1480 ± 2m
-1, 1383 ± 2cm
-1, 1361 ± 2cm
-1, 1279 ± 2cm
-1, 1240 ± 2cm
-1, 1181 ± 2cm
-1, 865 ± 2cm
-1There is characteristic peak at the place; New crystal B is at 3421 ± 2cm
-1, 3032 ± 2cm
-1, 2444 ± 2cm
-1, 1700 ± 2cm
-1, 1617 ± 2cm
-1, 1582 ± 2m
-1, 1479 ± 2cm
-1, 1352 ± 2cm
-1, 1280 ± 2cm
-1, 1270 ± 2cm
-1, 867 ± 2cm
-1There is characteristic peak at the place.
Asenapine maleate new crystal A of the present invention and B crystallization are carried out hot analysis and characterization.Differential scanning amount (DSC) is measured and is shown, new crystal A can be characterized by near the endothermic transition peak of feature 125 ℃, and new crystal B can be characterized by near the endothermic transition peak of feature 140 ℃.Thermogravimetric analysis (TG) shows, weight-temperature variation curve shows does not all have recrystallisation solvent to exist.
Adopt the JGM-H50 micronizer mill that asenapine maleate new crystal A of the present invention and B are carried out micronized and measure its powder X-ray--the ray diffraction collection of illustrative plates.The result shows: after the new crystal A micronization, still possessing the X-ray diffracting spectrum feature of front its powder of micronization, is 10.0 ± 0.1 ° in 2-θ reflection angle (2 θ angle) value namely, 10.6 ± 0.1 °, 12.0 ± 0.1 °, 15.1 ± 0.1 °, 19.9 ± 0.1 °, 22.2 ± 0.1 °, 24.3 ± 0.1 °, 25.2 ± 0.1 °, 25.9 ± 0.1 °, located characteristic peak for 30.4 ± 0.1 °.New crystal B still possesses the X-ray diffracting spectrum feature of front its powder of micronization, it is 6.6 ± 0.1 ° in 2-θ reflection angle (2 θ angle) value namely, 9.3 ± 0.1 °, 13.2 ± 0.1 °, 15.0 ± 0.1 °, 16.8 ± 0.1 °, 18.6 ± 0.1 °, 20.1 ± 0.1 °, 21.2 ± 0.1 °, 27.4 ± 0.1 °, located characteristic peak for 28.0 ± 0.1 °.
Represent asenapine maleate new crystal A of the present invention with the crystallography data, the result shows that it belongs to monoclinic another new crystal, and these data are referring to table 1a and 1b.Axial length among the table 1a typically represents particular value
Crystal angle typical earth surface registration value among the table 1a ± 0.2 °.Atom site (x, y, z) typical earth surface registration value among the table 1b ± 0.002.
The crystallography data of table 1a asenapine maleate new crystal A
The atom site crystallography data of table 1b asenapine maleate new crystal A
| x | y | z | U(eq) | |
| Cl(1) | 5088(2) | 7343(1) | 9937(1) | 96(1) |
| N(1) | 5273(4) | 5678(1) | 6043(3) | 59(1) |
| O(1) | 10987(3) | 6671(1) | 5964(2) | 68(1) |
| C(1) | 6782(5) | 7145(1) | 8726(3) | 66(1) |
| C(2) | 8602(6) | 7347(1) | 8334(4) | 82(1) |
| C(3) | 9961(6) | 7191(1) | 7395(4) | 78(1) |
| C(4) | 9500(5) | 6834(1) | 6848(3) | 58(1) |
| C(5) | 7666(4) | 6626(1) | 7240(3) | 55(1) |
| C(6) | 6305(5) | 6788(1) | 8185(3) | 62(1) |
| C(7) | 10254(5) | 6615(1) | 4529(3) | 59(1) |
| C(8) | 11676(6) | 6766(1) | 3569(4) | 76(1) |
| C(9) | 11167(8) | 6711(1) | 2131(5) | 94(1) |
| C(10) | 9233(8) | 6519(1) | 1641(4) | 91(1) |
| C(11) | 7855(6) | 6373(1) | 2578(3) | 76(1) |
| C(12) | 8337(5) | 6413(1) | 4055(3) | 58(1) |
| C(13) | 6685(5) | 6249(1) | 5023(3) | 61(1) |
| C(14) | 7366(5) | 6235(1) | 6603(3) | 56(1) |
| C(15) | 5545(5) | 5990(1) | 7135(3) | 59(1) |
| C(16) | 6025(6) | 5834(1) | 4676(3) | 76(1) |
| C(17) | 2969(5) | 5508(1) | 5916(4) | 85(1) |
| C(18) | 1848(6) | 5772(1) | -24(3) | 74(1) |
| C(19) | 31(5) | 5572(1) | 637(3) | 70(1) |
| C(20) | 43(5) | 5291(1) | 1572(3) | 69(1) |
| C(21) | 1975(5) | 5074(1) | 2301(3) | 62(1) |
| O(2) | 1418(5) | 6017(1) | -896(3) | 103(1) |
| O(3) | 3958(4) | 5685(1) | 402(3) | 108(1) |
| O(4) | 3968(4) | 5161(1) | 2119(3) | 91(1) |
| O(5) | 1490(4) | 4813(1) | 3097(3) | 87(1) |
New crystal A of the present invention and B add the conventional required pharmaceutical excipient of solid preparation, can be prepared into pharmaceutical composition, its formulation can be tablet, Sublingual tablet, powder, capsule etc., the total amount that wherein contains new crystal A of the present invention or B in every unit preparation is 7.03mg or 14.06mg, perhaps in unit formulation of the present invention, the content of new crystal A or B is 1wt%～50wt%, preferred 4wt%～20wt%.Described pharmaceutical excipient can select weighting agent such as lactose, N.F,USP MANNITOL, Xylitol, sucrose,
(Basf),
(Basf) etc., disintegrating agent such as low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, polyvinylpolypyrrolidone, croscarmellose sodium etc., lubricant such as Magnesium Stearate, stearic acid, polyethylene glycol 6000, sodium stearyl fumarate, stearyl fumarate calcium, micropowder silica gel etc., correctives such as aspartame etc.
Beneficial effect:
New crystal A of the present invention and B stable crystal form, the micronization performance is high, and new crystal A and B still can keep original crystal formation feature after the micronization, have good dissolution rate after the micronization in aqueous systems, and have good friability, are convenient for carrying.Micronized new crystal A and B add behind the conventional pharmaceutical excipient routinely technique can prepare the oral preparations that has excellent dissolution rate performance.
New crystal A of the present invention and B preparation technology are simple to operate, and energy consumption is low, and the cycle is short, and repeatability is strong.
Description of drawings
Fig. 1 is the powder x-ray diffraction collection of illustrative plates of new crystal A of the present invention.
Fig. 2 is the fourier-transform infrared collection of illustrative plates of new crystal A of the present invention.
Fig. 3 is the means of differential scanning calorimetry mensuration figure of new crystal A of the present invention.
Fig. 4 is the thermogravimetric mensuration figure of new crystal A of the present invention.
Fig. 5 is the size distribution curve of new crystal A of the present invention.
Fig. 6 is the powder x-ray diffraction collection of illustrative plates of new crystal B of the present invention.
Fig. 7 is the fourier-transform infrared collection of illustrative plates of new crystal B of the present invention.
Fig. 8 is the means of differential scanning calorimetry mensuration figure of new crystal B of the present invention.
Fig. 9 is the thermogravimetric mensuration figure of new crystal B of the present invention.
Figure 10 is the size distribution curve of new crystal B of the present invention.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described in further detail, but described embodiment does not limit protection scope of the present invention.
All testing apparatus situations of the application are as follows:
D/MAX 2550VB/PC x-ray powder polycrystalline diffractometer (Japanese Rigaku); Nexus 470FT-IR Spectrometer Fourier transform infrared spectrometer (U.S. Nicolet company); DSC 204F1
Differential scanning calorimeter (German Netzsch company); TG 209F3Tarsus thermogravimetric analyzer, Mastersizer 2000 laser fineness gages (Britain Malvern company); CCD Smart APEXX ray single crystal diffractometer (German Bruker company).
Take by weighing asenapine maleate 100g, place in the flask, add in the dehydrated alcohol of 400ml volume, 60 ℃ of left and right sides stirring and dissolving of water-bath add normal heptane 100ml, stir 10min, remove heating unit, naturally cooling is cooled to room temperature, leaves standstill crystallization, crystallization is rear the filtration fully, filter cake is with a small amount of cold mixing solvent (dehydrated alcohol/normal heptane=4/1, v/v) drip washing, 40 ℃ of vacuum-drying 8 hours, obtain solid 77.1g, mp:126.3 ℃.
Powder x-ray diffraction is analyzed: identify to belong to asenapine maleate new crystal A, its X-ray diffracting spectrum is 10.1 ° in 2 θ reflection angle values, 12.1 °, 15.1 °, located characteristic peak for 20.0 ° and 30.4 °, be 10.1 ° in 2 θ reflection angle values particularly, 10.6 °, 12.1 °, 15.1 °, 20.0 °, 22.2 °, 24.3 °, 25.2 °, 25.8 °, located characteristic peak for 30.4 °.
IR analyzes: at 3405cm
-1, 2954cm
-1, 2588cm
-1, 1703cm
-1, 1574cm
-1, 1480m
-1, 1385cm
-1, 1360cm
-1, 1278cm
-1, 1244cm
-1, 1189cm
-1, 864cm
-1There is characteristic peak at the place.
With asenapine maleate 100g, place in the flask, add in the dehydrated alcohol of 500ml volume, 60 ℃ of left and right sides stirring and dissolving of water-bath, after naturally cooling to room temperature, add sherwood oil 50ml, behind the stirring 10min, leave standstill crystallization, crystallization filters after fully, and filter cake is with a small amount of cold mixing solvent (dehydrated alcohol/sherwood oil=10/1, v/v) drip washing, 40 ℃ of vacuum-drying 8 hours obtains solid 69.5g.mp：125.3℃。
Powder x-ray diffraction is analyzed: identify to belong to asenapine maleate new crystal A, its X-ray diffracting spectrum is 10.0 ° in 2 θ reflection angle values, 12.1 °, 15.1 °, located characteristic peak for 19.9 ° and 30.3 °, be 10.0 ° in 2 θ reflection angle values particularly, 10.5 °, 12.1 °, 15.1 °, 19.9 °, 22.1 °, 24.3 °, 25.2 °, 25.9 °, located characteristic peak for 30.3 °.
IR analyzes: at 3401cm
-1, 2953cm
-1, 2587cm
-1, 1700cm
-1, 1578cm
-1, 1480m
-1, 1387cm
-1, 1361cm
-1, 1280cm
-1, 1241cm
-1, 1182cm
-1, 867cm
-1There is characteristic peak at the place.
Respectively micronization of asenapine maleate with embodiment 1,2 gained, namely obtain the micronization crystal formation of embodiment 3 and embodiment 4, carrying out powder X-ray-diffracting spectrum measures, finding that it keeps the characteristic peak of original X-ray diffracting spectrum, is 10.0 ° in 2 θ reflection angle values namely, 12.0 °, 15.1 °, 19.9 ° and 30.4 ° located characteristic peak, be 10.0 ° in 2 θ reflection angle values particularly, 10.6 °, 12.0 °, 15.1 °, 19.9 °, 22.2 °, 24.3 °, 25.2 °, 25.9 °, located characteristic peak for 30.4 °.
Powder x-ray diffraction is analyzed: embodiment 3～4 identifies and belongs to new crystal A.
IR analyzes (embodiment 3): at 3405cm
-1, 2955cm
-1, 2584cm
-1, 1706cm
-1, 1577cm
-1, 1481m
-1, 1385cm
-1, 1362cm
-1, 1279cm
-1, 1240cm
-1, 1181cm
-1, 868cm
-1There is characteristic peak at the place.
IR analyzes (embodiment 4): at 3403cm
-1, 2952cm
-1, 2585cm
-1, 1699cm
-1, 1577cm
-1, 1482m
-1, 1384cm
-1, 1363cm
-1, 1281cm
-1, 1241cm
-1, 1183cm
-1, 865cm
-1There is characteristic peak at the place.
Laser particle-size distribution (embodiment 3): d
(0.1)=2.9 μ m, d
(0.5)=6.0 μ m, d
(0.9)=11.7 μ m.
Laser particle-size distribution (embodiment 4): d
(0.1)=3.5 μ m, d
(0.5)=7.2 μ m, d
(0.9)=12.8 μ m.
Take by weighing Asenapine maleate 100g, place in the flask, add in the dehydrated alcohol of 200ml volume 60 ℃ of left and right sides stirring and dissolving of outer bath, complete remove heating unit after molten, naturally be cooled to room temperature, leave standstill crystallization, crystallization is rear the filtration fully, filter cake is with a small amount of cold dehydrated alcohol drip washing, 40 ℃ of vacuum-drying 8 hours obtains solid 75.4g, mp:139.7 ℃.
Powder x-ray diffraction is analyzed: identify to belong to new crystal B.
IR analyzes: at 3420cm
-1, 3033cm
-1, 2446cm
-1, 1701cm
-1, 1617cm
-1, 1582m
-1, 1476cm
-1, 1355cm
-1, 1281cm
-1, 1265cm
-1, 867cm
-1There is characteristic peak at the place.
With Asenapine maleate 100g, place in the flask, add in the dehydrated alcohol of 500ml volume 60 ℃ of left and right sides stirring and dissolving of outer bath, complete remove heating unit after molten, be cooled to subzero 15 ℃, leave standstill crystallization, crystallization is rear the filtration fully, filter cake is with a small amount of cold dehydrated alcohol drip washing, 40 ℃ of vacuum-drying 8 hours obtains solid 71.3g, mp:139.1 ℃.
Powder x-ray diffraction is analyzed: identify to belong to new crystal B.
IR analyzes: at 3421cm
-1, 3034cm
-1, 2444cm
-1, 1700cm
-1, 1618cm
-1, 1580m
-1, 1479cm
-1, 1354cm
-1, 1280cm
-1, 1269cm
-1, 869cm
-1There is characteristic peak at the place.
Respectively micronization of asenapine maleate with embodiment 5,6 gained, namely obtain the micronization crystal formation of embodiment 7 and embodiment 8, carrying out the powder x-ray diffraction collection of illustrative plates measures, finding that it keeps original X-diffractogram characteristic peak, namely be 6.6 ° and 18.6 ° in 2 θ reflection angle values and located characteristic peak, is 6.6 ° in 2 θ reflection angle values particularly, 18.6 °, 27.4 ° and 28.0 ° located characteristic peak, be 6.6 ° in 2 θ reflection angle values especially, 9.3 °, 13.2 °, 15.0 °, 16.8 °, 18.6 °, 20.1 °, 21.2 °, 27.4 °, located characteristic peak for 28.0 °.
Powder x-ray diffraction analysis: identify that embodiment 7～8 belongs to new crystal B.
IR analyzes (embodiment 7): at 3423cm
-1, 3031cm
-1, 2442cm
-1, 1701cm
-1, 1617cm
-1, 1585m
-1, 1481cm
-1, 1356cm
-1, 1282cm
-1, 1263cm
-1, 865cm
-1There is characteristic peak at the place.
IR analyzes (embodiment 8): at 3419cm
-1, 3032cm
-1, 2440cm
-1, 1693cm
-1, 1617cm
-1, 1582m
-1, 1481cm
-1, 1352cm
-1, 1279cm
-1, 1272cm
-1, 866cm
-1There is characteristic peak at the place.
Laser particle-size distribution (embodiment 7): d
(0.1)=2.1 μ m, d
(0.5)=4.2 μ m, d
(0.9)=13.4 μ m.
Laser particle-size distribution (embodiment 8): d
(0.1)=3.0 μ m, d
(0.5)=5.1 μ m, d
(0.9)=12.9 μ m.
The preparation of embodiment 9 Sublingual tablets
1) prescription:
2) preparation technology: new crystal A, micropowder silica gel, aspartame, the carboxymethylstach sodium of embodiment 3 preparations are crossed 100 mesh sieves mix, add
After mixing, add again after Magnesium Stearate mixes compressing tablet and get final product.
The preparation of embodiment 10 Sublingual tablets
1) prescription:
2) preparation technology: new crystal B, micropowder silica gel, aspartame, the carboxymethylstach sodium of embodiment 7 preparations are crossed 100 mesh sieves mix, add
After mixing, add again after sodium stearyl fumarate mixes compressing tablet and get final product.
The preparation of embodiment 11 orally disintegrating tablets
1) prescription
2) preparation technology: new crystal A, micropowder silica gel, aspartame, the carboxymethylstach sodium of embodiment 4 preparations are crossed 100 mesh sieves mix, add
After mixing, add again after sodium stearyl fumarate mixes compressing tablet and get final product.
Dissolution determination: get respectively Sublingual tablet that embodiment 9,10,11 makes and lyophilization preparation Sublingual tablet (
5mg, Schering-Plough) each 6, measure respectively with reference to the dissolution method among Chinese Pharmacopoeia two appendix XC of version in 2010 (the second method), acetate buffer solution with pH4.5 (is got sodium-acetate 18g, add Glacial acetic acid 9.8ml, adding water to again 1000ml and get final product) 500ml is solvent, rotating speed 50rpm, in accordance with the law operation.Respectively at 1min, 2min, 3min, 4min, 5min and 8min sampling, adopt ultraviolet spectrophotometry to measure stripping quantity at the 240nm place, the results are shown in following table 1.
The average stripping quantity (%) of table 1 (N=6)
Table 1 result shows, process 3min, and the stripping quantity of Sublingual tablet reaches 80%, and all strippings during through 8min are similar to the Sublingual tablet dissolution rate of lyophilization preparation.
Should be noted that at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although with reference to preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement the technical scheme of invention, and not breaking away from the spirit and scope of technical solution of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (10)
1. the crystal form A of asenapine maleate and B is characterized in that, the powder x-ray diffraction collection of illustrative plates that obtains with the Cu-K alpha-ray, crystal form A is 10.0 ± 0.1 ° in 2 θ reflection angle values, 12.0 ± 0.1 °, 15.1 ± 0.1 °, located characteristic peak for 19.9 ± 0.1 ° and 30.4 ± 0.1 °; Crystal form B is 6.6 ± 0.1 ° in 2 θ reflection angle values, 18.6 ± 0.1 °, has located characteristic peak for 27.4 ± 0.1 ° and 28.0 ± 0.1 °.
2. the crystal form A of asenapine maleate according to claim 1 and B is characterized in that, the powder x-ray diffraction collection of illustrative plates that obtains with the Cu-K alpha-ray, crystal form A is 10.0 ± 0.1 ° in 2 θ reflection angle values, 10.6 ± 0.1 °, 12.0 ± 0.1 °, 15.1 ± 0.1 °, 19.9 ± 0.1 °, 22.2 ± 0.1 °, 24.3 ± 0.1 °, 25.2 ± 0.1 °, 25.9 ± 0.1 °, located characteristic peak for 30.4 ± 0.1 °; Crystal form B is 6.6 ± 0.1 ° in 2 θ reflection angle values, 9.3 ± 0.1 °, 13.2 ± 0.1 °, 15.0 ± 0.1 °, 16.8 ± 0.1 °, 18.6 ± 0.1 °, 20.1 ± 0.1 °, 21.2 ± 0.1 °, 27.4 ± 0.1 °, has located characteristic peak for 28.0 ± 0.1 °.
3. the crystal form A of asenapine maleate according to claim 1 and 2 and B is characterized in that, the IR collection of illustrative plates of crystal form A is at 3403 ± 2cm
-1, 2953 ± 2cm
-1, 2586 ± 2cm
-1, 1701 ± 2cm
-1, 1575 ± 2cm
-1, 1480 ± 2m
-1, 1383 ± 2cm
-1, 1361 ± 2cm
-1, 1279 ± 2cm
-1, 1240 ± 2cm
-1, 1181 ± 2cm
-1, 865 ± 2cm
-1There is characteristic peak at the place; The IR collection of illustrative plates of crystal form B is at 3421 ± 2cm
-1, 3032 ± 2cm
-1, 2444 ± 2cm
-1, 1700 ± 2cm
-1, 1617 ± 2cm
-1, 1582 ± 2m
-1, 1479 ± 2cm
-1, 1352 ± 2cm
-1, 1280 ± 2cm
-1, 1270 ± 2cm
-1, 867 ± 2cm
-1There is characteristic peak at the place.
4. the crystal form A of asenapine maleate according to claim 1 and 2 and B is characterized in that, crystal A melting range is 125.0 ℃～127.5 ℃, and crystal B melting range is 138.5～140.0 ℃.
5. the preparation method of the crystal form A of asenapine maleate is characterized in that, may further comprise the steps:
1) asenapine maleate 100g is dissolved in 60 ℃ to the ethanol solution that refluxes, the dehydrated alcohol consumption is 400ml～500ml;
2) naturally cool to room temperature, add normal heptane, sherwood oil or diethyl ether solution, stir 10min～10h, wherein the add-on of n-heptane, sherwood oil or diethyl ether solution is 40ml～100ml;
3) leave standstill crystallization, filter, filter cake dehydrated alcohol/n-heptane, dehydrated alcohol/sherwood oil, or dehydrated alcohol/ether mixing solutions drip washing;
4) 30 ℃～80 ℃ vacuum-drying 5～24h, and get final product.
6. the preparation method of the crystal form B of asenapine maleate is characterized in that, may further comprise the steps:
1) asenapine maleate 100g is dissolved in 60 ℃ to the ethanol solution that refluxes, the dehydrated alcohol consumption is 200ml～500ml;
2) naturally cool to room temperature, leave standstill crystallization;
3) filter filter cake dehydrated alcohol drip washing;
4) 30 ℃～80 ℃ vacuum-drying 5～24h, and get final product.
7. a pharmaceutical composition is characterized in that, comprises claim 1 or 2 described asenapine maleate crystal form A or B and pharmaceutical excipients.
8. pharmaceutical composition according to claim 7 is characterized in that, described pharmaceutical excipient is selected from: weighting agent such as lactose, N.F,USP MANNITOL, Xylitol, sucrose,
Disintegrating agent such as low-substituted hydroxypropyl cellulose, carboxymethylstach sodium, polyvinylpolypyrrolidone, croscarmellose sodium; Lubricant such as Magnesium Stearate, stearic acid, polyethylene glycol 6000, sodium stearyl fumarate, stearyl fumarate calcium, micropowder silica gel, correctives such as aspartame.
9. a preparation that comprises pharmaceutical composition claimed in claim 7 is characterized in that, described preparation is tablet, Sublingual tablet, powder or capsule.
10. preparation according to claim 9 is characterized in that, containing right requirement 1 or 2 described asenapine maleate crystal form As or B in the per unit preparation is 4wt%～20wt%.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103772402A (en) * | 2014-01-07 | 2014-05-07 | 万特制药(海南)有限公司 | Novel refining method of asenapine maleate crude product |
| CN104447771A (en) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Stable asenapine maleate sublingual compound |
| CN109200025A (en) * | 2017-06-29 | 2019-01-15 | 哈尔滨莱博通药业有限公司 | A kind of asenapine maleate sublingual tablet |
| CN109288800A (en) * | 2018-10-30 | 2019-02-01 | 天津仁生医药科技有限公司 | Maleic acid asenapine piece and preparation method thereof |
| CN109330984A (en) * | 2018-11-20 | 2019-02-15 | 天津仁生医药科技有限公司 | A kind of Maleic acid asenapine sublingual tablet and preparation method thereof |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447771A (en) * | 2013-09-12 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Stable asenapine maleate sublingual compound |
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| US11337932B2 (en) | 2016-12-20 | 2022-05-24 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene |
| US11033512B2 (en) | 2017-06-26 | 2021-06-15 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer |
| CN109200025A (en) * | 2017-06-29 | 2019-01-15 | 哈尔滨莱博通药业有限公司 | A kind of asenapine maleate sublingual tablet |
| US11648213B2 (en) | 2018-06-20 | 2023-05-16 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system containing asenapine |
| CN109288800A (en) * | 2018-10-30 | 2019-02-01 | 天津仁生医药科技有限公司 | Maleic acid asenapine piece and preparation method thereof |
| CN109330984A (en) * | 2018-11-20 | 2019-02-15 | 天津仁生医药科技有限公司 | A kind of Maleic acid asenapine sublingual tablet and preparation method thereof |
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