Industrialized preparation of small-particle-size crystal-form I aripiprazole
A technology of aripiprazole and small particle size, applied in the field of industrialized preparation of small particle size aripiprazole crystal form I, can solve problems such as inability to dissolve, fail to pass, large energy consumption, etc., achieve stable structure, low energy consumption, etc. Hygroscopic, high bioavailability effect
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Embodiment 1
[0064] High-purity type I aripiprazole laboratory preparation process:
[0065] Through the research on ethanol recrystallization and drying methods of aripiprazole, we determined the preparation process of high-purity type I aripiprazole in the laboratory.
[0066] Feed 50 grams of aripiprazole and a certain amount of ethanol, heat to dissolve the aripiprazole, cool to precipitate crystals; dry the crystals under vacuum (-0.09Mpa) at 95 to 100°C for 1.5 hours to obtain type I aripiprazole Ripiprazole.
[0067] Table 1 shows the related data of the recrystallized aripiprazole in Example 1 and the related data of the obtained aripiprazole.
[0068] Table 1
[0069]
[0070] In Table 1, the melting points of the four batches of products are all around 139°C, indicating that type II aripiprazole is hardly contained.
[0071] The results in Table 1 show that when the aripiprazole is 50 g, the experiments numbered 1, 2, 3 and 4 all obtain pure type I aripiprazole. Combined w...
Embodiment 2
[0073] The laboratory process cannot be reproduced in industrialization, so we conducted a systematic study on the large-scale preparation of type I aripiprazole.
[0074] Study on the Preparation Technology of Aripiprazole Crystal Form
[0075] Recrystallization of aripiprazole in different proportions of ethanol
[0076] Add ethanol to the reaction kettle, mechanically stir (120 rev / min), add 1Kg of aripiprazole, heat to reflux, so that the aripiprazole is completely dissolved, and continue to stir for 15 to 20 minutes. Cool the reaction kettle with cold water. When the temperature drops to 75±2°C, adjust the stirring to 200 rpm, quickly cool (cooling rate: 5°C / min) to room temperature, cool to 0-5°C with ice water, and continue Stir for 1 hour. Filter, wash the solid with a small amount of ethanol, and dry the solid at 60°C for 4 hours under a vacuum of -0.09Mpa. Carry out melting point measurement (YRT-3 melting point apparatus, 129° C. into the sample, heating rate: 0....
Embodiment 3
[0082] Study on Drying Temperature and Drying Time of Recrystallized Samples
[0083] Get the No. 2 sample of embodiment 2, under vacuum-0.09Mpa, dry at different temperatures, and take samples at different time points for melting point determination, and ethanol content determination (ethanol determination method: gas phase method).
[0084] Table 3 shows the ethanol residue and melting point data of sample No. 2 of Example 2 after deethanolization at different drying temperatures and drying times.
[0085] table 3
[0086]
[0087] The data in Table 3 show that: when the mass ratio of ethanol to aripiprazole is 14:1, the ethanol can be dried under reduced pressure at 85-90°C, but the process is very slow and requires a long drying process. When the temperature rises, the ethanol removal time is shortened. During the heating and desolvation process, the product will change to type II aripiprazole for a long time or if the temperature is raised.
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