CN102372672B - 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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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 the preparation method and application of this crystal IV.
Background technology
Aripiprazole, chemical name 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone, is that one can be used for treating schizoid chlorpromazine compounds.
The 4th Japan-Korea S isolation technique Conference Papers collection (on October 6th～8,1996) point out, Aripiprazole anhydrous crystalline can exist with crystal I and crystal II crystal.Aripiprazole crystals I can be prepared by heating Aripiprazole monohydrate at the ethanolic soln crystallization of Aripiprazole or 80 ℃; And aripiprazole crystals II can heat anhydrous aripiprazole preparation in 15 hours at 130～140 ℃.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 preparing by above method has significant water absorbability, crystal II and other seven kinds of crystal are difficult for good repeatable technical scale preparation.
WO 2008/051541 provides a kind of method of preparing anhydrous aripiprazole.The salt heating that Aripiprazole or itself and acid are formed is dissolved in water miscible organic solvent, add after adjusting PH with base, decolouring, 70 ℃ add water and make that mixed solution is moisture is at least 5%, broadcast crystal seed aripiprazole crystals I in 25～78 ℃, stir and be cooled to 15～25 ℃, maintain crystallization more than 2 hours, the crystallization obtaining is carried out vacuum-drying being no more than at 80 ℃, to obtain final product.The Aripiprazole that the 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 of preparing agent of low hygroscopicity Aripiprazole.Form its hydrate A being defined as intermediate product by specific processing sequence, then carry out the Aripiprazole that suitable thermal conversion is agent of low hygroscopicity, wherein, the material that the preparation of hydrate A need to be defined as conventional hydrate to it grinds.The method technique 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 being converted on other agent of low hygroscopicity crystal.
The sign of the crystalline structure of the alleged agent of low hygroscopicity aripiprazole crystals IV of the present invention 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 differential heat scanning analysis, located endotherm(ic)peak at 117.8 ℃ and 141.6 ℃ respectively;
3), in thermogravimetric analysis, there is twice weightlessness (temperature rise rate: 10 ℃/min) at 110.3 ℃～117.8 ℃ and 291.2 ℃～337.3 ℃ respectively.
Test-results shows, the above-mentioned aripiprazole crystals IV of the present invention, and in 60 ℃ of temperature and 92.5% humidity environment, moisture uptake≤0.05% of 24 hours.
The analytical procedure that the present invention uses:
(1) X-ray diffraction
Use Cu (40KV, 30mA) conduct has the x-ray source of wide-angle goniometer, 1 ° of scatter slit, 0.30mm light are intercepted and captured slit, graphite secondary monochromator and scintillation counter.Under 2 θ continuous sweep patterns, with the sweep velocity of 4.0 °/min, in the scope of 2 °～80 ° with the scanning step data acquisition of 0.02 °.
(2) thermogravimetric/differential thermal analysis
Sample 5～10mg is placed in to the aluminium dish of crispaturaing, and under 15～400 ℃ and drying nitrogen with the heating rate heating of 10 ℃/min, a-aluminum oxide is as reference material.
(3) wettability test method
Get dry tool plug glass weighing bottle (external diameter is 50mm, high-order 15mm), be placed in suitable thermostatic drier (60 ℃/92.5%RH) the day before yesterday in test, accurately weighed weight is m
1.Get trial-product and be laid in above-mentioned weighing bottle, trial-product thickness is about 1mm, and accurately weighed weight is m
2.Weighing bottle is uncovered, and be placed in above-mentioned fixed temperature and humidity condition lower 24 hours with bottle cap is same; Build weighing bottle lid, accurately weighed weight m
3.Calculate 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 ': by any form Aripiprazole material dissolution of alleged non-the present invention crystal IV in by N, N-dimethylformamide and C
1-4the mixed solvent of alcohol composition.
Wherein, said any form Aripiprazole raw material, can comprise as aripiprazole crystals I, the II of existing bibliographical information, and/or the mixture of the various crystal such as the disclosed aripiprazole crystals A of WO 03/026659, B, C, D, E, F, G or its arbitrary form;
Said C
1-4alcohol can be at least one in the lower alcohols such as conventional methyl alcohol, ethanol, propyl alcohol or butanols;
Said N, N-dimethylformamide is DMF or N,N-dimethylacetamide;
While dissolving Aripiprazole with mixed solvent, Aripiprazole, N, N-dimethylformamide and C
1-4mass/volume/volume ratio of alcohol three is 1: (1～2): (5～8).
2 ': upper step solution is left standstill in≤10 ℃ of conditions, after abundant crystallize out, leaching crystal.Generally, along with the reduction of temperature, have crystal and separate out gradually.For improving the homogeneity of crystal formation, can in solution, add the crystal seed of said crystal IV to induce crystallization if desired.
3 ': the crystal that upper step is obtained is fully dry under≤70 ℃ of conditions, obtains said target product crystal IV.
In above-mentioned preparation method, further can comprise respectively by selection condition:
The dissolving of the 1st ' step is preferably carried out under 55 ℃～65 ℃ conditions;
The crystallization of the 2nd ' step preferably carries out under 0～10 ℃ of condition;
The crystallization of the 2nd ' step, preferably the crystallization time is 1～15 hour;
The 3rd ' step is to obtained crystal, preferably dry under 50 ℃～60 ℃ conditions.
Above-mentioned preparation method the 3rd ' step is fully dried obtained crystal, can adopts under normal pressure or reduced pressure and carry out.Test shows, for example, under condition of normal pressure at least dry 11 hours conventionally (under normal circumstances 11～20 hours), or at least dry 8 hours (for example conventionally can take off 8～16 hours) of decompression, can obtain said target product crystal IV under vacuum tightness >=0.085MPa condition.
Above-mentioned aripiprazole crystals crystal IV of the present invention, can be the same with other form crystal of Aripiprazole currently reported and/or that use, be directly used in corresponding pharmaceutical preparation preparation, can also be according to different application targets and/or needs, be converted into and have equally agent of low hygroscopicity aripiprazole crystals I, this aripiprazole crystals I has been reported in aforementioned documents.
Take aripiprazole crystals IV of the present invention as raw material, to have the method for agent of low hygroscopicity aripiprazole crystals I very simple in preparation: said aripiprazole crystals IV is at least heated 40 hours at 75 ℃～100 ℃ temperature, can obtain said aripiprazole crystals I target 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 while thering is equally agent of low hygroscopicity aripiprazole crystals I by aripiprazole crystals IV of the present invention, under condition of normal pressure, maintain at least 45 hours, or under the reduced pressure of vacuum tightness >=0.085MPa, maintain at least 40 hours, can obtain smoothly said aripiprazole crystals I product.
By transforming as stated above the aripiprazole crystals I preparing, adopt above-mentioned same testing conditions, 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%.The aripiprazole crystals I that shows to transform by aripiprazole crystals IV of the present invention preparation, equally also has 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 is strong, and the organic solvent of use is also easy to recovery, little to environmental hazard.Can make it change the aripiprazole crystals I equally with agent of low hygroscopicity into by aripiprazole crystals IV through simple heating, thereby for field of pharmaceutical preparations provides the more multi-form agent of low hygroscopicity aripiprazole crystals that preparation is produced of being convenient to, and/or obtain the approach like water absorbability aripiprazole crystals.
Below in conjunction with the embodiment by accompanying drawing illustrated embodiment, foregoing of the present invention is described in further detail again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.Without departing from the idea case in the present invention described above, various replacements or the change made according to ordinary skill knowledge and customary means, all should comprise within the scope of the invention.
Accompanying drawing explanation
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/differential thermal analysis collection of illustrative plates of the aripiprazole crystals IV of embodiment 1.
Fig. 4 is thermogravimetric/differential thermal analysis 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
The method providing according to the 4th Japan-Korea S isolation technique symposial, by 10g Aripiprazole heating for dissolving in 200ml aqueous ethanolic solution (water-content 20%), be cooled to gradually room temperature (2～3 hours), then be cooled to rapidly approximately 0 ℃ of crystallization, filter to obtain Aripiprazole monohydrate, in 80 ℃ of drying under reduced pressure 30 hours, to obtain final product.The anhydrous aripiprazole crystalline melt point obtaining is 139.5 ℃, consistent with the fusing point of existing bibliographical information.
The anhydrous aripiprazole crystallization of acquisition is remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, after 24 hours, moisture uptake is 1.73% (detecting as stated above).
According to the method described in day patent 191256/1990 of the present disclosure, with 150ml ethyl alcohol recrystallization 10g Aripiprazole, and at 80 ℃ by the crystallizing and drying of gained 40 hours, obtaining aripiprazole crystals, to record fusing point be 140.0 ℃, consistent with the fusing point that the document is recorded.
The aripiprazole crystals of acquisition is remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, after 24 hours, moisture uptake is 3.24%.
According to the method for preparing aripiprazole anhydride crystals I described in patent WO 2008/051541, 10g hydrochloric acid Aripiprazole is refluxed and is dissolved in 14ml Virahol, hydro-oxidation sodium regulates pH to make pH >=12, activated carbon decolorizing, filter to get filtrate, in 75～80 ℃, add water and make solution moisture approximately 20%, then approximately 60 ℃ of cooling solutions, add aripiprazole crystals I 0.5g as crystal seed, stir after 1 hour crystallization in 55～60 ℃, stir 1 hour crystallization in 45～50 ℃ again, after 2 hours, solution cools to 15～25 ℃ gradually, at this temperature, stir again 2 hours crystallizatioies, filter to obtain Aripiprazole wet product, in 60～65 ℃ of drying under reduced pressure 40 hours, obtain.The aripiprazole crystals I obtaining has the X-ray diffracting spectrum shown in Fig. 8.
The aripiprazole crystals I of acquisition is remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, after 24 hours, moisture uptake is 1.93%.
Embodiment 1
10g Aripiprazole is added in the mixed solvent of 16ml DMF and 64ml methyl alcohol, in 60 ℃ of stirring and dissolving.Mixed solution is down to 0～10 ℃, and insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, 70 ℃ of constant pressure and dries 11 hours, obtains 8.4g Aripiprazole.Obtain aripiprazole crystals IV of the present invention, its X ray diffracting spectrum 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/differential thermal analysis collection of illustrative plates is (temperature rise rate: 10 ℃/min) as shown in Figure 3, has respectively endotherm(ic)peak at 117.8 ℃ and 141.6 ℃; 110.3-117.8 ℃ of weightlessness 6.0%, then 291.2-337.3 ℃ of weightlessness 79.3%.
By the aripiprazole crystals IV obtaining at 100 ℃ of normal heatings after 45 hours, the X ray diffracting spectrum recording as shown in Figure 2, characteristic peak in 2 θ=10.8 °, 14.3 °, 16.5 °, 19.3 °, 20.3 °, 22.0 °, 26.6 °.Its characteristic peak is identical with the X ray diffracting spectrum of the WO2008/051541 aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.Hence one can see that, and aripiprazole crystals IV has obtained aripiprazole crystals I by this thermal transition.The aripiprazole crystals I obtaining has the thermogravimetric/differential thermal analysis collection of illustrative plates shown in Fig. 4 (temperature rise rate: 10 ℃/min), has endotherm(ic)peak, 284.7-337.5 ℃ of weightlessness 83.9% at 141.0 ℃.
The aripiprazole crystals IV of acquisition and the crystal I that conversion obtains are remained on respectively in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, and the moisture uptake after 24 hours is respectively 0.04% and 0.65%.
10g Aripiprazole is added in the mixed solvent of 10ml DMF and 70ml methyl alcohol, be heated to 65 ℃ of stirring and dissolving.Mixed solution is down to 0～10 ℃, and insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, 70 ℃, vacuum tightness 0.085MPa drying under reduced pressure 8 hours, obtain 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 °.
By the aripiprazole crystals IV obtaining at 100 ℃, vacuum tightness 0.085MPa decompression heating after 40 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
10g Aripiprazole is added in the mixed solvent of 13ml DMF and 67ml methyl alcohol, be heated to 60 ℃ of stirring and dissolving.Mixed solution is down to 0 ℃, and insulation leaves standstill crystallization 1 hour.Crystallization finishes suction filtration and obtains filter cake, 60 ℃ of constant pressure and dries 13 hours, obtains 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 °.
By the aripiprazole crystals IV obtaining at 75 ℃ of normal heatings after 60 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
Embodiment 4
10g Aripiprazole is added in the mixed solvent of 22ml DMF and 58ml methyl alcohol, be heated to 55 ℃ of stirring and dissolving.Mixed solution is down to 10 ℃, and insulation leaves standstill crystallization 15 hours.Crystallization finishes suction filtration and obtains filter cake, 60 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours, obtain 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 °.
By the aripiprazole crystals IV obtaining at 75 ℃, vacuum tightness 0.085MPa decompression heating after 48 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
Embodiment 5
10g Aripiprazole is added in the mixed solvent of 22ml DMF and 58ml dehydrated alcohol, be heated to molten clear.To add in the mixing solutions of Aripiprazole aripiprazole crystals IV as crystal seed after, be down to 0～10 ℃, insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, 50 ℃ of constant pressure and dries 16 hours, obtains 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 °.
By the aripiprazole crystals IV obtaining at 85 ℃, vacuum tightness 0.085MPa decompression heating after 43 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
The aripiprazole crystals IV of acquisition and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.67%.
Embodiment 6
10g Aripiprazole is added in the mixed solvent of 13ml DMF and 67ml propyl carbinol, be heated to molten clear.To add in the mixing solutions of Aripiprazole aripiprazole crystals IV as crystal seed after, be down to 0～10 ℃, insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, reduce pressure dry 15 hours at 50 ℃, vacuum tightness 0.085MPa, obtain 9.2g aripiprazole crystals IV, X ray diffracting spectrum as shown in Figure 5, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
By the aripiprazole crystals IV obtaining at 85 ℃ of normal heatings after 48 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
The aripiprazole crystals IV of acquisition and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.61%.
Embodiment 7
10g Aripiprazole is added in the mixed solvent of 13ml N,N-dimethylacetamide and 67ml methyl alcohol, be heated to molten clear.To add in the mixing solutions of Aripiprazole aripiprazole crystals IV as crystal seed after, be down to 0～10 ℃, insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, 55 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours, obtain 8.4g aripiprazole crystals IV, X ray diffracting spectrum as shown in Figure 6, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
By the aripiprazole crystals IV obtaining at 80 ℃, vacuum tightness 0.085MPa decompression heating after 45 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
The aripiprazole crystals IV of acquisition and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.04% and 0.68%.
10g Aripiprazole is added in the mixed solvent of 13ml N,N-dimethylacetamide and 67ml Virahol, be heated to molten clear.To add in the mixing solutions of Aripiprazole aripiprazole crystals IV as crystal seed after, be down to 0～10 ℃, insulation leaves standstill crystallization 11 hours.Crystallization finishes suction filtration and obtains filter cake, 55 ℃, vacuum tightness 0.085MPa drying under reduced pressure 10 hours, obtain 8.8g aripiprazole crystals IV, X ray diffracting spectrum as shown in Figure 7, characteristic peak in 2 θ=11.6 °, 17.4 °, 18.6 °, 19.9 °, 23.2 °, 24.5 °, 27.0 °.
By the aripiprazole crystals IV obtaining at 80 ℃, vacuum tightness 0.085MPa decompression heating after 45 hours, the X ray diffracting spectrum recording 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 is identical with the X ray diffracting spectrum of the aripiprazole crystals I shown in Fig. 8 with characteristic peak relative intensity.
The aripiprazole crystals IV of acquisition and the crystal I that conversion obtains are remained in 60 ℃ of temperature and 92.5% humidity level's moisture eliminator, and after 24 hours, its moisture uptake is respectively 0.03% and 0.64%.
Claims (7)
1. the preparation method of agent of low hygroscopicity aripiprazole crystals IV, this aripiprazole crystals IV has following characteristic parameter:
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) in differential heat scanning analysis, located endotherm(ic)peak at 117.8 ℃ and 141.6 ℃;
3) in thermogravimetric analysis, there is weightlessness twice at 110.3 ℃～117.8 ℃ and 291.2 ℃～337.3 ℃ respectively; It is characterized in that preparing in the following manner:
1 ': the Aripiprazole of any form is dissolved in by N to N-dimethylformamide and C
1-4the mixed solvent of alcohol composition,
2 ': upper step solution is left standstill in≤10 ℃ of conditions, and fully crystallize out can add the crystal seed of said crystal IV to induce crystallization if desired in solution,
3 ': the crystal that upper step is obtained is fully dry under≤70 ℃ of conditions, obtains said target product crystal IV,
Wherein, said N in the 1st ' step, N-dimethylformamide is DMF or N,N-dimethylacetamide, while dissolving Aripiprazole with mixed solvent, Aripiprazole, N, N-dimethylformamide and C
1-4mass/volume/volume ratio of alcohol three is 1:(1～2): (5～8).
2. preparation method as claimed in claim 1, is characterized in that said the 1st ' being dissolved under 55 ℃～65 ℃ conditions of step carry out.
3. preparation method as claimed in claim 1, is characterized in that the crystallization of said the 2nd ' step carries out under 0～10 ℃ of condition.
4. preparation method as claimed in claim 1, is characterized in that the crystallization time of said the 2nd ' step is 1～15 hour.
5. preparation method as claimed in claim 1, is characterized in that the 3rd ' step gained crystal is dry under 50 ℃～60 ℃ conditions.
6. preparation method as claimed in claim 1, is characterized in that the 3rd ' step gained crystal is at least dried 11 hours under normal pressure, or vacuum tightness >=0.085MPa decompression at least dry 8 hours.
7. preparation method as claimed in claim 5, is characterized in that the 3rd ' step gained crystal is at least dried 11 hours under normal pressure, or vacuum tightness >=0.085MPa decompression at least dry 8 hours.
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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 process for the preparation 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106674103B (en) * | 2016-12-08 | 2022-04-08 | 万全万特制药江苏有限公司 | Preparation method of aripiprazole new crystal form alpha |
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