CN102372672A - Low-hygroscopicity aripiprazole crystal IV, its preparation method and application - Google Patents
Low-hygroscopicity aripiprazole crystal IV, its preparation method and application Download PDFInfo
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- CN102372672A CN102372672A CN2010102609798A CN201010260979A CN102372672A CN 102372672 A CN102372672 A CN 102372672A CN 2010102609798 A CN2010102609798 A CN 2010102609798A CN 201010260979 A CN201010260979 A CN 201010260979A CN 102372672 A CN102372672 A CN 102372672A
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Abstract
The invention discloses a low-hygroscopicity aripiprazole crystal IV, its preparation method and application. The crystal IV has characteristic peaks in the X-ray diffraction pattern of a CuK-alpha source at values of two-theta at 11.6, 17.4, 18.6, 19.9, 23.2, 24.5, and 27.0 degrees, has endothermic peaks at 117.8 DEG C and 141.6 DEG C in the differential thermal sweep analysis, and has two weight losses at the temperature of 110.3-117.8 DEG C and at the temperature of 291.2-337.3 DEG C. The crystal IV has stable property and simple preparation method, and can be converted into the low-hygroscopicity aripiprazole I through simple heating. According to the invention, more forms of low-hygroscopicity aripiprazole crystals which are convenient for preparation production are provided for the medicinal preparation field.
Description
Technical field
The present invention relates to the new texture crystal of a kind of Aripiprazole (Aripiprazole), i.e. the aripiprazole crystals IV with agent of low hygroscopicity of the present invention definition, and preparation method and the application of this crystal IV.
Background technology
Aripiprazole, chemical name 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone is a kind of schizoid chlorpromazine compounds that can be used for treating.
The 4th Japan-Korea S's stripping technique Conference Papers collection (on October 6th～8,1996) points out that the Aripiprazole anhydrous crystalline can exist with crystal I and crystal II crystal.Aripiprazole crystals I can prepare through ethanolic soln crystallization or 80 ℃ of following heating Aripiprazole monohydrates of Aripiprazole; And aripiprazole crystals II can be through 130～140 ℃ of heating anhydrous aripiprazole preparations in 15 hours down.Patent WO 03/026659 also discloses aripiprazole crystals A, B, C, D, E, F, seven kinds of crystal formations of G.But the crystal I through above method preparation has significant water absorbability, and crystal II and other seven kinds of crystal are difficult for the technical scale preparation with good repeatability.
WO 2008/051541 provides a kind of method for preparing anhydrous aripiprazole.The salt heating that Aripiprazole or itself and acid are formed is dissolved in water miscible organic solvent, add adjusting PH with base after, decolouring; 70 ℃ add water and make that mixed solution is moisture to be at least 5%; Broadcast crystal seed aripiprazole crystals I in 25～78 ℃, stir and be cooled to 15～25 ℃, keep crystallization more than 2 hours; The crystallization that obtains is carried out vacuum-drying being no more than under 80 ℃, promptly get.The Aripiprazole that this method obtains in 60～65 ℃ of temperature and 100% humidity level's moisture eliminator 24 hours, moisture uptake is 1.8～3.2%, still can not be satisfactory.
CN 101579344A discloses a kind of method for preparing the agent of low hygroscopicity Aripiprazole.Form its hydrate A that is defined as as intermediate product through specific processing sequence, the thermal conversion that suits then is the Aripiprazole of agent of low hygroscopicity, and wherein, the preparation of hydrate A need be ground its material that is defined as conventional hydrate.This method technology is loaded down with trivial details, and control condition is strict, and large-scale industrial production has certain difficulty.
Summary of the invention
In view of the foregoing, the present invention can provide a kind of Aripiprazole (Aripiprazole) new texture crystal with agent of low hygroscopicity, i.e. the crystal IV of the present invention definition.The present invention also will further provide a kind of preparation method of this crystal IV, with and in the application that is converted on other agent of low hygroscopicity crystal.
The sign of the crystalline structure of the agent of low hygroscopicity aripiprazole crystals IV that the present invention is alleged can comprise:
1) in the X ray diffracting spectrum in CuK α source, its characteristic peak is 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °;
2) in the differential heat scanning analysis, located endotherm(ic)peak at 117.8 ℃ and 141.6 ℃ respectively;
3) in the thermogravimetric analysis, at 110.3 ℃～117.8 ℃ and 291.2 ℃～337.3 ℃ twice weightlessness (temperature rise rate: 10 ℃/min) is arranged respectively.
Test-results shows, the above-mentioned aripiprazole crystals IV of the present invention, and in 60 ℃ of temperature and 92.5% humidity environment, 24 hours moisture uptake≤0.05%.
The analytical procedure that the present invention uses:
(1) X-ray diffraction
(40KV 30mA) intercepts and captures slit, graphite secondary monochromator and scintillation counter as the x-ray source with wide-angle goniometer, 1 ° of scatter slit, 0.30mm light to use Cu.Under 2 θ continuous sweep patterns, with the sweep velocity of 4.0 °/min, in 2 °～80 ° scope, accomplish data gathering with 0.02 ° scanning step.
(2) thermogravimetric/DTA
Sample 5～10mg is placed the aluminium dish of crispaturaing, and 15～400 ℃ with drying nitrogen under with the heating of the heating rate of 10 ℃/min, the a-aluminum oxide is as reference material.
(3) wettability test method
Get exsiccant tool plug glass weighing bottle (external diameter is 50mm, high-order 15mm), place (60 ℃/92.5%RH), accurately claim that deciding weight is m of suitable thermostatic driers previous day in test
1Get trial-product and be tiled in the above-mentioned weighing bottle, trial-product thickness is about 1mm, and weight decided in accurate title is m
2Weighing bottle is uncovered, and with bottle cap with placing above-mentioned fixed temperature and humidity condition following 24 hours; Build the weighing bottle lid, weight m decided in accurate title
3Calculate weightening finish (moisture absorption) % by following formula:
The preparation of the above-mentioned agent of low hygroscopicity aripiprazole crystals of the present invention IV, can adopt following step to carry out:
1 ': with any form Aripiprazole material dissolution of the alleged crystal IV of non-the present invention in by N, N-dimethylformamide and C
1-4The mixed solvent that alcohol is formed.
Wherein, Said any form Aripiprazole raw material; Can comprise aripiprazole crystals I, II like existing bibliographical information, and/or the mixture of various crystal such as WO 03/026659 disclosed aripiprazole crystals A, B, C, D, E, F, G or its arbitrary form;
Said C
1-4Alcohol, can be in the lower alcohols such as methyl alcohol, ethanol, propyl alcohol or butanols commonly used at least a;
Said N, N-dimethylformamide are N, dinethylformamide or DMAC N,N;
During with mixed solvent dissolving Aripiprazole, Aripiprazole, N, N-dimethylformamide and C
1-4Mass/volume/volume ratio of alcohol three is 1: (1～2): (5～8).
2 ': will go up the step solution leave standstill in≤10 ℃ of conditions, fully separate out crystal after, the leaching crystal.Generally speaking, along with the reduction of temperature, have crystal and separate out gradually.For improving the homogeneity of crystal formation, the crystal seed that can in solution, add said crystal IV is in case of necessity induced crystallization.
3 ': will go up crystal thorough drying under≤70 ℃ of conditions that the step obtains, obtain said title product crystal IV.
In above-mentioned preparation method, but further selection condition can comprise respectively:
The dissolving in the 1st ' step is preferably carried out under 55 ℃～65 ℃ conditions;
The crystallization in the 2nd ' step preferably carries out under 0～10 ℃ of condition;
The crystallization in the 2nd ' step, the preferred crystallization time is 1～15 hour;
The 3rd ' step is to resultant crystal, and is preferably dry under 50 ℃～60 ℃ conditions.
Above-mentioned preparation method the 3rd ' step is carried out thorough drying to resulting crystal, can be employed under normal pressure or the reduced pressure and carry out.Test shows; Dry at least usually 11 hours (for example getting final product in generally 11～20 hours) under condition of normal pressure; Perhaps dry at least 8 hours (for example can take off usually and get final product in 8～16 hours) of decompression under vacuum tightness >=0.085MPa condition can obtain said title product crystal IV.
Above-mentioned aripiprazole crystals crystal IV of the present invention; Can be the same with other form crystal of Aripiprazole of existing report and/or use at present; Directly be used for corresponding preparation of pharmaceutical formulations; Can also be according to different application targets and/or needs, be converted into and have agent of low hygroscopicity aripiprazole crystals I equally, this aripiprazole crystals I is an existing report in the aforementioned documents.
It is very simple to be with aripiprazole crystals IV of the present invention that feedstock production has the method for agent of low hygroscopicity aripiprazole crystals I: said aripiprazole crystals IV was heated 40 hours under 75 ℃～100 ℃ temperature at least, can obtain said aripiprazole crystals I title product.
In the method for transformation of above-mentioned preparation aripiprazole crystals I, further optimal conditions is that said Heating temperature is 75 ℃～85 ℃.
Said conversion process can be carried out under condition of normal pressure, also can under reduced pressure, carry out.Test shows; Under above-mentioned heating condition; Be converted into when having agent of low hygroscopicity aripiprazole crystals I equally by aripiprazole crystals IV of the present invention; Under condition of normal pressure, kept at least 45 hours, perhaps under the reduced pressure of vacuum tightness >=0.085MPa, kept at least 40 hours, can obtain said aripiprazole crystals I product smoothly.
With transforming the aripiprazole crystals I for preparing as stated above, adopt above-mentioned similar detection condition, in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, keep after 24 hours, its moisture uptake is not more than 0.70%.Show the aripiprazole crystals I that transforms preparation through aripiprazole crystals IV of the present invention, equally also have agent of low hygroscopicity.
The stable in properties of the above-mentioned aripiprazole crystals IV of the present invention, preparation method and process are simple, favorable reproducibility, industrial operation property is strong, and the organic solvent of use also is easy to recovery set usefulness, and is little to environmental hazard.Can make it change the aripiprazole crystals I that has agent of low hygroscopicity equally into by aripiprazole crystals IV through simple heating; Thereby, and/or obtain approach like the water absorbability aripiprazole crystals for field of pharmaceutical preparations provides the more multi-form agent of low hygroscopicity aripiprazole crystals that preparation is produced of being convenient to.
Below in conjunction with embodiment, foregoing of the present invention is remake further detailed description by the accompanying drawing illustrated embodiment.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Description of drawings
Fig. 1 is the X-ray diffracting spectrum of the aripiprazole crystals IV of embodiment 1.
Fig. 2 is the X-ray diffracting spectrum of the aripiprazole crystals I of embodiment 1.
Fig. 3 is thermogravimetric/DTA collection of illustrative plates of the aripiprazole crystals IV of embodiment 1.
Fig. 4 is thermogravimetric/DTA collection of illustrative plates of the aripiprazole crystals I of embodiment 1.
Fig. 5 is the X-ray diffracting spectrum of the aripiprazole crystals IV of embodiment 6.
Fig. 6 is the X-ray diffracting spectrum of the aripiprazole crystals IV of embodiment 7.
Fig. 7 is the X-ray diffracting spectrum of the aripiprazole crystals IV of embodiment 8.
Fig. 8 is the X ray diffracting spectrum of the aripiprazole crystals I of WO2008/051541.
Embodiment
Reference embodiment 1
According to the method that the 4th Japan-Korea S's stripping technique symposial provides; With 10g Aripiprazole heating for dissolving in 200ml aqueous ethanolic solution (water-content 20%); Be cooled to room temperature (2～3 hours) gradually, be cooled to about 0 ℃ of crystallization then rapidly, cross and filter Aripiprazole monohydrate; In 80 ℃ of drying under reduced pressure 30 hours, promptly get.The anhydrous aripiprazole crystalline melt point that obtains is 139.5 ℃, and is consistent with the fusing point of existing bibliographical information.
The anhydrous aripiprazole crystallization that obtains is remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, moisture uptake is 1.73% (detecting as stated above).
According to day patent 191256/1990 described method of the present disclosure, with 150ml ethyl alcohol recrystallization 10g Aripiprazole, and under 80 ℃ with the crystallizing and drying of gained 40 hours, aripiprazole crystals to record fusing point be 140.0 ℃, consistent with the fusing point of document record.
The aripiprazole crystals that obtains is remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, moisture uptake is 3.24%.
Reference embodiment 3
According to the patent WO 2008/051541 described method for preparing aripiprazole anhydride crystals I, the backflow of 10g hydrochloric acid Aripiprazole is dissolved in the 14ml Virahol, hydro-oxidation sodium is regulated pH and is made pH >=12, activated carbon decolorizing; Cross and filter filtrating, in 75～80 ℃, add water and make solution moisture about 20%, cooling solution is about 60 ℃ then; Add aripiprazole crystals I 0.5g as crystal seed, in 55～60 ℃ stir 1 hour crystallization after, stir 1 hour crystallization in 45～50 ℃ again; After 2 hours, solution cools to 15～25 ℃ gradually, 2 hours crystallizatioies of restir under this temperature; Cross the wet article of Aripiprazole that filter,, promptly get in 60～65 ℃ of drying under reduced pressure 40 hours.The aripiprazole crystals I that obtains has X-ray diffracting spectrum shown in Figure 8.
The aripiprazole crystals I that obtains is remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, moisture uptake is 1.93%.
Embodiment 1
The 10g Aripiprazole is added 16ml N, in the mixed solvent of dinethylformamide and 64ml methyl alcohol, in 60 ℃ of stirring and dissolving.Mixed solution is reduced to 0～10 ℃, and insulation was left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake, 70 ℃ of constant pressure and dries 11 hours, promptly gets the 8.4g Aripiprazole.Obtain aripiprazole crystals IV of the present invention, its X ray diffracting spectrum is as shown in Figure 1, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °; Thermogravimetric/DTA collection of illustrative plates (temperature rise rate: 10 ℃/min), endotherm(ic)peak is arranged respectively as shown in Figure 3 at 117.8 ℃ and 141.6 ℃; 110.3-117.8 ℃ of weightlessness 6.0%, again 291.2-337.3 ℃ of weightlessness 79.3%.
In the heating of 100 ℃ of normal pressures after 45 hours, the X ray diffracting spectrum that records is as shown in Figure 2 with the aripiprazole crystals IV that obtains, characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °.Its characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of WO2008/051541 aripiprazole crystals I shown in Figure 8.Hence one can see that, and aripiprazole crystals IV has obtained aripiprazole crystals I through this thermal transition.Resulting aripiprazole crystals I has thermogravimetric shown in Figure 4/DTA collection of illustrative plates (temperature rise rate: 10 ℃/min), at 141.0 ℃ endotherm(ic)peak is arranged, 284.7-337.5 ℃ of weightlessness 83.9%.
Aripiprazole crystals IV that obtains and the crystal I that conversion obtains are remained on respectively in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and the moisture uptake after 24 hours is respectively 0.04% and 0.65%.
The 10g Aripiprazole is added 10ml N, in the mixed solvent of dinethylformamide and 70ml methyl alcohol, be heated to 65 ℃ of stirring and dissolving.Mixed solution is reduced to 0～10 ℃, and insulation was left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake; 70 ℃, vacuum tightness 0.085MPa drying under reduced pressure 8 hours; Promptly get 9.0g aripiprazole crystals IV, X ray diffracting spectrum is same as shown in Figure 1, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains at 100 ℃, vacuum tightness 0.085MPa decompression heating after 40 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Embodiment 3
The 10g Aripiprazole is added 13ml N, in the mixed solvent of dinethylformamide and 67ml methyl alcohol, be heated to 60 ℃ of stirring and dissolving.Mixed solution is reduced to 0 ℃, and insulation was left standstill crystallization 1 hour.Crystallization finishes suction filtration and gets filter cake, 60 ℃ of constant pressure and dries 13 hours, promptly gets 7.5g aripiprazole crystals IV, and X ray diffracting spectrum is same as shown in Figure 1, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains in the heating of 75 ℃ of normal pressures after 60 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 ° 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Embodiment 4
The 10g Aripiprazole is added 22ml N, in the mixed solvent of dinethylformamide and 58ml methyl alcohol, be heated to 55 ℃ of stirring and dissolving.Mixed solution is reduced to 10 ℃, and insulation was left standstill crystallization 15 hours.Crystallization finishes suction filtration and gets filter cake; 60 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours; Promptly get 7.7g aripiprazole crystals IV, X ray diffracting spectrum is same as shown in Figure 1, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains at 75 ℃, vacuum tightness 0.085MPa decompression heating after 48 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Embodiment 5
The 10g Aripiprazole is added 22ml N, in the mixed solvent of dinethylformamide and 58ml absolute ethyl alcohol, be heated to and dissolve clearly.In the mixing solutions of Aripiprazole, add aripiprazole crystals IV as crystal seed after, reduce to 0～10 ℃, the insulation left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake, 50 ℃ of constant pressure and dries 16 hours, promptly gets 7.4g aripiprazole crystals IV, and X ray diffracting spectrum is same as shown in Figure 1, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains at 85 ℃, vacuum tightness 0.085MPa decompression heating after 43 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Aripiprazole crystals IV that obtains and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.67%.
Embodiment 6
The 10g Aripiprazole is added 13ml N, in the mixed solvent of dinethylformamide and 67ml propyl carbinol, be heated to and dissolve clearly.In the mixing solutions of Aripiprazole, add aripiprazole crystals IV as crystal seed after, reduce to 0～10 ℃, the insulation left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake; Reduced pressure dry 15 hours at 50 ℃, vacuum tightness 0.085MPa; Promptly get 9.2g aripiprazole crystals IV, X ray diffracting spectrum is as shown in Figure 5, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains in the heating of 85 ℃ of normal pressures after 48 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Aripiprazole crystals IV that obtains and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.61%.
Embodiment 7
The 10g Aripiprazole is added in the mixed solvent of 13ml DMAC N,N and 67ml methyl alcohol, be heated to and dissolve clearly.In the mixing solutions of Aripiprazole, add aripiprazole crystals IV as crystal seed after, reduce to 0～10 ℃, the insulation left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake; 55 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours; Promptly get 8.4g aripiprazole crystals IV, X ray diffracting spectrum is as shown in Figure 6, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains at 80 ℃, vacuum tightness 0.085MPa decompression heating after 45 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Aripiprazole crystals IV that obtains and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.04% and 0.68%.
Embodiment 8
The 10g Aripiprazole is added in the mixed solvent of 13ml DMAC N,N and 67ml Virahol, be heated to and dissolve clearly.In the mixing solutions of Aripiprazole, add aripiprazole crystals IV as crystal seed after, reduce to 0～10 ℃, the insulation left standstill crystallization 11 hours.Crystallization finishes suction filtration and gets filter cake; 55 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours; Promptly get 8.8g aripiprazole crystals IV, X ray diffracting spectrum is as shown in Figure 7, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
With the aripiprazole crystals IV that obtains at 80 ℃, vacuum tightness 0.085MPa decompression heating after 45 hours; The X ray diffracting spectrum that records is identical with Fig. 2; Characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °, characteristic peak and characteristic peak relative intensity are identical with the X ray diffracting spectrum of aripiprazole crystals I shown in Figure 8.
Aripiprazole crystals IV that obtains and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's the moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.64%.
Claims (10)
1. agent of low hygroscopicity aripiprazole crystals IV is characterized in that:
1) 2 θ angles in the X ray diffracting spectrum in CuK α source are 11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 ° and have located characteristic peak;
2) located endotherm(ic)peak at 117.8 ℃ and 141.6 ℃ in the differential heat scanning analysis;
3) at 110.3 ℃～117.8 ℃ and 291.2 ℃～337.3 ℃ weightlessness is arranged twice respectively in the thermogravimetric analysis.
2. the method for preparing the said agent of low hygroscopicity aripiprazole crystals of claim 1 IV is characterized in that being undertaken by following step:
1 ': the Aripiprazole of any form is dissolved in by N N-dimethylformamide and C
1-4The mixed solvent that alcohol is formed,
2 ': will go up step solution and leave standstill in≤10 ℃ of conditions, and fully separate out crystal, the crystal seed that can in solution, add said crystal IV is in case of necessity induced crystallization,
3 ': will go up crystal thorough drying under≤70 ℃ of conditions that the step obtains, obtain said title product crystal IV,
Said N in above-mentioned the 1st ' step, the N-dimethylformamide is N, dinethylformamide or DMAC N,N, during with mixed solvent dissolving Aripiprazole, Aripiprazole, N, N-dimethylformamide and C
1-4Mass/volume/volume ratio of alcohol three is 1: (1～2): (5～8).
3. preparation method as claimed in claim 2 is characterized in that said the 1st ' being dissolved under 55 ℃～65 ℃ conditions of step carry out.
4. preparation method as claimed in claim 2 is characterized in that the crystallization in said the 2nd ' step carries out under 0～10 ℃ of condition.
5. preparation method as claimed in claim 2 is characterized in that the crystallization time in said the 2nd ' step is 1～15 hour.
6. preparation method as claimed in claim 3 is characterized in that the 3rd ' step gained crystal is dry under 50 ℃～60 ℃ conditions.
7. like claim 2 or 6 described preparing methods, it is characterized in that the 3rd ' step gained crystal under normal pressure dry 11 hours at least, perhaps vacuum tightness >=0.085MPa decompression dry 8 hours at least.
8. the aripiprazole crystals IV with claim 1 is the method that feedstock production has agent of low hygroscopicity aripiprazole crystals I; It is characterized in that said aripiprazole crystals IV was heated 40 hours under 75 ℃～100 ℃ temperature at least, obtain said aripiprazole crystals I title product.
9. preparation method as claimed in claim 8 is characterized in that said Heating temperature is 75 ℃～85 ℃.
10. like claim 8 or 9 described preparing methods, it is characterized in that normal pressure was kept 45 hours at least under said Heating temperature condition, perhaps kept at least 40 hours in vacuum tightness >=0.085MPa decompression.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674103A (en) * | 2016-12-08 | 2017-05-17 | 万全万特制药江苏有限公司 | Method for preparing aripiprazole novel crystal form alpha |
| WO2017139971A1 (en) * | 2016-02-19 | 2017-08-24 | 诺瑞特国际药业股份有限公司 | New crystal form of aripiprazole |
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| CN1463191A (en) * | 2001-09-25 | 2003-12-24 | 大塚制药株式会社 | Low hygroscopic aripiprazole drug substance and processes for prepn. thereof |
| WO2006077584A2 (en) * | 2005-01-18 | 2006-07-27 | Chemagis Ltd. | New crystalline forms of aripiprazole |
| CN1914174A (en) * | 2003-12-16 | 2007-02-14 | 特瓦制药工业有限公司 | Methods of preparing aripiprazole crystalline forms |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1463191A (en) * | 2001-09-25 | 2003-12-24 | 大塚制药株式会社 | Low hygroscopic aripiprazole drug substance and processes for prepn. thereof |
| CN1914174A (en) * | 2003-12-16 | 2007-02-14 | 特瓦制药工业有限公司 | Methods of preparing aripiprazole crystalline forms |
| WO2006077584A2 (en) * | 2005-01-18 | 2006-07-27 | Chemagis Ltd. | New crystalline forms of aripiprazole |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017139971A1 (en) * | 2016-02-19 | 2017-08-24 | 诺瑞特国际药业股份有限公司 | New crystal form of aripiprazole |
| CN108602774A (en) * | 2016-02-19 | 2018-09-28 | 诺瑞特国际药业股份有限公司 | The novel crystal forms of Aripiprazole |
| US10913721B2 (en) | 2016-02-19 | 2021-02-09 | Nanjing Noratech Pharmaceuticals Co., Ltd | Crystalline form of aripiprazole |
| CN108602774B (en) * | 2016-02-19 | 2021-07-27 | 南京诺瑞特医药科技有限公司 | Novel crystal form of aripiprazole |
| CN106674103A (en) * | 2016-12-08 | 2017-05-17 | 万全万特制药江苏有限公司 | Method for preparing aripiprazole novel crystal form alpha |
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| CN102372672B (en) | 2014-06-04 |
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